IAP Textbook of Pediatrics,5E (2013) [PDF] [UnitedVRG].pdf

IAP Textbook of i i

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IAP Textbook of i

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Fifth dition Chief Academic Editor

A Parthasarathy MD(Ped) DCH FIAP

P N Menon MD MNAMS FIAP S

Editor-in-Chief President Indian Academy of Pediatrics 1997 Distinguished Professor of Pediatrics The Tamil Nadu Dr MGR Medical University Senior Clinical Professor of Pediatrics (Retd) Madras Medical College Deputy Superintendent, Institute of Child Health and Hospital for Children, Chennai, Tamil Nadu

President Indian Society for Pediatric and Adolescent Endocrinology 2011−12 Consultant and Head, Department of Pediatrics, Jaber Al-Ahmed Armed Forces Hospital, Kuwait Former Professor of Pediatrics, All India Institute of Medical Sciences, New Delhi

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Piyush Gupta MD FAMS FIAP

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Editor-in-Chief Indian Academy of Pediatrics 2008−13 Professor Department of Pediatrics University College of Medical Sciences, Delhi

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Editorial Advisers

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President Indian Academy of Pediatrics 2012 Consultant Pediatrician Kohinoor Hospital and Chandra-Jyoti Children Hospital Mumbai, Maharashtra

TU ukumaran MD DCH MNAMS MPhil FIAP President Indian Academy of Pediatrics 2011 Professor Department of Pediatrics Pushpagiri Institute of Medical Sciences Thiruvalla, Kerala

Forewords S

P Bansal, ohit Agrawal, TU ukumaran R

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President Indian Academy of Pediatrics 2004 Professor of Pediatrics and Clinical Epidemiology Director, Child Development Centre Government Medical College Thiruvananthapuram, Kerala

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ohit Agrawal MD FIAP

MK Nair PhD MD M Med Sc MBA, FIAP C

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Academic Editors

IAP, National Publication House, Gwalior

JAYPEE BROTHERS MEDICAL PUBLISHERS (P) LTD. New Delhi • London • Philadelphia • Panama

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Jaypee Brothers Medical Publishers (P) Ltd.

Headquarters Jaypee Brothers Medical Publishers (P) Ltd. 4838/24, Ansari Road, Daryaganj New Delhi 110 002, India Phone: +91-11-43574357 Fax: +91-11-43574314 Email: [email protected]

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Overseas Offices

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Website: www.jaypeebrothers.com Website: www.jaypeedigital.com

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© 2013, Jaypee Brothers Medical Publishers

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Jaypee-Highlights edical ublishers Inc. City of Knowledge, Bld. 237, Clayton Panama City, Panama Phone: +507-301-0496 Fax: +507-301-0499 Email: [email protected]

 

J.P. Medical Ltd. 83, Victoria Street, London SW1H 0HW (UK) Phone: +44-2031708910 Fax: +02-03-0086180 Email: [email protected]

Jaypee Brothers Medical Publishers Ltd. The Bourse 111, South Independence Mall East Suite 835, Philadelphia, PA 19106, USA Phone: + 267-519-9789 Email: [email protected]

All rights reserved. No part of this book may be reproduced in any form or by any means without the prior permission of the publisher. Inquiries for bulk sales may be solicited at: [email protected] This book has been published in good faith that the contents provided by the contributors contained herein are original, and is intended for educational purposes only. While every effort is made to ensure accuracy of information, the publisher and the editors specifically disclaim any damage, liability, or loss incurred, directly or indirectly, from the use or application of any of the contents of this work. If not specifically stated, all figures and tables are courtesy of the editors. Where appropriate, the readers should consult with a specialist or contact the manufacturer of the drug or device.

IAP Textbook of Pediatrics First Edition: 1999, 2000 Second Edition: 2002,2003 Third Edition: 2006 Revised Reprint: 2007 Fourth Edition: 2009 Fifth Edition: 2013  

ISBN 978-93-5025-945-0 Printed at

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edicated to

The future citizens of India whose Care and Nurture are our Goal, Concern and Commitment

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Contributors AP ubey Director-Professor and Head Department of Pediatrics Maulana Azad Medical College New Delhi [email protected]

Abraham K Paul Consultant Pediatrician Cochin Hospital Kochi, Kerala [email protected]

Anju Aggarwal Associate Professor Department of Pediatrics University College of Medical Sciences Delhi [email protected]/ [email protected]

A Parthasarathy Distinguished Professor of Pediatrics The Tamil Nadu Dr MGR Medical University Senior Clinical Professor of Pediatrics (Retd) Madras Medical College Deputy Superintendent Institute of Child Health and Hospital for Children Chennai, Tamil Nadu [email protected]

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AK utta Director-Professor and Head Department of Pediatrics Lady Hardinge Medical College New Delhi [email protected]

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Amita Trehan Additional Professor Pediatric Hematology, Oncology and Advanced Pediatric Centre Postgraduate Institute of Medical Education and Research Chandigarh [email protected]

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Anoop Verma Consultant Pediatrician Swapnil Nursing Home Raipur, Chhattisgarh [email protected]

Anupam achdeva Director Pediatric Hematology and Oncology and Bone Marrow Transplantation Chairman Academics Convener Research Sir Ganga Ram Hospital New Delhi [email protected] Anupama Borker Associate Professor Department of Pediatrics In-Charge Pediatric Hematology and Oncology Kasturba Medical College, Manipal University, Manipal, Karnataka [email protected]

A iyaz Professor and Head Department of Pediatrics Government Medical College Kozhikode, Kerala [email protected] R

AJ hitkara Head Department of Pediatrics Max Hospital, Pitampura Max Super Speciality Hospital Shalimar Bagh, New Delhi [email protected]/ [email protected]

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Anju Virmani Senior Consultant Indraprastha Apollo, Max, Pentamed and Sunderlal Jain Hospitals, Delhi [email protected]

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Aditi inha Senior Research Associate Division of Pediatric Nephrology All India Institute of Medical Sciences New Delhi [email protected]

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Anita axena Professor Department of Cardiology All India Institute of Medical Sciences New Delhi [email protected] S

A Balachandran Pediatric Pulmonologist Mehta Children’s Hospital, Chetput Chennai, Tamil Nadu [email protected]/ [email protected]

Archana Kher Consultant Pediatrician Seven Hills Hospital Mumbai, Maharashtra Ex-Professor Pediatrics Seth Gordhandas Sunderdas Medical College and King Edward Memorial Hospital, Mumbai, Maharashtra [email protected]/ [email protected] Arun Bansal Assistant Professor Department of Pediatrics Postgraduate Institute of Medical Education and Research Chandigarh [email protected]

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Arun Phatak Professor and Head Department of Pediatrics KG Patel Children Hospital Vadodara, Gujarat [email protected]

B Bhaskar aju Professor and Head Department of Pediatric Gastroenterology (Retd) Institute of Child Health and Hospital for Children Chennai, Tamil Nadu [email protected]

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Ashok K Patwari Research Professor (International Health), Center for Global Health and Development (CGHD), Boston University School of Public Health Coordinator, CGHD India Country Program, New Delhi [email protected]/ [email protected]

Ashok Kumar Professor, Department of Pediatrics Institute of Medical Sciences Banaras Hindu University Varanasi, Uttar Pradesh [email protected]

Baldev Prajapati Professor Sheth LG General Hospital, AMC MET Medical College, Ahmedabad, Gujarat [email protected] Balvir Tomar Professor and Head Department of Pediatrics NIMS Medical College and Hospital Chancellor and Chairman NIMS University Jaipur, Rajasthan [email protected]/ [email protected] S

Bibek Talukdar Director-Professor and Head Department of Pediatrics Chacha Nehru Bal Chikitsalaya Delhi [email protected] B Nammalwar Professor of Pediatric Nephrolgy (Retd.) Institute of Child Health Hospital for Children Director of Medical Education Mehta Children Hospital Chennai, Tamil Nadu [email protected] R

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Ashok Kapse Pediatrician, Kapse Children Hospital Surat, Gujarat [email protected]

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Bala amachandran Consultant and Head Department of Intensive Care and Emergency Medicine Honorary Assistant Medical Director Kanchi Kamakoti Childs Trust Hospital Chennai, Tamil Nadu [email protected]/ [email protected] R

Ashish Bavdekar Associate Professor Consultant Pediatric Gastroenterologist Department of Pediatrics King Edward Memorial Hospital Pune, Maharashtra [email protected]

B Vishnu Bhat Professor of Pediatrics Head of Neonatology Division Jawaharlal Institute of Medical Education and Research Puducherry [email protected]

Bharat Agarwal Head Department of Pediatrics Hematology and Oncology Bai Jerbai Wadia Hospital for Children Mumbai, Maharashtra [email protected]

Brijesh Arora Associate Professor Department of Pediatric Oncology Tata Memorial Hospital Mumbai, Maharashtra [email protected] Thangadorai Senior Clinical Professor of Pediatrics (Retd) Madras Medical College Chennai, Tamil Nadu [email protected] C

Arvind Bagga Professor Department of Pediatrics All India Institute of Medical Sciences New Delhi [email protected]

B Gupta Professor and Head Department of Pediatrics Umaid Hospital Additional Principal Dr SN Medical College Senior Consultant Pediatrics Rajdadisa Hospital, Jodhpur, Rajasthan [email protected] D

ATK au Pediatric Hematologist-Oncologist Professor and Head Department of Pediatrics MS Ramaiah Medical College Bengaluru, Karnataka [email protected]

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Arun Kumar Gupta Professor and Head Department of Radiodiagnosis All India Institute of Medical Sciences New Delhi [email protected]/ [email protected]

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George F Moolayil Consultant Pediatrician Chazhikattu Hospitals Pvt Ltd Thodupuzha, Kerala [email protected]

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Jagdish handra Director-Professor Department of Pediatrics Kalawati Saran Children’s Hospital Lady Hardinge Medical College New Delhi [email protected] Jayakar Thomas Professor and Head Department of Dermatology Sree Balaji Medical College and Hospital Chennai, Tamil Nadu [email protected] Jaydeep houdhury Assistant Professor Department of Pediatrics Institute of Child Health Kolkata, West Bengal [email protected] C

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Geetha M Clinical Professor Pediatric Gastroenterologist Department of Gastroenterology and Hepatology Amrita Institute of Medical Sciences Kochi, Kerala [email protected]/ [email protected]/ [email protected]

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Gauri Kapoor Director Pediatric Hematology and Oncology Rajiv Gandhi Cancer Institute and Research Center New Delhi [email protected]

Ishwar Verma Sr Consultant and Director Center of Medical Genetics Sir Ganga Ram Hospital New Delhi [email protected]

Jeeson Unni Editor-in-Chief IAP Drug Formulary Consultant Pediatrician Dr Kunhalu’s Nursing Home Kochi, Kerala [email protected]/ [email protected] C

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igant hastri Pediatrician and CEO Killol Children Hospital, NICU and Vaccination Center Surat, Gujarat [email protected] D

Gadadhar arangi Professor, Department of Pediatrics Hi-Tech Medical College, Pandara Bhubaneswar, Odisha [email protected]

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heeraj hah Associate Professor Department of Pediatrics University College of Medical Sciences New Delhi [email protected]

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evendra Mishra Associate Professor Department of Pediatrics Maulana Azad Medical College New Delhi [email protected]

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eepak Ugra Consultant Pediatrician Lilavati Hospital and Research Centre Consultant Pediatrician Hinduja Health Care Pvt. Ltd. Visiting Consultant Pediatrician Breach Candy Hospital Mumbai, Maharashtra [email protected]

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eepak Bansal Additional Professor Hematology and Oncology Unit, Advanced Pediatric Center, Postgraduate Institute of Medical Education and Research Chandigarh [email protected]

K Agarwal Ex-Professor and Head Department of Pediatrics Banaras Hindu University Varanasi, Uttar Pradesh Secretary Health Care and Research Association Noida, Uttar Pradesh [email protected]

Indira Agarwal Professor and Head Department of Child Health Christian Medical College Vellore, Tamil Nadu [email protected]/ [email protected]

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ivya Prabhat Head Department of ENT Wadia Children Hospital Mumbai, Maharashtra [email protected]

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Vijayasekaran Associate Professor in Pediatrics and Respiratory Diseases Madras Medical College, ICH and HC Pediatric Pulmonologist and Bronchoscopist [email protected]

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H Paramesh Pediatric Pulmonologist Environmentalist, Medical Director Lakeside Medical Center and Hospital Director Lakeside Institute of Child Bengaluru, Karnataka [email protected]

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ilip Mukherjee Emeritus Professor of Pediatrics Ramakrishna Mission Seva Pratishthan Vivekananda Institute of Medical Sciences, Kolkata, West Bengal [email protected]/ [email protected]/ [email protected]

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Nirmala Professor and Head Department of Pediatric Gastroenterology Institute of Child Health and Hospital for Children Chennai, Tamil Nadu

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Kanishka as Professor and Head Department of Neonatal and Pediatric Surgery St John’s Medical College St John’s National Academy of Health Sciences Bengaluru, Karnataka [email protected]

Lalitha Kailas Professor and Head Department of Pediatrics SAT Hospital Government Medical College Thiruvananthapuram, Kerala [email protected]

Jugesh hhatwal Professor Department of Pediatrics Vice Principal (Postgraduate Studies) Christian Medical College and Hospital, Ludhiana, Punjab [email protected]

Ketan Parikh Consultant Pediatric Surgeon and Pediatric Laparoscopist Tara Neo-Surg Hospital Jaslok Hospital, LH Hiranandani Memorial Hospital Mumbai, Maharashtra [email protected]/ [email protected]

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K urendran Surveillance Medical Officer WHO – National Polio Surveillance Project, Chennai [email protected] R

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Kamer ingh ana Consultant Pediatrics and Pediatric Neurology Command Hospital x Pune, Maharashtra [email protected]

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KN Agarwal Professor of Pediatrics President Health Care and Research Association for Adolescents Noida, Uttar Pradesh [email protected]

M Vijayakumar Head Department of Pediatric Nephrology Mehta Children’s Hospital Chennai, Tamil Nadu [email protected]

Krishan hugh Director Institute of Health, Sir Ganga Ram Hospital, New Delhi Chairman Department of Pediatrics Director Pediatric Intensive Care Unit [email protected]

Madhulika Kabra Professor Division of Genetics, Department of Pediatrics All India Institute of Medical Sciences New Delhi [email protected]/ [email protected]

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Kishore Phadke Professor and Head Department of Pediatrics St John’s Medical College Hospital Bengaluru, Karnataka [email protected]

M Jayashree Additional Professor Department of Pediatrics Advanced Pediatrics Center Postgraduate Institute of Medical Education and Research Chandigarh [email protected]

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K Nedunchelian Associate Professor of Pediatrics Government Dharmapuri Medical College Dharmapuri, Tamil Nadu [email protected]

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M Indrashekhar ao Former Medical Superintendent Professor and Head Department of Pediatrics Institute of Child Health Niloufer Hospital Hyderabad, Andhra Pradesh Director Medical Education Government of Andhra Pradesh Member Executive Council NT Rama Rao University of Health Sciences, Vijayawada, Andra Pradesh [email protected]

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K lizabeth Professor of Pediatrics Consultant in Nutrition Sree Avittom Thirunal Hospital Government Medical College Thiruvananthapuram, Kerala [email protected]

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JP adhich National Coordinator Breastfeeding Promotion Network of India New Delhi [email protected]/ [email protected]

K Nagaraju Senior Consultant in Pediatric Allergy Kanchi Kamakoti Childs Trust Hospital Chennai, Tamil Nadu [email protected]

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L ubramanyam Senior Pediatrician and Pulmonologist Mehta Children’s Hospital Chennai, Tamil Nadu [email protected]

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Joseph L Mathew Assistant Professor (Pediatric Pulmonology) Advanced Pediatrics Center Postgraduate Institute of Medical Education and Research Chandigarh [email protected]/ [email protected]

Kamran Afzal Reader Department of Pediatrics Jawaharlal Nehru Medical College Aligarh Muslim University Aligarh, Uttar Pradesh [email protected]

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JN harma Professor and Head Department of Pediatrics Gauhati Medical College Guwahati, Assam [email protected]

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Meenakshi Mehta Head and Consultant Pediatrician Mahatma Gandhi Memorial Hospital Mumbai, Maharashtra [email protected]

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Munni ay Additional Professor of Pediatrics Postgraduate Institute of Medical Education and Research Chandigarh [email protected]

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Naveen Thacker Director Deep Children Hospital and Research Centre Kutch, Gujarat [email protected]/ [email protected] Neelam Mohan Director Department of Pediatric Gastroenterology, Hepatology and Liver Transplantation Medanta – The Medicity Hospital Gurgaon, Haryana [email protected]/ [email protected] Niranjan hendurnikar Consultant Pediatrician KG Patel Children Hospital Vadodara, Gujarat [email protected] Nitin hah Honorary Pediatric HematologistOncologist Bai Jerbai Wadia Hospital for Children Mumbai, Maharashtra Consultant Pediatrician PD Hinduja Hospital Mumbai, Maharashtra [email protected] S

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Meena P esai Honorary Consultant Endocrinology Division Bai Jerbai Wadia Hospital for Children and Institute of Child Health and Research Centre Honorary Pediatrician Sir HN Hospital and Research Centre Honorary Medical Advisor Sir HN Medical Research Society Mumbai, Maharashtra [email protected]

M Mahadeviah Honorary Professor Kempegowda Institute of Medical Sciences Honorary Consultant in Developmental Neurology Indira Gandhi Institute of Child Health Honorary Medical Director Spastics Society of Karnataka Bengaluru, Karnataka [email protected] R

Manorama Verma Former Professor of Pediatrics Christian Medical College Ludhiana, Punjab [email protected]

M Lokeshwar Ex-Professor, Department of Pediatrics LTMG Hospital and Medical College Mumbai, Maharashtra [email protected]

Naveen ankhyan Assistant Professor Department of Pediatrics, Advanced Pediatric Center Postgraduate Institute of Medical Education and Research Chandigarh [email protected]

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Manju Mehta Professor (Clinical Psychology) Department of Psychiatry All India Institute of Medical Sciences New Delhi [email protected]

Monjori Mitra Consultant Pediatrician Institute of Child Health Kolkata, West Bengal [email protected]

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Malathi athiyasekaran Consultant Pediatric Gastroenterologist Kanchi Kamakoti Childs Trust Hospital Apollo Children’s Hospital Sundaram Medical Foundation Chennai, Tamil Nadu [email protected]

ML Kulkarni Professor and Head Department of Pediatrics JJM Medical College Davanagere, Karnataka [email protected]

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Madhuri Kanitkar Consultant Pediatrics and Pediatric Nephrology Base Hospital Delhi Cantt, New Delhi Professor and Head Department of Pediatrics Army College of Medical Science New Delhi [email protected]

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Naveen Jain Associate Professor Department of Neonatology Kerala Institute of Medical Sciences Thiruvananthapuram, Kerala [email protected]

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MK Nair Professor of Pediatrics and Founder Director, Child Development Centre Thiruvananthapuram, Kerala [email protected]

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Narendra athi Consultant Pediatrician Rathi Children’s Hospital and Maternity Home Akola, Maharashtra [email protected]

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Milind Tullu Associate Professor Department of Pediatrics Seth Gordhandas Sunderdas Medical College and King Edward Memorial Hospital, Parel, Mumbai, Maharashtra [email protected]

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Madhumati tiv Pediatric Intensivist Program Director for ISCCM-IAP Certificate Course in Pediatric Intensive Care Kind Edward Memorial Hospital Pune, Maharashtra [email protected]

Narendra Kumar Arora Executive Director The INCLEN Trust International and Child Health and Nutrition Research Initiative Adjunct Professor (Research) Public Health Foundation of India [email protected]

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P amachandran Professor of Pediatrics, Sri Ramchandra Medical College and Research Centre, Porur, Chennai Tamil Nadu [email protected] PA Mohammed Kunju Professor and Head Department of Pediatric Neurology Government Medical College Thiruvananthapuram, Kerala [email protected] Pankaj Hari Additional Professor of Pediatrics All India Institute of Medical Sciences New Delhi [email protected] C

Panna houdhury Consultant Pediatrician (Retd.) Lok Nayak Hospital New Delhi [email protected] Parang N Mehta Consultant Pediatrician Mehta Hospital Surat, Gujarat [email protected]

PP Maiya Former Professor and Head Department of Pediatrics MS Ramaiah Medical Teaching Hospital Bengaluru, Karnataka [email protected]

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PK Baskar Director Sri Viveka Institute of Dental Sciences GN Chetty Road T Nagar, Chennai, Tamil Nadu [email protected]

Prisca olaco Professor Department of Pediatrics Mahatma Gandhi Mission’s Medical College Navi Mumbai Consultant Pediatrician and Pediatric Endocrinologist Holy Family Hospital Mumbai, Maharashtra [email protected] P N Menon Consultant and Head Department of Pediatrics Jaber Al-Ahmed Armed Forces Hospital Kuwait Ex-Professor Department of Pediatrics All India Institute of Medical Sciences New Delhi [email protected] S

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P aghupathy Professor Department of Pediatrics (Pediatric Endocrinology) Indira Gandhi Institute of Child Health Senior Consultant Pediatric Endocrinology Sagar Hospitals Bengaluru, Karnataka [email protected]

Piyush Gupta Professor Department of Pediatrics University College of Medical Sciences Delhi [email protected]

Preeti abadghao Associate Professor Department of Endocrinology Sanjay Gandhi Postgraduate Institute of Medical Sciences Lucknow, Uttar Pradesh [email protected]

Prakash P Kotwal Professor and Head Department of Orthopedics All India Institute of Medical Sciences New Delhi [email protected]

Pukhraj Bafna Head Department of Pediatrics United Hospital and Research Centre Rajnandgaon, Chhattisgarh [email protected]

Pratibha inghi Chief Pediatric Neurology and Neurodevelopment Advanced Pediatrics Centre Postgraduate Institute of Medical Education and Research Chandigarh [email protected]

Purna A Kurkure Professor Emeritus In-Charge After Completion of Therapy (ACT) Clinic Department of Pediatric Oncology Tata Memorial Hospital Mumbai, Maharashtra [email protected]

Praveen Khilnani Head Pediatric Critical Care Services BLK Superspeciality Hospital New Delhi [email protected]

Krishna Kumar Clinical Professor and Head Department of Pediatric Cardiology Amrita Institute of Medical Sciences Kochi, Kerala [email protected]/ [email protected] R

Nupur Ganguly Associate Professor Institute of Child Health Kolkata, West Bengal [email protected]

Paul wamidhas udhakar ussell Professor (Psychiatry) Child and Adolescent Psychiatry Unit Christian Medical College Vellore, Tamil Nadu [email protected]

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Noel Narayanan Formerly Professor and Head Department of Pediatrics Government Medical College Thiruvananthapuram, Kerala [email protected]

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anjan Kumar Pejaver Honorary Professor Department of Pediatrics Kalinga Institute of Medical Sciences Consultant Neonatologist Krishna Rajendra Hospital Head of Department St. Philomenas Hospital Bengaluru, Karnataka [email protected]

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rinivasan Professor and Head Department of Pediatrics Jawaharlal Institute of Medical Education and Research [email protected]/ [email protected]

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itabrata Kundu Professor Department of Pediatrics Institute of Child Health Kolkata, West Bengal [email protected]

amesh Consultant Pediatrician BRS Hospitals Chennai, Tamil Nadu [email protected]

K Agarwal Consultant Pediatrician RK Hospital Udaipur, Rajasthan [email protected]/ [email protected]

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Yamuna Pediatrician and Adolescent Physician Child and Adolescent Clinic Director Centre for Excellence in Parenting Chennai, Tamil Nadu [email protected]

K Anand Head Department of Pediatrics and Neonatology Jaslok Hospital and Research Centre Mumbai, Maharashtra [email protected]

Kamath Consultant Pediatrician Welcare Hospital Ernakulam, Kerala [email protected] SS

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Potdar Trustee and Hon. General Secretary Centre for the Study of Social Change. Pediatrician, Jeevak Children Hospital Mumbai, Maharashtra [email protected]

Balasubramanian Senior Consultant Pediatrician Kanchi Kamkoti Childs Trust Hospital Nungambakkam, Chennai, Tamil Nadu [email protected]

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aju P Khubchandani Consultant Pediatrician In-Charge Pediatric Rheumatology Clinic Jaslok Hospital and Research Center Mumbai, Maharashtra [email protected]

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hishikesh Thakre Professor Department of Pediatrics Division of Neonatology Mahatma Gandhi Medical College and Hospital Aurangabad, Maharashtra [email protected]/ [email protected]

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aju hah Professor and Head GCS Medical College Ankur Institute of Child Health Ahmedabad, Gujarat [email protected]

uchi Nimish Nanavati Professor and Head Department of Neonatology Seth Gordhandas Sunderdas Medical College King Edward Memorial Hospital Mumbai, Maharashtra [email protected]

ailesh Gupta Arushee Childcare Hospital and Ashna Children’s Hospital Mumbai, Maharashtra [email protected]/ [email protected]/ [email protected] S

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ekha Mittal Senior Consultant Department of Pediatric Neurology Pushpanjali Crosslay Hospital Ghaziabad, Uttar Pradesh [email protected] R

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ajniti Prasad Associate Professor Department of Pediatrics Institute of Medical Sciences BHU, Varanasi, Uttar Pradesh [email protected]/ [email protected]

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ajiv handra Mathur Consultant Pediatrician and Hepatologist Aditya Hospital Hyderabad, Andhra Pradesh [email protected]

ashmi Kumar Professor Department of Pediatrics Chhatrapati Shahuji Maharaj Medical University Lucknow, Uttar Pradesh [email protected]

ohit Agrawal Consultant Pediatrician Kohinoor Hospital and Chandra-Jyoti Children Hospital Mumbai, Maharashtra [email protected]/ [email protected]

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ajeshwar ayal Professor and Head Department of Pediatrics SN Medical College Agra, Uttar Pradesh [email protected]

ashmi alvi Consultant Pediatric Hematologist-Oncologist Professor and Head Department of Pediatrics Bombay Hospital and Institute of Medical Sciences Mumbai, Maharashtra [email protected]

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N rivastava Consultant Pediatric Nephrologist Apollo Indraprastha Hospitals New Delhi [email protected]/[email protected]

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Banerjee Head, Department of Pediatrics Islamia Hospital Kolkata, West Bengal [email protected]

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unanda K eddy Consultant Developmental Pediatrics and Community Health Chief NGO Functionary Centre for Applied Research and Education on Neurodevelopmental Impairments and Disability-related Health Initiatives New Delhi Adjunct Faculty, South Asia Centre for Disability Inclusive Development and Research Hyderabad, Andhra Pradesh [email protected]/ [email protected] S

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oonu Udani Head of Section of Pediatrics Hinduja Hospital Mumbai, Maharashtra [email protected]

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hashidhararao Nagabhushana Clinical Associate, CSI Hospital, Bangaluru Visiting Consultant, Columbia Asia Hospital, Hebbal, Bangaluru, Karnataka [email protected]/ xiv [email protected]

omu ivabalan Consultant Pediatrician and Pulmonologist Sundaram Medical Foundation Chennai, Tamil Nadu [email protected]

ukanta hatterjee Professor and Head Department of Pediatrics In-Charge Adolescent Health Clinic Medical College Kolkata, West Bengal [email protected]/ [email protected]

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rikanta Basu Associate Professor Department of Pediatrics Lady Hardinge Medical College and Kalawati Saran Children’s Hospital New Delhi [email protected]

uneeta Mittal Head Department of Obstetrics and Gynecology Director-in-Charge WHO-CCR in Human Reproduction Chief ART Centre and IVF Facility All India Institute of Medical Sciences New Delhi [email protected] S

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hashi N Vani Emeritus Professor of Pediatrics and Neonatology Pramukh Swami Medical College Karamsad, Gujarat Professor (Retd.) and Head of Department Pediatrics and Neonatology BJ Medical College Ahmedabad, Gujarat [email protected]

uchitra anjit Senior Consultant and Head Pediatric Intensive Care and Emergency Services Apollo Children’s Hospital Chennai, Tamil Nadu [email protected]

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eema Alam Department of Pediatric Hepatology Institute of Liver and Biliary Sciences New Delhi [email protected]

iddarth amji Director-Professor (Pediatrics) and Head Department of Neonatology Maulana Azad Medical College New Delhi [email protected] S

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avitri hrivastava Director, Department of Pediatric and Congenital Heart Disease Fortis Escorts Heart Institute New Delhi [email protected]

hubha Phadke Professor Department of Medical Genetics Sanjay Gandhi Postgraduate Institute of Medical Sciences Lucknow, Uttar Pradesh [email protected]

rinivas ankaranarayanan Consultant Pediatrics Gastroenterologist Apollo Children’s Hospital Chennai and Kanchi Kamakoti Childs Trust Hospital Chennai, Tamil Nadu [email protected] S

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heila Bhave Associate Professor Department of Pediatrics King Edward Memorial Hospital Research Centre Pune, Maharashtra [email protected]/[email protected]

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atya Prakash Yadav Consultant (Pediatric Hematology and Oncology and Bone Marrow Transplant Unit) Department of Pediatrics Institute of Child Health Sir Ganga Ram Hospital, New Delhi [email protected]

heffali Gulati Additional Professor and Chief Child Neurology Division Department of Pediatrics All India Institute of Medical Sciences New Delhi [email protected]/ [email protected] S

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atinder Aneja Director-Professor Department of Pediatrics Lady Hardinge Medical College New Delhi [email protected] S

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andeep B Bavdekar Professor and Head Department of Pediatrics Topiwala National Medical College and BYL Nair Hospital Central Mumbai, Maharashtra [email protected]

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Tanmay Amladi Consultant Pediatrician, Zulekha Hospital, Al Nahda, Dubai, UAE Tanu inghal Consultant Pediatrics and Infectious Disease, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute Mumbai, Maharashtra [email protected]/ [email protected]

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Uday B Nadkarni Consultant, Pediatric Intensive Care Seven Hills Hospital Mumbai, Maharashtra [email protected] Ujjal Poddar Associate Professor of Pediatrics Gastroenterology, Sanjay Gandhi Postgraduate, Institute of Medical Sciences, Lucknow, Uttar Pradesh [email protected] Uma Ali Head of Nephrology Division and PICU, BJ Wadia Hospital for Children, Mumbai Consultant Pediatrician, Lilavati Hospital Mumbai, Jupiter Hospital Thane, Maharashtra [email protected] Upreet haliwal Professor of Ophthalmology University College of Medical Sciences and GTB Hospital, Delhi [email protected] D

Utpal Kant ingh Professor and Head Department of Pediatrics Nalanda Medical College Patna, Bihar [email protected] S

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T avikumar Consultant Pediatrician Kanchi Kamakoti Childs Trust Hospital Chennai, Tamil Nadu [email protected]

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T Jacob John Emeritus Professor, Department of Virology, Christian Medical College and Hospital, Vellore, NA District Tamil Nadu [email protected]

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ushil K Kabra Professor, Pediatric Pulmonology Division Department of Pediatrics, All India Institute of Medical Sciences New Delhi [email protected]

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usan Uthup Additional Professor Department of Pediatric Nephrology Government Medical College Thiruvananthapuram, Kerala Honorary Consultant Pediatric Nephrologist Sree Chitra Thirunal Institute of Medical Science and Technology Thiruvananthapuram, Kerala [email protected]/ [email protected]

wati Y Bhave Senior Visiting Consultant, Advanced Center of Pediatrics Indraprastha Apollo Hospital, New Delhi Advisor Apollo Hospital Research and Education Foundation (AHERF) Former Professor of Pediatrics BJ Medical College, Pune, Maharashtra [email protected]

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S S S S

urjit ingh Professor Department of Pediatrics Advanced Pediatrics Centre Postgraduate Institute of Medical Education and Research Chandigarh [email protected]

warna ekha Bhat Professor, Pediatrics and Neonatology Head of the Department of Neonatology St Johns Medical College and Hospital Bengaluru, Karnataka [email protected]

Tulika eth Assistant Professor of Hematology All India Institute of Medical Sciences New Delhi [email protected]

ors

unit inghi Professor and Head Department of Pediatric Emergency and Intensive Care, Advanced Pediatrics Centre Postgraduate Institute of Medical Education and Research Chandigarh [email protected]

ushmita Banerjee Consultant, Calcutta Medical Research Institute and Institute of Child Health Kolkata, West Bengal [email protected]

TU ukumaran Professor of Pediatrics Pushpagiri Institute of Medical Sciences, Thiruvalla, Kerala [email protected]

r

unil Karande Professor and In-Charge Learning Disability Clinic Department of Pediatrics Seth Gordhandas Sunderdas Medical College and King Edward Memorial Hospital Mumbai, Maharashtra [email protected]

ushila ussell Lecturer in Clinical Psychology Department of Psychiatry Child and Adolescent Psychiatry Unit Christian Medical College Vellore, Tamil Nadu [email protected]

o

unil Gomber Professor Department of Pediatrics UCMS and GTB Hospital Delhi [email protected]

Vaman Khadilkar Consultant Pediatric Endocrinologist Jehangir Hospital, Pune and Bombay Hospital Mumbai, Maharashtra Assistant Professor Pediatric Endocrinology Bharati Vidyapeeth Medical College Pune, Maharashtra [email protected]

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Vijay Yewale Consultant Pediatrician and Neonatologist, Dr. Yewale’s Multispecialty Hospital for Children Mumbai, Maharashtra Honarary Pediatrician Mathadi Hospital Trust Consultant Pediatrician, Fortis Hospital [email protected]

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V avikumar Formerly Professor of Pediatric Surgery, Coimbatore Medical College Consultant Pediatric Surgeon G Kuppuswami Naidu Memorial Hospital, Coimbatore, Tamil Nadu [email protected] R

D

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Vibhawari ani Ex-Professor of Pediatrics, Ex-Dean Government Medical College Nagpur, Maharashtra [email protected]

Vimlesh eth Retired Senior Professor and Head Department of Pediatrics All India Institute of Medical Sciences New Delhi [email protected]/ [email protected] R

S

VH ankar Consultant Geneticist, Genetic Clinic Associate Professor of Pediatrics Department of Pediatrics, SAT Hospital, Medical College Thiruvananthapuram, Kerala [email protected]

Vrajesh Udani Consultant, Child Neurology and Epilepsy, PD Hinduja National Hospital Mumbai, Maharashtra [email protected]

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YK Amdekar Medical Director BJ Wadia Hospital for Children Mumbai and Consultant Pediatrician Jaslok Hospital and Research Center Mumbai, Maharashtra [email protected] Yogesh Govil (Late) Professor, Department of Pediatrics Chhatrapati Shahuji Maharaj Medical University (Upgraded King George’s Medical College) Lucknow, Uttar Pradesh [email protected]/ [email protected] C

Vikram atta Professor of Neonatology Department of Pediatrics Lady Hardinge Medical College New Delhi Secretary, National Neonatology Forum, India [email protected]

V ankaranarayanan Honorary Director of Pediatric Medical Education and HOD and Senior Consultant Department of Pediatric Gastroenterology and Hepatology Kanchi Kamakoti Childs Trust Hospital Chennai, Tamil Nadu [email protected] S

Vijayalakshmi Bhatia Professor of Endocrinology Sanjay Gandhi Postgraduate Institute of Medical Sciences Lucknow, Uttar Pradesh [email protected] D

S

Ved Prakash houdhry Director, Sunflag Pahuja Centre for Blood Disorders Sunflag Hospital [email protected] C

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Varinder ingh Professor of Pediatrics Lady Hardinge Medical College and Associated Kalawati Saran Children’s Hospital New Delhi [email protected]

Zulfiqar A Bhutta Professor and Founding Chair Division of Women and Child Health The Aga Khan University Karachi, Pakistan [email protected]

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Foreword









It gives me great pleasure to write the foreword for IAP Textbook of Pediatrics (Fifth Edition), a prestigious publication of Indian Academy of Pediatrics. We, as Pediatricians, are dealing with the health of more than 50 percent of the population. Infant and childhood morbidity continue to be very high and adolescent health problems are still not adequately addressed by medical profession. Thus, it is imperative that all of us need to have sound training to look after the children from birth to 18 years. The book has fulfilled this void very well. All previous editions of this book have been very popular amongst undergraduate and postgraduate students. The book has been well received in many developing countries having similar health scenario. Contributors of this book are renowned experts in their respective fields. An invariable problem with multiauthored texts is the diversity of presentations adopted by a multitude of contributors. Since inception, Dr A Parthasarathy, Editorin-Chief, an accomplished academician with tremendous zeal, managed this issue by carefully crafting a common editorial style. In this venture, he has been aptly assisted by other very well-known academicians, Dr PSN Menon, Dr Piyush Gupta and Dr MKC Nair, along with many highly reputed chapter editors. Keeping with time, the text of the book has been aptly modified and all the chapters have been thoroughly revised. The book is designed to be relevant to the need of the developing countries. Emphasis has been on common prevalent conditions though allied subjects seen in children have also received due attention. Section on Community Pediatrics deserves special mention as most textbooks with Western approach hardly provide any information in this respect. The book certainly will continue to remain as a very prestigious publication of Indian Academy of Pediatrics.

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P Bansal President Indian Academy of Pediatrics 2013

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Foreword







It indeed is a proud privilege and great honor for me to write the foreword for IAP Textbook of Pediatrics, an ultimate academic publication of the Indian Academy of Pediatrics, which is nothing less of an international class. If “Nelson” is considered as the “Bible of Pediatrics”, this creation should surely be taken as “Gita/Quran of Pediatrics”, at least for the pediatric health professionals of South Asia. The Indian Academy of Pediatrics is always been a front runner in dissemination of knowledge and academics being its citadel. The revolutionary concept, envisaged way back in the late 1990s, has undergone many revisions, and, today; the Fifth Edition is getting released on the 50th Golden Jubilee Year of Indian Academy of Pediatrics; will imprint itself in the golden letters in the golden history of Indian Academy of Pediatrics at the golden hands of His Excellency Dr APJ Abdul Kalam. This mission of Indian Academy of Pediatrics is a vision towards the cause of every pediatrician, a student, a practitioner or an academician alike, which may translate into better child health care services and reduction in child mortality… a humble attempt to achieve MDG-4. In its Fifth Edition, this textbook slowly but surely inching towards the “Nelson’s” textbook. Almost the entire gambit of pediatrics is being brilliantly and aesthetically crafted in this reader-friendly textbook by the editors. Latest and updated information is encompassed and compiled in their respective subspecialty sections by a team of learned section editors. The authors who contributed are Key Academic Opinion Leaders in their respective fields. A dedicated team of astute academicians, such as Dr A Parthasarathy, Editor-in-Chief, Dr PSN Menon, Chief Academic Editor, Dr Piyush Gupta and Dr MKC Nair, Academic Editors, have probably put in the best of their academic life for the last 2 years to bring out this “immortal” Fifth Edition of IAP Textbook of Pediatrics. My heartfelt gratitude, tributes and innumerable salutes to this “Immortal quartet”. R

ohit Agrawal President Indian Academy of Pediatrics 2012

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Foreword



It is my pleasure and privilege to write the foreword for the Fifth Edition of the IAP Textbook of Pediatrics. This textbook was published as an action plan of Dr A Parthasarathy who continues to excel as the Editor-in-Chief for the Fifth Edition of this remarkable book. The book is not only an accepted reference book of Pediatrics in India but is also widely accepted by all the academicians, postgraduates and practitioners around the country. There are a lot of unique features included in the Fifth Edition. Every chapter has been updated and rewritten by experts in their respective fields with a great acumen. I congratulate the dynamic editors Dr PSN Menon, Dr Piyush Gupta and Dr MKC Nair for their hard work to release the book during the Golden Jubilee Year of Indian Academy of Pediatrics in Pedicon (Kolkata, West Bengal, India). I also congratulate Dr Rohit Agrawal, President, IAP 2012, and Dr CP Bansal, President, IAP 2013, and all the contributors who have made this wonderful book possible.

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TU ukumaran President Indian Academy of Pediatrics 2011

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Preface to the Fifth Edition











The Editorial Board dedicates this new revised and updated Fifth Edition of the IAP Textbook of Pediatrics to children and adolescents—the future citizens of India whose Care and Nurture are our goal, concern and commitment. In a way, it is also our humble homage to the Indian Academy of Pediatrics, which has been in the forefront for the care of children of all hues and colors, at all ages and without barriers; and had trained and nurtured us as responsible professionals to care them with love and compassion. It is our honor and privilege that this dedication coincides with the time when the Indian Academy of Pediatrics is celebrating 50 years of its existence and active service. The last decade has witnessed rapid strides in medicine and technological advances in biological sciences. The specialty of Pediatrics has made substantial advances in preventive and therapeutic care. New vistas for care of children have been opened and many fresh thrust areas requiring our immediate or continued attention to decrease both morbidity and mortality have been delineated. These have provided fresh impetus to revise knowledge, harvest new information and thus continue the process of learning. The opportunities are limitless and it is for us to take advantage of these new frontiers. There was a felt need for publication of an updated Fifth Edition of this book after a gap of 4 years. This was also prompted by the enthusiastic response to the previous editions from practicing pediatricians, postgraduates, undergraduates as well as faculty of Departments of Pediatrics throughout India and other SAARC countries. It has been our endeavor to present this subject in a simplified and practical manner to provide adequate clinical guidance to pediatricians so that children derive the benefits of early diagnosis and optimal treatment. The basic simple and practical outline of the book is retained. We have tried our best to oversee that the “art and science” of Clinical Pediatrics maintains its central position without being overshadowed by newer technical advances. The main focus of the new edition has now shifted to practicing pediatricians as against the original concept of undergraduates. The Indian Academy of Pediatrics now has a membership of nearly 20,000 pediatricians and there is a felt need to continuously update our members—young and old—with the rapid advances in the field and the new national initiatives in the care of children. The previous editions were very popular amongst practitioners of pediatrics as well as family medicine. This is not a watered down version; efforts have also been made to keep a balance with incorporation of the curricular needs of the undergraduates and postgraduates and teachers in Pediatrics. The book represents a substantial revision and reorganization of the text based on a complete review of the field of Pediatrics. A major change in this edition is the concerted effort to condense the contents of the Fifth Edition in a single volume instead of the 1,565 pages of the Fourth Edition in two volumes. The number of chapters has been brought down to 21 from the original 36 in the previous edition. These changes are in accordance with the wishes expressed by several readers and also suggestions received from the publisher. The entire contents of this textbook were formulated to provide relevant clinical information and national priorities at one site. The text of the new edition was written afresh or revised and edited accordingly by selected reputed experts in respective fields. A judicious balance of old and young authors was made by retaining most authors as far as possible and at the same time inducting new experts in chosen fields. Almost all the chapters have been thoroughly revised and updated in a lucid and readable style. The Editorial Board and the Indian Academy of Pediatrics are indebted to these experts who made their valuable contributions without any remuneration or honorarium for their services to the Indian Academy of Pediatrics. Some of the thrust areas in this edition refer to felt needs of our country. It is our constant endeavor to inform, educate and update the reader about the current status of national community-oriented initiatives for children. We are justifiably proud of our achievements in preventive care with attainment of the status of polio-free nation among others, early this year. Strategies for incorporating newer technology and better coverage of immunization to contain communicable diseases and further reduction in disease burden, especially in the underprivileged areas of our society hence find a better thrust in this book. While we are able to combat infections at a better footing than before, the continued onslaught of newer infections and pandemics, especially from resistant microorganisms is our national priority. As pediatricians, our major commitment is to ensure a decrease in mortality and morbidity, especially among the under-fives. The use of simple strategies to improve health status (e.g. uniform growth charts and low cost food supplements); more complex issues such as the increasing disease burden of new epidemics of non-infectious chronic

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diseases like obesity, especially in the urban India; and screening for congenital disorders in the newborns thus find adequate mention in this book. Several new chapters have been added keeping in mind the changing concepts of Pediatric care in the global scenario. The Indian Academy of Pediatrics would like to place on record its appreciation to all the authors who have taken great pains to contribute and/or edit reader-friendly sections with practical guidelines amidst their busy professional and academic schedules. We are proud to inform you that we have about 75 new authors in this edition of the textbook with valuable contributions. We welcome the new section editors of this edition and gratefully acknowledge the efforts and time spent by Senior Editors and Chapter Editors who have devoted great deal of their time reviewing and editing the manuscripts. We do sincerely hope their efforts have made the book look more concise and precise. It is our earnest hope that this book will help in early diagnosis and efficient management leading to optimal outcome and improving the quality of patient care. Your valuable suggestions and comments are most welcome for improving the contents and quality of future editions.

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A Parthasarathy P N Menon Piyush Gupta MK Nair

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Preface to the First Edition









Pediatrics has grown and developed with significant milestones in preventive and therapeutic care over the past few decades. The WHO and UNICEF in their Primary Health Care (PHC) approach have given due importance for effective child survival programs. So the medical students need to be well oriented towards these approaches in Pediatrics as the future middle level managers in Primary Health Care. Several luminaries in the Indian pediatric scenario have contributed their might in bringing out books for the undergraduate medical students. However, the rapid advances made in the various pediatric subspecialties have necessitated the updating of these books from time to time. Nevertheless, the need for a full-fledged textbook was felt for long. The Indian Academy of Pediatrics thought it fit to shoulder the responsibility of bringing out such a need-based Textbook in Pediatrics for medical students. Our erudite and enthusiastic editors and contributors made it possible at a record time. The Indian Academy of Pediatrics owes its gratitude to all these experts for their worthy contribution. The book has been divided into several sections. A few chapters included in this book are entirely newer concepts, which are not usually found in the conventional pediatric textbooks. It has also worthy annexures to the main contents. However, editing the text to suit the needs of medical students was a Himalayan task. The idea is to equip the medical students with adequate knowledge in Pediatrics in order to make them confident to shoulder the responsibilities concerned with preventive and curative Pediatrics. Thus, it is hoped that the practitioners of Pediatric Medicine will benefit from this book. We are confident that this book will serve the needs of medical students, especially at a time when the Medical Council of India has made Pediatrics as a major examination subject. Thus, the publication of the book is not only timely but also out of necessity. The Indian Academy of Pediatrics would like to place on record its appreciation to the senior editors, chapter editors, contributors, and staff members of Indian Academy of Pediatrics Central Secretariat for help rendered in the creation of this book and M/s Jaypee Brothers Medical Publishers (P) Ltd., New Delhi, India, for their excellent cooperation in bringing out the First Edition at record time.

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A Parthasarathy P N Menon MK Nair

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Acknowledgments















We are indebted to the President and Members of the Executive Board 1997 of the Indian Academy of Pediatrics for the initiation and completion of the project of bringing out the first ever IAP Textbook of Pediatrics for the medical students and practitioners. We are also thankful to the successive Presidents and Members of the Executive Boards 1998–2012 for their encouragement in sustaining the project toward the publication of the Fifth Edition. Our grateful thanks go to the various contributors and chapter editors, past and present teachers of Pediatrics who have contributed to the Fifth Edition and made the “Himalayan task” of production of the current edition a reality by their precise and updated text. We are indebted to the faculty and residents of All India Institute of Medical Sciences, New Delhi, for shaping the contents of the First Edition which has made the production of the subsequent editions an easy task and to Ms Manju, Ms Chitra and Ms Suman for their assistance in typing and drafting the text of the book for the First Edition. The secretarial and organizational skills of Mr Joseph A Gonzalves and his supportive staff of Indian Academy of Pediatrics Central Office, Mumbai, the meticulous guidance and cooperation and coordination provided by Dr Rohit Agrawal, IAP President 2012, Dr TU Sukumaran, IAP President 2011, Dr CP Bansal, IAP President 2013, Dr Sailesh Gupta, IAP Honorary Secretary General 2012−13, Dr Pravin J Mehta, IAP Honorary Treasurer 2012−13, are gratefully acknowledged. Our grateful thanks to Mrs Nirmala, Mr R Janardhanan, Dr Pratibha, Ms Shruthi Pavana, Ms Swathi Pavana, Mr P Balaji, Ms Kavya and Ms Mahiya for secretarial assistance and to Mr D Prakash, Mr Ajay Kumar, Mr Shukla, Mr Sathiyathasan and Mrs Umadevi Sathish for help rendered in scrutiny and formatting of manuscripts, typesetting the editorial corrections, correspondence assistance, etc. to the Editor-in-Chief at Chennai need special mention for their untiring assistance in correspondence and formatting of the book with updated contents. Our grateful thanks are due to Mr Shaji Jacob Ninan and Dr Nazeer Ahmed at Kuwait for the assistance rendered to the Chief Academic Editor in editing, scrutinizing and proofreading of the individual chapter files. Our special thanks to Ms Anju Kumari and Mr RG Bhardwaj for assisting Dr Piyush Gupta, Academic Editor, at New Delhi and Mr N Asokan and Ms S Suja for assisting Dr MKC Nair, Academic Editor, at Thiruvananthapuram. Our sincere and grateful thanks go to M/s Jaypee Brothers Medical Publishers (P) Ltd., New Delhi, especially Shri Jitendar P Vij (Group Chairman); Mr Ankit Vij (Managing Director); Mr Tarun Duneja (Director-Publishing); Mr Tarun Vij (DirectorPharma); Mr KK Raman (Production Manager); Mrs Samina Khan (PA to the Director-Publishing); Dr Richa Saxena (Editorin-Chief); Mr Syed Amir Haider and Mr Amit Rai (Medical Editors); Ms Kamlesh Rawat (Proofreader); Mr Hemant Kumar (Typesetter); Mr Santosh Kumar Pandit (Graphic Designer) and other members of Jaypee Head Office, New Delhi, for their untiring coordination efforts in the production of the Fifth Edition. We also place on record our sincere appreciation of the help rendered by the local branch managers of the Jaypee Brothers—Mr Mukherjee (Branch Manager) and Mr Jayanandan (Senior Commissioning Editor), Chennai Branch Office, for the help rendered to the Editor-in-Chief and Academic Editors. All attempts have been made to acknowledge the sources of information and illustrations. Inadvertent omission, if any, is regretted.

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2

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1.2 History licitation

4





YK Amdekar

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16



C

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1.4

Parang N Mehta E





23



rc ountries

26



b

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2.1 Neonatal Nomenclature

27



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20

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Zulfiqar A Bhutta

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Saa

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O

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Narendra Kumar Arora





1.6



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32





B Vishnu Bhat

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2.4 Identification and Approach to a ick Newborn



2.5 Low Birth Weight

2.7 Neonatal Hyperbilirubinemia

44



42

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2.6 Parent ounseling





Vikram Datta









Ranjan Kumar Pejaver





2.8 Neonatal Infections

48





Rhishikesh Thakre

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55



D

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2.10

Ashok Kumar



2.11 Bleeding Neonate

59







51

Ruchi Nimish Nanavati





2.9 Neonatal eizures





Naveen Jain



35 39





Swarna Rekha Bhat







Siddarth Ramji

2.3



28





Siddarth Ramji

2.2 Neonatal esuscitation





63

evelopment

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JN Sharma

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Vaman Khadilkar

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DK Agarwal

evelopmental elay



Madhulika Kabra





MKC Nair

3.7 Failure to Thrive



D

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3.5 Normal evelopment



KN Agarwal





3.4 Growth and exual evelopment in Puberty



86



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3.3 W o Under-5 Growth tandards 2006



68

KN Agarwal





3.2 Growth—Birth to Puberty



64

Dilip Mukherjee





3.1 Growth and evelopment: Basic oncepts



S

18

George F Moolayil





1.5 Legal and thical Issues to Pediatric Practice







7

C Thangadorai





1.3 Physical xamination





T Ravikumar

Section 3: Growth and



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1.1 Pediatrics—Yesterday, Today and Tomorrow

Section 2:



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Section 1: Ba

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Contents

95 101 104 113

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RK Anand

4.4 Water oluble Vitamins

150



134



4.3 Malnutrition



S







Meenakshi Mehta

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4.5 Fat oluble Vitamins

153





Dheeraj Shah

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4.6 Trace lements

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Panna Choudhury



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i ea e

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KE Elizabeth

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5.2 Primary Immunodeficiency isorders

170





Naveen Thacker



ationale of election of Vaccines in National Immunization Program and IAP Immunization Time Table



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T Jacob John





5.3 The Principles and Practice of Immunization





Tanu Singhal

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Vijay Yewale

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5.4.1 Polio nd Game: Global and National Perspective













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5.7 Vaccine torage and Handling

198







194

Anju Aggarwal



Digant D Shastri E



AJ Chitkara

221

5.13 Kala-azar (Visceral Leishmaniasis)

226





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240



hikungunya Fever

Rajniti Prasad

243

AK Dutta

hickenpox (Varicella)

247

Lalitha Kailas

5.19 Mumps

252

5.20

254



250



5.18 Measles R



ubella



Jaydeep Choudhury Nupur Ganguly

abies

256



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5.21



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engue Illnesses

Ashok Kapse



C



Utpal Kant Singh



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5.17



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Jayakar Thomas

5.16 Poliomyelitis





5.12 Malaria

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5.11 An Approach to a hild with Fever and kin ash

5.15



209 213

PP Maiya

5.14

Ritabrata Kundu



Milind S Tullu



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5.22 Pediatric Human Immunodeficiency Virus (HIV) Infection or Acquired Immunodeficiency yndrome (AI )



203

5.10 Fever and Fever of Unknown rigin







5.9 Future Vaccines, Adjuvants and Immunization Techniques



M Indrashekhar Rao





5.8 Adverse vents Following Immunization and Their Management







Tanmay Amladi

5.6 Non UIP Vaccines in India



188 189 192





K Surendran

5.4.1.1 Global Perspective 5.4.1.2 National Perspective 5.5 The Universal Immunization Program (UIP) in India

177 188











4.2 Infant and Young hild Feeding



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Section 4:

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5.24.2 Tuberculous Lymphadenitis

280





Vimlesh Seth





282





Vimlesh Seth

5.24.3 Neurotuberculosis



5.24.4 Abdominal Tuberculosis

287





Vimlesh Seth

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5.24.5 National Tuberculosis ontrol Program D







297



304





5.29 Leprosy



309





Rajeshwar Dayal

5.30 Pandemic Influenza

314

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6.1 Neuroanatomic Localization in hildren

315



E

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entral

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Nitin Shah



Vrajesh Udani

S

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PA Mohammed Kunju

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D



367



E

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Rashmi Kumar

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384



hildhood Brain Tumors

Kamer Singh Rana

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aised Intracranial Pressure

Sunit Singhi

hildhood troke

392

Satinder Aneja

C



395

Bibek Talukdar

C

D

407



erebral Palsy, Mental etardation and Autism

MS Mahadeviah



Sunanda K Reddy



E

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6.18 Global evelopmental elay and arly Intervention



D

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Sunil Karande





6.17 Learning isabilities and Attention eficit Hyperactivity isorder





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Sheffali Gulati

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6.14 Floppy Infant- linical Approach



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6.12

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Arun Bansal

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6.11

371

Pratibha Singhi C

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6.10

C







6.9 Infections of the entral Nervous ystem







Anoop Verma

6.8



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Munni Ray

6.7 Movement isorders



358





Rekha Mittal

6.6 Headaches and Migraines in hildren



339



E

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336

Devendra Mishra





6.4 Neurocutaneous isorders

320 330

Naveen Sankhyan





6.3 Neurodegenerative isorders







6.2 Prenatal evelopment and entral Nervous ystem Malformations



D

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D

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ickettsial iseases in India

Narendra Rathi





5.28



299

Raju C Shah





5.27 Tetanus





Sailesh Gupta

Section 6:



294

Monjori Mitra





iphtheria





Vimlesh Seth

5.26 Pertussis



290





Vimlesh Seth

5.25

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Vimlesh Seth

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275





5.24 Tuberculosis in hildren

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273

S Ramesh

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5.23 Leptospirosis in hildren

412 415

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481

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L Subramanyam





8.10 Bronchial Asthma

H Paramesh

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9.1 Acute iarrhea Ashok K Patwari



s

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S

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S

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Neelam Mohan

540



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BD Gupta

VR Ravikumar

546



9.9 Abdominal Pain in hildren

D

543



9.8 Hirschsprung isease



C





Kanishka Das



Srinivas Sankaranarayanan

D



550 D

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Geetha M



Sheila Bhave

555

9.13

562



558



9.12 Viral Hepatitis



VS Sankaranarayanan



S

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A Riyaz



C

C

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C



Malathi Sathiyasekaran

9.14 Neonatal holestasis yndromes



535

D

9.6 Gastrointestinal Bleeding in hildren

R

531

C

9.5 Parasitic Bowel isease



527







522

Shashidhararao Nagabhushana





518

9.4 Vomiting in hildren and Gastroesophageal eflux isease

9.11



511 512

9.10 Hepatomegaly: A Practical iagnostic Approach



505

Ujjal Poddar

9.7



501



C

D

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9.3 Malabsorption yndrome in hildren

498

iver

9.2 Persistent and hronic iarrhea in hildren Gadadhar Sarangi

494



D

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Balvir S Tomar

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Basic Concepts of Child Care

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Pediatrics—Yesterday, Today and Tomorrow: YK Amdekar History Elicitation: T Ravikumar Physical Examination: C Thangadorai Communication and Counseling: Parang N Mehta Legal and Ethical Issues to Pediatric Practice: George F Moolayil Research in Office Practice: Narendra Kumar Arora Child Health in Saa Countries: Zulfiqar A Bhutta rc















1.1 1.2 1.3 1.4 1.5 1.6 1.7

Section Editor : Piyush Gupta

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Pediatrics—Yesterday, Today and Tomorrow YK Amdekar

Introduction Care, survival and development of children have always been our concern. The Government of India and Indian Academy of Pediatrics have undertaken several projects over last few decades to improve health of children and it is time to introspect their impact on the ultimate goal.

emography

isease Profile

In the 60s and 70s, antibiotics and vaccines appeared to have controlled infectious diseases. However, infectious diseases have returned with vengeance. Tripartite interaction between environment, microbes and host status decide outcome of infectious disease. There is complex struggle for survival between humans and microbes and microbes are exploiting human behavior. Early and frequent exposure to infections, varying nutritional and immune status, lifestyle changes, global travel and misuse of antibiotics have contributed to resurgence of old infections. Microbes have an inherent ability to mutate, change virulence and acquire resistance to antibiotics. This has made battle against infections more difficult. Besides, new organisms are being recognized. Forty new microbes have been recognized over 2 last 30 years. They include viruses such as rotavirus, ebola virus, hantavirus, parvovirus B19, human T-lymphotropic

Technological dvances A

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Due to a rapid rise in population in India that stands at 1.2 billion at present, there exists shortage of health personnel and facilities. Though there has been steady decline in infant and under-5 mortality rate, it is still high and neonatal mortality rate has not much changed over years. Breastfeeding is initiated within first hour only in 25% of neonates and exclusive breast-feeding in first 6 months is practiced in 45% of infants. Only 50% infants are timely weaned. More than 60% of children do visit health facilities for common illnesses but even then 40% have remained underweight, 45% stunted, 23% wasted, 75% anemic with 5% having severe anemia. Two to three percent children under 3 years of age suffer from acute severe malnutrition with 20–30% mortality in this group. In spite of availability of free vaccines in expanded program on immunization (EPI) program, there is no change over last decade in number of fully vaccinated children that stands at less than 50%. Similarly, only 45% children use oral rehydration solution (ORS) during diarrheal episodes. Thus, health indices have not much changed over last decade. It suggests that medical and paramedical personnel do not follow standard simple cost-effective preventive measures, in spite of contact opportunity with the community.

viruses type 1 and 2, hepatitis C and E, H5N1 avian strain of influenza, SARS, human metapneumovirus, H1N1 swine reassortent influenza, bacteria such as Legionella, Campylobacter jejuni, toxin producing staphylococci and streptococci, Borrelia, Helicobacter pylori and parasites such as Cryptosporidium and Cyclospora. Changing epidemiology has been observed in dengue fever, leptospirosis, brucellosis and Rickettsial fever. Due to a breakdown in public health measures, there is resurgence of malaria and tuberculosis. Co-infection with HIV has worsened scenario of tuberculosis. Many malignant conditions are now being attributed to an infectious agent. Hepatocellular carcinoma induced by hepatitis B and C infection and cervical cancer due to human papilloma virus are some of the examples of infection related malignancy. Many diseases of unknown etiology (Kawasaki syndrome, sarcoidosis and diabetes) are suspected to be induced by infections. Infections caused by antibiotic resistant organisms are on the increase. Multidrug resistant Staphylococcus aureus (MRSA), first detected in 1961 in UK, is now known both in nosocomial and community settings. Streptococcus pneumoniae has become resistant to penicillin almost all over the world; surprisingly, penicillin sensitivity is still maintained in India. Problem of resistance is mainly due to misuse of antibiotics in human as well as veterinary medicine and also due to genetic mutation by bacteria. Empirical use of antibiotics, non-adherence to standard protocols by physicians and noncompliant therapy by patients have resulted in multidrug resistant TB, malaria, and typhoid in the community. “ESKAPE” pathogens are problem pathogens—Enterococcus, Staphylococcus aureus, Klebsiella, Acinetobacter, Pseudomonas and enterobacteria species—and are difficult to eradicate. Besides, methicillin and vancomycin resistant Staphylococcus aureus, coagulase negative staphylococci, penicillin resistant pneumococci, macrolide resistant streptococci, multidrug resistant Salmonella and Shigella and extended spectrum betalactamase producing enterococci and Acinetobacter are also being reported more frequently. Non-infective illnesses such as lifestyle diseases, asthma, malignancy, autism spectrum disorders, metabolic disorders and immune deficiency disorders are being increasingly recognized. With a threat of epidemic of obesity, dual burden of malnutrition poses a stiff challenge.

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Etiological diagnosis of infections is possible today with modern culture techniques such as BACTEC; and polymerase chain reaction (PCR). Reversed transcription (RT-PCR)—is for amplification of RNA and real time PCR allows quantitative measurement of DNA or RNA. Southern blot is a method of probing a specific DNA sequence in DNA

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We need to change focus from disease to health. We must combine traditional wisdom with modern science. Indian Academy of Pediatrics (IAP) has formulated guidelines for standard management of many common diseases that should be followed meticulously. Constant updating is necessary to keep up with scientific advances and they should be used selectively. Science will undergo frequent changes as nothing is constant and ignorance is far more than knowledge. Hence we need to learn, unlearn and relearn.





1. Cavazzana-Calvo M, Thrasher A, Mavilio F. The future of gene therapy. Nature. 2004;427:(6977):779-81. 2. Gupta P, Shah D, Sachdev HPS, et al. National workshop on development of guidelines for effective home based care and treatment of children suffering from severe acute malnutrition. Indian Pediatr. 2008;43:131-9. 3. National Family Health Survey-3. Mumbai: IIPS; 2006. Available from: www.nfhsindia.org/nfhs3.shtml. Accessed 30 July, 2011.





Bibliography



A

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Pediatricians Must Change

Change in Clinical Practice Before the advent of modern science, physicians healed their patients with commitment, concern, and compassion.

fC

Before the era of super-specialization and technological advance, pediatricians were well trained in basics in clinical medicine. While super-specialization is a boon, it is expected that super specialist is an excellent generalist. New generation of pediatrician has a challenging task of keeping abreast to scientific advances but it should not be at the expense of basics. National Board of Examination has modified examination pattern that tests the candidates more thoroughly in actual life situations and hence training also has been suitably modified. This has been a better step forward in pediatric education.

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Change in Educational Reforms

dvances in Curative and Preventive Management Following a 40-year hiatus in discovering new classes of antibacterial compounds, three new classes of antibiotics have been brought into clinical use: (i) cyclic lipopeptides (daptomycin); (ii) glycylcyclines (tigecycline); and (iii) oxazolidinones (linezolid). Other “new” antibiotics are merely chemically modified old molecules. With increasing antibiotic resistance, “phage” therapy needs to be revived. Better drugs and improved understanding of their usage has modified outcome of malignant diseases. While minimal invasive surgery is fast replacing conventional open surgery, interventional radiology and cardiology provide better alternative to surgery in many conditions. Liver or kidney transplants are now available for such end-stage diseases, besides bone marrow transplant and stem cell therapy. The 20th century saw development of many new vaccines. One-third infectious disease mortality can be prevented by vaccination. Indian EPI program covers only 7 diseases unlike 12 or more diseases covered in national programs of many developed countries. Poor coverage of susceptible population and non-affordability of nonEPI vaccines are major hurdles. It is heartening that polio eradication efforts are nearing success. Till date, there has been just a single case of wild poliomyelitis reported in India in 2011. The time has come to phase out oral polio vaccine (OPV) slowly over next few years and replace with inactivated polio vaccine (IPV).

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They treated the child and family and not just the disease. As science developed, physicians started treating disease and not the child. Subsequently, they have learnt to treat diagnostic tests and not disease. Thus, modern clinical practice revolves around diagnostic tests, often without clinical correlation. Unfortunately, scientific advances have not translated into better health indices or quality of life for children at large. This is mainly because majority children need simple approach to their common problems. Modern science cannot replace basic clinical bedside methods. For example, kangaroo care and exclusive breastfeeding will save far more neonates than mechanical ventilation and modern facilities. Oral rehydration solution (ORS) has saved many lives. Nutritional advice, growth monitoring and immunization will contribute to better quality of life. Hence priority in clinical practice should be implementation of basic care and modern advances should be reserved only for most indicated situations.

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sample. Western blot measures antibodies against specific protein as for HIV diagnosis. Gene therapy—introducing functional gene into host genome, replacing abnormal gene—has been successful in cystic fibrosis, hemophilia, sickle cell disease and muscular dystrophy. Transfer of genes in brain using liposomes may prove to be useful for degenerative brain disorders. Inborn errors of metabolism can be diagnosed with certainty at birth and cost-effective screening of common metabolic disorders is now feasible. Availability of several immunological tests have opened up new vista to diagnose otherwise fatal immune deficiency disorders. Imaging modalities have improved tremendously. Ultrasonography (USG) has undergone great advances over last five decades. Color Doppler, digital subtraction angiography and transesophageal USG are some of the newer modalities. Computed tomography (CT) and MRI give anatomical diagnosis while positron emission tomography (PET) scan offers metabolic or functional profile. Many advances have taken place for better resolution and clarity such as diffusion MRI scan, FLAIR image, MR angiography and MR spectroscopy.

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History licitation

for the presenting complaint and other symptoms that will help in detecting associated conditions and in differential diagnosis should be enquired. The details of treatment given so far and the response should be noted.

ntroduction

The clinical interview and history elicitation are very important tools in the field of Pediatric Medicine. Though it is of much diagnostic value, the very process of interaction with the parents and the child during history taking also has therapeutic value. A pleasant and patient interaction is what any parent desires. There should be fewer distractions during the interview. It is good to use lay terms when talking to the parents and avoid medical terminologies as far as possible. While interviewing, the pediatrician should also observe the child to look for any clinical clues. In pediatrics the most important and distinct aspect is the fact that the person giving the history is usually not the patients (unless the child is about 4 or 5 years old). The parents are the usual source of information and in certain cases when caretakers (other than the parents) are bringing up the children then they will be the source of information.

Past History

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ontact History

History of contact with communicable diseases (e.g. TB and, chickenpox) must be elicited with tact and patience. It is often denied and repeated probing with leading questions may be necessary.

ntenatal History

As many illnesses in children have their origin in the womb it is important to get a good history about the period of pregnancy of the index child. A good guide for history elicitation would be the mnemonic of the three “I”s for the mother during pregnancy—illness, irradiation and injections (i.e. drugs). Maternal illness like syphilis, toxoplasmosis, AIDS, rubella, cytomegalovirus and herpes virus infections (STARCH) are associated with specific syndromes in the child. Folic acid supplementation during early pregnancy (the first trimester) prevents neural tube defects like meningomyelocele. B













The main problem or complaints for which the child has been brought for medical attention should be recorded in the informant’s own terms and should be recorded in chronological order with the duration of each complaint. Example: Fever—5 days Vomiting—4 days Loose motions—4 days Decreased urine output—2 days Lethargy—1 day Fast breathing—1 day

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Presenting omplaints

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emography

Make a note of the name of the child, his/her age in years (with months and days), parents’ names, address, date and time of interview, informant’s name and relationship to child and their reliability (with regard to the consistency of the information they provide).

Ask for details of relevant past illness, whose knowledge will help you in diagnosis or management. History of occurrence of similar complaints in the past should be noted. For example, in a child with chronic suppurative lung disease or malnutrition, a history of previous exanthematous illness or whooping cough will help; in failure to thrive, a history of recurrent diarrhea; and in a child with fever and seizures, a history of febrile fits will be supportive. Past medication history will also be helpful, e.g. past history of antiepileptic drugs or antituberculous drugs [history of red urine (rifampicin) while on treatment with antiTB drugs]. Information on previous significant hospitalization, accident or surgeries may also be helpful.

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History of Present llness It is important to gather more information and elaborate on the specific presenting complaints. Find out the onset of the complaints (the time up to which the child was apparently well). The evolution of the problems should then flow in a clear, concise, temporal sequence, leading up to the present moment. They should be recorded in order of occurrence and an account of any repeated episodes of 4 symptoms (like seizures or respiratory infections) should be given. Symptoms pertaining to complications expected

irth History

The actual events occurring during delivery must be enquired. The period of gestation, duration of labor, nature of delivery, drugs administered during labor and any complications during delivery (like cord around neck, low Apgar score) should be noted. The duration of every stage of labor (especially the second stage) is important as prolonged labor may result in fetal hypoxia. The normal first stage of labor, from the onset of labor pains to the rupture of membranes, is about 12–24 hours and 6–12 hours in a primi and multigravida respectively. The second stage of labor, from the rupture of membranes to

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Development is one aspect of pediatrics that makes it unique as compared to adult medicine. The developmental

 

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Gross motor

Fine motor

1 month

Grasp reflex

Starts to smile

2 months

Hands closed

Personal social

Language

Social smile

Cooing

Sustained social smile

Says ‘aah’

Head mostly held up but still Hand open most often bobs forwards

4 months

Head held steady

7 months

Rolls over, creeping-crawling, sits Reaches out and grasps larger Smiles at mirror with hands leaning forwards objects, palmar grasp, transfers objects from hand to hand

Babbling

10 months

Sits without support, cruises

Pincer grasp

Says ‘Baba, mama’

1 year

Walks with one hand held

Releases objects to other person Plays simple ball game on request/gesture

Says 2-3 words with meaning

15 months

Walks alone, crawls upstairs

Makes tower of 3 cubes

Follows simple commands

18 months

Runs stiff, goes upstairs by Makes tower of 4 cubes, initiates Feeds self. Dry by day holding the rails vertical stroke scribbles

2 years

Runs well, walks upstairs and Makes tower of 7 cubes, initiates Handless spoon well and helps Puts sentence of 3 words downstairs one foot at a time, jumps horizontal stoke to undress

2 1/2 years

Goes upstairs with alternating Makes tower of 9 cubes feet

3 years

Rides tricycle, stands momentarily Draws circle, tower of 10 cubes, Dresses and undresses fully Knows age and gender on one foot constructs bridge or 3 cubes when helped with buttons, joins in play

4 years

Hops on one foot, throws ball Draws cross and square, copies Plays with several children with Tells story overhead, climbs well a bridge, constructs a gate of 5 beginning of social interaction, cubes goes to toilet alone

5 years

Skips

Reaches for objects, grasps Excited at sight of food objects and brings to mouth, hands in midline

Draws triangle

B C pt

This history is highly problem oriented and age dependent. Details of the food and dietary patterns help in diagnosing

3 months

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Ch

ietetic History

V d

Table 1.2.1 Normal developmental milestones Milestones

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ild are

evelopment History

s of

The neonate and its state after birth should be enquired. The term of the child, birth weight, cry, activity and color immediately after birth should be noted. Presence of jaundice or cyanosis, resuscitation steps used (if any) and whether hospitalized after birth must be detailed. Poor cry and lethargy suggest perinatal depression. Paucity of movements of one side or a particular limb may suggest stroke or birth injury. The sucking effort of a child after delivery, usually gives a clue to the neurological status of the child. All infants pass meconium within the first 24 hours, any delay would suggest cystic fibrosis while absence of passage would indicate intentional obstruction or anal atresia. Most infants void urine on the first day while all will void within 48 hours, any delay would point towards an obstruction or agenesis of the renal system.

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Postnatal History

milestones that a child attains are a good reflection of its physical and neurological maturity. They may be divided into gross motor (head control, rolling over, crawling, sitting, standing, walking, etc.), fine motor or adaptive (grasping reaching transferring object, scribbling, etc.), social (smile, recognition, response to calls, etc.) and language (cooing, babbling, saying syllables, vocabulary, etc.). Tailor the development history to the child’s age. In case of more than one child in the family and if the other siblings are normal, the parents may be asked if the index child’s development mirrored that of the other siblings. The pace of development differs from child to child. As the child grows older the age range of attainment of specific developmental milestones usually widens. For example, a normal child may begin to sit without support between 5 months and 8 months as compared to a normal young infant developing social smile between 6 weeks and 8 weeks. Notice the range of normality becoming more in the older child. Always tabulate the attained milestones against the normal age for attainment of that particular milestone (Table 1.2.1).

asic once

the delivery of the child, is about 1–2 hours in a primi and ½–1 hour in a multigravida. The third stage, which is the delivery of the placenta, lasts about 15 minutes.

Waves bye-bye

Asks for objects by pointing

Helps put things away

Laughs out aloud

Speaks 10 words, identifies parts of the body

Knows full name

Dresses and undresses self. Asks Names 4 colors, repeats sentence question about meaning of words of 10 syllables

5

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amily History

S

three full generations should be recorded. Individuals of the same generations should be recorded in the same horizontal line and numbered from left to right using Arabic numerals. Males are usually placed on the left side of the pedigree and sib-ship listed in both orders. The maternal age at the time of child delivery is also important. Young mothers (less than 18 years) have more chance of preterm, IUGR babies while older mother (more than 32 years) have more chance of having children with Down syndrome and Klinefelter syndrome. In children with disease showing hereditary traits, an enquiry of a much wider circle of relatives must be made.

1 year

1000 kcal/day

20 g/day

2 years

1100 kcal/day

3 years

1200 kcal/day

4 years

1300 kcal/day

30 g/day

5 years

1400 kcal/day

30 g/day

6 years

1500 kcal/day

30 g/day

7 years

1600 kcal/day

40 g/day

8 years

1700 kcal/day

40 g/day

9 years

1800 kcal/day

40 g/day

10 years

1900 kcal/day

40 g/day

11 years

2000 kcal /day

50 g/day

12 years

2100 kcal /day

50 g/day

Adolescent boy

2400 kcal/day

70 g/day

Adolescent girl

2100 kcal/day

65 g/day

20 g/day

I

It is important to note down any known specific drug or food allergies in the child.

6





20 g/day

History of llergies A

2 g/kg

B

100–110 kcal/kg/day

ibliography 1. Barness LA. Pediatric history and physical examination. In: Oski’s Pediatrics—Principles and Practice, McMillan JA, DeAngelis CD, Feigin RD (Eds), 3rd edition. Philadelphia: JB Lippincott Williams and Wilkins; 1999. pp .39-52. 2. Harris R. The examination of children. In: Hutchison’s Clinical Methods, Swash M (Ed), 20th edition. London: ELBS-WB Saunders Co; 1995. pp .365-86. 3. Rees PE. Evaluating the newborn infant: Diagnostic approach. In: Pediatric Clinical Skills, 2nd edition. Philadelphia, Churchill Livingstone; 1997. pp .47-76. 4. Singh M. Pediatrics clinical methods, 1st edition. New Delhi: Sagar Publication; 1992;1-94:174-211.

1 month–year



Protein/day



 

Calories required/day

mmunization History

It is important to record the details of vaccines given to the child in chronological order. The vaccination schedule of the Indian Academy of Pediatrics or at least the Universal Immunization Program should have been followed. Special vaccines (e.g. pulse polio vaccine) must also be enquired. Look for BCG scar at the outer aspect of the left arm at the insertion of the deltoid. If any vaccine has not been given, note the reason for not doing so.



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Age

G R

V d

ti e

Table 1.2.2 The recommended caloric and protein requirements

This has a bearing on the type of disease the child might be suffering from and it also helps in planning rehabilitation and treatment options, in addition to helping in giving preventive advice. The following points are worthwhile noting: • Type of family: joint or nuclear • Occupation and employment history • Per capita income (total income divided by the number or dependent family members) • Type of housing, ventilation, toilet and potable water facilities • Psychiatric illness and substance abuse (alcoholism, drugs) in the family • Marital stability • Traditional beliefs and child rearing practices.



The health details of all the family members must be obtained. This includes their gender, present and past health status, treatment taken and their proximity to the child. History of similar illness in the family must be looked for. History of stillbirths or abortions in the family should be noted (habitual abortions occur in maternal syphilis). The birth of abnormal children or children with illness in the family and the reasons for death, if any, of children or young adults in the family should be specifically enquired into. The consanguinity pattern with the degree of relationship may be helpful for genetic disorders. The pedigree chart will help record the family history in a pictorial manner helping us to derive the inheritance pattern of a particular illness. Usually

ocio-economic History



F

t

t

Tex book of Pedia rics

protein energy malnutrition and failure to thrive. In addition it helps us to formulate a diet plan for nutritional rehabilitation of the child for a specific disease. The calculation of the dietary values of the food consumed should provide the actual value of proteins, calories and fats and must mention whether it is sufficient in vitamins, minerals and other micronutrients. Always state the amount of calories and proteins the child is getting for that age as compared to what is recommended (Table 1.2.2) which will help us to calculate the calorie and protein gap. Any problem like feeding difficulty, regurgitation or vomiting should be noted. Any possible natural toxins in the food consumed (fungal aflatoxins, copper, etc.) and feeding patterns during times of illness should also be mentioned. In young children, the complete breastfeeding history including whether colostrum was given, duration of exclusive breastfeeding, weaning pattern, etc. must be elucidated. In children given other milk, it is important to note its dilution, bottle-fed or cup and spoon-fed, frequency and the amount taken during each feeding.

vip.persianss.ir

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ntroduction

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The physical examination in a child is distinct in certain areas from that of the adult. In this discussion, only the facts that differ from that of an adult examination have been stated. As far as possible, no child should cry or get irritated while you are examining. “If a child cries when you examine it, then it’s probably your fault”. This statement by John Apley sums up the care one should take, while handling the child. Physical examination starts even as the child and the attendant walk into the room. Even while eliciting history an observant eye needs to be kept on the child, to watch for clinical clues. There is no definite order to be followed while examining a child. Individualize the examination for every child. Do the invasive and potentially discomforting examinations at the end. Allow the child to be in its most comfortable position, and place it in the mother’s lap. Both the child and the mother must feel secure and confident about the examining doctor.

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hysical xamination

Basic oncepts of hild are

1.3

E

General xamination

­



Figure 1.3.1 The different shapes of the head  



Before starting general examination; analyze the history and based on that, look for the specific features that would be relevant to the history which will help you to give a perfect diagnosis. Examining aimlessly is unhelpful, time consuming and irritating to the child and parents. General examination must be thorough from head to foot. Always examine the child’s throat irrespective of the complaint. The golden rule is “Head to foot and back, but forget not the ear, throat and urine”. The sensorium (e.g. stuporous or unconscious in intracranial pathology), posture and attitude (e.g. frog like and limp in a floppy infant), activity (e.g. apathetic in kwashiorkor), looks (e.g. acutely or chronically ill looking) and nutrition (i.e. marasmic, undernourished or moderately nourished) need special mention. Note the shape of the head (Fig. 1.3.1) whether microcephaly, macrocephaly, plagiocephaly (asymmetrical due to lying of the normal infants with their heads persistently on one side), scaphocephaly (boat shaped with increased AP diameter due to premature closure of the sagittal suture), brachycephaly (decreased AP diameter) and oxycephaly (tower-shaped skull). The size of the anterior fontanelle (AF; normal of about 2.5 cm × 2.5 cm) must be measured across the borders as shown in Figure 1.3.2. It normally closes by 9–18 months. Delayed closure is seen in rickets, hypothyroidism, hydrocephalus, Down syndrome, achondroplasia and mucopolysaccharidoses. The AF in a quiet child usually shows a very slight depression from the surface and may pulsate. It is bulging when the child cries and in

hydrocephalus, intracranial hypertension and pseudotumor cerebri, (i.e. after drugs like nalidixic acid, tetracyclines and steroids, and hypervitaminosis A). A sunken fontanel is a sign of dehydration. The posterior fontanel can be felt by running the finger along the sagittal suture to its junction with the lambdoid suture. It normally closes by 2–4 months of age. Ridging and overriding of sutures may normally be seen in the first few hours after birth, due to moulding of the skull during delivery. It may also be seen in craniostenosis due to premature fusion of the sutures. Sutures normally 7 get ossified by 6 months of age (Fig. 1.3.3).

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Figure 1.3.3 The different cranial sutures at birth

 

Figure 1.3.2 The method of measuring anterior fontanelle size

 

Table 1.3.1 Few of the features to be looked for in the head and the associated conditions Features

Important associated conditions

Microcephaly

Familial, craniostenosis, intrauterine infections Trisomy 13 and 21 (Down syndrome)

Macrocephaly

Hydrocephalus, hydranencephaly, porencephaly, some neurodegenerative disorders like metachromatic leukodystrophy, Alexander and Canavan disease, certain intrauterine infections

Frontal bossing

Rickets, congenital syphilis, mucopolysaccharidoses, polysaccharidoses

Cranio-tabes (ping-pong skull)

Physiological (in preterm), rickets, congenital syphilis

Increased inter-pupillary distance (hypertelorism)

Genetic (racial), Down syndrome, Cri-du-chat syndrome, hypothyroidism

Proptosis (Sclera is visible above and below the cornea)

Thyrotoxicosis, orbital leukemic deposits, orbital cellulites, arteriovenous aneurysm (pulsatile), cavernous sinus thrombosis, neurofibromatosis, Crouzon disease

Cataract

Idiopathic, traumatic, intrauterine infections, galactosemia, diabetes mellitus, Down syndrome

Mongoloid eyes (upward slant)

Down syndrome, racial, Prader-Willi syndrome

Antimongoloid slant (downward slant) Turner syndrome, Cri-du-chat syndrome, Treacher-Collins syndrome Depressed nasal bridges

Down syndrome, mucopolysaccharidoses, hypothyroidism, familial

Low set ears

Down syndrome, mucopolysaccharidoses, Turner syndrome, Potter facies (renal agenesis)

Facial puffiness

Renal disorder, kwashiorkor, congestive cardiac failures, angioneurotic edema, cavernous sinus thrombosis

Large tongue

Hypothyroidism, mucopolysaccharidoses, glycogen storage disorders, Down syndrome (relative)

Small mandible

Pierre Robin syndrome

Short neck

Turner syndrome, Down syndrome, mucopolysaccharidoses, hypothyroidism





The Macewen’s sign is useful in clinically detecting raised intracranial tension after the sutures have closed. It is the crack pot sound elicited by percussing the skull. Transillumination of the skull in a dark room is useful in children below one year, to detect subdural effusion or hematoma, if translucency extends beyond 2 cm in the frontal and 1 cm in the occipital region. The face must be observed for any dysmorphic features 8 that may suggest chromosomal or developmental anomalies.

Table 1.3.1 shows some common abnormal features and a few conditions where they are seen. The inter-palpebral line of the eyes when continued horizontally backwards, normally divides the ears into the upper one-third and lower two-thirds. If the line passes above the ears, it is suggestive of low set ears. The neck should be examined for lymph node enlargement, short neck (normal neck length: height ratio is 1:13) and low hair line (below C5). The examination should also include the hair (e.g. pale hair with “flag sign”

vip.persianss.ir

emperature

 

Figure 1.3.4 Method of restraining a child for ENT examination

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R

espiratory ate

The rate of respiration in children is important for diagnosing respiratory disease and certain other nonrespiratory conditions like acidosis and congestive cardiac failure. The rate varies different age groups (Table 1.3.2). But for practical purposes, the guidelines offered in the Reproductive and Child Health (RCH) Program, serve as a good guide to clinically suspect respiratory disease (Table 1.3.3). The pattern of respiration must also be noted whether regular, irregular, Cheyne-Stokes respiration (oscillation of breathing between apnea and hyperpnea with a crescendodecrescendo pattern usually seen in congestive cardiac failure, stages 1 and 2 REM sleep), acidotic, etc. In children the respiration is predominantly abdominothoracic. P

Oral temperature should be taken in children older than 5 years while in infants and younger children the thermometer

may be placed in the axilla. The groin or the rectum can be used. The temperature in the axilla or the groin is about 0.5° C lower and the rectal temperature about 0.5° C higher than the oral temperature. The normal temperature in children is between 36.5° C and 37.5° C. Temperature above 41° C is hyperpyrexia. In conditions like PEM, where hypothermia is a problem, special low reading thermometers (30–40° C) must be used.

ulse ate R

T

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Vital igns

Figure 1.3.5 Method of examining skin turgor in a child with dehydration

R





C

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Basic oncepts of hild are

in kwashiorkor), eyes (signs of vitamin A deficiency, icterus, pallor, etc.), ears (examine tympanic membrane for acute otitis media or chronic suppurative otitis media), oral cavity (with special reference to the dentition), extremities (limb deformities in skeletal dysplasia, widened wrists in rickets), nails (koilonychia in anemia) and skin (for pallor, icterus, scabetic lesions, impetigo, etc.). Fundus examination is important to make out papilledema, optic atrophy or retinitis pigmentosa. The mouth is examined for the state of the gums, dental caries and dentition. Delayed dentition may be familial or due to rickets or osteogenesis imperfecta. The correct position for doing the ear, nose and throat examination is shown in Figure 1.3.4, but this should be done preferably at the last. While examining lymph nodes, note the site, size, consistency, tenderness, warmth, matting and scarring. Always remember to examine the drainage areas, for focus of sepsis, if there is significant lymph node enlargement. In older children, discrete and non-tender lymph node enlargement up to 1.5 cm in the cervical and inguinal region may not be significant. The skin is examined (Fig. 1.3.5) by rolling a fold of loosely adherent skin on the abdominal wall between the thumb and forefinger to determine its consistency, the amount of subcutaneous tissue present and the degree of hydration. Examination of the hips must always be carried out in younger children and infants, to look for dislocation. The Ortolani or Barlow procedure is done and the typical clunk of the hip moving in and out of its socket is looked for. Infants and younger children do not exhibit classical pedal edema as they are confined the bed hence sacral edema should be looked for in them.

The pulse is felt mainly over the radial artery at the wrist. The character, regularity and volume must be observed. All the peripheral palpable vessels must be examined. The superficial temporal, carotid, brachial, radial, femoral, popliteal, posterior tibial and dorsalis pedis arteries are easily accessible. In infants and very young children, it may not be possible to palpate the peripheral vessels and in such situations, the heart rate must be counted by auscultation. The normal heart/pulse rates in the different age groups in children are given in Table 1.3.4. For practical purposes, a 9 heart rate of more than 200 per minute in newborns, more

vip.persianss.ir

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Blood ressure

 

Age groups

Normal respiratory rate (per minute)

Newborn

40

1 year

30

5 years

20

10 years

18

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ext ook of ediatrics

Table 1.3.2 Normal respiratory rate in children of different age groups

 

Table 1.3.3 Tachypnea indicating significant respiratory disease (From RCH Program) Age groups

Normal respiratory rate (per minute)

Below 2 months

60 or more

2 to 12 months

50 or more

12 months to 5 years

40 or more

 

Table 1.3.4 The normal heart rates in children of different age groups Age groups

Normal heart rate (per minute)

Newborn

140

1 year

110

3 years

100

8 years

90

10 years

80

than 150 per minute in infants and more than 120 per minute in older children can be taken as significant tachycardia. The radial and femoral pulse must be palpated simultaneously to look for any radio-femoral delay. Remember, the heart rate in a struggling or crying child will be more.

Recording of the blood pressure is one of the most important aspects in a pediatric examination. Yet it is surprising, how often it is neglected. The correct size of the cuff must be used, i.e. the cuff should be two-thirds size of the arm. A large cuff will give an erroneously low reading while a small cuff will give a high reading. In infants, the “flush method” may be used to check the pressure. Here the child’s arm is raised and a tight bandage is applied up to the level of the cuff so as empty the blood from the upper limb. Now, the cuff is inflated and the bandage is removed so that the limb will be pale and bloodless. Deflate the cuff slowly and note the reading at which the skin flushes and the limb becomes red again. This corresponds, approximately to the systolic pressure. In younger children where auscultation at the cubital fossa is difficult, the systolic reading obtained by palpation may suffice. The Doppler technique of measuring blood pressure is more accurate and can be used in children, if available. For every pediatric examination, both the upper limb and lower limb pressures must be recorded to detect coarctation of aorta, while in any child with a suspected cardiac illness, the pressure must be recorded in all four limbs. Normally, the pressure recorded in the lower limbs is about 10 mm Hg higher than the upper limbs. Reserve recording the pressure to the last in order not to irritate or scare the child. Normal blood pressure readings in children in the different age groups are given in Table 1.3.5. Normal blood pressure is defined as systolic and diastolic pressure, less than 90th percentile for that age and sex. Hypertension is defined as average systolic and/or diastolic blood pressure equal to or greater than the 95th percentile for that age and sex, on at least three occasions. As per the American Heart Association (Pediatric Advanced Life Support Course) recommendations, a formula has been devised to calculate the 50th percentile of systolic pressure in children over the age of 2 years [(90 + (2 × age in years)]. The lower limit of

 

Table 1.3.5 Weech’s formulae for estimating weight and height for age of normal children Weights

Kilograms

At birth

3.25

3–12 months

Pounds 7

age in months + 9

age in months + 11

2 1–6 years

(age in years × 2) + 8

7–12 years

(age in years × 7) + 5

(age in years × 5) + 17 (age in years × 7) – 5

2 Heights

Centimeters

Inches

At birth

50

20

At 1 year

75

30

2–12 years

(age in years × 6) + 77

(age in years × 2) + 30

10

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The height of the child is a good indicator of the chronicity of any debilitating illness. Height is ideally measured using Harpenden stadiometer. The child should stand against a wall with his bare feet touching each other, the heel, calf, buttock, upper back and occiput touching the wall and

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The child must be weighed during every examination. The weight of the child is also useful for calculating the right dosage of the drugs to be given. The newborn loses up to 10% of its weight during the first week, but regains it in the next few days. The child doubles its birth weight by 4 months, triples it by 1 year and increases it 4 times by 2 years. For calculating expected normal weight, the formula shown in Table 1.3.5, may be used. While interpreting the weight of the child, the present weight must be compared to the expected weight for age and the percentage must be calculated in order to find out which grade of nutrition the child falls under (as per Tables 1.3.6 and 1.3.7). Weight is recorded on a weigh scale which should be frequently checked with standard weights and zero error must be adjusted before weighing.

the child looking straight ahead. A firm scale is pressed to the head to mark the point indicating height. The standing height can be measured for children more than 2 years old, while for younger children, the recumbent length should be measured using the infantometer (Fig. 1.3.6). In exceptions like a child with quadriplegic cerebral palsy, where the height or length could not be measured, the length of various segments of the body are measured separately and added together to get the length. The formula shown in Table 1.3.5 may be used for calculating the height for the age or alternatively the increase in height as shown in Table 1.3.8 may be used for calculating the expected height. While measuring the height, it is also important to measure the upper segment (from the vertex to the pubic symphysis) and the lower segment (from the pubic symphysis to the sole of the foot). The rate of growth of the upper and lower segments varies with age as shown in Table 1.3.9. Hence, any difference in the proportion expected for that age may suggest the presence of specific growth disorders (Table 1.3.10). Stature should also be defined with parent’s height being taken into account, referred to as the mid-parental height.

Weight

Figure 1.3.6 The infantometer method of measuring the length of child

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A

nthropometry

The measuring of the various anthropometric data is essential for assessing the growth of the child and its nutritional status. It is also important for planning the diet and following up the child especially while recuperating from an illness or during nutritional rehabilitation.

H

Basic oncepts of hild are

the systolic blood pressure has been approximated by the formula 70 + (2 × age in years). An observed fall of 10 mm Hg in systolic pressure suggests a shock.

 

Table 1.3.6 The Wellcome classification of nutritional status Nutritional status

Expected weight for age

Presence of edema

Normal

More than 80%

No

Undernutrition

60–80%

No

Kwashiorkor

60–80%

Yes

Marasmus

Less than 60%

No

Marasmic kwashiorkor

Less than 60%

Yes

 

Table 1.3.7 Indian academy of pediatrics—classification of nutritional status Level of undernutrition*

Expected weight for age

I degree

60–69%

II degree

60–69%

III degree

50–59%

IV degree

Less than 49%

*The prefix ‘k’ is added to indicate presence of edema

11

vip.persianss.ir

ext ook of ediatrics

Age

Height

At birth

50 cm

6 months

+12 cm (62 cm)

1 year

75 cm

2 years

85 cm (86–87 cm)

2–5 years

6–8 cm/year

5 years and above

5 cm/year

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Table 1.3.8 Rate of increase in height in children

 

T

Table 1.3.9 Normal upper segment/lower segment ratio in children Age

Upper segment/Lower segment

At birth

1.8/1

3–4 years

1.3/1

9 years

1/1

18 years

0.9/1

 

Figure 1.3.7 Method of measuring head circumference Table 1.3.11 Head circumference growth velocity

 

 

Table 1.3.10 Conditions with altered upper segment/lower segment ratio

Delayed adolescence, hypopituitarism, constitutional dwarfism, nutritional dwarf

High ratio (Upper segment > lower segment)

Hypothyroidism, chondrodystrophy, achondroplasia, Ellis-van Creveld syndrome, Turner syndrome

Low ratio (upper segment < lower segment)

Hurler syndrome, Morquio syndrome, hypogonadism

For girls: Approximate projected adult height (in cm)



Mother’s height + (Father’s height-13) 2

For boys: Approximate projected adult height (in cm) (Mother’s height + 13) + Father’s height













=



2

Till 3 months

2 cm/month

3 months to 1 year

2 cm/3 months (1/3rd of initial velocity)

1 to 3 years

1 cm/6 months (1/12th of initial velocity)

3 to 5 years

1 cm/year (1/24th of initial velocity)

Table 1.3.12 Formula for estimating head circumference in the first year (after Dine et al. ) Normal range of head circumference in cm (5th to 95th percentile) (Length in cm + 9.5) + 2.5 2

35 cm at one year, from 43 cm to 46 cm and from 48 cm to 51 cm at 5 years. The expected head circumference for the age may be calculated from (Tables 1.3.11 and 1.3.12). The adult head size is reached between 5 years and 6 years. Microcephaly is defined as head circumference, more than 3 standard deviations below the mean or less than the 5th percentile for the age and sex. Head size more than the 95th percentile for age suggests macrocephaly.

ead ircumference C

H

The size of the head is a good indicator of the size of its contents, viz. the brain and the ventricles. Any abnormality in the head circumference should alert the doctor towards any problem with the brain or its related structures. Head circumference is measured with a non-stretchable tape passing through the maximum point of the external occupational protuberance posteriorly and a point just above 12 the glabella anteriorly (Fig. 1.3.7). It varies from 32 cm to

hest ircumference C

C









=

Head circumference growth velocity

 

Proportionate (normal ratio for age)





Upper segment/Lower segment Probable disorder ratio

Height for age

This is measured at the level of the nipples (Fig. 1.3.8). In the infant, the chest circumference is lesser than the head circumference by about 2.5 cm, and the two become equal by one year after which the chest circumferences exceeds the head circumference. In undernutrition, the chest circumference remains lower than the head circumference even beyond one and half years whereas in well-nourished children, the chest circumference may exceed the head circumference even before one year.

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This is calculated as shown below: Weight for height (WFH) = (weight of child ÷ weight corresponding to height of child) × 100

Values above 90% are normal, while values below 90% indicate malnutrition and values above 120% indicate overweight. I

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Body Mass ndex

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Weight for eight

Basic oncepts of hild are

young children it is 1 cm to 2 cm less than the length or height. It equals the height at 10 years, and after 10 years it is from 1 cm to 2 cm more than the height. Increased arm span is seen in Marfan syndrome and homocystinuria.

It is calculated as: Body mass index (BMI) = Weight in kg ÷ (height in meter)2

For adults, BMI of 18.5–24.99 is considered normal, 25–29.99 is overweight (pre-obese), above 30 is obese and less than 18.5 is underweight (WHO). Body mass index (BMI) less than 16 is severe thinness, 16.00–16.99 is moderate thinness, 17.00–18.49 is mild thinness, 30.00–34.99 is obese class-I, 35.00–39.99 is obese class-II and more than 40 is obese class-III. For children, BMI 85th–95th percentile is overweight while that greater than 95 percentile is obesity.

rm pan S

See Table 1.3.13. E

evelopmental xamination

Here, the developmental history obtained must be confirmed by examining the child for the milestones attained or lost. A large number of accepted methods are available for assessing development. Of this, the Gesse ll developmental scale and the Bayley developmental scale are commonly used. The Baroda Developmental Screening Tests and the Trivandrum Developmental Screening Chart are useful for field assessment of children’s development. The development quotient (DQ) must be calculated separately for motor and mental development. DQ = Developmental age × 100





It is the distance between the tips of the middle fingers with both arms held wide open, i.e. spread apart. Normally, in

Growth atterns

S





Chronological age Developmental evaluation is of special value in children with neurological diseases like neurodegenerative disorders and chromosomal anomalies like Down syndrome. It is also useful for following up children with birth asphyxia or established cerebral palsy and mental retardation. The common developmental/primitive reflexes to be examined are shown in Table 1.3.14. The absence of appearance of the primitive reflexes at the expected time or their persistence beyond the time that they should normally disappear should lead to a suspicion of significant brain damage.

 

Figure 1.3.9 Method of measuring midarm circumference

exual Maturity ating R

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The midarm circumference (MAC) is taken as the name suggests, at the midpoint between the acromion and the olecranon with the arm hanging by the side of the body (Fig. 1.3.9). It is useful to detect malnutrition in young children (1–4 years). Values more than 13.5 cm may be considered normal, while values less than 12.5 cm indicate significant wasting and undernutrition. Shakir tape is used for measuring MAC in the community and has color bands. Green color indicates MAC is greater than 13.5 cm, yellow color a MAC between 13.5 cm and 12.5 cm and red color a MAC lesser than 12.5 cm.

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Figure 1.3.8 Method of measuring chest circumference

Sexual maturity rating (SMR) in boys and girls is shown in 13 Table 1.3.15. Please refer to Chapter 3 for more details.

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Table 1.3.13 Growth Patterns Age

Approximate daily weight gain (g)

Growth in length (cm/ month)

Growth in head circumference (cm/month)

0–3 months

30

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3–6 months

20

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6–9 months

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9–12 months

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1–3 years

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4–6 years

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Table 1.3.14 Primitive reflexes to be examined during developmental assessment Reflexes

Age of appearance

Age of disappearance

Stepping

Birth

6 weeks

Placing

Birth

6 weeks

Moro

Birth

3 months

Sucking and rooting

Birth

4 months while awake

Palmar grasp

Birth

6 months

Plantar grasp

Birth

10 months

Tonic neck

2 months

4–6 months

Landau

3 months

24 months

Neck righting

4 months

24 months

Parachute

9 months

Persists

SMR Stage

Pubic hair (boys/girls)

Breasts

Penis

Testes

1.

Preadolescent

Preadolescent

Preadolescent

Preadolescent

2.

Sparse, slightly pigmented

Breast and papilla Slight enlargement elevated, areolar diameter increased

Enlarged scrotum, pink

3.

Darker, beginning to curl

Breast and areola enlarged, no contour separation

Longer

Larger

4.

Coarse, curly, abundant but less than adult

Areola and papilla form secondary mound

Larger

Larger, scrotum dark

5.

Adult distribution, spreads to medial surface of  thighs

Mature, nipple projects

Adult size

Adult size

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Table 1.3.15 Sexual maturity rating (SMR) in boys/girls

It is beyond the scope of this chapter to cover the examination of every system in detail, it can be obtained from any standard textbook of clinical examination. Here we have attempted to give salient points in clinical examination that are different in children when compared to adults. S

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espiratory ystem 14 Inspect the chest wall for any deformities. Costochondral beading is seen in rickets (broad and dome shaped), in scurvy (sharp due to posterior subluxation of the sternum)

and in chondrodystrophy. Look for working of the accessory muscles of respiration, i.e. flaring of alae nasi, sternomastoid contraction, suprasternal and subcostal and intercostal retractions which would indicate dyspnea. Observe for indrawing of the lower ribs (Harrison’s sulcus) which indicates chronic obstructive airway disease like bronchial asthma. Vocal fremitus is rarely of value in young children. Grunting respiration in a child indicates severe respiratory disease. Percuss lightly in infants and small children, tap the chest wall directly rather than using another pleximeter finger. Due to the thin chest wall, the chest is more resonant than adults. Before starting to auscultate, allow the child

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bdomen The best place to examine the child’s abdomen is the mother’s lap, preferably while the child is feeding. Even if the child is struggling, it may be put on the mother’s shoulder and the abdomen is palpated from behind by “ballottement”, i.e. palpation just when the child breathes and the abdomen relaxes. Unlike in adults, it is not necessary to fold the legs of the child while palpating the abdomen. Young children normally have a protuberant abdomen. Look for umbilical (which may be normally seen in infants) and inguinal hernia. The liver is normally palpable in children till the age of 4 years, i.e. up to 2 cm below the costal margin. In view of this it is necessary to measure the span of the liver in order to make out actual enlargement. It is carried out by percussing the upper margin of dullness and by palpating the lower edge of the liver in the midclavicular line. The liver span ranges from about 4.5–5 cm at 1 week of age to approximately from 7 cm to 8 cm in males and from 6 cm to 6.5 cm in females by 12 years of age. The spleen may be normally palpable in infants, up to from 2 months to 3 months. Examine the genitalia and scrotum for hydrocele/hernia, intersex, phimosis, undescended testis, hypospadias or epispadias. The anus is examined for anal excoriation and pinworms.

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he ractice of ifferential iagnosis

During situations when the diagnosis of the child is not very clear (which may be the case quite often), it becomes necessary to make a set of most probable diagnoses. This is called differential diagnosis. This should be based on the history, clinical symptoms and clinical signs that have been elicited. The differential diagnoses thus made will help us to plan out investigations towards proving or disproving each probable cause. Hence, to be of practical value the list should be as short as possible and should only include conditions that could reasonably explain most of the child’s history, symptoms and signs. The list should be given in descending order of probability of the various likely diagnoses, based on the positive and negative points towards each.

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15 Figure 1.3.10 Model diagrammatic representation of recording deep tendon reflexes  

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ervous ystem Neurological examination of the young child is quite diffi cult, especially sensory examination and requires ingenuity on the part of the doctor to get the child’s cooperation. Developmental screening and assessing of the primitive reflexes should be carried out as already mentioned. Much information regarding the neurological status of the child can be learnt by just observing the child, as the history is being elicited. Coordination is best tested by watching the child,

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ardiovascular ystem In a neonate the apical impulse is located slightly outside the midclavicular line in the 4th intercostal space. By 2 years, it comes to the midclavicular line in the 4th intercostal space and comes to the adult position, i.e. 5th intercostal space 1 cm medial to the midclavicular line between 4 years to 7 years. In infants the right ventricles are dominant as compared to adults (where left ventricle is dominant). Due to the short neck of infants and young children, it is difficult to see the jugular venous pulse and pressure. Use a pediatric stethoscope with a small diaphragm to auscultate, as the intercostal spaces are narrow. It is preferable to auscultate the heart while the infant is comfortably sleeping or feeding from the mother. It is easier to hear the normal splitting of the heart sounds and P2 is louder in young children, i.e. less than 5 years. Functional systolic flow murmurs and venous hum are often heard in normal children.

play. Orientation is best tested only in children above 4–5 years. Handedness becomes apparent at about 3 years of age. Signs of meningeal irritation, i.e. neck stiffness, Kernig’s sign, Brudzinski’s sign must be looked for. They may not be present in infants and in the presence of severe undernutrition or overwhelming sepsis. Fundus may be normally pale in infants. Lifting the child gives a good idea about the muscle tone. If it is hypotonic the child will slip through the hands. The plantar reflex may be extensor up to 1 year of age. But persistence of extensor plantar beyond 2 years is definitely pathological. Tendon reflexes in young infants tend to be brisk. The deep tendon reflexes may be diagrammatically represented as shown in Figure 1.3.10, using the notations shown below: 0 = bsent + = luggish ++ = ormal +++ = risk ++++ = xaggerated History taking and clinical skill development in pediatrics are therefore to be learnt by repeated exposure to case interviews and hands on training in physical examination. The more a student gets this type of exposure, the more he can engage himself in self-analysis, which will help him to carry out the clinical examination thoroughly.

Basic oncepts of hild are

to play with your stethoscope, to allay its fears. Often it is less threatening to examine the back of the chest first. Due to the thin chest wall, breath sound are louder in children than in adults and their character is more like the bronchial breathing of adults. This is called puerile breathing. Do not be disheartened with a crying child, as breath sounds can be auscultated better in them. Be careful to distinguish the conducted sounds from the upper respiratory tract as in laryngomalacia, upper respiratory tract infection, etc.

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ommunication and ounseling

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Table 1.4.1 Advantages of good communication

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The chief goals of communication are: • Creation of a good interpersonal relationship • Facilitating exchange of information • Including patients and parents in decision making. Communication skills contribute to a doctor’s respect, a patient’s belief, and adherence to treatment, among other advantages (Table 1.4.1). A doctor with these skills is more likely to have happy, satisfied patients, than an equally technically competent doctor who does not bother about communication. Even if a pediatrician’s diagnosis and treatment are accurate, thoroughly rational, and successful, poor communication leaves parents unhappy and resentful. 16 This is especially so with chronic or incurable diseases, which are associated with anxiety, stress, and uncertainty for the whole family.



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The two most important barriers are not knowing what patients want from us (Table 1.4.2), and not realizing the importance of good communication. Some other barriers are: • Lack of time: History taking, physical examination, and prescription writing are seen as essential parts of a clinical encounter. When time is short, it is the communication with parents that is sacrificed • rrogance: Doctors expect patients and their parents to follow commands unquestioningly. Explanations are considered unnecessary • hyness: Shyness, from the patient or the doctor, stands in the way of adequate information being exchanged • Language and jargon: Communication with people speaking different languages can be problematic, and needs a special effort. If an interpreter is used, he should

Table 1.4.2 What patients want  

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The mportance of ommunication and ounseling kills

Patients and parents do not have the knowledge to judge the quality of a doctor’s examination, diagnosis, or prescription. Most complaints in health care systems, both public and private, arise from poor communication. Parents are angered by the doctor’s refusal to spend time with them, refusal to give explanations, and a lack of courtesy and care. When these are followed by a poor treatment outcome, complaints, quarrels, and legal action are likely. Good communication can play a significant part in avoiding complaints and malpractice claims.

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These are, quite simply, the skills that allow human beings to communicate effectively. For the pediatrician, communication skills consist of: • The ability to talk with parents. Not to parents, not at parents, but with them. Listening is an essential part; communication must be a two-way process • The ability to communicate well enough with patients and parents to understand their concerns, problems, and beliefs, and to elicit relevant information • The ability to explain the child’s illness clearly, and in language that the parents can easily understand. The treatment options should be explained clearly and completely, so that they can make informed decisions about treatment • The ability to convince parents to follow a treatment plan. This is especially important when embarking on prolonged, expensive, difficult, or culturally unacceptable treatment for a child • The ability to establish a relationship with the parents and child, based on mutual respect and trust • “Soft skills” like being able to put all classes of parents at their ease and being able to generate confidence. These components of a “good bedside manner” were once considered an important attribute of a successful practitioner.

Facilitation of comprehension of medical information Better identification of patients’ needs, perceptions, and expectations Patient satisfaction, leading to regular visits and referrals Feeling of empowerment and control Adherence to treatment plans Loyalty even if treatment is not immediately effective Less chances of complaints and legal action in the event of a mistake Doctors with good communication skills have better clinical and commercial success, less stress and more job satisfaction 

•  •  •  •  •  •  •  • 

Communication skills are a core competence for clinicians. Good communication enhances patients’ understanding and adherence to therapy, and improves outcomes. Poor understanding of the disease and treatment issues by parents is associated with poor outcomes.

•  •  •  •  •  •  •  •  • 

Clarity and directness Listening Honesty More and better information about their illness, treatment plan, and expected outcome More openness about the hazards and side-effects of treatment More information about the relief of symptoms and other concerns Advice on what they can do to help themselves Information on other treatments available A supportive, nonjudgmental, empathetic doctor 

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uild confidence: The parents’ efforts and views deserve respect. A little specific praise for the parents’ efforts helps significantly in building confidence and helping parents to cope. Some suggestions for future care improve their confidence that they will be able to manage the situation. Giving false hope is wrong, but information can be given in a positive manner. • peak truth: Parents deserve the truth, but the bald truth can be harsh and shocking. Disclosure must be tempered with common sense and empathy. Sometimes, the whole picture may need to be delivered in small parts spread out over two or more visits. However, withholding information leads to distrust. • e simple and clear: Many people do not comprehend words like “growth” and “tumor”. “Cancer” sounds shoc king, but may be necessary to drive home the problem to parents. • e tolerant: Blame, anger, a sudden outpouring of grief—these are common reactions. They should be met with understanding and support. • mpathize: Parents of sick children are going through a difficult experience. They appreciate the fact that their doctor understands their situation and their difficulties. Many other factors affect communication positively or negatively (Table 1.4.3). Good communication and counseling is an art that is acquired, developed and improved by experience. Efforts in this direction will lead to better patient/parent satisfaction and perhaps better clinical outcomes. It is well to remember that compassion, explanation, and reassurance are valued by patients and their families as much as a diagnosis, treatment, and cure. S

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trategies for mproving ommunication and ounseling

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1. Ammentorp J, Mainz J, Sabroe S. Patients’ priorities and satisfaction with acute pediatric care. Arch Pediatr Adolesc Med. 2005;159:127-31. 2. Bartel DA, Engler AJ, Natale JE, et al. Working with families of suddenly and critically ill children. Arch Pediatr Adolesc Med. 2000;154:1127-33. 3. Bull SA, Hu XH, Hunkeler EM, et al. Discontinuation of use and switching of antidepressants: influence of patient-physician communication. JAMA. 2002;288:1403-9. 4. Fong J, Longnecker N. Doctor-patient communication: a review. The Ochsner Journal. 2010;10:38-43. 5. Moore PJ, Adler NE, Robertson PA. Medical malpractice: the effect of doctor-patient relations on medical patient perceptions and malpractice intentions. West Med. 2000;173:244-50.

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heck what the parents know: Many parents have faulty knowledge, acquired from magazines, lay books, and the internet. • ssess what the parents want to know: Some parents want to know every little fact and detail about their child’s condition. Others simply want a prescription and assurance. • ssess understanding: Emotional distress, poor comprehension skills, language problems, etc. can hinder parents’ comprehension. Understanding can be improved by giving time to absorb, and by repetition. • evelop listening skills: Listening well is an essential part of communication. This requires the provision of adequate time and patience, and the willingness to listen to parents’ concerns. A quiet room, lack of interruptions, provision of chairs for the parents, sitting at an appropriate distance, good eye contact, etc. are helpful. D

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When faced with a chronic/permanent condition, most parents want to know: • What treatment can achieve for their child-relief of symptoms, prolongation of life, shortening of the course of the disease, etc. • Expected progress of the child during treatment • What to expect by way of improvement, side effects, fresh problems • Chances of complete cure; and • Treatment options. Parents also often want to know about advertised alternative medicine, and it is necessary to explain the unscientific and unproven nature of such “magic remedies”.

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be given small bits of information to translate at a time, especially when the prescription is dealt with. Speaking in technical/medical language leaves the parents confused and uninformed. It is important to talk in language that a non-medical person can understand • eafness: Speaking loudly, slowly and distinctly helps parents with hearing impairment. Other useful measures are voice amplification devices, a quiet room, and the use of written communication • Phones: Phones are ubiquitous now, and calls can interrupt and hinder communication terribly.

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Look at your watch frequently Appear to be in a hurry Use too many medical terms Talk with your hand on the door handle, or foot outside the door Interrupt all the time Start examination and then write out a prescription before the main problem has been identified Give long lectures as explanation Ignore concerns mentioned by parents

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Don’ts

Greet the child and parent by name Smile Sit down when talking Try to talk in the patient’s language Direct the conversation to relevant directions At the end of the consultation, ask if the parents have any questions Engage the parents in a dialogue Give time for the parents to absorb and understand the content of your explanations, then to ask questions

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Table 1.4.3 Dos and don’ts of communication

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Legal and thical ssues to Pediatric Practice

Doctor-patient relationship has undergone a sea change from the olden times. Decades back, medical professionals were never questioned in their actions. If any death or other mishaps used to occur, it was attributed to the act of God and the public used to accept it without any adverse reactions. As the times have gone by, medical professionals are being viewed with suspicion and are being dragged into the court for genuine or frivolous reasons. Deterioration in moral values, increased value for materialistic things, commercialization of the profession, higher expectation of the patients, awareness of rights and privileges of the patients, increasing consumer activism, media sensationalism, undue interference by the politicians, etc. contribute to worsening of the doctor-patient relationship. It is prudent on the part of the doctor to have an understanding of what constitute medical negligence and how to prevent it along with improvement in doctor-patient relationship by good ethical practice.

Medical Negligence Medical negligence has been divided into civil negligence and criminal negligence. In civil negligence the affected party takes the doctor to the court for monetary compensation whereas in criminal negligence the prosecution is done by the State and the punishment is usually fine or imprisonment. C

ivil Negligence A doctor can be found guilty under civil negligence by an act of omission or commission in a situation where he has failed to act in a manner which an ordinary professional of his standing would have been expected to act; or acted in a manner which an ordinary professional of his standing would not have been expected to act. The essential components of the modern tort of negligence propounded by Percy and Charlesworth are as follows: • • •

The existence of a duty to take care, which is owed by the defendant to the complainant. The failure to attain that standard of care, prescribed by the law, thereby committing a breach of such duty; and Damage, which is both causally connected with such breach and recognized by the law, has been suffered by the complainant.



Standard of care is the standard of the ordinary skilled man exercising and professing to have that special skill at that particular time. A man need not possess the highest expert skill. It is a well established law that it is sufficient if he exercises the ordinary skill of an ordinary competent man exercising that particular art. He is not negligent if he has acted in accordance with the practice accepted as proper by a responsible body 18 of medical practitioners skilled in that particular art. Failure

in attaining that average standard, leads to a claim for civil negligence. Compensation can be claimed under Law of Contract, Law of Tort or under Consumer Protection Act. C

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riminal Negligence

The jurisprudential concept of negligence differs in civil and criminal law. What may be negligence in civil law may not necessarily be negligence in criminal law. For an act to amount to criminal negligence, the degree of negligence should be much higher, i.e. gross or of a very high degree. Negligence which is neither gross nor of a higher degree may provide ground for action in civil law, but cannot form the basis for prosecution. To prosecute a medical professional for negligence under criminal law, it must be shown that the accused did something or failed to do something which in the given facts and circumstances no medical professional in his ordinary senses and prudence would have done or failed to do. The hazard taken by the accused doctor should be of such a nature that the injury which resulted was most likely imminent.

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Action can be taken against the medical professional under the Indian Medical Council Act for failure to follow the provisions of Code of Medical Ethics or under infamous conduct. Penal action also can be taken against the doctors for failing to follow various other rules concerning medical professionals like PNDT, Drugs and Cosmetic Act, Transplantation of Human Organs Act, Biomedical Waste Act, MTP Act, etc.

Precautions to be Taken during Treatment In the practice of medical profession, some precautions have to be taken to make the defense strong in cases of litigations. A doctor may be treating the patient in the correct manner. But many cases have been lost due to failure in proving the same in the Judicial Forums. D

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ocumentation

A physician should document the following facts: • Name, age, gender, religion and address of the patient • Date, month and year along with the time of examination • All relevant history including details of previous illness along with any history of drug allergy should be noted. If there is no history of drug allergy, it has to be noted. If the patient develops allergy to a drug subsequently, the date of occurrence • The complete examination details including the positive and relevant negative findings

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A good ethical practice should have the following elements: • tandard: A doctor should keep up high standard of behavior as prescribed in Code of Medical Ethics, 2002 of Indian Medical Council.

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To conclude, a good doctor-patient relationship will decrease the adverse incidents in the practice of medical profession. A good understanding of the laws involving the medical profession and taking proper precautions will help the medical professional in dealing with litigations.



ibliography 1. Bag RK. Medical Negligence and Compensation, 2nd edition, Calcutta: Eastern Law House Pvt. Ltd; 2001. 2. Lahoti RC. Jacob Mathew Vs. State of Punjab. KLT. 2005; 3:967.

thics in Practice and Good octor-Patient elationship

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Patient has the right to refuse treatment. In situations where there is refusal of treatment the consequences should be explained to the patients/parents in front of a witness and it is better to get the refusal signed by them. The doctor has also got the right to refer the patients elsewhere if the treatment is refused. If the refusal involves the welfare of a minor or an unborn baby, the courts can override the objections of the parents. When a medical personnel advances a plea that the patient did not give his consent to the treatment suggested by him, the burden is on him to prove that non-administration of the treatment was on account of the refusal to give consent thereto.

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hoice: The patient should be given the choice of treatment and doctor. If there is request for reference, proper reference letter should be given. ccessibility: The patient should have accessibility to the best treatment in the hospital or referred to a higher center for better care, if necessary. The doctor will earn the respect of the patient and the relatives by doing so. Nondiscrimination: No discrimination should be shown to the patients on the basis of religion, caste or social standing. Transparency: The doctor should be transparent with the patients and relatives on all possible matters. All matters regarding the bill, etc. should be explained and there should not be any practice of dichotomy (receiving commission from scan centers, lab, etc. for sending the patient for investigations and for referrals). ccountability: The doctor should be accountable to the patient for the treatment. mparting information: The parents and the relatives should be made aware of the condition of the patient. A proper communication can avoid misunderstandings later on. Imparting of information should be done in a sensitive manner. Quality of service: Expectations on the part of the patients and relatives are quite high regarding the quality of medical service. So a medical professional should update his medical knowledge by regular attendance at continuing medical education programs. ealing with complaints: A medical professional should give serious consideration to complaints brought by the patients and relatives and do proper investigation on the complaints. I f the complaint is genuine, an apology to pacify them is necessary and if the complaint is due to some misunderstanding, the matter should be explained.

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Currently the courts unanimously treat lack of informed consent as a matter of negligence of the doctor to disclose necessary information. So the doctor is duty bound to disclose the information as to the risk which can arise from the treatment of the patient. Risk is defined as exposure to a chance of an injury or loss. A majority of the courts require the doctor to disclose information that other physician possess of the same skills or practicing in the same community would disclose in the same situation. Any person of sound mind who has attained the age of 18 years may give a legally valid consent. A consent given by a child under 12 years is invalid, between 12 years and 18 years is valid if the court feels that the patient has understood the implication of the consent. In a situation where there was no proper informed consent and if some medically acceptable complication occurs as a treatment outcome, the doctor can be punished under medical negligence as it can be always claimed that if there was an awareness of the complications the consent would not have been given and hence the doctor will be held responsible for the complications.

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A record of investigations advised with reports A provisional diagnosis and a working diagnosis should be there before starting a particular line of management Final diagnosis; and Proper follow-up advice with review dates should be given.

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Next step in the process is to locate the best evidence that attempts to answer the research question identified. There are a number of online information and electronic data bases that the clinician may tap to find the evidence. ‘Medline’ is the most commonly accessed resource through “PubMed”. ‘Google Scholar’ is another search engine to find current evidences to your scientific queries. There are several websites that are modeled to facilitate evidence based medicine. These websites provide consolidated information on a wide range of clinically relevant areas and questions. The critical appraisal of the literature is an important step. The literature should be relevant to the research question and the findings valid and applicable to the settings in which the physician is working. Study design and how the potential biases have been handled are critical factors determining the validity of the findings of an article. Findings of a study on the compliance of anti-tubercular therapy done in Latin America may not be applicable in Indian settings due to various social, cultural and economic factors but do give an idea about the methods for studying the problem in your practice environment.

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It is important to distinguish between descriptive and analytic studies. Descriptive studies ask simpler questions about what is going on in the practice environment. For example: • How many children with diarrhea have visible blood in my practice? • What proportion of patients with cough longer than 10 days benefit from bronchodilator therapy? • How many typhoid patients have I seen during MarchJune of the current year? Analytic studies compare one or more interventions or exposures. For example: • What is the duration of diarrhea if antibiotic is not given versus given? • How many doses of anti-pyretic are sufficient after DPT shot?

earching Literature and its ritical ppraisal

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The majority of pediatric patients in India and developing countries are being treated in ambulatory clinics. If we assemble a cohort of 1000 children, less than 2 are likely to receive treatment in a teaching hospital. Major differences exist between the two settings. Patients seen in office practice have a wide spectrum of severity and differ significantly to that seen in hospitals. Such patient mix precludes generalization and application of results from studies that are mostly done in teaching hospitals. Equally important is the frequently encountered psycho-social morbidity in primary care office practice but uncommon in hospital settings. Thus, research in primary care office practice has several advantages. The sample represents the true population sample and the prevalent problems; accurate character of the disease and natural history; research on psychosocial issues is enabled; allows for health care services research; large sample sizes can be accrued; and it helps to improve quality of care. Office based research makes a clinician feel “alive”; prevents boredom of sitting in the OPD and writing prescriptions and broadens the scope of physician beyond the basic service delivery; excitement of office based research also includes intellectual stimulation, collaboration with academic colleagues, presentations in academic and scientific forums, and a sense of personal fulfillment. Office based research has the potential for improving the effectiveness, efficiency, delivery, feasibility, and reach of clinical care and behavioral interventions.

How is malnutrition associated with increased risk of infections? The best ideas for research come from everyday clinical problems. When an idea comes, think, and reflect on this for a few days or weeks, and think it through your colleague(s). Once research question is defined, it is important to think about how it will be answered. A good research question has four characteristics: feasibility (availability of adequate number of subjects, technical expertise, availability of ancillary services and investigations, time, funds, and scope); interesting to the investigator (passion of physician is essential); newness (confirms or refutes previous findings in your settings, provides new insights to the subject); ethical and relevant (to your practice, scientific knowledge, policy, future research directions).

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All research questions should lead to formulation of hypotheses. Every hypothesis has also four components: the research question, patient population and its description, study design to be applied and expected outcome. Most of the practicing physicians will require consulting an academic colleague to choose the appropriate study design.

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Where to Get unds for ffice ased esearch? Funding for practice based research is definitely a major barrier but not that is insurmountable. Obtaining grants by individuals is more difficult compared to when PBRN approach for funding. Professional associations such as Indian Academy of Pediatrics may be able to facilitate and mobilize funds from donors, foundations and government agencies. Collaboration with universities or medical schools is other option to generate resources. International agencies like AHRQ (The Agency for Healthcare Research and Quality) support PBRN. The support from the industry is justified provided issues related to conflict of interest are taken care of and independence along with scientific rigor of the work are consistently maintained. C

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The practice based research network can be considered the research laboratory of the primary care setting. PBRN were initially set-up as a surveillance network to report on common diseases and clinical problems or diseases of public health importance. Subsequently these networks have been involved to answer and shed new light on the complex, adaptive processes of primary care practices and imperatives. The key elements in a PBRN are: participation of moti vated practicing pediatricians, research projects, com munication and the academic framework. The design of such network studies have to be kept simple and easy; study duration should preferably be short with quick results to keep the motivation high, budgetary require ments need to be reasonable and they should not have ethic related complexity. The research coordinator is of critical significance; the person ought to have good research method knowledge, be able to carry network partners together and accomplish the task with consistent implementation of quality assurance steps during execution of study protocol. Managing network brings with it some unique challenges as well. PBRN must receive approval from many ethics committees to conduct research in several locations and practice settings. In a network, there are issues of selection bias, sampling errors, and data collection standardization, which are method aspects that may not be easy to control in busy and varied practice settings.

Office based practitioners can answer many important clinical questions that are not necessarily important for those attending big hospitals. Some examples may include: assessing severity of diarrhea and respiratory tract infections; determining indications for giving antibiotics in febrile child; when to order for investigations after a head concussion; assessing and managing first time pain abdomen which does not respond to antispasmodics; positive Mantoux test in a child with recently treated pulmonary tuberculosis; and many other such difficulties. Sentinel surveillance; counting and characterizing clinical encounters; understanding primary care encounters; comparing approaches to manage patients; modifying patient/clinician behavior; conducting pragmatic clinical trials; comparing approaches to deliver services in practice and monitoring outcomes are some of the broad areas where questions may be developed and research done. Studies such as these most often result from joint contributions of office based physicians and hospital based consultants, and has their major impact in community practice, where the results are most applicable.

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Practice ased esearch etwork

reas of esearch

i d are

There are difficulties in accomplishing good primary care research: perceived lack of time; translating potential research ideas into coherent research questions and proposals; training in research methods; obtaining ethical clearances; funding; analysis and writing of manuscripts; and working out research collaborations with academic colleagues. Loneliness of solo practitioners and emotional involvement with patients are additional barriers. This has restricted the opportunity for pediatricians and family physicians to improve the quality of care in office practices. During last two decades, there is worldwide movement to encourage and rope in clinicians in primary care to engage in the much needed research. Research networks have been set-up. Practice Based Research Network (PBRN) is a number of primary care clinics grouped together in a structure of a network for the purpose of performing research in the community.



s of

arriers to esearch in ffice Practice and ome olutions- ormation of esearch etworks

Collecting research data in geographically dispersed network environment requires proactive efforts at coordination, accuracy and timely transmission of data. Data collection must not put too much burden on the busy practitioner. Electronic data collection at the point of care is a feasible solution. It is important that data collection methods match the study design for accuracy and comfort.

asic once

Descriptive study designs are: cross-sectional studies; casecontrol; case reports and case series. Natural history of common childhood diseases can also be easily researched. Clinical trials are examples of analytic studies. Simple trials can be done in office practice.

onclusion

This is an era of shifting patient care from hospitals into the community and provides new and challenging opportunities to young and experienced alike for office based research and improved education. Keeping in mind the methodological limitations and potential biases, office 21 based patient material represents the “real world” situations

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1. Ipp M. Office based research: a new era and new opportunities. Pediatric Child Health. 2002;7:445-6. 2. John M. Westfall. Card Studies for Observational Research in Practice. Ann Fam Med. 2011;9:63-8. 3. Lindbloom EJ, Ewigman BG, Hickner JM. Practice based research network—the laboratories of primary care research. Medical Care. 2004;42:III45-49.





ibliography

4. Pace WD, Fagnan LJ, David WR. The Agency for Healthcare Research and Quality (AHRQ) Practice Based Research Network (PBRN) relationship: Delivering on an opportunity, challenges, and future direction. J Am Board Fam Med. 2011;24:489-92. 5. Slora EJ, Harris DL, Bocain AB. Wasserman RC. Pediatric Clinical Research Networks: Current Status, Common Challenges, and Potential Solutions. Pediatrics. 2010;126:740-45. 6. Wasserman R, Slora E, Bocian A, et al. Pediatric research in office settings (PROS): A national practice based research network to improve children’s health care. Pediatrics. 1998;102:1350-7.

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and research findings have the possibility of wide community applicability to improve effectiveness, efficiency and equity of care particularly in resource constraint environments.

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hild ealth in aarc ountries

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Basic oncepts of hild are

1.7



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ommon eonatal roblems in aarc ountries N

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Although there has been a reduction in child mortality globally, annually around 8.8 million children die before reaching their fifth birthday, the majority within the neonatal period (Fig. 1.7.1). During the neonatal period, preterm/low birth weight birth, perinatal asphyxia, and sepsis are the leading causes of death whereas infectious diseases like pneumonia, diarrhea, and malaria are the leading causes of death beyond the neonatal period. The majority (82.6%) of these deaths are taking place in South Asia and Africa. Southeast Asia including majority of the SAARC countries accounts for 27% of these deaths. The SAARC region represents countries with overlapping WHO and UNICEF regions and includes parts of Asia with the highest mortality rates. The combined population of SAARC countries is around 1.57 billion, representing approximately 23% of the total world’s population. With the inclusion of Afghanistan, the region now houses countries with the highest child mortality rates in Asia. Of the eight SAARC countries, Afghanistan ranked 2nd (under-5 mortality rate of 199) and Sri Lanka ranked 128th (under-5 mortality rate of 13) in the list of 257 countries (Table 1.7.1). In the year 2000 the Millennium development goals (MDG) were set with

specific targets for mortality reduction by two-thirds by the year 2015. A recent countdown review indicates that out of the five SAARC countries surveyed, only two (Bangladesh and Nepal) are “on track”, two (India and Pakistan) have “insufficient progress”, and one (Afghanistan) had “no progress”.

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ntroduction

Neonatal deaths account for 50–60% of all infant deaths and the majority of these deaths and simple interventions to address prematurity are available and can be scaled up. These include appropriate care of the mother in pregnancy, use of antenatal steroids in preterm labor, antibiotics for preterm premature rupture of membranes, appropriate care in the first 48 hours after birth. The principal causes of neonatal mortality in the region include perinatal asphyxia, prematurity and sepsis. The exact burden of prematurity is unknown in the region. While it may be difficult to prevent prematurity, cost effective care at birth and prevention of hypothermia are possible. There have been moderate to large scale evaluations of appropriate skin to skin care after birth in

I

Zulfiqar A Bhutta

23  

Figure 1.7.1 Leading causes of death in children under 5-year of age in Southeast Asia

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1990

2009

2

260

199

Pakistan

37

130

87

Bhutan

41

148

79

India

48

116

66

Bangladesh

57

149

52

Nepal

59

142

48

Maldives

118

111

15

Sri Lanka

128

29

13

P P

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neumonia

Community acquired pneumonia, is one of the leading causes of death in children in the region (majority due to Hib and pneumococcal infections). Hib and pneumococcal vaccines are being rolled out in many SAARC countries either through national investments or GAVI funding. Additional preventive interventions include strengthening of routine immunization, addressing low birth weight, promotion of exclusive breastfeeding, environmental hygiene and reduction in exposure to indoor air pollution. Notwithstanding the role of preventive strategies, there is the importance of appropriate management. Currently most SAARC countries have policies in place for appropriate management through IMNCI trainings of all health care providers looking after children. The basic emphasis of IMNCI training is to recognize pneumonia at an early stage (using a classification on the basis of respiratory rate and presence or absence of subcostal recessions) and initiation of treatment at first or second level of health care. There is also the provision of referral in the event of deterioration or danger signs at presentation. Given the difficulties in referral in some instances, there is also an increasing focus on community-based care (dete ction and management of pneumonia) and preliminary findings from several studies in the region indicate promising outcomes.

24

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iarrhea

Despite vast improvements in our understanding of the risk factors and strategies for the control of diarrheal disease as well as economic growth, diarrhea remains a leading cause of death in children in the SAARC region. Almost half of the childhood diarrhea deaths globally are in five countries of which two (India and Pakistan) are in the SAARC region. A major reason for poor progress is in this area is the relative lack of investment in large scale water and sanitation projects and the fact that between 20% and 30% of the population still does not have access to improved and safe water and over a third of the rural population practices open defecation. Prevention and treatment of dehydration is the key for successful management. Provision of diet and zinc during the diarrheal episode helps not only to treat current episode but prevent malnutrition as well as respiratory morbidity. Given findings that rotavirus infections account for almost a third of all diarrhea deaths, the newer rotavirus vaccines may offer a unique opportunity for prevention of severe diarrheal disease and mortality in the region. O

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rural India as well as the use of insulated beds. The use of surfactant and mechanical ventilation may only be available in larger cities in the private sector hospitals but there is great potential for development of low cost surfactant and equipment, especially CPAP units which could make a lot of difference to survival. Perinatal asphyxia can account for up to half of all newborn deaths in the first week of life and can also be associated with significant neonatal morbidity and developmental disability. Many cases of perinatal asphyxia cannot be predicted and hence appropriate facilities for recognition and neonatal resuscitation must be made available in all birthing facilities. While there have been efforts at promoting domiciliary resuscitation in the hands of birth attendants, there are encouraging trends of reduction in perinatal mortality with facility based births. At the very basic level, encouraging facility-based births in the hands of skilled birth attendants with appropriate basic equipment is a key intervention. Although there have been remarkable reductions in neonatal tetanus, neonatal sepsis remains a major cause of morbidity and mortality in newborn and although vertical transmission is possible, the majority of these infections are community acquired and hence potentially preventable. Hand hygiene, and the use of birth kits, followed by appropriate cord care are important interventions to prevent infection. Emerging evidence from various SAARC countries indicates that the use of cord chlorhexidine may be associated with significant reduction in the risk of neonatal omphalitis and sepsis. Given the high rates of infections in community settings and potential delays in recognition and referral, there is increasing attention to community based detection and management of potential neonatal infections and other problems. This includes the training of health care providers in IMNCI, as this approach can be used to recognize and treat serious infections at an early stage and impact outcomes.

A

*Source: State of the World’s Children 2011





Afghanistan

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b T

Value

Rank

P

Country

ommon roblems Beyond eonatal eriod P

ext ook of ediatrics

Table 1.7.1 Comparison of under 5 mortality rates in 1990 and 2009 with present ranking according to current under 5 mortality rates*

Maternal and child undernutrition is an important determinant of child mortality and long-term adverse outcomes including

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1. Acuin CS, Khor GL, Liabsuetrakul T, et al. Maternal, neonatal, and child health in Southeast Asia: towards greater regional collaboration. Lancet. 2011;377:516-25. 2. Arifeen SE, Hoque DM, Akter T, et al. Effect of the Integrated Management of Childhood Illness strategy on childhood mortality and nutrition in a rural area in Bangladesh: a cluster randomised trial. Lancet. 2009;374:393-403.





Bibliography

3. Baqui AH, Arifeen SE, Rosen HE, et al. Community-based validation of assessment of newborn illnesses by trained community health workers in Sylhet district of Bangladesh. Trop Med Int Health. 2009;14:1448-56. 4. Bhandari N, Mazumder S, Taneja S, et al. Effectiveness of zinc supplementation plus oral rehydration salts compared with oral rehydration salts alone as a treatment for acute diarrhea in a primary care setting: a cluster randomized trial. Pediatrics. 2008;121:e1279-85. 5. Bhutta ZA, Ahmed T, Black RE, et al. What works? Interventions for maternal and child undernutrition and survival. Lancet. 2008;371:417-40. 6. Bhutta ZA, Chopra M, Axelson H, et al. Countdown to 2015 decade report (2000-10): taking stock of maternal, newborn, and child survival. Lancet. 2010;375:2032-44. 7. Black RE, Cousens S, Johnson HL, et al. Global, regional, and national causes of child mortality in 2008: a systematic analysis. Lancet. 2010;375:1969-87. 8. Darmstadt GL, Bhutta ZA, Cousens S, et al. Evidence-based, cost-effective interventions: how many newborn babies can we save? Lancet. 2005;365:977-88. 9. Million Death Study Collaborators, Bassani DG, Kumar R, et al. Causes of neonatal and child mortality in India: a nationally representative mortality survey. Lancet. 2010;376:1853-60. 10. UNICEF. State of the world’s children, New York. 2011.

Basic oncepts of hild are

development. Given the high burden of low birth weight, stunting and wasting in the SAARC region, even among countries where mortality rates have improved, there is much need to focus on these determinants. In addition to poverty and maldistribution of resources, the status of women in society, empowerment, ethnicity and race play a critical role in existing inequities in care and access. Most people living in rural areas and urban slums live in abysmal conditions and have limited access to quality health care services. Appropriate targeting, poverty alleviation strategies such as conditional cash transfers, employment schemes and good governance are essential elements in provoking change. An essential element in the quest for targeting the poor, especially in areas with shortage of trained medical staff, is the strategy for task shifting and scaling up of interventions through lay workers and community health workers.

25

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Section

2 Care of the Newborn





















2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 2.10 2.11

























Section Editor : Siddarth Ramji Neonatal Nomenclature: Siddarth Ramji Neonatal Resuscitation: Siddarth Ramji Care of the Normal Newborn: B Vishnu Bhat Identification and Approach to a Sick Newborn: Swarna Rekha Bhat Low Birth Weight: Vikram Datta Parent Counseling: Ranjan Kumar Pejaver Neonatal Hyperbilirubinemia: Rhishikesh Thakre Neonatal Infections: Naveen Jain Neonatal Seizures: Ruchi Nimish Nanavati Respiratory Distress: Ashok Kumar Bleeding Neonate: JN Sharma

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Neonatal Nomenclature

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Siddarth Ramji

Perinatal Period

F

The period from 28 weeks of fetal life up to the first 7 days after birth is the perinatal period.

etal Period

Early Fetal Period

wb rn

Post-term Neonate A neonate who is born after 41 weeks of completed gestation is a post-term neonate.

Birth Weight Related Low Birth Weight Any neonate who at birth has a weight of less than 2,500 g irrespective of gestation is a low birth weight (LBW) neonate.

Very Low Birth Weight A neonate with a birth weight of less than 1,500 g is a very low birth weight (VLBW) neonate.

xtremely Low Birth Weight

A neonate with a birth weight less than 1,000 g is an extremely low birth weight (ELBW) neonate.

Small for Dates (S D)/Small for Gestation Age (SGA)/ Intrauterine Growth Retardation (IUGR) F

This refers to a period of gestation up to 22 weeks. Usually the fetus at this period weighs less than 500 g and has a crown rump length (CRL) of less than 25 cm.

A neonate who is born before 37 weeks of completed gestation is a preterm neonate.

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Gestational Age Related

Preterm Neonate

o

There are several terms that are used in reference to newborn infants and their care. This section will briefly summarize the commonly used terms in reference to the newborn infant. Newborn/Neonate: Any infant who is up to 28 days of life is termed a newborn or neonate. Early neonatal period: The period from birth up to 7 days of life is the early neonatal period. Late neonatal period: The period from day 7 up to day 28 of life is the late neonatal period.

This refers to the period of gestation from 22 weeks to 27 weeks of fetal life. The fetus usually weighs 500–999 g and has a CRL of 25 cm up to 35 cm.

Late Fetal Period This refers to gestations greater than 27 weeks and the fetus usually weighs 1,000 g or more and has a CRL of at least 35 cm.

Appropriate for Dates (A D)/Appropriate for Gestation Age (AGA) It refers to a neonate whose birth weight is between 10 centile and 90 centile or –2 and +2 standard deviation of the reference standard for a given gestational age.

Large for Dates (L D)/Large for Gestation Age (LGA)

T

F

Neonate

These are synonymous terms often used interchangeably and refer to a neonate whose birth weight is less than 10th centile or less than –2 standard deviation of the reference standard for a given gestational age. F

Intermediate Fetal Period

erm Neonate

A neonate born between 37 weeks and 41 weeks of completed gestation is a term neonate.

It refers to a neonate whose birth weight is greater than 90 centile or greater than +2 standard deviation of the reference standard for a given gestational age.

27

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Neonatal esuscitation Siddarth Ramji

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To identify neonates who would need resuscitation at birth, ask the following two questions: 1. Is the baby crying or breathing? (Identified by observing chest rise, which should be visible and regular) 2. Is there a good muscle tone? (Identified by noting the posture, which should show generalized flexion at upper and lower limbs).

Apgar score is traditionally used to identify birth asphyxia (Table 2.2.1). Birth asphyxia has been defined variously as Apgar score less than 7 at 1 min, no breathing at birth or gasping respiration at birth. It is the most common neonatal emergency in the delivery room. It is estimated that about 5–10% of newborn infants do not establish adequate breathing efforts at birth and need assistance to establish adequate breathing or ventilation. Asphyxia contributes to almost 25% of neonatal deaths.

dentifying Newborns Needing esuscitation at irth



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What is irth sphyxia?

If the answer to both the questions is “Yes”, then the newborn needs to be dried and kept warm. Both these actions can be performed with the newborn lying on the mother’s chest and should not require separation of mother and baby. If the answer is “No” to any of these questions, then the neonate is depressed or nonvigorous and needs resuscitation. The newborn must be assessed to determine the need for one or more of the following actions in sequence:

tiology

The risk factors associated with the need for neonatal resuscitation are given in Table 2.2.2. Not all infants born depressed at birth have these associated risk factors. Thus, all personnel in the delivery room must be trained in basic neonatal resuscitation and every birth must be treated as a potential emergency needing resuscitation at birth.



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Table 2.2.1 Apgar score Parameters

0

1

2

Respiratory effort

Absent

Gasping

Good cry

Heart rate

Zero

< 100/min

> 100/min

Color

Central cyanosis

Peripheral cyanosis

Pink

Tone

Flaccid

Partial flexion of extremities

Complete flexion

Response to nasal catheter

None

Grimace

Sneeze

 

Table 2.2.2 Risk factors associated with need for neonatal resuscitation

28

Antepartum factors

Intrapartum factors

•  •  •  •  •  •  •  •  •  •  •  •  •  •  •  • 

•  •  •  •  •  •  •  •  •  •  • 

Maternal diabetes Pregnancy-induced hypertension Anemia Antepartum hemorrhage Maternal infection Maternal cardiac, renal or pulmonary disease Polyhydramnios Oligohydramnios Premature rupture of membranes Post-term gestation Multiple gestation Fetal malformation Maternal substance abuse Diminished fetal activity No antenatal care Maternal age < 16 or > 35 years

Emergency cesarean section Forceps or vacuum-assisted delivery Breech or other abnormal presentation Premature labor Chorioamnionitis Prolonged labor (> 24 hours) Fetal bradycardia Use of general anesthesia Narcotics administered to mother within 4 hours of delivery Meconium-stained amniotic fluid (MSAF) Abruptio placentae or placenta previa

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Dry all babies soon after birth. Assess for the breathing and tone of the baby while drying is being done. Neonates who are vigorous should not be separated from the





Initial steps for stabilization (dry and provide warmth, position, assess airway, stimulate to breathe) • Ventilation • Chest compression • Medications. Progression to the next step is initially based on the simultaneous assessment of respiration and heart rate. Progression to the next step occurs only after the successful completion of the preceding step. Approximately 30 seconds are allotted to complete each of the first two steps successfully, re-evaluate and decide whether to progress to the next step. The first minute of life is termed the “golden minute” and is critical to minimize postnatal hypoxia to the neonate (Flow chart 2.2.1 provides the algorithm for neonatal resuscitation). Successful resuscitation in the delivery room needs appropriate equipment. The list is provided in Table 2.2.3.

are of he Ne bor

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Table 2.2.3 List of resuscitation equipment

n

w

Radiant warmer Oxygen (central supply or cylinder) Suction device (mucus extractor or central suction facility) Self-inflating resuscitation bag (250–500 mL) with oxygen reservoir and pop-off valve Face masks (sizes 0 and 1) Laryngoscope (straight blade No. 0, 1) Endotracheal tubes (sizes 2.5 mm, 3 mm, 3.5 mm internal diameter) Drugs: Adrenaline (1:1000), naloxone, normal saline and Ringer’s lactate Intravenous cannula, umbilical catheters, syringes, needles

 

Flow chart 2.2.1 Algorithm for neonatal resuscitation

29

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Positive Pressure Ventilation



Rate of Ventilation If adequate chest rise has been established, the rate of ventilation must be sufficient to provide 40–60 breaths/ min.

Initiate Ventilation with 21% Oxygen (Room Air)



Current evidence strongly supports initiating resuscitation with room air rather than 100% oxygen in infants greater than 32 weeks. In preterms less than 32 weeks, resuscitation may be initiated with 100% oxygen or lower inspired oxygen concentration if blenders are available and oxygen delivery titrated if there is access to pulse oximetry in the delivery room. Infant color in the delivery room is a poor marker of hypoxia. Good response to assisted ventilation after 30 seconds of ventilation is indicated by: • Appearance of spontaneous breathing efforts • Rise in heart rate to more than 100/min. C

hest ompression

Chest compression (cardiac massage) is indicated when the heart rate is less than 60/min after 30 seconds of assisted ventilation. Chest compression requires two personnel—one to continue assisted ventilation and the other to perform chest compressions. The thumb for compression is placed over the lower-third of the sternum. Assisted ventilation and chest compression are coordinated in a ratio of 30 ventilations to 90 chest compressions (3:1). Chest compression is discontinued when heart rate rises to above 60/min. D

Positive pressure ventilation (PPV) can be provided with bag and mask, or bag and endotracheal tube. A small towel 1 inch thick is placed under the infant’s shoulder. The self-inflating bag used for neonates must have a volume

between 250 mL and 500 mL, with an oxygen reservoir. One must select the correct-sized mask (zero size for preterm and size one for term infants) for resuscitation. The correct fit mask when placed over the infant’s face should cover the chin, mouth and nose and not the eyes. Ensure that the mask makes a good seal around the mouth and nose such that when the bag is inflated there is visible chest rise in the infant. If the chest does not rise, the possible reasons could be: • The seal is inadequate • Airway is blocked • Insufficient inflation pressure.

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mother and should be kept warm by placing on mother’s chest and covering the baby with a sheet of cloth. In vigorous babies, cord clamping should be delayed for at least 1 min, as there is strong evidence of the benefit of the additional transfer of blood to the baby in preventing anemia in the latter months of infancy. For nonvigorous babies who need resuscitation, clamp and cut the cord immediately and place the baby under a radiant warmer to provide warmth. Open airway and position the head. To open the airway, slightly extend the neck and maintain this position by placing a folded towel (about 1 inch thick) under the shoulder. Suction the baby’s mouth and then the nose using a mucous extractor or Dee Lee trap. If the amniotic fluid is meconium stained, current evidence does not recommend peripartum suctioning. Suctioning mouth should only be restricted to nonvigorous neonates irrespective of the color of the amniotic fluid. If amniotic fluid is meconium stained and the baby is not vigorous, suction the baby’s mouth and nose. If one has the expertise, the trachea may also be cleared by suctioning under direct laryngoscopy. Provide tactile stimulation. If the infant is not breathing even after suction, provide tactile stimulation by flicking the sole or gently rubbing the back (Fig. 2.2.1). Do not slap the back or squeeze the rib cage. Reassess the neonate. A prompt increase in heart rate remains the most sensitive indicator of resuscitation efficacy. Auscultate over the precordium for 10 seconds and multiply by 10 to get the infant’s heart rate. If the heart rate is below 100/min or the neonate is gasping or apneic, it is an indication to initiate positive pressure ventilation.

rugs

Adrenaline It is indicated whenever the heart rate remains less than 60/ min in spite of chest compression. The dose is 0.1–0.3 mL/ kg of 1:10,000 solution given intravenously or intratracheal. The dose may be repeated after 3–5 min as indicated.

Naloxone

Figure 2.2.1 Methods to provide tactile stimulation  

30

It is a narcotic antagonist. It is indicated to reverse respiratory depression in an infant whose mother has received narcotics within 4 hours of delivery. The dose is 0.1 mg/kg given intravenously, intratracheal or if perfusion is adequate, intramuscular or subcutaneously.

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It is indicated in neonates in shock—poor pulses, pale and cold extremities. Dose is 10 mL/kg of normal saline or Ringer’s lactate given by intravenous (IV) push over 5–10 min. Nonresponse to volume expansion with 20 mL/kg of crystalloid would be indication for ionotropes such as dopamine or dobutamine. At present there is not sufficient evidence to recommend use of sodium bicarbonate in the delivery room.

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ey Messages

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Volume Expanders

It may be appropriate to consider discontinuing resuscitation if no heart rate is detected for 10 min after birth.

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1. McDonald SJ, Middleton P. Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes. Cochrane Database Syst Rev. 2008;(2):CD004074. 2. Perlman JM, Wyllie J, Kattwinkel J, et al. Part 11: Neonatal resuscitation: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation. 2010;122:S516-S538. 3. Rabi Y, Rabi D, Yee W. Room air resuscitation or the depressed newborn: a systematic review and meta-analysis. Resuscitation. 2007;72:353-63. 4. Taeusch HW, Ballard RA, Gleason GA. Avery’s Diseases of the Newborn, 8th edition. Philadelphia: Saunders; 2005.



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When to iscontinue esuscitation

ibliography



Neonates who needed only initial steps of resuscitation can be provided observational care by monitoring them when roomed-in with their mothers. Neonates who needed more intensive resuscitative assistance such as assisted ventilation, chest compression or drugs need to be shifted to an neonatal intensive care unit (NICU) or special care newborn care unit, and monitored more intensely with clinical and biochemical monitoring. Many of these infants would need IV fluids, ionotropes, supplemental oxygen and even mechanical ventilation.



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• About 5–10% neonates would require resuscitation at birth and almost half occur amongst women with no risk factors. • Resuscitation sequence should be swift, and in apneic infants assisted ventilation should start within 1 min. • Sequence of interventions is initial steps, assisted ventilation, chest compression and medication. • Initiate PPV with room air. Use oxygen supplementation cautiously in preterm infants. • All infants who need advanced resuscitative intervention should be shifted to an NICU for postasphyxial care.

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are of the Normal Newborn B Vishnu Bhat suture lines. It is usually noticed after 2 days of birth and disappears after 6–8 weeks. It usually does not require treatment.

Normal eatures in Newborn

Urine and tool Passage

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espiration, Heart ate and lood Pressure

kin hanges C

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A newborn may have periodic breathing and the normal rate may vary from 40/min to 60/min. The heart rate is usually 120–160 beats/min. The systolic blood pressure will vary from 40 mm Hg to 60 mm Hg and diastolic 25–40 mm Hg.

mportant xamination indings in Newborn

Anterior and posterior fontanels are open at birth. Large posterior fontanel or both anterior and posterior communicating is usually abnormal. Similarly, if anterior fontanel is very small and there is ridging of suture lines, it may indicate craniosynostosis. Natal teeth may rarely be present. They may be loose and sometimes may result in injuries to mother’s nipple in which case, they may need to be extracted. Phimosis is normal during this period but the meatus is visible when prepuce is retracted in more than 85% of babies. Mucosal tags may be seen at the introitus in female babies. Liver palpable 2–3 cm below the costal margin and palpable spleen tip are normal. Usually both testes are in the bottom of the scrotum in term male babies. If the testes are not palpable or abnormally placed, it should be recorded and investigated.

32

Jaundice, which usually appears after 2–3 days and disappears by 7–10 days of life and does not stain the palms and soles is usually physiologic. Enlargement of the breast during first 3–7 days of life is known as mastitis neonatorum and does not require any treatment. This enlargement is related to maternal transfer of hormones. A female baby may have vaginal discharge and bleeding during that period, which is also hormone-related and disappears within a few days. There may be molding of the head and caput succedaneum over the presenting part, which disappears within 2–3 days. Caput should be differentiated from cephalhematoma. The latter is due to collection of blood under periosteum and hence does not cross the

mportant Neonatal eflexes R

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Physiologic vents

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Mongolian spots are bluish patches seen over the buttocks and back due to deposition of melanin pigment and disappear in 6 months to 2 years’ time. Milia are whitish pin head size papular lesions seen over the face due to obstruction to sebaceous glands. They disappear in 2–3 weeks. Erythema toxicum are erythematous papular, macular or rarely pustular lesions present over the body surface. They usually appear after 2 days and disappear during the first week. Epstein’s pearls are whitish papular lesions usually seen over the palate and sometimes over the prepuce and disappear after a few days. Small hemangiomas may be seen over the body surface, which disappear within 2 years of life.

F

The average birth weight of babies in India is 2,900 g. The length may vary from 47 cm to 52 cm and head circumference 32–35 cm. Generally, the head circumference is 2–3 cm more than chest circumference at birth and they equal by 1 year after which chest circumference exceeds that of the head.

A newborn usually passes urine within 48 hours and meconium during the first 24 hours of life. If there is no distension of abdomen, delayed passage of urine indicates inadequate feeding. Distension of bladder in a male baby suggests posterior urethral valve. When there is delay in passage of meconium, a soft rubber catheter should be passed into the rectum to confirm patency. The fingertip or thermometer should not be used for checking patency since these may result in injury. Prematurity, meconium plug, congenital megacolon, meconium ileus and hypothyroidism may result in delayed passage of meconium. A baby may pass frequent yellow-colored watery to semisolid stools during first 3–7 days of life known as transitional stools. Some babies may pass stools once in 2–3 days. Hypothyroidism should be excluded in babies with constipation. E

nthropometry

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A

F

S

Normal newborn is an infant born at term with birth weight greater than 2,500 g without any asphyxia, major congenital malformations or birth injuries.

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2.3

Rooting Reflex Rooting Reflex helps the baby to locate the mother’s nipple without her directing the baby’s mouth. The infant turns toward the point where the cheek is touched. When the corner of the mouth is touched, the lower lip is lowered and the tongue is brought forward toward the contact. If the finger is moved away, the head turns to follow it.

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Sucking and Swallowing Reflexes

 

are of

Table 2.3.1 Danger signs in newborn

eeding

Temperature Maintenance and Monitoring

Vitamin

All babies should receive vitamin K prophylaxis of 0.5 mg (for < 34 weeks) to 1 mg (for > 34 weeks) intramuscularly after birth to prevent hemorrhagic disease of the newborn.

anger igns S

D

Normal body temperature of newborn ranges from 36.5°C to 37.5°C. Newborns are uniquely susceptible to hypothermia because they have a large body surface area, which causes heat loss and have reduced subcutaneous insulation. They are dependent on caregivers to keep them warm and dry. The temperature of the delivery room should be at least 26 ± 2°C and free from draft of air. The infant should be received in prewarmed sterile linen and should be dried thoroughly from head to foot. The wet linen should be removed and replaced with a dry cloth. The baby should be made to wear cap and socks. Kangaroo care position is the most ideal. Skin to skin contact with the mother not only prevents hypothermia, but also promotes breastfeeding and bonding. A bath is delayed until the temperature is stabilized. It is better if baby bath is not given in hospital for fear of cross infection. Mother can be taught the simple technique of monitoring the baby’s temperature by touching the periphery and observing for color change. Cold extremities with blue or pale color indicate inadequate warmth.

Mother should be informed about danger signs and the need to get medical advice as and when they are observed. Some of the danger signs are given in Table 2.3.1. D

It is elicited by touching the baby’s palm from the ulnar side with finger or any other suitable object. The fingers close and grasp the object. When the dorsum of the hand is touched, the fingers open. The grasp becomes stronger if the head is turned to the opposite side and the stimulating finger is moved toward the fingers. Similar reflex can be elicited in the lower limb by stimulating the sole. Persistence of grasp after 3 months of age may indicate cerebral palsy.

K

Management

Breastfeeding should be initiated soon after birth and exclusive breastfeeding is advised till 6 months of age in normal term babies. A baby should receive 7–8 feeds a day during the first few weeks. The pregnant mother should be explained the benefits of breastfeeding and the family members are encouraged to support her. It is important not to separate the newborn from the mother without a justifiable reason. The initial alert period is utilized to start breastfeeds as babies tend to sleep a lot after that. Health workers caring for newborns should learn the signs of good attachment; which include: mouth wide open, more areola seen above than below, chin touching the breast and lower lip everted. Excessive weight loss of more than 8–10% in the first 3–4 days indicates inadequate breastfeeding or illness in the baby.

Grasp Reflex

n

C

E

ord and ye are

The umbilical stump should be cleaned with spirit and kept dry. Local application of antiseptics is not required. Usually the stump will fall in 7–10 days’ time. The eyes should be cleaned with sterile wet cotton. There is no need to instill antibiotic drops into eye except in areas with high incidence of vertically acquired conjunctivitis. F

It is a vestibular reflex, which disappears by 3–5 months of age. It can be elicited by raising the shoulder for 45° from ground and then dropping by 30°. There will be abduction and extension of arms with opening of fingers. This is followed by flexion and adduction of arms. The reflex may be accompanied by crying, extension of trunk and neck with movements of legs. It is exaggerated when there is cerebral irritation caused by hypoxia, infection, hyperbilirubinemia, etc. It is decreased with sedation, central nervous system (CNS) depression or prematurity. Asymmetrical response is seen with Erb’s palsy, clavicular or humerus fracture, or shoulder dislocation.

C

Moro Reflex

Poor sucking/cry Fever/hypothermia Persistent vomiting Abdominal distension Pallor Jaundice involving extremities Bleeding Convulsions

th

•  •  •  •  •  •  •  • 

e Newbor

These are elicited by introducing clean finger or mother’s teat in the mouth. They disappear when voluntary control of feeding is achieved. They are decreased or absent when there is neurological depression, hypotonia or immaturity. A baby would have usually crossed 34 weeks of gestation when he/she can take full feed from breast.

ischarge Planning

It is ideal to discharge a normal newborn after 48–72 hours of life. The baby should be free of illness, significant jaundice, and the mother should be confident about breastfeeding. The baby should have received initial immunization with bacille Calmette Guerin (BCG), oral polio and Hepatitis B vaccines; and have passed meconium and urine. If the baby is discharged early, he or she should be reviewed at home

33

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B









1. Behrman RE, Kliegman RM, Jenson HB (Eds). Nelson Textbook of Pediatrics, 18th editon. Philadelphia: Elsevier Saunders; 2007. 2. Bhat BV. Neonatal care. In: Parthasarathy A, Menon PS, Nair MK, Bhave SY (Eds). Partha’s Fundamentals of Pediatrics, 1st edition. New Delhi: Jaypee Brothers; 2007. pp. 29-62. 3. Cloherty JP, Echenwald EC, Stark AR (Eds). Manual of Neonatal care, 6th edition. Philadelphia: Lippincott Williams and Wilkins; 2008. 4. Illingworth RS. The Normal Child. Some Problems of the Early Years and their Treatment, 10th edition. Edinburgh: Churchill Livingstone; 1997. 5. Taeusch HW, Ballard RA, Gleason CA. Avery’s Diseases of the Newborn. 8th edition. Philadelphia: WB Saunders; 2005.



Temperature control and prevention of hypothermia is vital. Breastfeeding is initiated as soon as possible. All babies should receive vitamin K prophylaxis. Initial immunization should be given before discharge. Growth and development should be monitored during follow-up.



ey Messages

ibliography



K







• • • • •



t

t

Tex book of Pedia rics

or hospital after 48 hours. Babies should be followed up and anthropometry recorded in a growth chart. The growth and development should be evaluated monthly during the first few months and 3-monthly thereafter.

34

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A

dentification and pproach to a Sick Newborn

I



Care of the Newbor

2.4

Swarna Rekha Bhat

 

Table 2.4.2 Features of significant illness on history Danger signs •  Lethargy •  Breathing difficulty •  Temperature instability •  Failure to pass urine/meconium in first 24/48 hours •  Vomiting •  Diarrhea •  Cyanosis •  Jaundice •  Abdominal distension •  Convulsions •  Bleeding •  Excessive weight loss

ho is a Sick Newborn?

valuating a Sick Newborn istory E

H

E



A sick newborn may be described as one who is: • Not feeding well • Lethargic • Has any systemic illness and • Has poor weight gain. These are infants who require additional support such as oxygen, IV fluids, etc.

Following history should be elicited to determine nature of illness, and presence or absence of risk factors (Table 2.4.1): • Age of neonate in hours/days • Antenatal history to identify any risk factors • Intrapartum history to identify risk factors • Mode of delivery • Apgar score or crying or breathing immediately after delivery • Feeding history: Any feed given/is feeding adequate/is baby on breastfeeds • One should also elicit history suggestive of significant illness (Table 2.4.2).

xamination

Examination of a sick neonate can provide useful clues to the etiology of sickness and also provides a basis for the management plan. Important signs and their utility are summarized below.

Temperature Instability Hypothermia (< 36°C) could be due to environmental factors or as a result of sepsis. Hyperthermia is less common; could be environmental or a manifestation of sepsis.

Respiratory Distress Breathing problems in a neonate can be tachypnea (respiratory rate > 60/min), chest indrawing, stridor or apnea. The severity of respiratory distress (RD) can be monitored using the respiratory distress score (Table 2.4.3).

 

Table 2.4.1 Risk factors: maternal and fetal

n

W

Early identification of a sick newborn is the key to successful management and improving neonatal outcome.

Antenatal risk factors •  Maternal diabetes mellitus •  Pregnancy-induced hypertension (PIH); eclampsia •  Urinary tract infections (UTI) •  Any illness •  Rh negative mother •  Oligo- or polyhydramnios Fetal •  Intrauterine growth retardation (IUGR) •  Abnormal ultrasonogram (USG) •  Abnormal Doppler study •  Preterm delivery Intrapartum •  Premature rupture of membranes (PROM) •  Abnormal nonstress test (NST) •  Meconium-stained amniotic fluid (MSAF) •  Difficult delivery •  Operative delivery

Cyanosis The two most serious causes of cyanosis are congenital cyanotic heart disease and respiratory illness such as respiratory distress syndrome (RDS), meconium aspiration syndrome (MAS) or pneumonia. However, simpler problems such as polycythemia and hypoglycemia can also present as cyanosis.

Shock It can be due to fluid/blood loss, asphyxia, duct-dependent cardiac lesions, sepsis or inborn errors of metabolism (IEM).

Pallor Pallor may indicate anemia (due to blood loss or hemolysis), but may also indicate hypothermia, hypoxia, hypotension and sepsis.

35

vip.persianss.ir

cs

 

Features

0

1

2

Respiratory rate/min

< 60

60–80

> 80

Cyanosis

Nil

Nil on 40% O2

Requires > 40% O2

Retractions

Nil

Mild

Moderate to severe

Grunting

Nil

Audible with stethoscope

Audible without stethoscope

Air entry

Normal

Decreased

Barely audible

Convulsions The critical point is recognition of convulsions. Any abnormal movement needs to be reported, jitteriness and sleep myoclonus needs to recognized, subtle seizures are often missed. Seizure can be a pointer for several illnesses.

neonate, it could be due to thrombocytopenia. Intracranial bleed is a serious problem and is more common in preterm neonates.

Jaundice

Lethargic, Poor Feeding, Unresponsiveness

Neonatal jaundice is often physiologic, but high bilirubin levels can be associated with neuronal damage. In neonates with persistent jaundice after day 14, always check for color of stool. Pale colored stool could indicate cholestatic jaundice such as biliary atresia.

A sleeping neonate may appear lethargic. A simple method of determining whether a neonate is lethargic or sleeping is to observe if the neonate is responsive to stimulation. If a neonate does not change state during examination or handling, it indicates that the sensorium is not normal. The etiology of lethargy may range from simpler causes like hypoglycemia and polycythemia to more severe ones including sepsis, meningitis, intracranial bleed and hypoxic brain injury. Neonates with IEM usually present with lethargy and poor feeding.

The most likely reason is poor milk intake; however other more serious problems, which can present as poor weight gain include any systemic illness and IEM. A

V d

Vomiting

n U

A neonate presenting with vomiting may be having something as physiologic as regurgitation or it could be due to an intestinal obstruction. Bilious vomiting and persistent vomiting associated with abdominal distension or lethargy indicates need for further evaluation and admission.

Abdominal Distension

Abdominal distension usually indicates a serious underlying problem such as sepsis, paralytic ileus, intestinal obstruction or Hirschsprung’s disease. It is uncommon for a well neonate to have abdominal distension. Occasionally, medications used for colic (e.g. antispasmodics) can lead to abdominal distension and constipation.

Bleeding Bleeding can be from any site; it could be skin bleeds, mucosal bleeds (GI bleed) or visceral bleed. The most common cause of gastrointestinal bleed in a neonate is due to hemorrhagic 36 disease of newborn. Skin bleeds usually indicate sepsis, disseminated intravascular coagulopathy (DIC), but in a well



Inconsolable, excessive and incessant crying may indicate severe illness. Stage I hypoxic ischemic encephalopathy (HIE) is one example of a CNS problem presenting as excessive crying. Pain, as in arthritis, sepsis, myocarditis, intracranial bleed and hypoxia can all manifest as excessive cry and irritability in the initial stages of the illness.

ssessment of llness Severity

Severity of illness can be assessed at admission by assessing the physiologic alterations in the baby using the score for neonatal acute physiology and perinatal extension (SNAPPE II). Details of this score have been provided in Table 2.4.4. Scores greater than 15 are usually associated with higher mortality. Neonates who will require high dependency care or shift to a tertiary center will include: • VLBW and ELBW neonates • Any neonate requiring ventilator support • A sick neonate requiring constant monitoring (multiple seizures) • A sick neonate requiring cardiovascular support (shock) • Any sick neonate who needs constant monitoring (refractory hypoglycemia, oliguria) • Suspected or proven IEM. T

ti e

Excessive Crying, Irritability and Restlessness

G R

Inadequate Weight Gain

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extbook of Pediatri T

Table 2.4.3 Respiratory distress (RD) score

riaging Sick Neonates

All neonates should be assessed for emergency signs: • Assess for hypothermia. If present, arrange for rewarming of the baby. • Check for severe respiratory problem and if present, arrange to oxygenate the baby. • Determine if the child is in shock or has encephalopathy or convulsions and if so initiate urgent steps to manage. The triaging process is outlined in Flow chart 2.4.1. Only after initiating emergency measures, proceed to investigate the neonate. Proceed to treat the neonate for underlying disorder based on the clinical examination and investigations.

vip.persianss.ir

T

E

 

Give mergency reatment

Value

Score

Maintain emperature

Mean blood pressure

29 mm Hg 20–29 mm Hg < 20 mm Hg

0 9 19

Core temperature

> 35.6°C 35–35.6°C < 35°C

0 8 15

Place the neonate under a warmer and bring the temperature to 36.5°C–37.5°C. Keep the baby dry, and the head, hands and feet should be covered. Maintain the temperature within this range.

Birth weight

999 g 750–999 g < 750 g

0 10 17

2.49 1–2.49 0.3–0.99 < 0.3

0 5 16 28

Lowest serum pH

7.19 7.1–7.19 < 7.1

0 7 16

Urine output

> 0.9 mL/kg/hr 0.10.9 mL/kg/hr < 0.1 mL/kg/hr

0 5 18

Multiple seizures

No Yes

0 19

Apgar at 5 min

>7 <7

0 18

A

n

Place the child in sniffing position. Place a shoulder roll under the shoulder to position the child. Clear the airway of secretions by suctioning the mouth first and then the nose.

ssist reathing B

PaO2/FiO2 ratio

Maintain the irway

A

0 12

T

Parameter

Small for gestation age (SGA) < 3rd centile No Yes

Care of the Newbor

Table 2.4.4 Score for neonatal acute physiology and perinatal extension (SNAPPE II)

Support the child’s respiration if there is distress. This can be done by using nasal prongs, which can be placed just inside the nostrils and secured with a tape. The flow rate can maintained be around 1–2 L/min. The child could also be placed under an oxygen hood with an oxygen flow rate of 5–8 L/min. The oxygen can be monitored by a pulse oximeter targeting the saturation at 88–93%.

G R

Support Circulation

ti e

V d

If the child is in shock, give an IV bolus of normal saline or Ringer’s lactate at the rate of 10 mL/kg over 20–30 min. Repeat if features of shock persist. Initiate dopamine in a dose of 5–20 µg/kg/min and dobutamine at 5–20 µg/kg/ min if the neonate remains in shock despite fluid boluses.

 

Flow chart 2.4.1 Flow diagram for triaging sick neonates

n U

If any sign is positive: give treatment(s), call for help, and draw blood for emergency laboratory investigations (e.g. Glucose).

37

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1. CRIB Investigators group. The CRIB score: a tool for assessing initial neonatal risk and comparing performance of neonatal intensive care units. Lancet. 1993;342:193-8.









G R

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ibliography



B













• Sick neonates should be triaged for emergency signs immediately at arrival to a health facility. • Initiate emergency treatment first and then do investigations. • After stabilization, take detailed history and clinical examination to determine underlying etiology for sickness and then initiate appropriate specific treatment.

2. Lee KG. Identifying the high risk newborn. In: Cloherty JP, Eichenwald EC, Stark AR (Eds). Manual of Neonatal Care, 6th edition. Lippincott: Williams and Wilkins; 2008. pp. 41-58. 3. Munshi UK. Identifying the newborn who requires special care. In: McLnermy TK (Ed). AAP Textbook of Pediatric Care. New Delhi: Jaypee; 2009.pp.666-73. 4. Richardson DK, Corcoran JD, Escobar GJ, et al. SNAP-II and SNAPPE-II: Simplified newborn illness severity and mortality risk scores. J Pediatr. 2001;138:92-100. 5. Sarkar PK. Evaluation of sick neonate. In: Guha DK (Ed). Guha’s Neonatology. Principles and Practice, 3rd edition. New Delhi: Jaypee; 2005. pp. 481-7. 6. Singh M. Care of the Newborn, 5th edition. New Delhi: Sagar Publications; 1999. 7. Volpe JJ. Neurologic examination. In: Volpe JJ (Ed). Neurology of the Newborn, 5th edition. Philadelphia: Saunders Elsevier; 2008. pp. 121-53.

K

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extbook of Pediatri T

ey Messages

38

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W

B





Low irth

Vikram Datta Table 2.5.1 Etiology of low birth weight (LBW)

Low birth weight has been defined as a birth weight of less than 2,500 g. The prevalence of LBW in India has been reported to range from 21% to 33%. These infants have nearly 40 folds higher risk of mortality compared to normal weight neonates. They also have a higher risk of neonatal morbidities, childhood growth failure and developmental problems.

Preterm birth

Fetal growth retardation

Maternal •  Pre-eclampsia •  Chronic maternal conditions •  Infection •  Drug abuse •  Premature rupture of membranes •  Polyhydramnios •  Iatrogenic Placental •  Placental dysfunction •  Placenta previa •  Abruptio placentae Uterine •  Incompetent cervix •  Uterine malformation Fetal •  Multiple gestation •  Malformations

Maternal •  Anemia •  Hypertension •  Renal disease •  Chronic illness •  Addictions (alcohol and narcotics) Fetal •  Chromosomal disorders •  Intrauterine infections (TORCH) •  Congenital anomalies •  Multiple gestation

tiology

A neonate may be LBW either due to being born prematurely (one-third of all cases) or being intrauterine growth retarded (birth weight less than 10th centile for gestational age—SGA, two-thirds of all cases). The problems that these babies encounter are largely dependent on the cause of LBW. Various maternal risk factors contribute commonly to premature delivery and SGA neonates. The common causes are shown in Table 2.5.1.

Sole Creases

E

Anterior one-third of the sole reveals a deep transverse skin crease in preterm neonates, and in term neonates they are present over the anterior two-thirds.

xternal Genitalia

In males, the scrotum does not have rugae and testes are not descended into the scrotum. In female infants, the labia are widely separated, not covering the labia minora, resulting in the prominent appearance of the clitoris.

Skin The skin of preterm neonate is thin, transparent and gelatinous, whereas that of a term neonate is thick and keratinized.

n



ppearance

In addition, SGA infants have an emaciated look and loose folds of skin because of lack of subcutaneous tissue. These are particularly prominent over the buttocks and thighs. They look alert and often plethoric.

Problems of Low irth

eight

Specific problems of the preterm infants include the following: • Perinatal asphyxia • Temperature instability • Feeding problems due to absence of a coordinated sucking and swallowing reflex and absence of a mature intestinal peristaltic pattern • Hyperbilirubinemia • Pulmonary diseases: Apnea, RDS • Metabolic disturbances: Hypoglycemia, hypocalcemia, hyperkalemia, hypernatremia, hyponatremia and hypo magnesemia • Patent ductus arteriosus • Increase susceptibility to infections 39 • Necrotizing enterocolitis • Retinopathy of prematurity • Intraventricular hemorrhage. ­

Breast nodule measures less than 5 mm in preterm neonates (also in growth retarded newborns) and 5 mm or more in term babies.

The back of the preterm babies has abundant growth of fine hair called lanugo, which are absent or sparse in term neonates.

W

B

reast Nodule

H

B

n U

The external ear or the pinna is soft and devoid of cartilage in preterm neonates and hence, it does not recoil back promptly on being folded. In a term baby, there is instant recoil.

Lanugo air

B

E

Low birth weight can be preterm or intrauterine growth retarded (SGA). The clinical features, which help in recognition of these subtypes are summarized below:

ar Cartilage

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ti e

T

W

R

Clinical ecognition of Low irth eight ypes

G R

A

E



 

Definition

Care of the Newbor

2.5

vip.persianss.ir

 

Table 2.5.2 Fluid requirements of neonates (mL/kg body weight)

eight abies B

B

Management of Low irth

W



Delivery oom Management

Day of life Birth weight > 1,500 g

Birth weight 1,000 to 1,500 g

1

60

80

2

75

95

3

90

110

4

105

125

5

120

140

6

135

155

7 onwards

150

170

R

The delivery room management consists of an expert resu scitation—maintaining good thermoregulation, minimal handling, and use of nasal continuous positive airway pressure (CPAP) and intubation when required for preterm births. Low birth weight neonates who need care in a special care unit include those with birth weight less than 1,800 g, gestation less than 34 weeks, any neonate who is unable to feed from the breast and any sick neonate.

Low birth weight babies are more prone to develop hypothermia due to deficient heat regulatory mechanisms. Soon after delivery, the unclothed baby with the head and feet covered should be placed in between the breasts of the mother in skin-to-skin contact position (Kangaroo mother care). It not only maintains the temperature of the baby but also helps in the prompt initiation of breastfeeding. If the baby requires resuscitation or hospitalization, she may be placed under a servo controlled radiant warmer with the temperature probe attached to the trunk of the baby. In absence of a servo device, the baby should be covered with at least 3–4 layers of clothes, socks, mittens and cap. In a special care newborn unit, the infants may be kept warm using overhead radiant warmer or incubator. Regular monitoring of axillary temperature at least once every 6–8 hours should be carried out in all hospitalized babies. Devices that provide direct heating of the baby like hot water bags, hot air blowers and direct heaters should be avoided. F

luids

If a LBW needs fluids, then in the first 48 hours after birth, neonates less than 1,250 g should be provided 5% dextrose

B

F

E

V d

ti e

n U

G R

eight Neonate

The goal of nutritional management of the LBW infant should be to achieve full enteral nutrition as soon as possible. Breast milk is the best milk for the neonate and the mother should be supported and counseled for the maintenance of regular lactation and the need for expression and its technique. The guidelines for providing enteral feeds to the LBW neonate are summarized in Table 2.5.3. Neonates can undergo gradual transition from gastric feeding to spoon feeding and then onto breastfeeding. In infants less than 34 weeks, transition from tube to breast can be facilitated by allowing the infant to suck on empty breast of mother (nonnutritive sucking) before each gavage feeding session. Daily assessment of the sucking efforts of the neonate will provide indication of when and how fast the transit from one mode to another mode of feeding should be undertaken.

T

hermoregulation

nteral eeding of the Low irth

W

and those more than 1,250 g should receive 10% dextrose. The fluid requirements volumes are given in Table 2.5.2. Sodium and potassium should be added after 48 hours or earlier if there is more than 6% weight loss from the birth weight in the first 48 hours.

­

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extbook of Pe iatri T

• • • • • • •

Specific problems of SGA infants include the following: Perinatal asphyxia Meconium aspiration syndrome Infections Hypoglycemia Polycythemia Hypothermia Dysmorphology.

Monitoring for Feed Intolerance The signs of feed intolerance are: an increase in the abdominal girth by more than 2 cm from the baseline, vomiting of feeds and a prefeed residue of greater than 25–50%. Presence of such signs in the baby may prompt a cessation of feeding and initiating investigation into the cause of feed intolerance.

 

Table 2.5.3 Guidelines for the modes of feeding for low birth weight (LBW) neonates

40

Birth weight (g) Gestation (week) Condition

< 1,200 < 30

1,200–1,800 30–34

> 1,800 > 34

Initial

Intravenous fluids; Try gavage feeds if not sick

Gavage

Breastfeeding; if unsatisfactory, give spoon or paladai feeds

After 1–3 days

Gavage

Spoon or paladai feeds

Breastfeeding

Later (1–3 weeks)

Try spoon or paladai feeding

Breastfeeding

Breastfeeding

After some more time (4–6 weeks)

Breastfeeding

Breastfeeding

Breastfeeding

vip.persianss.ir

Vitamin and Mineral Supplementation

F

Low birth weight neonate can be considered for discharge if the infant has had a smooth transition to breastfeeding or breast and spoon/paladai feeds, is gaining weight consistently for at least 3 days, maintains temperature when being cared with mother, is not receiving any oxygen





K





B







Discharge Policy

1. Agostoni C, Buonocore G, Carnielli VP, et al. Enteral nutrient supply for preterm infants: commentary from the European Society for Pediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition. J Pediatr Gastroenterol Nutr. 2010;50(1):85-91. 2. Bombell S, McGuire W. Early trophic feeding for the very low birth weight infants. Cochrane Database Syst Rev. 2009;(3):CD000504. 3. Lucas A, Fewtrell M. Feeding low birth weight infants. In: Rennie JM (Ed). Roberton’s Textbook of Neonatology, 4th edition. Edinburgh: Churchill Livingstone, 2005. pp. 314-24. 4. Papageorgiou A, Pelausa E, Kovacs L. The extremely low birth weight infant. In: Mhairi G MacDonald, Martha D Mullett, Mary M K Seshia (Eds). Avery’s Neonatology: Pathophysiology and Management of the Newborn, 6th edition. Lippincott: Williams and Wilkins; 2005. pp. 461-89.



I

Avoid routine oxygen administration, prophylactic use of IV immunoglobulins, antibiotics, indomethacin or high doses of vitamin E. Unnecessary blood transfusions (maintain hematocrit above 35% in sick newborns), formula feeds and rough handling, excessive light and sound should be avoided.

ibliography





A

hat to void

V d

ey Messages

• Care for LBW babies at health facilities where optimum care can be provided. • Provide breast milk to all LBW babies. Those who have poor sucking feeding by gavage or use spoon or paladai to assist feeding of expressed breast milk is recommended. • Use adequate vitamin (vitamin D) and minerals (calcium, phosphorus and iron) supplements till at least 12 months of age. • Use Kangaroo mother care at hospital and also train families to provide the same after discharge from hospital at home. • Follow-up LBW for growth, development (especially vision and hearing) and illness till at least 12–18 months of age.

ti e

n U

G R

Mortality of LBW babies is directly related to the birth weight and gestational maturity. Lesser the weight and gestation, the poorer the prognosis. In general, over 90% of all LBW babies have no major neurodevelopmental handicaps.

dequacy of Nutrition

All vaccines should be administered as per schedule according to the chronological age irrespective of birth weight or period of gestation. Hepatitis B, BCG and birth dose of oral polio vaccine (OPV) and can be safely and effectively given to LBW or preterm babies after stabilization. W

Prognosis

n

B

F A

According to the Cochrane review, multicomponent human milk fortification leads to short-term increase in weight gain, linear growth and head circumference growth. There is still insufficient evidence in contemporary literature to recommend routine fortification of human milk. The cost, greater risk of contamination and theoretical risk of hypercalcemia are some factors, which are to be borne in mind before prescribing human milk fortifier to LBW infants.

mmunization

ollow-up Protocol

After discharge from the hospital, babies should be regularly followed up and screened for the following parameters: • Feeding and nutrition • Anemia and osteopenia • Growth and development: Neurobehavioral problems • Immunization • Retinopathy of prematurity, vision, strabismus and hearing • Problems resulting from previous morbidities, e.g. bronchopulmonary dysplasia.

ortification of Preterm reast Milk

The key measure of optimal feeding is the weight pattern of the baby. A preterm LBW baby loses up to 1–2% weight every day amounting to 10% cumulative weight loss during the first week of life. Birth weight is regained between 10th day and 14th day. Babies start gaining weight by the second week of life at the rate of about 15–20 g/day and this is considered adequate. Excessive weight loss or inadequate weight gain indicates inadequate feeding, cold stress, excessive insensible water loss or systemic illness (like anemia, sepsis, late metabolic acidosis, etc.).

Care of the Newbor

Supplementation should be started as soon as the infant is receiving at least 120–150 mL/kg of enteral feeds. All preterm should receive daily supplement of 400 IU of vitamin D and 120–140 mg/kg/day (110–130 mg/100 kcal) of highly bioavailable calcium with 60–90 mg/kg/day (55– 80 mg/100 kcal) of phosphate is recommended. At 4 weeks of age, iron supplements should be started in a dose of 2–3 mg/kg/day. At present there is no evidence for routine zinc supplement or protein fortification of breast milk.

or antibiotics, and the mother is confident in handling the baby. Assessment of the home environment prior to discharge may be particularly useful in cold climates.

41

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Parent ounseling Ranjan Kumar Pejaver

Parent counseling is the process of providing assistance and guidance by giving information to the parents at various points during the perinatal period. It is the art of presenting facts enabling the parents to make the decisions.

regarding possible sequelae, further continuation of care or withdrawal of care. C

Predischarge ounseling

Preconception

B

There is a history of recurrent pregnancy loss, stillbirths or neonatal deaths. Parents would want to know why that has happened and is there a way of preventing it in the next pregnancy.

Neonatal Period Preterm infant has had a stormy stay in the intensive care unit resulting in severe damage to various organ systems. 42 Intact survival is unlikely. Parents may need information



­



ounseling: pecific Technical spects A

Baby needed extensive resuscitation, has survived and what are the repercussions. Baby is extremely LBW or premature, or in case of antenatally undiagnosed abnormalities, parents may need information regarding the management and prognosis.

S

D

mmediately fter elivery A

I

Baby is receiving extensive resuscitation and does not seem to be responding. They may need counseling regarding continuation/stopping of resuscitation measures.



S

A

D

A

It has revealed some congenital abnormality or findings like growth restriction, oligo- or polyhydramnios and need for information regarding the seriousness of the same and fate of the current pregnancy and the fetus.

t elivery

V d

C

n U

bnormal ntenatal Ultrasound can

The counseling should be conducted in a quiet and comfortable room. It should be conducted by a senior member of the team. It is preferable that the session is conducted in a language the parents understand. If necessary, a reliable interpreter may be used. It should be done in strict privacy, preferably with both parents being present. Some key decision makers in the family or supportive elders may be allowed to be present with permission of the parents. It is good to involve nurses and other specialists who are involved or likely to be involved in the care of the infant. Counseling should be nondirective and nonjudgmental. Be careful not to hurt the local, traditional, family, cultural and religious sentiments of the parents. Provide information in simple, nontechnical language. The depth of the infor mation should be commensurate with the educational level and the understanding ability of the listeners. Be patient, be ready to repeat the advice, give time to the parents to understand, think and then convey the decisions. Calmly answer the queries and be sympathetic. As they are overwhelmed by the situation, they are confused, less receptive and may not be able to quickly process the information given. If there is any written material relevant to the discussion, it is helpful and may be given to the parents. It is a good habit to summarize the discussion and decisions arrived at; write it down and take the signatures of the parents after they have read it. Signatures of the counselor and witness are also important.

D

A A

Parents are of extreme ages and may be suffering from conditions like severe diabetes, hypertension and systemic diseases. Parents would like to know how the next pregnancy and baby will be affected by these diseases.

C

C

General Principles of Parent ounseling

ti e

ge and Health of Parents

G R

If a baby has demised or stillbirth has occurred.

Health of Previous hild Previous child of the parents or any members of the immediate family of either of the spouses suffering from inherited disorder, congenital abnormalities, developmental delay and dysmorphic features. Parents would like to know information like what are the chances of the next pregnancy resulting in the same.

ereavement ounseling C

Which Parents Need ounseling?

Parents of NICU graduates would need information regarding danger signs to watch out, follow up plans and other instructions like feeding, medications, immunizations, etc. or in case of postoperative state. Parents need information regarding home care and any follow-up procedures—timing, cost and prognosis.

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2.6

iagnosis

Wherever applicable, diagnosis should be known as far as possible. Where it is not known, the same should be

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S

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B









1. American Academy of Pediatrics Committee on Fetus and Newborn. The initiation or withdrawal of treatment for highrisk newborns. Pediatrics. 1995;96:362-3. 2. Baker K, Kuhlman T, Magliaro B. Homeward bound: discharge teaching for parents of newborns with special needs. Nursing Clin North Am. 1989;24(3):655-64. 3. Freer Y, Lyon A, Stenson B, et al. BabyLink—improving communication among clinicians and with parents with babies in intensive care. Br J Healthcare Comput Inform Manag. 2005;22(2):34-6. 4. Harmon RJ, Glicken AD, Siegel RE. Neonatal loss in the intensive care nursery: Effects of maternal grieving and a program for intervention. J Am Acad Child Psychiatry. 1984;23:68-71. 5. Leslie L, Harris LL, Douma C. End-of-life Care in the NICU: a family-centered approach. NeoReviews. 2010;11:e194-e199. 6. Munson D. Withdrawal of mechanical ventilation in pediatric and neonatal intensive care units. Pediatr Clin North Am. 2007;54:773-85.



ibliography



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S

This is devastating to the family. There is a feeling of loss, guilt, shame, inadequacy and anger in the parents. Compassionate counseling is required stressing on the point that neither of the parent is responsible for it. It may be essential that a diagnosis be arrived at in view of future pregnancies even it may not help in the current one. Especially if genetic disorders or metabolic defects are suspected, investigations such as chromosomal

• Parents need counseling at several stages of perinatal period. It is the responsibility of care providers to support parents to make informed choices. • Counseling should be conducted by trained personnel respecting the privacy of families. • Counseling should be nonthreatening, nontechnical but supportive.



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Pregnancy Loss, tillbirth, eath of a Neonate

ey Messages

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Withdrawal of are

n U

G R K

Resuscitation is not successful all the time. Discontinuation is justified if there are no signs of life (no heart beat and no spontaneous respirations) after 10 minutes of full resuscitation. Parents should be informed if possible about the progress and status of the baby at various steps. In major congenital abnormalities incompatible with life, discussion with parents is essential before taking decision to discontinue resuscitation. A concurrence of another colleague is ideal.

The same applies to question of parental request for withdrawal of care in babies receiving intensive care, having multiple organ systems involved, with remote possibility for ultimate survival or likelihood of severe neurological sequelae is almost certain. Clinical indicators, laboratory investigations and imaging studies showing bad prognostic signs should be documented and shown to parents. Decisions like “do not resuscitate”, “withdrawal of care” and “discharge against medical advice by parents” warrant due deliberation, proper documentation and authorized personnel’s and parents’ concurrence in black and white. Legal sanction for any of the above does not exist at present time!

w



esuscitation



R

It should be known and quoted where necessary, e.g. survival percentage of very LBW infants and premature infants. It will guide the parents to decide roughly on the outcome and whether to seek transfer to higher centers if available.



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S

tatistical ata upports

e Ne bor

Family history, pedigree construction, knowledge of the prevalence of the disorder, modes of inheritance and recurrence chances should be ascertained.

n

A

C

ounseling on Genetic spects

analysis, autopsy, infantogram, clinical photographs, tissue biopsy, blood and other body fluid analysis should be done. Informed consent of parents is needed for this. In cases of neonatal deaths, a meeting with the parent should be arranged after a few weeks when they would be more receptive having gone through the stages of bereavement and results of all investigations are available to have a more fruitful counseling. Future reproductive options, perinatal preventive strategies like folic acid consumption, investigations, antenatal management as “high-risk” pregnancy, planning of delivery and neonatal care could be discussed. Visits by a social worker to the abode of the unfortunate couple at least during the first few months after the tragedy to counsel will be very beneficial. Parental counseling is an important aspect of perinatal care. It should be given its due priority. It is ideal that every unit has a person who has had some formal training in counseling.

are of

conveyed to the parents. If a visit to higher center would be helpful, then sufficient information about that should be supplied.

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Neonatal Hyperbilirubinemia

efinition

 

Table 2.7.1 Causes of indirect (unconjugated) hyperbilirubinemia

tiopathogenesis

Hyperbilirubinemia is the result of an imbalance between bilirubin production and its elimination. In majority, early neonatal jaundice is due to rise in unconjugated (indirect) bilirubin. The etiological basis for progressive hyperbilirubinemia is usually multifactorial. Table 2.7.1 summarizes the important causes.

R

B

Jaundice within 24 hours of life, peak bilirubin greater than 15 mg/dL and persistence beyond 2 weeks are not physiologic and needs to be investigated. Rate of rise of bilirubin greater than 0.5 mg/dL/hour or bilirubin level greater than 25 mg/dL increase the risk of bilirubin toxicity in neonates. Bilirubin is a potential neurotoxin. Areas of the brain most commonly affected are the basal ganglia and brainstem nuclei for oculomotor and auditory function. Bilirubin toxicity or kernicterus can cause permanent sequelae characterized by tetrad of choreoathetoid cerebral palsy, high frequency central hearing loss, vertical gaze palsy and dental enamel hypoplasia. A

linical ssessment

All newborns should be examined for jaundice at least once a day during the first 72 hours. Jaundice is assessed 44 by inspecting the baby’s skin, sclera or mucous membranes





E

D

ssessment in Neonates ischarged arly

All newborns should be assessed for presence of risk factors at the time of discharge (Table 2.7.2). The more risk factors present, the greater the risk of severe hyperbilirubinemia, and the risk is extremely low if risk factors are absent. If neonates are discharged within 24 hours, those with risk factors should be seen within 24–48 hours, and those without risk factors within 72 hours of discharge. If facilities are available then serum bilirubin can be estimated by use of transcutaneous bilirubinometer on each of these visits.

Table 2.7.2 Risk factors for significant hyperbilirubinemia  

n U

Nonphysiologic Jaundice and isk of ilirubin Toxicity

V d

ti e

The functional immaturity in bilirubin metabolism viz. increased enterohepatic circulation, increased fetal erythrocyte breakdown, decreased hepatic excretion and immature hepatic conjugation predisposes to early jaundice which is transient, requiring no treatment. It usually appears after 24 hours, peaks between 3 days and 5 days in term and 5–7 days in preterm and disappears by 2 weeks of life. The peak bilirubin is under 15 mg/dL.

G R

preferably in natural light. The skin is blanched by digital pressure over bony parts to reveal underlying yellowing. Jaundiced newborns should also be examined for bruising, cephalhematoma, lethargy, vomiting, excessive weight loss, pallor, plethora and hepatosplenomegaly. Abnormality in tone, cry or sensorium should alert to possibility of bilirubin neurotoxicity. In infants presenting with jaundice extending beyond 2 weeks, one must enquire for pale or white stools, which may indicate obstructive jaundice such as biliary atresia. A

Physiological Jaundice

C

•    •    •    •  •   

Physiological jaundice Breastfeeding jaundice, breast milk jaundice Increased production –  Blood group incompatibility (Rh, ABO, minor blood group) –  RBC membrane defects (hereditary spherocytosis, elliptocytosis) –  RBC enzyme defects (G6PD deficiency, pyruvate kinase deficiency) Disorders of bilirubin uptake –  Gilbert’s syndrome Disorders of conjugation –  Crigler-Najjar Types I and II, hypothyroidism, pyloric stenosis Enhanced enterohepatic circulation –  Small or large bowel obstruction or ileus Idiopathic Others –  Prematurity, sepsis, polycythemia, infant of diabetic mother, extravascular blood (cephalhematoma, bruising) 

•  •  •       

Hyperbilirubinemia is a common neonatal problem. It is defined as an increased level of bilirubin in the circulation. A small proportion of these neonates develop jaundice that is significantly high to warrant treatment. Approximately, 60% of term and 80% of preterm babies develop jaundice during the first week of life. About 5% develop pathological jaundice. Studies suggest the possible impact of genetic polymorphisms on ethnic variation in the incidence and severity of jaundice.

•  •  •  •  •  •  • 

Primipara mother Visible jaundice at discharge Gestation < 38 weeks History of jaundice requiring treatment in previous sibling ABO/Rh incompatibility Geographic prevalence for G6PD deficiency Weight loss at discharge > 3% per day or > 7% cumulative weight loss. 

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Rhishikesh Thakre

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2.7

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n

Treatment of Unconjugated Hyperbilirubinemia The decision making in jaundice management is based on gestation, weight, well-being and age of the infant. Tables 2.7.4 and 2.7.5 provide guidelines of how to decide if an infant needs treatment—phototherapy (PT) or exchange transfusion (ET).

 

Table 2.7.3 Investigations for significant hyperbilirubinemia •  •  •  •  •  •  • 

e Newbor

In all neonates with jaundice that is not considered physiologic, investigations need to be done to assess the severity of jaundice (for planning treatment) and etiology of the jaundice. Table 2.7.3 summarizes the important investigations that need to be done. Cord blood is collected for typing the baby blood group if mother’s blood group is Rh negative or O Rh positive or blood group is not known. If an Rh negative mother has an Rh positive baby, the cord blood is subjected to direct Coombs test, total serum bilirubin (TSB), reticulocyte count, peripheral smear and hemoglobin.

th

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I

End-tidal carbon monoxide measurement (ETCO) in exhaled air may serve as indirect marker of ongoing hemo lysis as equimolar concentrations of CO and bilirubin are formed following breakdown of RBC. Synthetic heme analogs, metalloporphyrins, are competitive inhibitors of heme oxygenase and their use has been proposed as an attractive alternative strategy for preventing or treating severe hyperbilirubinemia.

nvestigations

Total and direct bilirubin Mother and baby blood group Hemoglobin or packed cell volume (PCV) Peripheral blood smear (for RBC shape and evidence of hemolysis) Reticulocyte count Direct Coombs test (if mother is “O” or Rh negative) G6PD assay

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Phototherapy

Phototherapy is the mainstay of treatment. When bilirubin is exposed to blue light (in the range of 420–480 nm), it undergoes change in structure to a product called lumirubin, which can be excreted in the urine without undergoing conjugation in the liver. The efficacy of PT depends on spectrum of light (460–480 nm), irradiance (8–30 mW/cm2/nm) and surface area of infant’s skin exposed to light. The choice of device depends upon the severity of jaundice. For majority of infants, standard PT (six special blue lights of Philips TL 52, 20 W each) is effective. When the

V d

Sick infant with jaundice or prolonged jaundice (> 3 weeks) •  Complete blood count •  Urine examination and culture •  Evaluate for infection as indicated •  Urine for reducing substances •  Thyroid profile (T4, TSH) •  Evaluate for cholestasis (if direct bilirubin is elevated)

ti e

 

Table 2.7.4 Treatment guidelines for jaundiced neonates with less than 35 weeks of gestation Birth weight (g)

n U

Phototherapy (mg/dL)

Healthy infant

< 1,000

5–7

1,001–1,500

7–10

1,501–2,000

10–12

2,001–2,500

Exchange transfusion (mg/dL)

Sick infant

12–15

4–6

Variable

6–8

Variable

8–10

Variable

10–12

Variable

 

Table 2.7.5 Treatment guidelines for jaundiced neonates born at or greater than 35 weeks of gestation (beyond 24 hours) Total serum bilirubin levels (mg/dL)

Low risk

Medium risk

High risk

≥ 38 weeks and well

≥ 38 weeks + risk factors* or 35–37 6/7 weeks and well

35–37 6/7 weeks + risk factors*

Age (hours)

PT

Intensive PT

ET

PT

Intensive PT

ET

PT

Intensive PT

ET

24

9

12

19

7

10

17

5

8

15

48

12

15

22

10

13

19

8

11

17

72

15

18

24

12

15

21

10

13

18.5

96

17

20

25

14

17

22.5

11

14

19

> 96

18

21

25

15

18

22.5

12

15

19

i

*Risk factors: soimmune hemolytic disease, G6PD deficiency, asphyxia, significant lethargy, temperature instability, sepsis, acidosis or albumin less than 3.0 g/dL Abbreviations: PT, Phototherapy; ET, Exchange transfusion

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Table 2.7.6 Causes of conjugated (direct) hyperbilirubinemia



Administering Phototherapy

•  Bacterial sepsis •  Neonatal hepatitis   –  Toxoplasmosis, cytomegalovirus, rubella, herpes, syphilis, parvovirus B19 •  Biliary obstruction   –  Biliary atresia, choledochal cyst, inspissated bile plug •  Metabolic disease   –  Hypothyroidism, galactosemia, alpha-1-antitrypsin deficiency •  Genetic disease   –  Dubin-Johnson syndrome, Rotor syndrome, cystic fibrosis, Alagille syndrome •  Others   –  Drugs, cholestasis associated with total parenteral nutrition •  Idiopathic

Phototherapy is administered continuously and interrupted only for nursing and feeding purpose. The infant is placed naked with genitalia and eyes covered. Close attention is paid to the infant’s temperature, daily weight and intake output. Breastfeeding is continued frequently. Hypoxia, hypothermia, hypoglycemia, acidosis and sepsis need to be prevented, and if present, treated aggressively. Intravenous fluids are given only to infants who have inadequate oral intake, significant weight loss (> 10%) or are dehydrated.



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bilirubin is rapidly rising or nearing ET range, intensive PT [using high-intensity light-emitting diodes (LED)] lights or double surface standard PT tubes) is provided.

Monitoring

Prevention

V d

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I

ntravenous mmunoglobulin

Practice Points and Tips •

•

Treatment of irect Hyperbilirubinemia

•

D

Intravenous immunoglobulin (IVIG) 500 mg/kg is used when serum bilirubin is rising despite intensive PT or the value is within the ET range in antibody-mediated hemolysis (Rh, ABO) settings.

•

ey Messages

46







• Neonatal hyperbilirubinemia is usually multifactorial in origin. • The most common cause of neonatal hyperbilirubinemia is physiological jaundice, which is a diagnosis of exclusion. • Conjugated hyperbilirubinemia is always pathological, and expert help should be sought early, especially to identify biliary atresia. • Systematic approach in the form of clinical evaluation, assessment of risk factors and interpreting bilirubin with age in hours paves way to rational management.



­

Direct hyperbilirubinemia (Table 2.7.6) is defined as conjugated bilirubin level greater than 2 mg/dL or 15% of the TSB. It is an uncommon but potentially serious condition that indicates hepatobiliary dysfunction. Evaluation should include total and direct bilirubin, urine examination and urine culture, evaluation for infection (as indicated) and thyroid profile. Further evaluation should be tailored with expert consultation to rule out surgical cause. Treatment is directed at the specific underlying cause if any, and remains largely supportive with diet rich in calories, medium chain triglycerides, adequate proteins, and supplementation of fat and water-soluble vitamins. Early detection and diagnosis are important for successful treatment for a favorable prognosis.

Hyperbilirubinemia may develop both in the absence of identifiable risk factors and without clinically significant jaundice having been present at the time of discharge. Hence clinicians should remain alert for jaundice during first postnatal week. Do not rely on visual inspection alone to estimate the bilirubin level in a baby with jaundice. Interpret bilirubin levels according to the infant’s age in hours. Do not subtract conjugated bilirubin from TSB when making decisions. K

ti e





xchange Transfusion

Exchange transfusion is indicated for infants whose bilirubin levels cross the threshold indicated in Tables 2.7.4 and 2.7.5 or those who have clinical features of bilirubin encephalopathy. During ET, twice the infant’s blood volume (160 mL/kg) is exchanged; this procedure can decrease the bilirubin level by approximately 50%. The procedure is invasive and carries a small risk of complications (1– 5%)—fluid overload, infection, electrolyte imbalance, hypoglycemia, thrombocytopenia, thrombosis and death. I

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1. Test during pregnancy for ABO and Rh blood types and provide appropriate prenatal care. 2. Assess all infants for risk factors for jaundice prior to discharge, and re-evaluate on day 3–5 when the bilirubin level is highest. 3. Inform parents to look for jaundice and report if there are any concerns. 4. Provide appropriate support and advice to breastfeeding mothers. 5. Follow-up neonates with severe jaundice for hearing loss and other neurodevelopmental sequelae.

E

Total serum bilirubin is monitored every 4–12 hours depending on patient’s age and bilirubin level. Phototherapy is usually discontinued when TSB levels reach a level below PT threshold (Tables 2.7.4 and 2.7.5). It should not be used to treat infants with conjugated hyperbilirubinemia because of the risk of bronze baby syndrome.

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B

e Newbor

1. American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114(1):297-316. 2. Bell R, Bhutani VK, Bollman DL, et al. (2005). Severe hyperbilirubinemia prevention toolkit, California Perinatal Quality Care Collaborative (CPQCC). [online] Available from http://www.cpqcc.org/quality_improvement/qi_toolkits/ severe_hyperbilirubinemia_prevention_rev_october_2005 [Accessed July, 2011].

3. Guruprasad G, Chawla D, Aggarwal S. (2010). Management of neonatal hyperbilirubinemia. In: NNF Clinical Practice Guidelines. [online] Available from http://nnfpublication.org/ Uploads/Articles/0b79b423-4675-4420-98e6-5d14dd6fceaa. pdf [Accessed July, 2011]. 4. Kaplan M, Wong RJ, Sibley E, et al. Neonatal jaundice and liver disease. In: Martin RJ, Fanaroff AA, Walsh MC (Eds). Fanaroff and Martin’s Neonatal-Perinatal Medicine: Diseases of the Fetus and Infant, 9th edition. Philadelphia: Mosby Elsevier publications; 2011. 5. Yaccha SK. Consensus report on neonatal cholestasis syndrome. Indian Pediatr. 2000;37:845-51.

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ibliography

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Neonatal nfections I





t

Naveen Jain –

Suspected (clinical syndrome like perforation of viscus, petechial or purpuric rash, chest X-ray consis tent with pneumonia or white cells in normally sterile fluid). ­

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efinition

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2.8

pidemiology

•

-

• • • •

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O

E

Maternal fever (> 37.8°C) in the period from onset of labor to delivery Prolonged rupture of membranes (PROM) for more than 18 hours Spontaneous preterm (< 37 weeks) onset of labor (SPTOL) Preterm (< 37 weeks) premature rupture of membranes (pPROM) Maternal sepsis, urinary tract infection (UTI) or diarrhea within 7 days to the date of delivery Clinical chorioamnionitis in the mother.

E

S

O

tiological gents acteria

Common pathogens in India are Klebsiella, Staphylococcus, Escherichia coli and Pseudomonas. This is very different from the developed nations where Group B streptococci, coagulase negative staphylococci (CONS) and fungi dominate.

–



–

F

–

–

–

–

–

–

B

Low birth weight Babies admitted to NICU and undergoing invasive procedures (ventilation, parenteral nutrition through central catheters, not feeding orally, admission to inadequately staffed units, poor compliance to unit policy on prevention of infections).

A

–

-

– –



isk actors for Late nset Neonatal epsis F

R

• •

-

-

-

-

–

-

-

-

•

isk actors for arly nset Neonatal epsis F

R

Classically sepsis has been differentiated into early onset neonatal sepsis (EONS) and late onset neonatal sepsis (LONS) based on onset before 72 hours of life or after. These two types of sepsis have different risk factors or settings.

-

-

–

-

–



E

t

Sepsis in the newborn is defined when it meets the following criteria: (1) any two clinical signs and (2) any two laboratory signs, (3) in the presence of or as a result of suspect or proven infection (European Consensus statement 2010). 1. Any two clinical signs: – Temperature instability - Core temperature greater than 38.5°C or less than 36°C – Cardiovascular instability - Tachycardia (heart rate 180 beats/min) in the absence of external stimulus or pain or drugs, i.e. “unexplained” increase in heart rate for 0.5–4 hours - Bradycardia (heart rate 100 beats/min) for 0.5 hours in the absence of heart block, external vagal stimulus, beta-blockers - Rhythm disturbances - Reduced blood pressure (systolic BP less than 65 mm Hg in first week and less than 75 mm Hg between 1 week and 1 month) - Mottled skin and impaired peripheral perfusion - Decreased urine output (less than 1 mL/kg/hour) – Respiratory instability - Apneic episodes - Respiratory rate greater than 2 SD (> 50 beats/ min in first week and 40 beats/min between 1 week and 1 month) - Increased oxygen need - Ventilation for acute process for causes other than neuromuscular or general anesthesia – Gastrointestinal - Feed intolerance, abdominal distension, poor sucking – Petechial rash or sclerema – Nonspecific: lethargy, irritability, hypotonia 2. Any two laboratory tests: – Abnormal leukocyte count (> 20,000 × 109/L or less than 4000 × 109/L) – Immature to total neutrophil (I/T) ratio (> 0.2) – Platelet count less than 100,000 × 109/L – C-reactive protein (CRP) greater than 15 mg/L – Procalcitonin (PCT) greater than 2 ng/mL – Metabolic acidosis; base excess (BE) greater than –10 – Blood sugar greater than 180 mg/dL or less than 45 mg/dL confirmed at least two times on ageappropriate infusions 3. Evidence of infection: – Proven (positive culture or microscopy or polymerase 48 chain reaction)

ungi

Fungal infections are more common in babies weighing less than 1,500 g and are likely to be associated in babies with parenteral nutrition, central catheters, abdominal surgeries, broad-spectrum antibiotics or steroids. Both Candida albicans and non-albicans are isolated.

vip.persianss.ir

Herpes infection should be considered in a baby with sepsis like syndrome (presenting after 1 week of life) if markers of bacterial infection are negative. Other viral infections that neonates can be exposed to include chickenpox, vertically transmitted rubella and cytomegalovirus infections.

Procalcitonin is a promising screening tool but the cost and availability are still limited. For the diagnosis of LONS, the PCT test showed better accuracy than the CRP test. Procalcitonin rises earlier in the course of infection.

Parasites

Although the gold standard, blood culture can be negative in infected neonates due to prior use of antibiotics, sampling issues or poor laboratory resources. The value of cultures lies mostly in guiding antibiotic changes in treatment failures and planning antibiotic policy for empiric therapy in that population.

Clinical features of systemic sepsis can be varied and nonspecific and have been described above under definition of sepsis. In neonates with systemic signs of sepsis, presence of convulsions, neck retraction or bulging fontanel must raise the possibility of meningitis. Neonates with septic arthritis or osteomyelitis may not have systemic symptoms and may present with painful limb movement and localized swelling with signs of inflammation. I

Localized nfections

iagnosis

ematological ndices I

H

t n

C

E

F

Meningitis requires modifications in the choice of antibiotics, dose and duration, and hence cerebrospinal fluid examination must be performed in all symptomatic neonates or CRP/ blood culture positive neonates on antibiotics. Cerebrospinal fluid cytology of greater than 30 cells (more than 50% polymorphs), with raised protein (> 100 mg/dL) and/or sugar less than 30 mg/dL may suggest meningitis.

Urine ulture It should be done in infants with failure to thrive, prolonged jaundice and fever since these could be features of UTI. In all infants with obstructive uropathy who are ill, urine cultures should be done. Samples for cultures should be collected by suprapubic puncture.

Total leukocyte count (TLC) has to be interpreted against age-specific normative data (Monroe, Zipurusky). The values as high as 24,000 and as low as 5,000 may be normal and do not suggest infection. Immature to total neutrophil (I/T) ratio (> 0.2) and absolute neutrophil counts have higher specificity, but are often normal early in the course of infection. R

- eactive Protein

C-reactive protein has value in ruling out infection. Once started on antibiotics on clinical suspicion, two negative CRPs 24 hours apart after the baby is asymptomatic gives 99% confidence to stop antibiotics. Also in settings of EONS where antibiotics are started empirically, CRP at 48–72 hours helps in differentiating infected sick infants from those symptomatic due to noninfectious causes. A positive CRP is usually a value greater than 10 mg/L.

A

Treatment

Neonatal sepsis is a serious disease and early diagnosis and treatment is crucial. Currently available tests like total white blood cell count, immature/total ratio and CRP do not have the ability to correctly identify or confirm sepsis early. There are newer tests like interleukin-6 (IL-6) and PCT, but they too have been disappointing.

C

erebrospinal luid xamination

ntibiotics

The indiscriminate use of broad-spectrum antibiotics without appropriate blood cultures and the practice of not stopping their use when no infection is documented have resulted in high antibiotic resistance rates amongst organisms isolated in India. The current data published from India suggests cefotaxime must be avoided as an empiric antibiotic. There is also high resistance to ampicillin and gentamicin. Some evidence suggests that use of amikacin and piperacillin-tazobactam may have low failure rates. There may be a justification in using cloxacillin if the incidence of Staphylococcus is high in a given set-up. Antibiotics like carbapenems and vancomycin should be treated as reserve drugs and be used only if primary treatment plan fails. The recommended duration of antibiotic therapy for uncomplicated culture positive neonatal sepsis (no meningitis, bone and joint or staphylococcal infections) is 7–10 days. Antibiotics may be stopped at 2–3 days in babies in whom these were started empirically, when cultures and CRP are negative and there is improvement symptomatically. In neonates with meningitis or staphylococcal sepsis, the duration of treatment may be 2–3 weeks and for up to 4–6 weeks in bone infections.

D

Infections of the eye (purulent discharge), umbilicus (pus discharge and/or erythema of surrounding skin) and pustules are superficial infections.

lood ulture

C

ystemic nfections I

S

Infection can be local or systemic.

C

F

C

linical eatures

are of he Newbor

Common parasitic infections that neonates can be exposed include toxoplasmosis, malaria and syphilis.

C

Procalcitonin

B

Viruses

49

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Intravenous Immunoglobulins There is no proven benefit of IVIG in prevention or treatment of neonatal sepsis (INIS trial). This expensive blood product is not without side effects. Its expensive “off label” use for expected benefits must be discouraged.

•

•

50

Use appropriate drug doses and schedules; refer drug formularies for right diluents, storage, interactions and adverse events expected.















Practice Points and Tips



S

Prevention of epsis Sepsis in the neonate can be prevented by promoting exclusive breastfeeding and simple hand hygiene at the household level and also by preventing applications on the umbilical cord during the first few days of life. Hospital acquired infections can be minimized by goof hand hygiene, promoting provision of breast milk to sick LBW neonates, good adherence to asepsis protocols and strict antibiotic policy that limits its use when required.



Sepsis remains the leading cause of neonatal mortality world over. In the acute phase, hypoglycemia, coagulopathy, organ failures like pneumonia, pulmonary hypertension, shock due to myocardial dysfunction and capillary leaks, renal failure and cholestatic jaundice are not uncommon with Gramnegative sepsis. Meningitis can result in complications such as hydrocephalus and developmental delay.



C

omplications



C

S

upportive are Sepsis is a multiorgan disease that can result in death and disability. Antibiotics alone cannot change the outcome. Supportive care includes ventilation, inotropes, blood products, glucose, and acid-base monitoring and correction, and is the most important determinant of outcome.



Pentoxyphylline and recombinant human activated protein C have been tried, but with no demonstrated benefits.

1. Craft AP, Finer NN, Barrington KJ. Vancomycin for prophylaxis against sepsis in preterm neonates. Cochrane Database Syst Rev. 2000;(2):CD001971. 2. Darmstadt GL, Miller-Bell M, Batra M, et al. Extended-interval dosing of gentamicin for treatment of neonatal sepsis in developed and developing countries. J Health Popul Nutr. 2008;26(2):163-82. 3. Foster J, Richards R, Showell MG. Intravenous in-line filters for preventing morbidity and mortality in neonates. Cochrane Database Syst Rev. 2006;(2):CD005248. 4. Hofer N, Müller W, Resch B. Non-infectious conditions and gestational age influence C-reactive protein values in newborns during the first 3 days of life. Clin Chem Lab Med. 2011;49(2):297-302. 5. Isaacs D. Unnatural selection: reducing antibiotic resistance in neonatal units. Arch Dis Child Fetal Neonatal Ed. 2006;91(1):F72-F74. 6. Lubell Y, Ashley EA, Turner C, et al. Susceptibility of community-acquired pathogens to antibiotics in Africa and Asia in neonates-an alarmingly short review. Trop Med Int Health. 2011;16(2):145-51. 7. McClure EM, Goldenberg RL, Brandes N, et al. The use of chlorhexidine to reduce maternal and neonatal mortality and morbidity in low-resource settings. Int J Gynaecol Obstet. 2007;97(2):89-94. 8. Rossi P, Botgros R. (2010). Report on the expert meeting on neonatal and pediatric sepsis. [online] EMA. Available from http://www.ema.europa.eu/docs/en_GB/document_library/ Report/2010/12/WC500100199.pdf [Accessed September 2012]. 9. Webster J, Pritchard MA. Gowning by attendants and visitors in newborn nurseries for prevention of neonatal morbidity and mortality. Cochrane Database Syst Rev. 2003;(3):CD003670. 10. Wynn JL, Wong HR. Pathophysiology and treatment of septic shock in neonates. Clin Perinatol. 2010;37(2):473-9. 11. Yu Z, Liu J, Sun Q, et al. The accuracy of the procalcitonin test for the diagnosis of neonatal sepsis: a meta-analysis. Scand J Infect Dis. 2010;42(10):723-33.

Others

ibliography



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Single-volume Exchange Transfusion A few studies (from India) have demonstrated good benefit in neonates with advanced sepsis—sclerema, persistent hypotension, coagulopathy and metabolic acidosis. Con cerns about use of blood products have limited research in this direction.

•



Granulocyte Colony Stimulating Factors or Granulocyte Monocyte Colony Stimulating Factors The routine use of granulocyte colony stimulating factors (GCSF) or granulocyte monocyte colony stimulating factors (GMCSF) is not recommended. When used in severely neutropenic neonates with proven sepsis, a survival benefit was demonstrated in some studies.

torage of antibiotics: Certain antibiotics like ampicillin, gentamicin and cefotaxime are so inexpensive (the disposable syringe costs more!) that keeping the vials for further use is only associated with risk of nosocomial sepsis. Some antibiotics like meropenem and teicoplanin have a short shelf life of less than 48 hours after reconstitution. Do not combine antibiotics with similar toxicities, e.g. vancomycin and gentamycin. Be willing to de-escalate to a lower antibiotic if culture suggests so. Stop antibiotics if cultures, infection markers and clinical signs allow. No benefit is known by completing a “course of 7–14 days”.



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Neonatal Seizures





Care of the Newbor

2.9

Ruchi Nimish Nanavati

 

   

 

 

 

 

 

 

 

Perinatal events •­ Hypoxic ischemic encephalopathy (HIE) •­ Intracranial hemorrhage (ICH): Germinal matrix intraventricular hem­ orrhage (IVH), subdural hemorrhage, primary subarachnoid hem­ orrhage (well baby with seizures) Metabolic •­ Hypoglycemia: Preterm, low birth weight (LBW), infant of diabetic mother (IDM), sick baby •­ Hypocalcemia –­ Early: Preterm, asphyxia, IDM –­ Late: Top feeding •­ Hypomagnesemia •­ Hyponatremia/hypernatremia •­ Pyridoxine dependency •­ Inborn errors of metabolism (IEM): Non ketotic hyperglycinemia, urea cycle defects, maple syrup urine disease (MSUD), glutaric aciduria II, propionic aciduria, methylmalonic aciduria, mitochondrial disease, Menkes disease, glucagon transporter deficiency Infections •­ Bacterial meningitis •­ Nonbacterial infections: Toxoplasmosis, herpes simplex, Coxsackie B, rubella, Cytomegalovirus Developmental problems •­ Cerebral cortical dysgenesis •­ Lissencephaly, schizencephaly •­ Neuronal migration disorders •­ Pachygyria, polymicrogyria Miscellaneous •­ Passive drug withdrawal •­ Accidental injection of local anesthetic into fetal scalp •­ Drug toxicity •­ Polycythemia •­ Hypertensive encephalopathy •­ Neonatal epileptic syndromes: Benign familial NS, benign idiopathic NS (fifth day fits), early myoclonic encephalopathy, early infantile epileptic encephalopathy (Ohtahara’s syndrome)

Causes

Relative deficiency of inhibitory neurotransmitter

Pyridoxine dependency

Membrane alteration with increased Na+ influx

Hypocalcemia and hypomagnesemia

-

 

Hypoxemia, ischemia and hypoglycemia

 

 

Excess of excitatory neurotransmitter

 

Failure of Na+ - K+ pump secondary Hypoxemia, ischemia and to reduced energy production hypoglycemia

 

 

Probable mechanism

 

 

Table 2.9.1 Mechanisms of seizure

 

 



A seizure results from excessive synchronous electrical discharge, i.e. depolarization of neurons produced by the inward migration of sodium ions. The probable mechanisms for excessive depolarization are shown in Table 2.9.1. The electrical discharges readily generated in the neonatal brain do not propagate sufficiently leading to fragmentary seizures whose electrical activity may not spread to surface electroencephalography (EEG) electrodes. The more advanced development within the limbic system with connections to the midbrain and brainstem explain the higher frequency of subtle features. Dramatic fall in brain glucose within 5 minutes of onset of seizures with concomitant rise in brain lactate may interfere with DNA synthesis, glial proliferation, differentiation and myelination. A single bout of seizures permanently inhibited DNA

Table 2.9.2 Etiology of neonatal seizures (NS)

 

tiopathogenesis

Benign familial neonatal seizure is an autosomal dominant disorder with primary generalized seizures on day 2 or 3 of life without any obvious risk factors. Seizures may recur and gradually resolve over weeks. Later epilepsy is seen in less than 10%.

 

The incidence of NS ranges from 2.8 per 1,000 in term to 57.5 per 1,000 in VLBW infants. Hypoxic ischemic encephalopathy, intracranial hemorrhage (ICH), intracranial infections and developmental defects account for 80–85% of all cases of NS. Indian data is limited.

F

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enign amilial Neonatal Seizure

 

pidemiology

n

E

H

This is the most common cause; seizures generally start within 24 hours, increase in frequency over 24–36 hours and usually burn out by day 4–5. Subtle seizures are most common.

 

E

Seizure is a paroxysmal alteration in neurological function— behavioral, motor or autonomic.

E

ypoxic Ischemic ncephalopathy

 

Definition

synthesis in the neonatal rat brain. Evidence suggests that NS may predispose to impaired cognitive and behavioral functions or susceptibility to epilepsy later in life. The most common etiologies are listed in Table 2.9.2.

 

Seizures represent the most distinctive manifestation of neurological disease in the newborn period. The tendency toward recurrent seizures and status epilepticus is far greater in the newborn period. It is critical to recognize neonatal seizures (NS), determine their etiology and treat them, as they usually relate to significant illness requiring specific therapy, and seizures themselves may be a cause of brain injury and potential long-term sequelae.

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arly Myoclonic ncephalopathy

It starts as focal motor fragmentary seizures and later evolves into typical infantile spasms. It is usually associated with non-ketotic hyperglycinemia. EEG reveals burst suppression pattern with poor long-term outcome.

­

­



Investigations The following tests are required with first seizure episode: • Blood sugar • Serum calcium, phosphorus, magnesium • Serum electrolytes • Cerebrospinal fluid study • Cranial ultrasonogram (USG)

 

Table 2.9.3 Neonatal seizures and time of onset Time of onset

Etiology

< 24 hours

Hypoxic ischemic encephalopathy (HIE), severe birth trauma, congenital central nervous system (CNS) anomalies, pyridoxine dependency, hypoglycemia, hypocalcemia, drug withdrawal, intracranial hemorrhage (ICH)

1–3 days

All above + intracranial infections, subarachnoid hemorrhage, inborn errors of metabolism (IEM), benign familial neonatal seizures

> 3 days

Late hypocalcemia, sepsis, meningitis, progressive hydrocephalus, epileptic syndromes, herpes encephalitis, IEM

­

T









Neonatal seizures are difficult to recognize because they are brief, fragmentary, asymmetrical, lack organization and may be associated with non-motor phenomenon. Four patterns are described which are as follows: 1. Subtle seizures: These are the most common sub types (50%), include broad spectrum of behavioral phenomena: • Ocular: Tonic horizontal deviation, ocular fixation, repetitive blinking • Oral-facial-lingual movements • Limb movements: Cycling, peddling • Autonomic phenomena: Tachycardia, bradycardia, irregular respiration, increased blood pressure • Apnea: Rarely the only manifestation, rarely lasts for more than 10–20 seconds, initial tachycardia is common At bedside, subtle seizures are distinguished by their insensitivity to tactile stimulation or restrain and frequent association with autonomic effects. 2. Clonic seizures: These are well localized stereotypic and repetitive biphasic movements. They may be unifocal, multifocal (progression from one part to another in nonordered fashion) or generalized, and are usually not associated with loss of consciousness. Primary generalized clonic seizures are extremely rare. They are provoked by metabolic disturbances, focal traumatic injury, subarachnoid hemorrhage and focal infarct. The most common cause of clonic seizures that remain unifocal is neonatal stroke. EEG reveals unifocal or multifocal abnormality and prognosis is good. 3. onic seizures: They are characterized by sustained extension or flexion of axial or appendicular muscle group and resemble decerebrate or decorticate posture. They may be focal or generalized, often associated 52 with eye deviation or apnea and are most common in preterms with ICH or diffuse CNS disease. Generalized



F

Clinical eatures



These are brief tonic spasms presenting between days 10 and 90 of life. They are usually associated with structural disorders. EEG reveals burst suppression pattern with poor long-term outcome.





E

E

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arly Infantile pileptic ncephalopathy ( htahara’s Syndrome)

tonic seizures may not be associated with timesynchronized EEG discharges. EEG may depict burst suppression pattern and prognosis is poor. 4. Myoclonic seizures: These are characterized by syn chronous single or multiple slow jerks and are asso ciated with diffuse CNS pathology. Focal and multifocal myoclonic seizures are most commonly unassociated with, while generalized myoclonic seizures are more likely to be associated with time-synchronized EEG discharges. EEG may reveal burst suppression or hypsarrhythmia pattern and prognosis is poor. Seizure mimics certain behavioral phenomena, which may be confused with NS. 1. Jitteriness is characterized by tremulous movements (5–6/s), is stimulus sensitive, not associated with abnormal autonomic changes or eye movements and is terminated by passive flexion of extremities. EEG is normal. 2. Benign sleep neonatal myoclonus usually presents in the first week and resolves spontaneously over weeks. It occurs during non-rapid eye movement (non-REM) sleep, abolishes on arousal and never occurs during wakefulness. Neurological examination and EEG are normal. Transient dysmaturity of the brainstem reticular activating system is postulated. Anticonvulsants are not indicated. Long-term outcome is normal. Later epilepsy does not develop. 3. Hyperekplexia is a rare autosomal dominant disorder characterized by hypertonia, hyperreflexia and an exaggerated startle response. The mutation of inhibitory glycine receptor is described. Therapy with clonazepam/ diazepam causes marked improvement. The timing of seizure can also provide some clue to etiology (Table 2.9.3).

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Benign idiopathic neonatal seizures have onset between days 4 and 6 of life in term infants with normal neurological state and diagnostic testing. They are probably related to transient zinc deficiency. Long-term outcome is favorable and later epilepsy does not develop. E

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G: Indicated in all cases of NS requiring anticonvulsant therapy. Ictal EEG is useful for the diagnosis of suspected seizures, while interictal EEG is useful for predicting long-term prognosis. Abnormal background activity indicates a high risk for long-term neurological sequelae. EE

have raised concerns. Attempts should be made to stop AEDs and wean the baby to only phenobarbitone (Flow chart 2.9.2). Monotherapy is most appropriate.

Prognosis

dditional Investigations

Prognosis mainly depends upon gestational age, nature and cause of seizures, neurological examination, EEG and neuroimaging findings. A rough guide of prognosis is provided in Table 2.9.4.

•

ecent dvances

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• Neuroimaging: Computed tomography (CT) scan is advisable when etiology is undetermined after first line investigations and is especially good for hemorrhages and calcifications. Magnetic resonance imaging (MRI) provides better resolution of anatomy and details of function and perfusion with diffusion-weighted MRI, spectroscopy and angiography. Neuroimaging has more value in prognostication. • Metabolic work-up: Inborn errors of metabolism should be suspected with family history of unexplained fetal or neonatal deaths, mental retardation, seizures occurring after introduction of feeds, or those asso ciated with unexplained lethargy, coma and vomiting. Initial work-up includes blood gases (arterial blood gas), blood ammonia, serum and urinary amino acids, serum lactate and pyruvate, and urinary reducing substances. • Sepsis work-up • TORCH screen • Karyotyping • Toxic drug screen • As per suspected etiology.

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Criteria for determination of adequacy of therapy had always remained controversial. Current research highlights that the elimination of all seizure activity

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Flow chart 2.9.1 Algorithm for the management of neonatal seizures

T

reatment







Neonatal seizure is a medical emergency and mandates prompt treatment. The algorithm for management of NS is given in Flow chart 2.9.1. Other drugs used in resistant seizures include: • Lidocaine: Intravenous bolus dose of 4 mg/kg followed by 2 mg/kg/hour • Paraldehyde: Intramuscular 0.1–0.2 mL/kg/day or rectal paraldehyde 0.3 mL/kg/day • Pyridoxine: Therapeutic trial of pyridoxine is warranted in refractory seizures. Pyridoxine dependency is diagnosed on rapid cessation of EEG seizures following 50–100 mg IV pyridoxine. • Valproic acid: As adjunctive or maintenance therapy; 20 mg/kg IV/PR/PO is followed by 5–10 mg/kg/day in two divided doses. Concern about hepatotoxicity, hyperammonemia and hyperglycinemia limits its use. • Primidone, carbamazepine, lamotrigine and vigabatrin have been tried in refractory seizures. Importance of history and physical examination to detect the cause of seizures cannot be overemphasized. Treatment of the underlying cause is essential.

Long-term Planning and Prognostication The possible adverse effects on developing CNS of continuing antiepileptic drugs (AEDs) for several months

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should be the goal of therapy and not merely elimination of clinical seizures. Fosphenytoin has proved to be a major advance in therapy of neonatal status epilepticus. Topiramate and bumetanide causing inhibition of excitation at excitatory amino acid receptors with potent anticonvulsant and neuroprotective properties hold promising future.

 

atr

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Flow chart 2.9.2 Weaning of anticonvulsant therapy

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1. du Plessis AJ. Neonatal seizures. In: Cloherty JP, Eichenwald EC, Stark AR (Eds). Manual of Neonatal Care, 6th edition. Philadelphia: Lippincott Williams and Wilkins; 2008. pp. 483-98. 2. Laoria N. Controversies in diagnosis and management of neonatal seizures. Indian Pediatr. 2000;37:367-72. 3. Rennie JM. Seizures in the newborn. In: Rennie JM, Roberton NR (Eds). Textbook of Neonatology, 3rd edition. Edinburgh: Churchill Livingstone; 2000. pp. 1213-22. 4. Tekgul H, Gauvreau K, Soul J, et al. The current etiologic profile and neurodevelopmental outcome of seizures in term newborn infants. Pediatrics. 2006;117:1270-80. 5. Volpe JJ. Neonatal seizures. In: Volpe JJ (Ed). Neurology of the Newborn, 5th edition. Philadelphia: Saunders Elsevier; 2008. pp. 203-44.



ibliography



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T



• The diagnosis of seizures requires a high index of suspicion, careful clinical observation and often EEG. • Neonatal seizures may predispose to cognitive, behavioral or epileptic complications later in life. • Elimination of all seizure activity should be the goal of therapy and not merely elimination of clinical seizures. • Phenobarbitone is the preferred anticonvulsant for initial and maintenance therapy. • Long term prognostication should be guarded in recurrent or resistant seizures or those with EEG abnormalities.

 

Table 2.9.4 Prognostic outcome in neonatal seizures % Normal

Hypoxic ischemic encephalopathy (HIE)

50

Intracranial hemorrhage (ICH) with hemorrhagic infarct

< 10

Primary subarachnoid hemorrhage

90

Hypocalcemia - Early

50

Hypocalcemia Late

100

Hypoglycemia

50

Bacterial meningitis

50

Central nervous system (CNS) malformation

0

Background EEG

Neurosequelae

Normal

< 10

Severe abnormalities

≥ 90

Moderate abnormalities

~ 50

-

Neurologic disease

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Ashok Kumar

Meconium spiration Syndrome (M S)

R

Respiratory distress affects nearly 5–10% of all newborns. The etiology of RD depends on the age of onset of symptoms, gestational age, and maternal factors. Table 2.10.1 summarizes the common causes of RD in newborn. The pathogenesis of the most common causes is outlined in this section.

Clinical eatures F

TT

T

T

ransient achypnea of the Newborn (

N)

It is a benign, self-limiting disorder which commonly occurs in term and late preterm (34–36 weeks) newborns. It is

 

Table 2.10.1 Etiology of respiratory distress (RD) in newborn

                     

 

 

 

 

   

 

 

 

 

 

 

 

 

 

 

 

 

•  Respiratory system – Respiratory distress syndrome (RDS) – Transient tachypnea of the newborn – Intrauterine pneumonia – Meconium aspiration syndrome – Pneumonia – Aspiration pneumonia – Air leak syndromes – Surgical causes: Tracheoesophageal fistula, diaphragmatic hernia, bilateral choanal atresia, and congenital lobar emphysema •  Cardiovascular system – Congestive heart failure •  Central nervous system – Perinatal asphyxia – Intracranial hemorrhage •  Metabolic – Hypoglycemia – Metabolic acidosis •  Miscellaneous – Hypothermia – Polycythemia

In a newborn presenting within the first 6 hours of birth with RD, one should consider the possibilities of RDS, TTN, MAS, congenital pneumonia, air leaks or malformations as the etiology. Neonates with RDS are preterms who present with tachypnea, chest retractions, expiratory grunt, cyanosis, and apneic spells. Neonates with TTN usually have mild to moderate RD with tachypnea, chest retractions and flaring of alae nasi. However, the baby remains active and alert despite severe tachypnea. Quick recovery by 2–3 days helps to differentiate this condition from pneumonia or MAS. In MAS, RD develops soon after birth, manifesting as tachypnea, retractions, and hyperinflated chest, and occasionally grunting. There is history of meconium stained amniotic fluid and/or meconium staining of the skin and babies are often born depressed at birth, requiring resuscitation in the delivery room. If there is history of chorioamnionitis in the mother one may consider the possibility of congenital pneumonia. Air leak should be suspected in any newborn that has received positive pressure ventilation at birth and would have features of decreased air entry and increased resonance on percussion on the side of the air leak and mediastinal shift to the opposite site. If facilities for transillumination are available then air leak can be confirmed on the bed side by the bright transillumination on the side of the air leak. Cardiac disease usually presents beyond the first day of life and features of congestive heart failure, murmurs on cardiac auscultation with or without cyanosis may provide clues to a cardiac etiology.

Surgical Causes of espiratory Distress Suspect esophageal atresia (with/without tracheoeso phageal fistula) if a newborn presents soon after birth with increased salivation, and choking during feeds. Failure to pass a feeding tube into the stomach confirms the diagnosis. Respiratory distress in a baby with scaphoid abdomen and 55 a mediastinal shift should suggest diaphragmatic hernia. Bilateral choanal atresia presents as cyclic RD, particularly ­

The incidence is inversely related to the gestational age. Approximately 50% of newborns delivered at 26–28 weeks of gestation develop RDS, whereas the disease becomes infrequent after 34 weeks. Compared to the West, incidence of RDS is relatively less in India. Factors like male gender, infants of diabetic mothers, multiple gestation, perinatal asphyxia, and cesarean section increase the risk of disease. It is caused by deficiency of surfactant in lungs which is a composite mixture of phospholipids and proteins produced by type II epithelial cells of alveoli.

R

R

espiratory Distress Syndrome

 

Meconium staining of amniotic fluid (MSAF) occurs in 10–15% of deliveries. Approximately, 5% of babies born through MSAF develop MAS. It is common in term and post-term babies, especially those with intrauterine growth restriction.



E

tiopathogenesis of espiratory Distress

A

Respiratory distress (RD) in newborn is the presence of one or more of the following features: respiratory rate greater than or equal to 60/min, chest retractions and grunt.

caused by delayed clearance of fetal lung fluid. Risk factors for Transient tachypnea of the newborn (TTN) include poor respiratory effort at birth, cesarean delivery without the benefit of labor, multiple gestations, delayed cord clamping, male gender, and maternal diabetes. A

Definition

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espiratory Distress

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ssessment of the Severity of espiratory Distress R

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during feeding that disappears on crying or opening mouth, as it bypasses nasal obstruction. Inability to pass a catheter through nose into nasopharynx establishes the diagnosis.

The severity of RD can be judged clinically by the Respiratory Score (Downe Score) as given in Table 2.10.2. The score is used in babies who are breathing spontaneously, including those receiving CPAP. A score of less than 5 indicates mild RD, a score of 5 to 8 moderate RD, and a score of greater than 8 severe RD.

Diagnosis Chest Skiagram

Figure 2.10.1 Chest X-ray of respiratory distress syndrome (RDS) showing diffuse haziness, blurring of cardiac margins and air bronchogram  

This is the most useful investigation that can help in the etiological diagnosis of RD in the newborn. In RDS the radiological features include symmetrical fine reticulogranular pattern, reduced lung volume, diffuse haziness (ground glass appearance), air bronchograms (Fig. 2.10.1) and complete white out of lungs in late stages. In TTN the chest X-ray shows normal or increased lung inflation, streaky perihilar infiltrates, and fluid in horizontal fissure (Fig. 2.10.2). In MAS, chest X-ray shows hyperinflation, coarse irregular opacities and sometimes pneumothorax (Fig. 2.10.3). Air leaks, esophageal atresia, diaphragmatic hernia can all be diagnosed by typical radiological features. Pneumonia may show varying degrees of lung opacities and would have to be correlated clinically. T

Shake est

ther ests T

O

The test is based on the premise that if there is sufficient amounts of surfactant present in the amniotic fluid (or gastric aspirate taken within 30 min of birth), it would generate a stable foam layer at air-liquid interface when mixed with ethanol. Inadequate foam layer could suggest insufficient surfactant and an indirect support for the diagnosis of RDS.

In case pneumonia is suspected then blood culture, CRP, total leukocyte count and absolute neutrophil count should be done.

 

Figure 2.10.2 Chest X-ray of transient tachypnea of the newborn (TTN) showing streaky perihilar infiltrates

 

Table 2.10.2 Respiratory score (Downe score) Score

0

1

2

Respiratory rate

40–60/min

60–80/min

> 80/min

Oxygen requirement

None

≤ 50%

> 50%

Retractions

None

Mild to moderate

Severe

Grunting

None

With stimulation

At rest

Breath sounds

Normal

Decreased

Barely heard

Prematurity

> 34 weeks

30–34 weeks

< 30 weeks

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Care of the Newbor Figure 2.10.4 Chest X-ray of the same baby as in Figure 2.10.1, showing considerable clearing of lungs 5 hours after giving surfactant

R

xygenation

Provide oxygen by head box to maintain target oxygen saturations (SpO2) in the 88–95% range. Oxygen therapy must be monitored by pulse oximeter to avoid hypoxia or hyperoxia, both of which are harmful to the baby. A

Continuous Positive irway Pressure In neonates with RDS, continuous positive airway pressure (CPAP) is a simple, safe, and effective method to improve oxygenation. It works by preventing alveolar atelectasis, thereby reducing work of breathing. Continuous positive airway pressure is utilized in spontaneously breathing babies. Intractable apnea is a contraindication for CPAP. Early CPAP use is more effective and may reduce the need of mechanical ventilation. Continuous positive airway pressure is best delivered through short nasal prongs. Begin CPAP at 5–6 cm H2O pressure (maximum 8 cm H2O). Insert orogastric tube to prevent gastric distension from swallowed air (CPAP belly). Inability to maintain SpO2 greater than 85% at 60– 80% FiO2 indicates need for mechanical ventilation.

Mechanical Ventilation Mechanical ventilation should be considered in infants with RD who fail CPAP or have recurrent apneas or are in shock or have evidence of respiratory failure (blood gas revealing PaCO2 greater than 50 mm Hg and PaO2 lesser than 50 mm Hg).

­

Surfactant replacement therapy (SRT) should be consi dered in neonates with RDS. Surfactant is instilled directly into the lungs through endotracheal tube. In symptomatic babies early rescue therapy (within 2 hours) is better than delayed therapy. Prophylactic SRT (before the onset of RD) is indicated for newborns under 26 weeks’ gestation and to those preterms who require intubation for stabilization in delivery room. Natural surfactants are better than synthetic preparations. The dose is 100– 200 mg/kg. Single dose suffices for most infants. Dose may be repeated 6–12 hours later, if significant distress persists. Monitor baby carefully after SRT. Within a few minutes, there is improvement in gas exchange, oxygen requirement comes down and ventilator settings must be adjusted to prevent ventilator induced lung injury. Figure 2.10.4 shows radiological improvement in lung status after surfactant therapy.

ntibiotics

When pneumonia is suspected, appropriate antibiotics such as ampicillin/cephalosporin and an aminoglycoside should be initiated along with other supportive care.

Complications Acute complications include air leaks, patent ductus arteriosus (PDA), intracranial hemorrhage, and infection. Long term complications in preterms include retinopathy of prematurity, bronchopulmonary dysplasia (BPD), neuro developmental impairments, and other complications of prematurity. ­

O

Treatment is largely supportive. The infant should be nursed under a radiant warmer. Most newborns with RD are not usually capable of being fed and need to be initially kept on IV fluids.

T

Surfactant eplacement herapy

reatment

A

T

 

 

Figure 2.10.3 Chest X-ray of meconium aspiration syndrome (MAS) showing patchy hyperaeration and heterogeneous opacities in lung fields

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1. Guha’s Neonatology. Principles and Practice (Volume 2). In: Guha DK, Saili A, Bhat S, Shenoi A (Eds), 3rd edition. Jaypee Brothers: New Delhi; 2005. 2. Sweet DS, Carnielli V, Greisen G, et al. European consensus guidelines on the management of neonatal respiratory distress syndrome in preterm infants–2010 update. Neonatology. 2010;97:402-17. 3. Warren JB, Anderson JM. Core concepts: respiratory distress syndrome. NeoReviews. 2009;10:e351-61. 4. Welty S, Hansen TN, Corbet A. Respiratory Distress in the Preterm Infant. In: Taeusch HW, Ballard RA, Gleason CA (Eds). Avery’s Diseases of the Newborn, 8th edition. Philadelphia: Saunders; 2005. pp. 687-703.



• The most common cause of RD in preterm newborns is RDS and TTN in late preterm and term newborns. • Good supportive care improves outcome. • Monitor oxygen therapy with pulse oximetry. Unmonitored oxygen use is dangerous. • Oxygen administration by hood is effective in mild RD. • Continuous positive airway pressure is effective and cheap method to provide respiratory support in mild to moderate RD.



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• Mechanical ventilation is the modality of choice for treating severe RD. • Always obtain blood culture and sepsis screen before starting antibiotics. • Single course of antenatal steroids between 24 weeks and 34 weeks of gestation reduces the incidence of RDS by 50%. • Surfactant replacement therapy is most effective when it is given within 2 hours of development of symptoms (early rescue therapy).

Respiratory distress syndrome can be prevented by using antenatal corticosteroids to pregnant women between 24 weeks and 34 weeks of gestation with threatened preterm labor. A complete course consists of two doses of betamethasone (12 mg IM) at 24-hourly interval or four doses of dexamethasone (6 mg IM) at 12-hourly intervals. Betamethasone is better than dexamethasone. Multiple courses of steroids are not recommended in view of modest incremental benefit and real risk of brain damage to the fetus.

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leeding Neonate JN Sharma

The hemorrhagic disorders in the newborn are a group of disorders with different etiologies, which have in common an abnormal tendency to bleed. This abnormal tendency to bleed is due to a defect in the mechanism of hemostasis.

A hemorrhagic disorder should be suspected when there is: • Spontaneous bleeding into the skin, mucous memb­ rane and internal tissues, joints. Bleeding from gastrointestinal tract is a common form of mucosal bleeding in the newborn due to hemorrhagic disorders. • Excessive or prolonged bleeding following trauma or surgery: A postoperative or traumatic bleed may be the first manifestation of a coagulation disorder • Bleeding from more than one site • Associated family history of abnormal bleeding. Points in history should include gestation and birth weight, day of onset of bleeding, type of bleeding viz. skin, bleeding per rectum, hematemesis, bleeding from IV sites, family history of bleeding disorder, maternal history of idiopathic thrombocytopenic purpura (ITP), systemic lupus erythematosus (SLE), maternal drug ingestion, history of birth trauma and complicated delivery and administration of vitamin K at birth. What is not a bleeding disorder? There are some conditions which present with bleeding or mimic bleeding but are not due to a bleeding disorder. They include the following: • Swallowed maternal blood by the newborn • Bleeding from an umbilical granuloma • Hormone withdrawal vaginal bleeding • Urate crystals which stain the nappy • Subconjunctival hemorrhage and retinal hemorrhage and petechiae of the skin of head and neck region, which are common during passage through the birth canal or may result from venous obstruction. In vascular disorders, the bleeding is usually confined to the skin and may cause petechiae and ecchymosis. In platelet disorders, petechial bleeding is common, ecchymosis present is usually not larger than 2 cm in diameter and bleeding from mucous membranes is prominent. In coagulation disorders, petechial hemorrhage is rare. Ecchymosis tends to be larger than in platelet and vascular disorders. Bleeding more frequently occurs in deeper tissues. Time of onset of bleeding manifestations often gives a clue to diagnosis. Onset of bleeding between 2 days and 6 days indicates classical hemorrhagic disease of newborn. Immune mediated thrombocytopenia usually manifest within first 48 hours of age. Early onset bleeds are associated with intrapartum events and maternal status whereas late onset bleeds are usually secondary to infections.

Pathogenesis The newborn has reasons to be susceptible to bleeding complications due to physiological handicaps. None of the coagulation factors cross the placenta from the mother to the fetus. At birth, the concentration of vitamin K dependent factors (factors V, factor VII, factor IX and factor X) and contact factors (factor XI and factor XII) are reduced to about 50% of normal adult values and are further lower in preterm infants. Both thrombin generation and thrombin inhibition are reduced in the neonatal period and there are low levels of plasminogen.

n



-

–

–

–

–

–

–

–

–

The causes of bleeding in the neonate may be: • Hemorrhagic disease of newborn (HDN) • Platelet disorders – Qualitative disorders, e.g. Glanzmans disease (throm­ bosthenia), use of aspirin by mothers – Quantitative disorders, e.g. autoimmune and alloim­ mune thrombocytopenia, disseminated intravascu­ lar coagulation, giant hemangioma, necrotizing en­ terocolitis, renal vein thrombosis • Inherited deficiency of clotting factors – Sex linked recessive (expressed in males): Hemo­ philia, Christmas Disease – Autosomal dominant (expressed in both sexes with one parent affected): von Willebrand disease, dysfibrinogenemia, factor XI deficiency. – Autosomal recessive (expressed in both sexes with parents as carriers): Deficiency of clotting factors I, II, V, VII, X, XII, XIII, variants of von Willebrand disease. • Increased capillary fragility and supporting structures causing bleeding into skin (e.g. breech delivery, trau­ matic delivery) intraventricular hemorrhage. • Traumatic causes – Rupture of liver and spleen associated with breech delivery – Retroperitoneal or intraperitoneal bleeding – Subdural hematoma, cephalhematoma, subgaleal hemorrhage.



tiology

F

Clinical eatures

E

Introduction

59

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•

The management of a bleeding neonate includes supportive treatment with blood component therapy and identification and treatment of the cause.

If there is significant hemorrhage and the infant is in shock, it will present with cold peripheries, tachycardia, CRT greater than 3 seconds and a blood pressure less than 35 mm Hg. The hemoglobin level may not fall for 2–3 hours. The infant in shock requires a rapid transfusion of 15–20 mL/kg of uncross matched O negative blood or 10–20 mL/ kg of normal saline over 5–15 min. If there are no signs of recovery from shock another bolus should be given over 15–20 min. S

Infant not in hock • •

• •

If the infant is not in shock, administer vitamin K 1 mg IV immediately if not given at birth. The infant may need a transfusion with packed red cells 10 mL/kg over 2–3 hours to raise Hb to 10–12 g/dL. It needs mention that 10 mL/kg of packed red cells will raise Hb by 2–3 g/dL or the hematocrit (Hct) by 10%. All critically ill infants should be given IV fresh frozen plasma (FFP), 10 mL/kg if PT and PTT are prolonged. Platelet transfusion should be given when platelet count is less than 20,000/cumm.

Neonatal lloimmune hrombocytopenia T



Infant in hock S

Essential investigations for all cases include Hb esti­ mation, red cell morphology, total leukocyte count, differential leukocyte count, platelet count and reti­ culocyte count. • pt test: This test should be performed when there is only gastrointestinal bleeding in a well neonate in the first 48 hours of life and is used to distinguish maternal from neonatal blood. One part of vomitus is mixed with five parts of distilled water and centrifuged. To the pink centrifuged supernatant fluid, 1 mL of 1% sodium hydroxide is added and wait for 1–2 min. If the solution changes to yellow brown color it favors possibility of swallowed maternal blood (HbA gets denatured by alkali while HbF stays pink). • Screening tests for hemorrhagic disorders include platelet count and examination of blood film for number, morphology and presence of platelet clumping, the bleeding time, prothrombin time (PT), activated partial thromboplastin time (APTT) and thrombin time. • Special tests are required to (a) identify the deficient coagulation factor, (b) to determine the degree of deficiency and (c) to detect and quantitate immune inhibitors. They include prothrombin consumption test, coagulation factor assays and platelet function tests. A neonate who has a positive bleeding history or is having active bleeding should have a platelet count, bleeding time, PTT and PT done. If the results are normal, a thrombin time and von Willebrand factor (vWF) testing should be considered. If the initial test results are abnormal, special tests should be planned. Table 2.11.1 provides a differential diagnosis of the causes of bleeding based on clinical status and screening laboratory tests. Table 2.11.2 provides a differential diagnosis of coagulation disorders based on laboratory tests while Table 2.11.3 gives the etiology of neonatal thrombocytopenia.

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Management

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Laboratory iagnosis

Therapeutic interventions include platelet transfusion and administration of IVIG. Platelet transfusion is indicated when platelet count is less than 30 × 109/L. In infants with no bleeding, but platelet counts between 30–50 × 109/L use of IVIG in the dose of 1 g/kg/day on two consecutive days can effectively raise the platelet count.

 

Table 2.11.1 Diagnostic possibilities based on laboratory tests Clinical evaluation

Platelet count

PT

APTT

Diagnostic possibilities

Sick neonate

Decreased

Increased

Increased

DIC

Decreased

Normal

Normal

Platelet consumption (infection, NEC, renal vein thrombosis, giant hemangioma, polycythemia)

Normal

Increased

Increased

Liver disease, heparin

Normal

Normal

Normal Neonate

Altered vascular integrity (hypoxia, acidosis, extreme prematurity, hyperosmolarity)

Decreased

Normal

Normal

Immune thrombocytopenia, thrombosis, bone marrow hypoplasia

Normal

Increased

Increased

Hemorrhagic disease of newborn

Normal

Normal

Increased

Hereditary clotting factor deficiencies

Normal

Normal

Normal

Bleeding from local factors, swallowed maternal blood, qualitative platelet abnormalities, factor XIII deficiency (rare)

Healthy neonate

60

Abbreviations: PT, Prothrombin time; APTT, Activated partial thromboplastin time; DIC, Disseminated intravascular coagulopathy; NEC, Necrotizing enterocolitis

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Care of the Newbor

Abnormality

Diagnosis

Long PTT + normal PT + normal platelets + normal bleeding

Factor VIII, IX, XI, XII deficiency

Long PTT + normal PT + normal platelets + long bleeding time

von Willebrand disease

Long PTT + long PT + normal platelets

Vitamin K deficiency

Long PTT + long PT + decreased platelets

DIC or generalized coagulopathy

Normal PTT + long PT

Factor VII deficiency

Normal PTT + normal PT + normal platelets + normal bleeding time + bleeding especially umbilicus

Factor XIII deficiency

Normal PTT + normal PT + low platelets

ITP, aplasia, leukemia, etc.

Many petechiae and normal platelets

HSV, CMV, infections

n

 

Table 2.11.2 Differential diagnosis of clotting disorders

Abbreviations: PT, Prothrombin time; PTT, Partial thromboplastin time; ITP, Idiopathic thrombocytopenic purpura; DIC, Disseminated intravascular coagulopathy; HSV, Herpes simplex virus; CMV, Cytomegalovirus  

Table 2.11.3 Causes of fetal and neonatal thrombocytopenia Time of onset

Possible etiology

Fetal thrombocytopenia

1. 2. 3. 4.

Early onset neonatal thrombocytopenia (< 72 hours)

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

Late onset neonatal thrombocytopenia (> 72 hours)

1. Late onset sepsis 2. NEC 3. Congenital infections (e.g. CMV, Toxoplasma, rubella, HIV)

Placental insufficiency (PET, IUGR, diabetes) Perinatal asphyxia Perinatal infections (e.g. E. coli, Group B streptococci, H. influenzae) DIC Alloimmune thrombocytopenia Autoimmune thrombocytopenia (maternal ITP, SLE) Congenital infections (e.g. CMV, Toxoplasma, rubella, HIV) Thrombosis (e.g. aortic, renal vein) Kasabach-Merritt syndrome Metabolic diseases (e.g. Propionic and methyl malonic acidemia) Congenital inherited syndromes (e.g. TAR, CAMT)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Alloimmune thrombocytopenia Congenital infections (e.g. CMV, Toxoplasma, rubella, HIV) Aneuploidy (trisomy 13, 18, 21) Autoimmune thrombocytopenia (ITP, SLE, severe Rh hemolytic disease)

Abbreviations: CMV, Cytomegalovirus; HIV, Human immunodeficiency virus; ITP, Idiopathic thrombocytopenic purpura; PET, Positron emission tomography; IUGR, Intrauterine growth restriction; DIC, Disseminated intravascular coagulopathy; TAR, Thrombocytopenia with absent radii; CMAT, Congenital amegakaryocytic thrombocytopenia; NEC, Necrotizing enterocolitis; SLE, Systemic lupus erythematosus

• Bleeding is more common and severe in preterm and LBW infants due to exaggeration of this deficiency state with or without superimposed problems, e.g. sepsis, asphyxia, etc. • The most common cause of bleeding neonate is classical HDN, which can be prevented. Hence all neonates should receive one dose of vitamin K after birth as a prophylactic measures.

B

1. Andrew M, Paes B, Milner R, et al. Development of the coagulation system in the full term infant. Blood. 1987;70:165 172. 2. Andrew M, Paes B, Milner R, et al. Development of the human coagulation system in the healthy premature infant. Blood. 1988;72:1651 7. -



61

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• Coagulation factors do not cross the placenta. The coagulation mechanism is handicapped in the newborn due to physiological deficiency of vitamin K dependent coagulation factors resulting in prolongation of PT and PTT however, not necessarily associated with clinical bleeding.

ibliography



ey Messages



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The mother should be advised prednisolone 10–20 mg qid for 10–14 days or IVIG prior to delivery. The baby should be delivered by lower segment cesarean section (LSCS) if fetal scalp platelet count is lesser than 50 × 109/L. Postnatally the neonate should be treated with platelet transfusion, steroid and IVIG.



T

A

Neonatal utoimmune hrombocytopenia

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-







-

-



-



-





T



8. Kuhle S, Mitchell L, Massicotte P, et al. Hemostatic disorders of Newborn. In: Taeusch HW, Ballard RA, Gleason EA (Eds). Avery’s Diseases of the Newborn, 8th edition; 2003. 9. Pramanik AK. The Bleeding Neonate. In: Meherban Singh (Ed). Medical Emergencies in Children, 3rd edition. New Delhi: Sagar Publications; 2000. 10. Roberts I, Murray NA. Neonatal Thrombocytopenia: causes and management. Arch Dis Child Fetal Neonatal Ed. 2003;88:F359 F364.







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3. Anupama Deka Roy. Bleeding Neonate. In: Sharma JN (Ed). Manual of Care of Critical Newborn, 2nd edition. New Delhi: Peepee Publishers and Distributors (P) Ltd; 2011. 4. Arasan DG. Approach to Bleeding Neonate. Indian J Pract Pediatr. 2010;12:401 11. 5. Buchman CR. Coagulation disorders in neonates. Pediatr Clin N Am. 1986;33:203 20. 6. Homans A. Thrombocytopenia in the neonate. Pediatr Clin North Am. 1996;43:737 53. 7. Jadav D, Chandra J. Petechial rash in neonates: Management algorithm. J Neonatol. 2008;22:19 27.

62

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Section

3 Growth and Development













3.1 3.2 3.3 3.4 3.5 3.6 3.7

















Section Editor : KN Agarwal Growth and Development: Basic Concepts: Dilip Mukherjee Growth—Birth to Puberty: KN Agarwal Who Under-5 Growth Standards 2006: Vaman Khadilkar Growth and Sexual Development in Puberty: KN Agarwal Normal Development: DK Agarwal Developmental Delay: MKC Nair Failure to Thrive: Madhulika Kabra

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3.1

Growth and Development: Basic Concepts

ssessment of Growth and Development



Growth can be measured in terms of: • Physical anthropometry (weight, height, circumferences of head, chest, abdomen and pelvis) • Assessment of tissue growth (skin fold thickness and measurement of muscle mass) • Bone age (radiological by appearance and fusion of the various epiphyseal centers) • Dental age (by counting the number of erupted teeth) • Biochemical and histological means. Development can be studied under motor (gross and fine motor), linguistic, adaptive and personal social behavior category.

Length Until 24 or 36 months of age, length in recumbency is measured using an infantometer (see Chapters 1.3 and 3.2). The length is recorded in centimeters up to one decimal point.

Height After the age of 2 years, standing height is recorded by a stadiometer. The details have been provided in the Chapters 1.3 and 3.2. For community survey, portable types of anthropometric rods are also used. For recording stature (height), the subject should remove his/her socks and shoes and stand perfectly straight with arms relaxed by his/her sides and ankles and knees together. Before measurement starts, a gentle pressure may be applied over the spine with one hand while other hand holds the anthropometric rod. The subject’s head is positioned in Frankfort plane [a line passing through the inferior margin of the orbit (orbitale) and upper margin of external auditory meatus (porion)].

A

Physical nthropometry

get expanded due to repeated use, may get rusted and variation of temperature may give false reading. A special type of new weighing scales is recently devised in Japan, which in addition to the weight of an individual, also notes body mass index (BMI) and amount of subcutaneous fat.

Growth denotes an increase in size of an individual due to increase in the number and diameter of the cells, and development denotes functional maturity of the child. Growth and development are not synonymous but they are assessed simultaneously. The growth performance in a child should be coupled with assessment of the development to get an idea of the child’s performance in overall growth. Growth and development begin at conception and end at maturity. They are unique characteristics of children and any obstacle in this process at any stage can possibly result in aberration of growth and/or development. A

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Dilip Mukherjee

Physical anthropometry should be done in every child from birth till maturity at regular intervals. The methods of assessment are given in chapters 3.2 and 3.4. It needs to be emphasized that the growth measurement needs to be done meticulously with absolute precision and recorded, so as to allow us on subsequent visit, to ascertain whether the child has grown optimally. The measurements should preferably be done by the same person on calibrated checked equipment to avoid personal human errors.

Weight



The weighing scales best suited are those, which are designed on balance arm principle. Accuracy up to 0.1 kg is acceptable. For smaller babies, machines of more accuracy are required as 0.1 kg forms a higher percentage of total body weight. More recently, many electronic weighing scales giving accuracy up to 0.01 kg have been made available. The weighing scales should be checked for accuracy using known weight from time to time. The beam scales are better instruments for all purposes rather than spring 64 weighing scales, i.e. bathroom scales, as the spring may

Sitting Height For recording sitting height, the subject is made to sit on a table or other convenient hard surface so that his/her head lies in Frankfort plane. The back should be straight, thighs horizontal and comfortably positioned. The feet should be supported on the foot board and hands should rest comfortably on the subject’s lap. To ensure that the subject’s back is fully extended, the observer may run his/ her index finger up the spine applying pressure to the lumbar and sacral regions, causing the subject to set up a reflex action. The head board should be lowered and made to touch the head of the subject, and reading should be recorded to the nearest completed unit.

Body Proportions The total body length is divided into two segments. The upper segment (US) is from head to symphysis pubis and lower segment (LS) from symphysis pubis to the toes. The upper to lower segment ratio is 1.7:1 at birth. By 6–7 years, it reaches 1:1. If the ratio is infantile after 1 year of age, it suggests short limb dwarfism due to bone disorders, such as rickets and hypothyroidism.

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Midarm/Head Circumference Ratio

This measurement is done for special purposes and is not used in routine clinical practice. It is measured with a special caliper, skinfold caliper.

Triceps Skinfold Thickness -

The skinfold is picked up over the posterior surface of the triceps muscle, 1 cm above the mark on a vertical line passing upward between bony point identified for taking measurement, maintaining a pressure of 10 g/mm2 on the caliper and freeing the skinfold from the underlying muscle with left hand between thumb, index and middle finger and holding caliper with the other hand. The reading is recorded to the nearest 0.1 mm, maintaining pressure of caliper as before.

Biceps Skinfold Thickness For recording biceps, the child is made to stand erect, facing the observer with arm on side and palm facing forward. The skinfold is picked up over the belly of biceps and 1 cm above the line marked for the upper arm circumference and triceps skinfold on a vertical line joining antecubital fossa to the head of humerus. The caliper is applied at the marked level and reading is recorded to 0.1 mm.

Bone ge or Skeletal

It is based on the relationship between weight and height and is expressed as weight (kg)/height (cm) × 100. Normal value varies from 0.14 to 0.16. In gross malnutrition, it is less than 0.14. It is a quite reliable ratio for assessing malnutrition.

Mid-upper Arm/Height Ratio It is also a very good indicator of nutritional status. A ratio of less than 0.29 indicates gross malnutrition, while the normal value ranges from 0.32 to 0.33.

aturity

Appearance and fusion of various epiphyseal centers follow a definite sequence related to chronologic age from birth to maturity. Radiological examination of left wrist and elbow is usually considered for bone age assessment. X ray of the lower end of femur, and talus is used for the assessment of maturity of newborn babies. The details of appearance and fusion of various centers are given in subsequent sections. -

Quetlet’s Index

wt p





Tissue Growth

A

It is a simple and useful criterion for detection of malnutrition. A ratio 0.280–0.314 indicates early malnutri­ tion, 0.250–0.279 moderate, and less than 0.249 denotes severe malnutrition.

Cube root of body weight (kg) Ponderal index (PI) is similar to BMI and used in defining newborn with intrauterine growth retardation (IUGR).

-

The degree of wasting can be measured by comparing the child’s weight with expected weight for a healthy child of the same height. Combinations of these measurements have been used to distinguish different types of malnutrition. Waterlow suggested that weight for height can be used to distinguish between malnutrition of recent origin, i.e. wasting and malnutrition due to a considerable period of month, i.e. stunting. In chronic malnutrition the child is stunted with the weight for age and height for age being low. In acute malnutrition, height for age is normal but weight for age is low (wasting). In nutritional dwarf (short stature) the weight/height is equal; the child may pass off as a normal child of lower age if the chronological age is not known. These have been discussed in the Chapter 4.3 “Malnutrition.”





Weight for Height

nd



Height (cm)

nt



PI =



As the MAC is relatively constant between 16.5 cm and 17.5 cm in 1–5 years of age, this measurement may be considered as an age independent variable up to 5 years of age. Any child whose MAC is less than 12.5 cm up to 5 years of age, is considered malnourished. Shakir’s tape also measures the MAC. A bangle of 4 cm in diameter, used in field studies is not a reliable method (Bangle test).

M

A

I

Ponderal Index

A

Midarm Circumference

Height (m)2 Body mass index (BMI) is similar to Quetlet’s except that the values are in SI units. Body mass index values can be used to draw standardized percentile curves in children and adolescents. It is especially useful for defining obesity. Body mass index values above 95th percentile for age are usually used to define obesity.

Develo me

ge ndependent nthropometry

Weight (kg)

BMI =

ha

The details of measuring head and midarm circumference (MAC) are given in Chapter 1.3. It should be kept in mind that upper arm circumference can be measured both in flexed and extended positions and also either at the maximum circumference of biceps muscle or midpoint, as the difference between the two is negligible. Chest circumference for boys, prepubertal girls and men can be recorded at the level of nipples during normal breathing. It is recorded to the nearest 0.1 cm.

Body Mass Index

Gro

Body Circumferences

Dental Development Eruption of teeth follows a definite sequence. Eruption of temporary or deciduous teeth begins at about 6 65

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Cross-sectional Study This is a very convenient, easy, less time consuming and economical method to study physical anthropometric growth. For example, healthy children of each age group and gender (minimum being 200 at each point) are measured for their weight, height and other parameters are recorded and an average is found out. These groups of children are studied just once in 20 years to develop national norms. L

inear or ongitudinal Study

In this type of study, the same child is measured from birth to maturity at previously decided regular intervals. It is difficult to study very large number of children in this type of study and hence, the linear studies have comparatively less sample size. The longitudinal study helps us to determine the growth velocity and effect of nutrition, illness and environment on growth.

Concept of Percentiles

-

While making various calculations, the use of terms like mean or average and standard deviation (SD) are well known. While expressing the growth, the term percentile or centile is often used. This may be explained in a simple way, e.g. the height of hundred 1 year old normal children is not exactly the same. They are arranged in such a way that the shortest is number 1 and the tallest is number 100. Rows of children are thus made. The mean of each number is worked out. The child at number 1 is 1 percentile, number 10 is 10th centile, and number 50 is 50th centile and so on. The child -



-

Development refers to qualitative and quantitative changes and acquisition of a variety of competencies for functioning optimally in a social milieu. Further, development is a continuous process from birth to maturity. It depends on maturation and myelination of brain; unless that has occurred, no amount of practice can make the child learn that skill. The process of development is an interaction between the child and his/her required environment. It may be stressed that besides 10% prevalence of development delay, the early identification remains difficult. Although severe disorders can be recognized, in infancy, it is usual to diagnose speech impairment, hyperactivity or emotional disorders before the age of 3 or 4 years, and learning disabilities are rarely recognized before children start schooling. If one can diagnose early stage developmental delay in early stages of growth, the intervention can minimize long term quantum of disability. It takes a long time, great patience and perseverance to assess the development of a child. It should be done with cooperation of the child and parents. The development is assessed by Gesell’s method, Denver Development Screening Test (DDST), Bayley Scale of Infant Development, Brazelton Neonatal Behavioral Assessment Scale (NBAS), Baroda Scale, Trivandrum Developmental Screening Chart (TDSC) and others (Table 3.1.1). The detailed discussion on development assessment is given in Chapters 3.5 and 3.6.

Growth Studies and Percentiles

L

ssessment of Development

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months with upper or lower central incisors, followed by lateral incisor. By 1 year of age 4–8 teeth are present. The permanent teeth begin to erupt at 6 years. Details of dental development are provided in subsequent chapters.

 

Table 3.1.1 Developmental screening tests that can be used for children less than 3 years

66

No.

Name of the test

Age range

Domains of development identified

Administration time (in minutes)

I

Developmental observation card

0–1 year

Social smile, head holding, sitting, standing

3

II

Trivandrum developmental screening chart

0–2 years

Personal social, fine motor, language and gross motor

5

III

Baroda development screening test

0–2.5 years

Gross motor, fine motor, cognitive, language

10

IV

Denver developmental screening test

2 weeks to 6 years

Personal social, fine motor, language, gross motor

20

V

Gesell developmental schedules

4 weeks to 6 years

Language, fine and gross motor, cognitive and personal social

Not specified

VI

Receptive expressive emergent language scale

0–3 years

Receptive language and expressive language

20

VII

Vineland adaptive behavior scale

0–19 years

Communication, daily living skills, socialization and motor skills

25

VIII

STYCAR vision test

6 months to 7 years

Integrity of vision

20

IX

STYCAR hearing test

6 months to 7 years

Integrity of hearing

20

X

Checklist for autism in toddlers

18–36 months

Screening for autism

10

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Britain, Tanner’s growth charts are used. In India, Indian Academy of Pediatrics (IAP) has come out with chart based on studies on affluent Indian children. Presently, the World Health Organization (WHO) growth charts are being preferred, especially for children less than 5 years of age.



nd

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on 10th centile on height chart means that 9 children are less in height and 90 children are more in height. The 50th centile is the median value and is also termed the standard value. Accepted range for normal is between 3rd percentile and 97th percentile. The SD charts are based on distribution of data above and below a mean value. The average normal range falls above and below 2 SD expressed as 2 SD. ±1 SD is equal to 84th centile and −1 SD is equal to 16th centile. ±2 SD corresponds to 97th centile and −2 SD corresponds to 3rd centile. The mean ± SD curves are useful for quantifying the degree of retardation exactly.

Develo me

1. Agarwal DK, Agarwal KN, Upadhyay SK, et al. Physical and sexual growth pattern of affluent Indian children from 5 to 18 years of age. Indian Pediatr. 1992;29:1203 83. 2. Agarwal DK, Agarwal KN. Physical growth in Indian affluent children (Birth to 6 years). Indian Pediatr. 1994;31:377 413. 3. Falknar F, Tanner JM. Human Growth, 2nd edition, 3 vol. New York: Plenum; 1986. 4. Khadilkar VV, Khadilkar AV, Choudhury P, et al. IAP growth monitoring guidelines for children from birth to 18 years. Mumbai: Indian Academy of Pediatrics; 2005. 5. Mukherjee D, Nair MKC. Growth and Development. New Delhi: Jaypee Brothers; 2008. 6. Tanner JM. Growth at Adolescence, 2nd edition. Oxford: Blackwell Scientific Publication; 1962. 7. Tanner JM. Physical growth and development. In: Textbook of Pediatrics, Forfar JO, Arneil GC (Eds), 2nd edition. London: Churchill Livingstone; 1978. pp. 249 303. 8. Tanner JM, Whitehouse RH, Cameroon N, et al. Assessment of Skeletal Maturity and Prediction of Adult Height, 2nd edition. London: Academic Press; 1983.

nt









-

-

These charts are developed by long term longitudinal studies. Velocity charts show the rate of change, which could be due to chronic illness, nutrition or growth hormone (GH) deficiency. Different countries may use their own growth charts. In Great





Velocity Growth Charts



Growth chart is the most important tool in assessment of growth of an individual child. A standard chart contains weight for age, height for age and weight for height. The head circumference is included for first 3 years of life. They depict mean, ±SD or percentile values at each age. The available charts are discussed in Chapters 3.2 and 3.3.



Growth Charts



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Bibliography

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Growth— irth to Puberty

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KN Agarwal

Growth is a continuous process commencing at conception and progressing at a varying pace till its completion about 2 decades later. The process of “growth” is accompanied with increase in body size and/or mass at varying rates. It is multifactorial and complex, still remarkably predictable. Boys and girls grow differently and each child has his or her distinct growth pattern. Growth charts (curves) are used to measure growth. The distance growth curve (Fig. 3.2.1) is a measure of size over time; it records height, weight, and/or skull circumference as a function of age and gets higher with age. The velocity growth curve measures the rate of growth at a given time for a particular body feature (such as height or weight). The height velocity curve is highest in infancy, up to 2 years of age, with more consistent annual growth afterwards and increases again at puberty (Fig. 3.2.1). Any faltering in growth process may indicate disease. Therefore, frequent and accurate growth assessment is of primary importance.

Genetic actors F

efinition

Racial Influence Growth potential of children of different races varies despite of similar environments. Asians tend to be smaller than Europeans while Afro-Americans are taller than White Americans.

Parental Influence Tall parents tend to have taller children. The midparental height reflects the genetic potential for growth for an individual.

Gender

Genetic Disorders Certain genetic disorders can adversely influence growth. These include chromosomal disorders (e.g. Down syndrome and Turner syndrome) and genetic mutations (e.g. mucopolysaccharidosis). F

nvironmental actors

Prenatal Growth



­

The size at birth is primarily influenced by maternal health and uterine environment. Common causes of fetal growth retardation in India are maternal malnutrition and anemia. Disorders leading to placental insufficiency like preg nancy-induced hypertension, multiple pregnancies, chronic systemic disorders and maternal tobacco/alcohol abuse are other important causes of fetal growth retardation. Maternal diabetes, by stimulatory insulin production in the fetus, is an important cause of excessive intrauterine growth leading to a large for date baby.

Growth is influenced by interaction of both genetic and environmental factors. Children generally grow to their genetic height potential with little outside assistance. What parents can do to help their child’s optimal growth and development is to create the best possible environment for their growth to take place.

With same genetic potential and environment, boys tend to be taller and heavier than girls. The difference is obvious from early childhood and gets more pronounced during puberty.

E

actors nfluencing Growth I

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3.2

Postnatal Growth

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• Nutrition: During the first 2 years of life, undernutrition has far reaching consequences; growth deficit that occurs during this period is never fully recoverable. • hronic systemic diseases: Chronic disorders especially congenital heart disease, recurrent pneumonia, persistent diarrhea, recurrent urinary tract infection, tuberculosis, etc. lead to growth failure by causing catabolism and poor nutrition intake. This may become irreversible if there is inadequate disease free period to allow catch up growth.

 

Figure 3.2.1 Distance growth curve. Increase in height with age in boys (birth to 18 years). The broken line is velocity height curve with peak height velocity

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Brain growth occurs very rapidly during fetal life and infancy. Although brain cell formation is almost complete before birth, brain maturation continues after birth. The brain of the newborn is not yet fully developed. It contains about 100 billion brain cells that have yet to be connected into functioning networks. But brain development up to age one is more rapid and extensive than was previously  

Table 3.2.1 Growth periods Embryo: mplantation to 8 weeks of gestation Fetus: 9th week of gestation to birth Infant: birth to 1 year of age Toddler: 1–3 years of age Preschool: 3–5 years of age School age: 5–12 years Adolescence: 10–19 years i

•  •  •  •  •  •  • 

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egulation of Growth

Fetal growth is critical to a person’s eventual height. Before birth, the key measure is the crown-rump length. The fastest growth rate for a human is during embryonic life (rate being 50–60 cm/year). The growth of the embryo and fetus is mainly mediated by maternal nutrition and by growth factors, such as fibroblast and epidermal growth factors, transforming growth factors alpha and beta, insulin and insulin-like growth factors (IGF-I and IGF-II). The GH only begins to play a role in growth in the final weeks before birth. The three components of postnatal growth, that are infancy, childhood and puberty, represent different modes of growth regulation. The growth rate during infancy is rapid but sharply decelerating and is principally dependent on nutrition. The GH and thyroxine have an increasingly important role from 1 year of age. During the first 2 years, the infants establish their own growth trajectory (path); later from about 2 years of age to the onset of puberty, growth occurs in relatively constant annual increments.

linical pplications A

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rain ( ead ircumference- rain ize) H

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The general body growth is rapid during fetal life and first 1–2 years of age. The growth velocity slows later during mid-childhood and accelerates once again during puberty (Fig. 3.2.1). The limbs and arms grow faster than the trunk so that body proportions undergo marked variation as an infant grows into an adolescent.

It grows at different rates around 9–11 years in girls and 11–13 years in boys. The sexual development is complete by 19–20 years of age.



B

General ody

eproductive ( exual) evelopment



The various growth periods are shown in Table 3.2.1.

The growth of lymphoid tissue is the highest during midchildhood when children are often observed to have enlarged tonsils and lymph nodes, maximum being at 8–9 years of age and later decreases in size.

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Growth Pattern of ifferent ody ystems

ymphoid Tissue Growth

Physical growth begins to slow at around age 1 year. As growth slows, children need fewer calories and parents may notice a decrease in appetite. Two-year-old child can have very erratic eating habits that sometimes make parents anxious. It seems as though some children eat virtually nothing yet continue to grow and thrive. Actually, they eat little 1 day and then make up for it by eating everything in sight the next day. Rapid early growth in low birth weight or healthy fullterm infants (centile crossing) is associated with later fatness, obesity, hypertension, hypercholesterolemia and 69

Pediatricians should remember that the first thing that springs to most parents’ minds when they hear the phrase “physical growth” used in the context of child development is height. Height or how tall a child grows can easily be measured. It is by no means the only facet of physical growth in children. In addition to height, the development of gross motor skills, fine motor skills and coordination are all important indicators of physical growth. • Growth is a fundamental characteristic of childhood. • Despite being influenced by many factors, it remains remarkably predictable. • Normal growth is an indicator of optimum health. • Deviation from the normal pattern is indicative of a pathological process. • Periodic assessment facilitates early detection of growth faltering, which may be the first manifestation of undernutrition/infection/disease.

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mportance of Growth ssessment

realized. At birth, the brain of the infant is 25% of the adult size. At the age of 1 year, the brain has grown to 75% of its adult size and to 80% by age three, reaching 90% by age seven. The influence of the early environment on brain development is crucial. Infants exposed to good nutrition, toys and playmates have better brain function at age 12 than those raised in a less stimulating environment. The rapid brain growth is reflected by an increase in head circumference.

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ormonal influences: After first 6–8 months of life, the GH and thyroxine deficiency, and in addition these hormones during puberty, the sex hormones, have also an important role in induction of the pubertal growth spurt. • motional factors: Emotional deprivation, anxiety and insecurity influence the neurochemical regulation of GH and may affect a child’s growth.

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Growth ssessment in nfancy and hildhood

infants tend to be shorter throughout the life than infants whose size is appropriate for their gestational age.

ength on an nfantometer I

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Tools for nthropometry Infant lying straight with his shoulders and buttocks flat against the measuring surface, eyes looking up, second person holds head to touch the head piece, align the body and extend both legs by one hand on knees, and bring the foot-piece firmly against the heels. Record the length to the nearest 0.1 cm (Fig. 3.2.2) (See Chapters 1.3 and 3.1). H



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insulin resistance; the key risk factors for coronary vascular disease. Buyken et al. showed that breastfeeding reduces these risks. Early growth and the brain in undernutrition and/ or anemia induce structural changes. Studies show that the impact of undernutrition in brain growth induces structural changes (loss of frontal lobe asymmetry); impairs higher mental functions; and there is persistence of soft neurological signs. Maternal anemia (iron-deficiency) affects development of neurotransmitters irreversibly. Puberty is fueled by the secretion of GH and sex steroids. Puberty is the process of physical maturation from child to adult. The timing of this growth spurt is extremely variable. At puberty, a second growth spurt occurs, being earlier in girls by 1 1/3–2 years than in boys, giving rise on the average, to a difference in adult height between men and women of about 14–15 cm.

eight

It is measured standing for a child with minimum clothing without shoes and socks, standing with feet parallel on an even platform, stretching fullest, arms hanging on the sides, and buttocks and heels touching the rod. The head is held erect with lower border of the eye orbit in the same horizontal plane as the external canal of the ear (Frankfort plane). The head piece is lowered to touch the top of the head (Fig. 3.2.3).

ength

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It is measured on an anthropometric rod or a stadiometer, if the child can stand (> 2 years of age). In general, length in normal term infants increases about 30% by 5 months of age and more than 50% by 12 months of age. Infants grow 25 cm during the first year; and height at 4 years is about double of the birth length. In boys, half the adult height is attained around 2 years of age; while in girls, height at 19 months is about half the adult height. Some small-for-gestational-age

Figure 3.2.3 Stadiometer for height measure: note the position  

70

Figure 3.2.2 Infantometer for length: help of two measurers is required  

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It is measured on an infantometer in children too young to stand until 2 years of age.

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Anterior Fontanel

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This is measured on the left upper arm mid-way between the acromion and olecranon processes. It measures 9.8 cm at birth, 14.5 cm around 1 year with slow increase from 14.8 cm to 16.2 cm between 1 year and 5 years of age. In field surveys, it helps in diagnosis of mal/under nutrition: a value more than 13.5 cm is taken as normal nourished, 12.5–13.4 cm as borderline, 11.5–12.4 cm as mild to moderate undernutrition and less than 11.5 cm as severe undernutrition. C

Anterior fontanel (AF) is a diamond-shaped open gap situated in midline at the junction of the coronal and sagittal

idarm ircumference

hest ircumference C



This is measured over the most prominent part of the occipital and just above the supraorbital ridges, using a flexible, nonstretchable tape. Position the tape just above the eyebrows, above the ears and around the biggest part on the back of the head. Pull the tape snugly to compress the hair and take reading nearest to 0.1 cm (Fig. 3.2.6). The head circumference measurement in infancy serves as a guide to brain growth; it is related to intelligence and cognition. Large infants have larger head circumference.

Posterior Fontanel (PF), placed between the intersection of the occipital and parietal bones, closes within 6–8 weeks of life. An open PF in later life is noted in congenital hypothyroidism. M

C

ead ircumference

Posterior Fontanel

A

At birth, chest circumference is 3 cm less than the head circumference. It equals or exceeds head circumference by 10–12 months of age. In prepubertal children, it can be recorded at the level of nipples.

rm pan S

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Infant/child should be naked or in minimal clothing. Ideal is to use sliding beam balance scale or electronic scale (Figs 3.2.4 and 3.2.5). Weighing scale is checked for zero, center the infant on the scale tray and weigh to the nearest 10 g; older child is weighed standing to the nearest 50 g.

sutures (size around 2 × 2 cm) that close by 18 months (range 10–18 months). Small or closed AF is a warning sign, i.e. microcephaly. Large AF may be present in hydrocephalus, hypothyroidism, Down syndrome, achondroplasia, osteo genesis imperfecta and mucopolysaccharidosis.

Grow h a d evelo me

eight

Measure outstretched arms from fingertip to fingertip. In children of European origin, the arm span should approximate the height (intermediate-length arms). Asians have proportionally shorter arms than Europeans, and Africans have significantly longer arms.  

Figure 3.2.4 Electronic weighing scale

Figure 3.2.6 Crossover technique to measure head circumference by fiber glass tape  

 

Figure 3.2.5 Seca scale to measure height and weight

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Waist-to-hip ratio (WHR) is measured over the highest palpable points of the iliac crests in the midaxillary lines, by a fiber glass tape. Hip is measured on the maximum extension of the buttocks. • Waist-to-hip ratio index of 0.7 for women and 0.9 for men have been shown to correlate strongly with general health and fertility • Women within the 0.7 range have optimal levels of estrogens and are less susceptible to major diseases such as diabetes, cardiovascular disorders and ovarian cancers • Men with WHR around 0.9, similarly, have been shown to be more healthy and fertile with less prevalence of prostate and testicular cancers.

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Percentiles describe the frequency distribution of anthropometric parameters like weight, height, skull circumference, BMI, etc. Fiftieth percentile is the average (median) line for the given population. It describes the percent of children expected to be on or below that line, e.g. 50th centile means that 49% of the observations are below and 50% above that observation. A child’s growth parameters may be on the centile line or between two centile lines. Conventionally, for all parameters, 3rd and 97th percentiles are the lowest, and highest 94% of observations. Any child with parameters below or above these limits or those who cross percentiles after 2 years of age needs careful evaluation.

Examples •

If height and weight consistently are on the 60th percentile line until a child is 5-year-old, then the height has dropped to the 30th percentile at age 6, that might indicate that there is a growth problem (catch down-retardation of growth) because the child is not following his or her previous growth pattern. This indicates disease. • Boy with height in 40th percentile and weight in the 85th percentile (he is taller than 40% of the kids of his age, but weighs more than 85% of kids his age). There might be a health problem (overweight/obesity). On the other hand, if he is in the 85th percentile for height and weight, and follows that pattern consistently over time, that usually means that he is a normal child just larger than average.

Z Scores It is calculated as below: Z score =

Observed value − median reference

SD of reference population A value of –2 Z score corresponds to 3rd percentile. Z scores are labeled as 1, 2, 3, –1, –2, and –3. These indicate

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Around 50% of body fat is located under the skin. Measurement of triceps and biceps skinfold thickness (SFT) gives estimate of peripheral fat, and subscapular and suprailiac SFT indicates amount of central fat. The Lange’s or Harpenden’s skinfold calipers are used. Measurements are done as follows: • iceps: At the midpoint of their muscle belly, a point generally opposite the nipple • Triceps: Between the tip of olecranon process of ulna (elbow) and the acromion process of the scapula (shoulder), a point is marked on the back of the arm • ubscapular: Below inferior angle of scapula 45° to vertical • uprailiac: Above iliac crest in midaxillary line (approximately 2.5 cm above hip bone).

Percentiles



kinfold Thickness

Growth charts consist of a series of percentile curves. It means graphical representation of growth reference standards and consists of a series of percentile curves that illustrate the distribution of body measurements in the study population (Figs 3.2.7 to 3.2.12).



S

Body mass index (BMI) is the ratio of weight in kilogram to the square of height in meters (wt/ht2). This is a good indicator of variability of energy status. If more than 95th centile, it suggests obesity and less than 5th centile, undernutrition (thin). In adolescents, calculate with the weight and height values in relation to the sexual maturity. The BMI values for Indian children are different than the National Center for Health Statistics (NCHS)—BMI values.

Growth harts



ass ndex I

ody

M

Subtract the LS from the height. The US/LS ratio is calculated by dividing the US by the LS. In children of European origin, this ratio is about 1.7 at birth and decreases to 1 at about age 10, where it remains throughout adulthood. Asians have proportionally shorter legs (therefore, larger US/LS ratio) and Africans have longer legs (therefore lower US/LS ratio).



Upper Segment

Values less than 0.5 exclude central obesity but values more than 0.5 indicate central obesity even in children with normal weight and height. Waist-to-height ratio may predict cardio-metabolic risk in normal weight as well as in overweight/obese children, according to results from the Bogalusa Heart Study, 2011.



Measure from the symphysis pubis to the floor.

aist-to- eight atio



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Lower Segment

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Upper and ower egments

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Table 3.2.2 provides the summary of the details of physical growth in Indian children related to weight and height gain. Table 3.2.3 provides a summary of the changes in head circumference at different ages in children.

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hoice of Growth urve for ndian hildren

The data on affluent Indian children were collected during 1989–1991 by the Nutrition Foundation of India from birth to 5 years (seven states); only full term with birth weight more than or equal to 2500 g (boys 433 and girls 346) were followed during first year of life at 3, 6, 9 and 12 months of age with minimum of three readings for every infant (cohort I). In cohort II, from 12 months to 5 years of age, 1011 boys and 874 girls were followed on their birthday and 6 monthly with minimum of three measurements for

Grow h a d evelo me

how far points are above or below the mean (Z score 0). A range of ±2 Z scores includes 95.4% of all observations and is the conventionally accepted limits of normality.

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Figure 3.2.7 The growth curves (data) for height, weight and skull circumference for girls from birth to 2 years Source: Agarwal et al. Indian Pediatrics; 1994

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Table 3.2.3 Summary of changes in head circumference

each child up to 72 months of age. Children had received exclusive breast milk for 3–4 months of life in cohort I and II (as prevalent in those years). The Indian Council of Medical Research (ICMR) crosssectional data for physical growth and sexual development for 5 years to 17 years in girls and from 5 years to 18 years in boys (9 states, 23 schools, 12893 boys and 10,941 girls), on affluent Indian children were collected during 1989–1991. These two data sets were collected around same time on affluent Indian children – “birth to adolescence.” These data sets on physical growth and sexual development (birth to 18 years of age) continue to serve as the baseline reference data for assessing physical growth and sexual development; assessed by the same measurers at all centers for seeing secular trend in height and percentile of children becoming overweight and obese. These “growth charts” (Figs 3.2.7 to 3.2.12; Tables 3.2.4 to 3.2.13) give height, weight, skull circumference and BMI for age and 74 gender.

 

B

At birth irth to 3 months

35 cm 2 cm/month

3–6 months

1 cm/month

6–9 months

0.5 cm/month

9–12 months

0.25 cm/month

On first birthday

46–47 cm, 35% increase from birth size

At 2 years age

48 cm

At 5 years

50–51 cm

12 years

52 cm

B







t

Anthropometric measures of normal full term newborns: •  Birth weight: 2.5–4.0 kg •  Length: 50 cm (around) •  Head circumference: 34–35 cm Weight gain: Neonates generally lose 5–8% (maximum being 10%) weight during first 2–3 days of life, which is regained by the 10th day. Average daily weight gain during: •  First 3 months: 30 g •  3–6 months: 20 g (birth weight doubles by 5–6 months of age) •  6–9 months: 15 g •  9–12 months: 12 g (birth weight triples by first birthday) •  1–3 years: 8 g (around 3 kg/year). irth weight quadruples by 2 years of age. •  4–6 years: 6 g (around 2 kg/year); this rate of gain continues till the onset of puberty Length/height gain (height velocity): •  Birth to 3 months: 3.5 cm/month •  3–6 months: 2.0 cm/month •  6–9 months: 1.5 cm/month •  9–12 months: 1.2 cm/month •  1–3 years: 1.0 cm/month •  4–6 years: 5 cm/year (at 4 years = 100 cm; double of birth length) Gains in length •  During first year of life: 25 cm •  During second year of life: 12.5 cm •  During third year of life: 7.5–10 cm •  7 cm/year at 3–4 years •  6 cm/year at 5–6 years •  5 cm/year till puberty •  In immediate prepubertal period, growth velocity slows down before the pubertal spurt begins (adrenarche) Abnormal growth: •  Less than 7 cm/year for less than 4 years of age •  Less than 6 cm/year for 4–6 years •  Less than 4.5 cm/year for 6 years–onset of puberty

WHO Multicenter Growth Reference Study The WHO growth data, in India were collected from south Delhi area and pooled in the international data. The WHO Multicenter Growth Reference Study (MGRS) was undertaken between 1997 and 2003 to generate new growth curves for assessing the growth of infants and young children around the world. The MGRS collected primary growth data and related information from approximately 8500 children from widely different ethnic backgrounds and cultural settings (Brazil, Ghana, India, Norway, Oman and the USA). The new growth curves are expected to provide a single international standard that represents the best description of physiological growth for all children from birth to 5 years of age and to establish the breastfed infant as the normative model for growth and development. These growth charts depart from the growth reference model in several ways. Children from six countries provided the data measurements, which were not representative of their country of residence, and were selected on the basis of sociodemographic criteria and child’s nutrition as per WHO guidelines (see Chapter 3.3 for more details).

Comparing Agarwal and Khadilkar Data Sets Comparing Agarwal et al. school data (ICMR) against recently available Khadilkar et al. data set, the changes in height vary from 1% to 2.5% among boys and 1% to 3% in girls. The median final height in boys is higher by 0.7 cm but the 97th percentile is higher by 1.7 cm whereas in girls the median is same but 97th percentile is higher by 2.4 cm. The changes in weight vary from 20% to 29% among boys and 18% to 25% among girls. Therefore, Khadilkar et al. data showed marginal secular trend for height with marked increase in obesity which is in line with the data from the Western countries such as United Kingdom. Their observations are similar to those recently published by Marwaha et al. Khadilkar and Marwaha data sets of school children have important health implications, alarming increase in obesity, which needs immediate action to control or prevent and create nationwide awareness. Redoing the curves in response to increasing weight alone will have the effect of “normalizing” the weight

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Table 3.2.2 Growth pattern in infancy and early childhood: summary of changes in weight and height

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Figure 3.2.8 The growth curves (data) for height, weight and skull circumference for girls from birth to 2 years Source: Agarwal et al. Indian Pediatrics; 1994

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Figure 3.2.9 The growth curves (data) for height and weight for girls from 2 years to 17 years Source: Agarwal et al. Indian Pediatrics; 1992, 1994 and 2001  

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Figure 3.2.10 The growth curves (data) for height and weight for boys from 2 years to 17 years Source: Agarwal et al. Indian Pediatrics; 1992, 1994 and 2001

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Figure 3.2.11 The growth curves (data) for body mass index for girls from birth to 17 years Source: Agarwal et al. Indian Pediatrics; 1992, 1994 and 2001

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Figure 3.2.12 The growth curves (data) for body mass index for boys from birth to 17 years Source: Agarwal et al. Indian Pediatrics; 1992, 1994 and 2001

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Table 3.2.4 Weight (kg) percentiles for girls (birth–6 years of age): affluent Indians Age (months)

Percentiles 3rd

5th

10th

25th

50th

75th

90th

95th

97th

0

2.6

2.6

2.7

2.9

3.1

3.4

3.7

3.8

3.9

3

4.4

4.5

4.8

5.2

5.6

6.0

6.4

6.6

6.7

6

5.6

5.7

5.9

6.4

6.9

7.4

7.9

8.2

8.4

9

6.9

7.0

7.3

7.5

8.0

8.5

8.9

9.2

9.5

12

7.8

8.0

8.2

8.6

9.1

9.7

10.0

10.4

10.6

18

8.7

9.0

9.5

10.0

10.5

11.4

11.8

12.1

12.4

24

9.4

9.6

10.0

10.9

11.6

12.2

13.0

13.5

13.9

30

9.9

10.2

10.6

11.7

12.5

13.0

13.9

14.4

14.8

36

10.5

10.8

11.4

12.4

13.4

14.2

15.0

15.7

16.4

42

11.4

11.8

12.1

13.2

14.2

15.2

16.5

17.2

17.8

48

11.9

12.2

12.9

13.9

15.0

16.5

17.5

18.2

18.9

54

12.9

13.3

14.0

14.8

16.0

17.5

18.7

19.7

20.0

60

13.4

13.9

14.5

15.4

17.0

18.4

19.9

20.0

21.0

66

14.2

14.9

15.6

16.2

17.9

19.2

20.1

21.0

21.4

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Table 3.2.5 Height/length (cm) percentiles for girls (birth–66 month of age): affluent Indians  

ti e

Age (months)

Percentiles

3rd

5th

10th

25th

50th

75th

90th

95th

97th

0

47.5

48.0

48.3

49.1

50.0

51.0

51.8

52.3

52.7

3

55.3

56.4

57.5

58.5

59.3

60.9

62.0

63.1

63.8

6

61.0

61.7

62.5

63.7

65.2

66.6

68.3

69.0

69.8

9

65.3

66.2

67.3

68.5

69.6

70.9

72.4

73.1

73.9

12

70.2

70.9

72.0

73.9

74.0

75.4

76.5

77.1

77.8

18

73.5

74.8

75.9

78.5

80.0

81.5

83.4

84.7

85.0

24

77.7

79.0

80.6

82.7

84.0

86.2

88.1

89.4

89.8

30

82.0

82.7

84.7

86.9

89.3

91.3

93.0

94.2

95.0

36

85.3

86.1

87.9

90.7

92.9

95.4

97.5

99.1

99.9

42

88.1

89.9

91.0

93.0

96.7

99.0

101.4

102.7

104.5

48

91.2

92.9

94.9

97.4

99.9

102.4

104.8

106.9

107.9

54

94.5

95.8

97.3

100.5

103.0

105.5

107.0

109.0

110.0

60

96.9

98.4

100.1

103.1

106.0

109.1

111.1

112.5

113.7

66

100.8

102.0

103.6

106.3

109.4

112.2

114.7

116.0

117.0

n U

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Table 3.2.6 Weight (kg) percentiles for boys (birth–66 months of age): affluent Indians

25th

50th

75th

90th

95th

97th

0

2.6

2.6

2.7

3.0

3.1

3.5

3.6

3.8

3.9

3

4.7

4.8

5.0

5.4

5.8

6.2

6.7

6.9

7.0

6

6.0

6.1

6.2

6.5

7.1

7.7

8.2

8.5

8.7

9

7.1

7.3

7.5

8.0

8.4

8.8

9.4

9.8

10.0

12

8.2

8.4

8.7

9.1

9.6

10.0

10.4

10.8

11.1

18

8.7

9.0

9.8

10.1

10.9

11.4

12.0

12.5

12.8

24

9.7

10.0

10.4

11.1

11.9

12.6

13.4

14.1

14.9

30

10.7

11.0

11.4

12.1

12.9

13.7

14.7

15.4

15.9

36

11.4

11.5

12.0

12.8

13.7

14.6

15.9

16.5

17.0

42

11.8

12.2

12.7

13.6

14.5

15.5

16.9

17.8

18.5

48

12.4

12.8

13.4

14.4

15.4

16.4

17.7

18.8

19.6

54

13.1

13.7

14.1

15.0

16.2

17.6

19.0

20.0

20.1

60

13.8

14.5

15.0

16.1

17.2

18.5

20.0

20.5

21.8

66

14.4

15.2

16.0

17.1

18.1

19.7

20.9

21.0

22.0

G R

58.7

V d 60.1

61.5

62.7

63.4

64.3

64.0

65.5

67.0

68.9

70.5

71.8

69.3

70.3

71.6

73.0

73.8

74.2

73.7

74.7

75.9

76.9

78.0

78.6

79.1

80.9

82.0

83.3

84.6

85.2

81.4

83.4

85.7

87.1

88.7

90.1

90.5

85.8

88.1

90.4

92.3

94.0

95.3

95.9

89.9

92.4

94.2

96.4

98.5

99.9

100.7

92.4

95.1

97.9

99.9

102.7

104.1

105.5

94.1

95.4

97.9

100.7

103.3

106.2

108.4

109.4

96.3

98.1

100.6

103.7

106.9

109.9

112.0

113.0

97.9

99.3

101.4

103.9

106.9

109.9

113.4

114.9

116.2

100.8

102.0

104.3

107.6

110.0

113.2

116.8

118.0

119.4

n

10th

D

5th

p

3rd

t

Percentiles

nt

Age (months)

 

Table 3.2.7 Height/length (cm) percentiles for boys (birth– 66 months of age): affluent Indians

ti e

Age (months) 3rd

5th

10th

0

47.6

47.8

48.3

3

56.3

56.7

6

62.0

62.3

9

67.1

67.4

12

71.7

72.2

18

75.3

76.0

24

78.9

79.9

30

84.7

85.0

36

87.7

88.6

42

89.8

91.1

48

92.5

54

95.6

60 66

n U 57.3 63.0 68.1 72.7 76.9

25th 49.1

Percentiles

50th

75th

90th

95th

97th

50.1

50.8

51.9

52.4

52.9

81

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Table 3.2.8 Head circumference (cm) percentiles for girls (birth–36 months): affluent Indians

t

t

Age (months)

Percentiles N

3rd

5th

10th

25th

50th

75th

90th

95th

97th

0

269

33.1

33.2

33.6

34.1

34.5

35.2

35.5

36.0

36.4

3

299

37.4

37.3

38.2

39.0

39.6

40.3

41.0

41.3

41.4

6

308

39.7

40.1

40.3

41.8

42.4

42.9

43.4

43.8

44.0

9

302

42.2

42.5

42.8

43.4

43.9

44.5

44.9

45.3

45.5

12

290

43.1

43.5

44.1

44.6

45.1

45.7

46.1

46.4

46.5

18

135

43.9

44.4

44.9

45.7

46.4

47.0

47.8

48.0

48.0

24

179

44.7

45.0

45.5

46.2

47.0

47.7

48.3

48.7

48.9

30

206

44.9

45.4

45.8

46.7

47.8

48.4

49.1

49.7

50.0

36

266

45.3

45.7

46.0

47.0

48.0

49.0

49.9

50.4

50.9

G R

 

Table 3.2.9 Head circumference (cm) percentiles for boys (birth–36 months): affluent Indians Age (months)

Percentiles

46.9

V d 47.7

48.5

49.0

49.5

49.9

47.4

48.2

48.8

49.6

49.9

50.4

47.9

48.7

49.5

50.0

50.9

51.0

3rd

5th

10th

25th

0

33.2

33.5

33.8

34.2

3

38.1

38.2

38.6

39.3

6

40.3

40.7

41.3

9

42.5

42.9

43.2

12

43.7

44.0

44.4

18

44.8

44.9

45.4

24

44.5

45.8

30

46.2

46.4

36

46.1

46.7

ti e

n U 46.3 46.8 47.0

42.1 43.7 44.9 46.1



gains you are seeing at the higher end of the scale since the definition of “normal” weight will shift to the right, potentially putting more children who today are classified as overweight into the normal weight category. At the bottom of the scale, some children who are today classified as normal weight will be classified as underweight. On both the high and low ends of the scale, creating new reference curves with these changes may not be beneficial from a public health perspective. Secondly, Khadilkar et al. data line for 3rd centile flattens after 14 tears if age (sjewubg as cinoared ti Agarwak et al. and Marwaha et al. Thirdly, it is important to take lesson from the “methods including the data source in construction of the Centers for Disease Control and Prevention (CDC) 2000 growth charts”, as weight data from the National Health and Nutrition Examination 82 Survey (NHANES) III (1988–1994) were excluded from the weight for age and BMI-for-age curves because of a secular

50th

75th

90th

95th

97th

34.7

35.3

35.9

36.3

36.5

40.0

40.7

41.4

42.0

42.5

42.7

43.3

43.8

44.2

44.7

44.2

44.8

45.3

45.8

46.2

45.4

45.9

46.5

46.9

47.3

47.0

48.0

48.4

48.7

48.9

trend in body weight that occurred between NHANES II (1976–1980) and NHANES III.

Recommendations Presently, the choice remains using IAP recommended 2007 growth charts based on data (birth to 18 years of age) by Agarwal et al. This was also recommended in growth chart evaluation study by Khadgawat et al. The WHO curves may be used up to 2 years of age to assess growth as practiced in USA. It is important to note that in spite of unprecedented economic growth since 1991, Indian women remain short by 5.5 cm as compared to the average height, in 54 developing countries. The Indian affluent children at 18 years of age are still shorter than the NCHS/WHO data. Thus, we must examine our children in nationally collected growth data sets, as calculated BMI values are also different as compared to the WHO/NCHS values.

vip.persianss.ir

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Table 3.2.10 Weight (kg) percentiles for girls (6–17 years): affluent Indians 97th 23.7 25.4 27.5 29.8 32.3 34.9 37.7 40.5 43.4 46.4 49.3 52.2 55.1 57.9 60.7 63.2 65.7 67.9 70.0 71.8 73.3 74.6 75.6

75th 115.9 118.4 121.3 124.4 127.5 130.7 133.8 136.9 139.8 142.7 145.4 147.9 150.3 152.5 154.4 156.2 157.6 158.8 159.7 160.4 160.4 160.5 160.5

97th 123.3 126.0 129.3 132.8 136.4 139.8 143.1 146.2 149.0 151.7 154.2 156.5 158.5 160.4 162.1 163.5 164.7 165.8 166.5 167.1 167.4 167.6 168.0

G R

V d

ti e

75th 19.2 19.9 20.9 22.2 23.6 25.3 27.2 29.3 31.4 33.7 36.0 38.4 40.7 42.9 45.1 47.1 48.9 50.5 51.8 52.9 53.6 54.0 53.9

n

50th 17.8 18.3 19.0 19.9 20.8 22.0 23.5 25.1 26.9 28.9 30.9 32.9 35.0 37.1 39.1 41.0 42.7 44.3 45.7 46.8 47.7 48.2 48.4

D

25th 16.4 16.9 17.3 18.0 18.7 19.6 20.7 22.1 23.6 25.3 27.1 28.9 30.8 32.6 34.5 36.2 37.8 39.3 40.6 41.7 42.5 43.0 43.3

p

6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5 11.0 11.5 12.0 12.5 13.0 13.5 14.0 14.5 15.0 15.5 16.0 16.5 17.0

5th 15.2 15.5 15.8 16.2 16.4 16.8 17.6 18.5 19.7 21.0 22.4 24.0 25.6 27.2 28.9 30.6 32.1 33.6 35.0 36.2 37.3 38.1 38.7

t

Percentiles 3rd 14.1 14.4 14.8 15.3 15.9 16.4 17.1 18.3 19.5 20.9 22.3 23.7 25.1 26.5 27.9 29.3 30.7 32.1 33.4 34.6 35.7 36.7 37.6

nt

Age (years)

 

Table 3.2.11 Height (cm) percentiles for girls (6– 17 years): affluent Indians Age (years) 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5 11.0 11.5 12.0 12.5 13.0 13.5 14.0 14.5 15.0 15.5 16.0 16.5 17.0

3rd 102.1 104.5 107.1 109.7 112.3 115.0 117.8 120.6 123.4 126.1 128.8 131.4 133.9 136.3 138.5 140.6 142.4 144.1 145.5 146.6 147.5 148.0 148.3

n U 5th 104.5 107.0 109.4 111.6 113.9 116.2 118.8 121.4 124.1 126.9 129.7 132.4 135.0 137.5 139.8 141.9 143.8 145.4 146.6 147.5 148.0 148.1 148.5

25th 108.8 111.1 113.7 116.4 119.3 122.2 125.1 128.0 130.8 133.7 136.4 139.0 141.5 143.8 145.9 147.8 149.4 150.8 151.8 152.6 152.9 152.9 153.0

Percentiles

50th 112.5 114.9 117.4 120.3 123.2 126.2 129.2 132.3 135.2 138.1 140.9 143.5 146.0 148.3 150.4 152.2 153.8 155.1 156.0 156.6 156.8 156.5 157.0

83

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Table 3.2.12 Weight (kg) percentiles for boys (6–18 years): affluent Indians Age (years)

Percentiles 3rd 15.2 15.7 16.2 16.8 17.5 18.2 19.2 19.9 20.9 21.9 22.9 24.1 25.3 26.7 28.1 29.6 31.2 32.9 34.6 36.5 38.5 40.6 42.8 45.2 47.6

6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5 11.0 11.5 12.0 12.5 13.0 13.5 14.0 14.5 15.0 15.5 16.0 16.5 17.0 17.5 18.0

5th 15.7 16.4 16.9 17.5 18.0 18.6 19.4 20.2 21.2 22.3 23.5 24.9 26.3 27.8 29.3 31.0 32.7 34.5 36.3 38.1 40.0 41.9 43.9 45.8 47.8

25th 18.0 18.6 19.4 20.0 20.7 21.3 22.0 22.9 24.1 25.5 27.1 28.9 30.7 32.7 34.7 36.8 38.8 40.9 42.8 44.7 46.5 48.1 50.0 52.0 54.0

50th 19.0 20.0 21.0 22.0 22.6 23.5 24.4 25.6 27.0 28.7 30.6 32.7 34.8 37.1 39.4 41.8 44.1 46.3 48.5 50.5 52.4 54.0 55.5 57.2 58.6

97th 25.4 27.7 29.7 31.6 33.5 35.5 37.7 40.1 42.7 45.4 48.2 51.1 54.1 57.1 60.0 63.0 65.9 68.7 71.4 73.9 76.3 78.5 80.5 82.2 83.6

75th 118.0 120.7 123.0 125.2 127.4 129.8 132.5 135.3 138.3 141.5 144.7 147.9 151.1 154.2 157.3 160.2 162.9 164.4 167.7 169.6 171.2 172.4 173.1 173.4 173.4

97th 125.9 128.4 130.8 133.2 135.8 138.5 141.4 144.5 147.7 151.0 154.3 157.5 160.8 163.9 166.9 169.7 172.7 174.7 176.8 178.5 179.8 180.7 181.2 181.1 181.6

G R

V d

ti e

75th 20.7 21.9 22.9 23.9 25.0 26.3 27.7 29.4 31.3 33.4 35.6 37.9 40.3 42.7 45.1 47.6 50.0 52.4 54.6 56.8 58.8 60.6 62.3 63.7 64.9

 

Table 3.2.13 Height (cm) percentiles for boys (6–18 years): affluent Indians Age (years)

84

6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5 11.0 11.5 12.0 12.5 13.0 13.5 14.0 14.5 15.0 15.5 16.0 16.5 17.0 17.5 18.0

3rd 103.7 106.1 108.5 110.9 113.3 115.2 118.0 120.3 122.7 125.1 127.5 129.9 132.4 134.9 137.4 140.0 142.6 145.2 148.0 150.8 153.6 156.6 159.6 162.7 161.0

n U 5th 105.5 107.5 109.8 111.3 114.4 116.2 118.5 120.9 123.4 125.9 128.5 131.1 133.8 136.5 139.2 141.8 144.5 147.2 149.8 152.4 154.9 157.4 159.8 163.1 163.5

25th 112.0 113.5 115.9 117.8 119.7 121.9 124.2 126.7 129.4 132.4 135.6 138.0 141.0 143.9 146.8 149.7 152.4 155.0 157.4 159.6 161.6 163.3 165.0 167.5 168.8

Percentiles 50th 114.2 117.3 119.7 121.6 123.6 125.7 128.2 130.8 133.6 136.6 139.6 142.7 145.8 148.9 152.0 154.9 157.6 160.2 162.5 164.6 166.3 167.7 168.7 169.3 169.8

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G R

















B

1. Agarwal DK, Agarwal KN. Physical growth in affluent Indian children (birth- 6 years). Indian Pediatr. 1994;31:377- 413. 2. Agarwal KN, Agarwal DK, Benkappa DG, et al. Growth performance of affluent Indian children (Under-Fives). Nutrition Foundation of India; 1991. 3. Agarwal KN, Agarwal DK, Seth A. The growth infancy to adolescence, 2nd edition. New Delhi: CBS Publishers; 2007. pp. 1-34 and 87-93. 4. Agarwal KN, Agarwal DK, Upadhaya SK, et al. Physical and sexual growth pattern of affluent Indian children from 5-18 years of age. Indian Pediatr. 1992;92:1203-82. 5. Agarwal KN, Saxena A, Bansal AK, et al. Physical growth assessment in adolescence. Indian Pediatr. 2001;38:1217-35. 6. Buyken A. Karaolis-Danckert N, Renner T, et al. Effects of breastfeeding on trajectories of body fat and BMI throughout childhood. Obesity (Silver Spring). 2008;16:389-95. 7. Greulich WW, Pyle SI. Radiographic Atlas of Skeletal Development of the Hand and Wrist, 2nd edition. Stanford, CA: Stanford University Press; 1959.

8. Gupta P. Anthropometry: Assessment of Growth. In: Gupta P (Ed). Clinical Methods in Pediatrics. 2nd edition. New Delhi: CBS Publishers; 2011. pp. 58-110. 9. Khadgawat R, Dabadghao P, Mehrotra RN, et al. Growth charts for evaluation of Indian children. Indian Pediatr. 1998;35:859-65. 10. Khadilkar VV, Khadilkar AV, Cole TJ, et al. Cross sectional growth curves for height, weight, and body mass index for affluent Indian children, 2007. Indian Pediatr. 2009;46:47785. 11. Kuczmarsi RJ, Ogden CL, Guo SS, et al. 2000 CDC Growth charts for the United States: methods and development. Vital Health Stat 11. 2002;246:1-190. 12. Marwaha RK, Tandon N, Singh Y, et al. A study of growth parameters and prevention of overweight and obesity in school children of Delhi. Indian Pediatr. 2006;43:943-52. 13. Marwaha RK, Tandon N, Ganie MA, et al. Nationwide reference data for height, weight and body mass index of Indian School children. Natl Med J India. 2011;24:269-77. 14. WHO Multicenteric Growth Reference Study Group: WHO Child Growth Standards based on length/height, and weight and age. Acta Pediatr Suppl. 2006;450:76-85.

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ibliography

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Who Under-5 Growth tandards 2006 Vaman Khadilkar

C

Why New Growth harts? The linear growth patterns of these highly selected, healthy infants were strikingly similar between countries, supporting the view that they represent a standard against which the growth of all children can be assessed, wherever they live and however they are fed. Government of India has given a directive to use WHO growth charts for all children under the age of 5 years and IAP has accepted these standards for children under 5-year-old. C



O

C

C

I

nterpretation of Who harts and ut ffs

Doctors and health care workers find it difficult to interpret various cut offs for diagnosis of underweight, overweight, stunting, wasting, etc. These have therefore been clearly spelt out in the new WHO Multicenter Growth Reference Study and are given in Tables 3.3.1 and 3.3.2. These make it easy for the practicing pediatrician and health care worker to follow as a guideline for management and referral (Tables 3.3.3 to 3.3.8; Figs 3.3.1 to 3.3.5). I

pplicability of Who harts in ndia and round the World C

A



The list of charts available is as follows: • Length/height-for-age • Weight-for-age • Weight-for-length • Weight-for-height • Body mass index-for-age • Head circumference-for-age • Arm circumference-for-age • Subscapular skinfold-for-age • Triceps skinfold-for-age • Motor development milestones WHO growth charts can be downloaded from the site http://www.who.int/childgrowth/standards/en/

V d

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Where to Get Who Growth harts?

A

Growth charts are an essential component of the pediatric toolkit. Their value resides in helping to determine the degree to which physiological needs for growth and development are met during the important childhood period. Beyond their usefulness in assessing children’s nutritional status, many government and United Nation agencies rely on growth charts to measure the general wellbeing of populations, formulate health and related policies, and plan interventions and monitor their effectiveness. The relative magnitude of different measures of nutritional status is affected by the choice of reference charts used. In April 2006, WHO released child growth standards for children up to the age of 5 years, to provide a multiethnic benchmark for breastfed children. The standards are derived from children who were raised in environments that minimized constraints to growth such as poor diets and infection. In addition, their mothers followed healthy practices such as breastfeeding and not smoking during and after pregnancy. Because WHO standards depict physiological human growth under optimal environmental conditions, they provide an improved tool for assessing growth. These charts thus are prescriptive standards and not descriptive references. These standards provide an opportunity to redefine and revitalize actions to promote optimal child growth, foster the adoption of “best practices,” such as incorporating height and BMI to assess the dual burden of under and overnutrition (stunting and overweight), and provide coherence between national and international infant feeding guidelines that recommend breastfeeding as the optimal source of nutrition during infancy. Thus these charts are recommended for assessing the pattern of infant growth and harmonize growth assessment systems within and between the countries. A second feature of the study that makes it attractive as a basis for an internationally applicable standard is that it included children from a diverse set of countries: Brazil, Ghana, India, Norway, Oman and the USA. By selecting privileged, healthy populations, the study reduced the impact of environmental variation. Another key characteristic of the new standards is that they explicitly identify breastfeeding as the biological norm and establish the breastfed child as the normative model for growth and development. The method used to construct the WHO standards generally relied on the Box-Cox power exponential distribution and the final selected models simplified to the LMS model.

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t

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3.3

Different countries have adopted different policies on the use and acceptability of WHO growth charts. In USA, CDC recommends use of WHO charts up to the age of 2 years and CDC charts from 2 years to 18 years. In United Kingdom,

86

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p

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Figure 3.3.1 WHO Multicenter Growth Reference Study Group. WHO child growth standards based on length/height, weight and age. Acta Paediatr. 2006;95(suppl 450):76-85

87

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Figure 3.3.2 WHO Multicenter Growth Reference Study Group. WHO child growth standards based on length/height, weight and age. Acta Paediatr. 2006;95(suppl 450):76-85

88

vip.persianss.ir

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Gro nt

p

D

n

h a d evelo me

 

Figure 3.3.3 WHO Multicenter Growth Reference Study Group. WHO child growth standards based on length/height, weight and age. Acta Paediatr. 2006;95(suppl 450):76-85

89

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Figure 3.3.4 WHO Multicenter Growth Reference Study Group. WHO child growth standards based on length/height, weight and age. Acta Paediatr. 2006;95(suppl 450):76-85

90

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Figure 3.3.5 WHO Multicenter Growth Reference Study Group. WHO child growth standards based on length/height, weight and age. Acta Paediatr. 2006;95(suppl 450):76-85

91

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Table 3.3.1 Correlation between percentiles and Z scores for WHO charts Z score

Exact percentilesi

Rounded percentilesi

0

50

50

-1

15.9

15

-2

2.3

3

-3

0.1

1

1

84.1

85

2

97.7

97

3

99.9

99

 

Table 3.3.2 Growth parameters and their interpretation for the WHO charts Z score (percentile)

Length/height-for-age

Weight-for-age

Body mass index (BMI)for-age

> 3 (99)

May be abnormal

May be abnormal (use BMI)

Obese

> 2 (97)

Normal

Use BMI

Overweight

> 1 (85)

Normal

Use BMI

Risk of overweight

0 (50)

Normal

Use BMI

Normal

< −1 (15)

Normal

Normal

Normal

< −2 (3)

Stunted

Underweight

Wasted

< −3 (1)

Severely stunted

Severely underweight

Severely wasted

 

Table 3.3.3 Weight (kg) by age of boys and girls aged 0–2 years (WHO) Percentiles for boys

Percentiles for girls

Age in months

3rd

5th

25th

50th

75th

95th

97th

3rd

5th

25th

50th

75th

95th

97th

0

2.5

2.6

3.0

3.3

3.7

4.2

4.3

2.4

2.5

2.9

3.2

3.6

4.0

4.2

3

5.1

5.2

5.9

6.4

6.9

7.7

7.9

4.6

4.7

5.4

5.8

6.4

7.2

7.4

6

6.4

6.6

7.4

7.9

8.5

9.5

9.7

5.8

6.0

6.7

7.3

7.9

8.9

9.2

9

7.2

7.4

8.3

8.9

9.6

10.6

10.9

6.6

6.8

7.6

8.2

8.9

10.1

10.4

12

7.8

8.1

9.0

9.6

10.4

11.5

11.8

7.1

7.3

8.2

8.9

9.7

11.0

11.3

15

8.4

8.6

9.6

10.3

11.1

12.3

12.7

7.7

7.9

8.8

9.6

10.4

11.8

12.2

18

8.9

9.1

10.1

10.9

11.8

13.1

13.5

8.2

8.4

9.4

10.2

11.1

12.6

13.0

21

9.3

9.6

10.7

11.5

12.5

13.9

14.3

8.7

8.9

10.0

10.9

11.8

13.4

13.8

24

9.8

10.1

11.3

12.2

13.1

14.7

15.1

9.2

9.4

10.6

11.5

12.5

14.2

14.6

 

Table 3.3.4 Weight (kg) by age percentiles of boys and girls aged 2–5 years (WHO) Age

92

Percentiles for boys

Percentiles for girls

Year

Month 3rd

5th

25th

50th

75th

95th

97th

3rd

5th

25th

50th

75th

95th

97th

2

0

10.1

11.3

12.2

13.1

14.7

15.1

9.2

9.4

10.6

11.5

12.5

14.2

14.6

9.8

2

6

10.7

11.0

12.3

13.3

14.4

16.2

16.6

10.1

10.4

11.7

12.7

13.8

15.7

16.2

3

0

11.4

11.8

13.2

14.3

15.6

17.5

18.0

11.0

11.3

12.7

13.9

15.1

17.3

17.8

3

6

12.2

12.5

14.1

15.3

16.7

18.9

19.4

11.8

12.1

13.7

15.0

16.4

18.8

19.5

4

0

12.9

13.3

15.0

16.3

17.8

20.2

20.9

12.5

12.9

14.7

16.1

17.7

20.4

21.1

4

6

13.6

14.0

15.9

17.3

19.0

21.6

22.3

13.2

13.7

15.6

17.2

18.9

22.0

22.8

5

0

14.3

14.7

16.7

18.3

20.1

23.0

23.8

14.0

14.4

16.5

18.2

20.2

23.5

24.4

vip.persianss.ir

Gro

 

Table 3.3.5 Weight (kg) by age of boys and girls aged 5–10 years (WHO) 3rd

5th

15th

25th

50th

75th

85th

95th

wt

Percentiles Age (years)

97th

h a d evelo me

14.7

16.7

18.3

20.1

23.0

23.8

16.6

17.9

18.8

20.5

22.5

23.6

25.8

26.7

7

17.9

18.4

19.9

20.9

22.9

25.2

26.5

29.1

30.1

8

19.8

20.4

22.0

23.1

25.4

28.1

29.7

32.7

34.0

9

21.6

22.3

24.2

25.4

28.1

31.3

33.2

36.9

38.6

10

23.6

24.4

26.6

28.0

31.2

34.9

37.3

41.9

43.9

5

14.0

14.4

16.5

18.2

20.2

23.5

24.4

6

15.5

16.0

18.3

20.2

22.4

26.2

27.3

D

14.3 16.1

p

5 6

n

Boys

17.4

23.7

7

17.0

17.6

19.2

20.2

22.4

24.9

26.5

29.5

30.8

8

18.9

19.5

21.3

22.5

25.0

28.0

29.8

33.4

34.9

9

21.1

21.8

23.9

25.3

28.2

31.7

33.9

38.1

40.0

10

23.7

24.5

26.9

28.5

31.9

35.9

38.5

43.5

45.7

nt

Girls

 

Table 3.3.6 Length (cm) by age of boys and girls aged 0–2 years (WHO) Age (months)

3rd

5th

25th

Percentiles for boys 50th

75th

95th

97th

3rd

5th

25th

Percentiles for girls 50th

75th

95th

97th

0

46.3

46.8

48.6

49.9

51.2

53.0

53.4

45.6

46.1

47.9

49.1

50.4

52.2

52.7

3

57.6

58.1

60.1

61.4

62.8

64.8

65.3

55.8

56.3

58.4

59.8

61.2

63.3

63.8

6

63.6

64.1

66.2

67.6

69.1

71.1

71.6

61.5

62.0

64.2

65.7

67.3

69.5

70.0

9

67.7

68.3

70.5

72.0

73.5

75.7

76.2

65.6

66.2

68.5

70.1

71.8

74.1

74.7

12

71.3

71.8

74.1

75.7

77.4

79.7

80.2

69.2

69.8

72.3

74.0

75.8

78.3

78.9

15

74.4

75.0

77.4

79.1

80.9

83.3

83.9

72.4

73.0

75.7

77.5

79.4

82.0

82.7

18

77.2

77.8

80.4

82.3

84.1

86.7

87.3

75.2

75.9

78.7

80.7

82.7

85.5

86.2

21

79.7

80.4

83.2

85.1

87.1

89.9

90.5

77.9

78.6

81.6

83.7

85.7

88.7

89.4

24

82.1

82.8

85.8

87.8

89.9

92.8

93.6

80.3

81.1

84.2

86.4

88.6

91.7

92.5

 

Table 3.3.7 Height-for-age percentiles for boys and girls 2–5 years of age (WHO)

y

Age 2

ear

Percentiles for boys

Percentiles for girls

Month

3rd

5th

25th

50th

75th

95th

97th

3rd

5th

25th

50th

75th

95th

97th

0

81.4

82.1

85.1

87.1

89.2

92.1

92.9

79.6

80.4

83.5

85.7

87.9

91.0

91.8

2

6

85.5

86.3

89.6

91.9

94.2

97.5

98.3

84.0

84.9

88.3

90.7

93.1

96.5

97.3

3

0

89.1

90.0

93.6

96.1

98.6

102.2

103.1

87.9

88.8

92.5

95.1

97.6

101.3

102.2

3

6

92.4

93.3

97.2

99.9

102.5

106.4

107.3

91.4

92.4

96.3

99.0

101.8

105.7

106.7

4

0

95.4

96.4

100.5

103.3

106.2

110.2

111.2

94.6

95.6

99.8

102.7

105.6

109.8

110.8

4

6

98.4

99.4

103.7

106.7

109.6

113.9

115.0

97.6

98.7

103.1

106.2

109.2

113.6

114.7

5

0

101.2

102.3

106.8

110.0

113.1

117.6

118.7

100.5

101.6

106.2

109.4

112.6

117.2

118.4

WHO growth charts are used for children up to 4 years of age and thereafter British charts are used. The reason to adopt WHO growth charts for use in young children is because it establishes the growth of breastfed infants as the norm for

growth; the WHO standards provide a better description of physiological growth in infancy and WHO standards are based on a high-quality study designed explicitly for 93 creating growth charts.

vip.persianss.ir

Tex book of Pedia rics

 

Table 3.3.8 Height (cm) by age of boys and girls aged 5–10 years (WHO)

t

Height-for-age percentiles Age (year)

3rd

5th

5

101.2

102.3

6

106.7

107.8

7

111.8

113.0

15th

25th

50th

75th

106.8

110.0

113.1

110.8

112.6

116.0

119.3

116.3

118.2

121.7

125.3

85th

95th

97th

117.6

118.7

121.1

124.1

125.2

127.2

130.4

131.7

t

Boys

8

116.6

118.0

121.4

123.5

127.3

131.1

133.1

136.6

137.9

9

121.3

122.7

126.3

128.5

132.6

136.6

138.8

142.5

143.9

10

125.8

127.3

131.2

133.5

137.8

142.1

144.4

148.3

149.8

5

100.5

101.6

106.2

109.4

112.6

117.2

118.4

6

105.5

106.7

111.7

115.1

118.6

123.5

124.8

Girls 109.8

120.4

7

110.5

111.8

115.1

117.1

120.8

124.5

126.5

129.8

131.1

8

115.7

117.0

120.5

122.6

126.6

130.5

132.6

136.1

137.5

9

121.0

122.4

126.2

128.4

132.5

136.6

138.8

142.5

144.0

10

126.6

128.1

132.0

134.3

138.6

143.0

145.3

149.2

150.7



B







1. de Onis M. Growth curves for school age children and adolescents. Indian Pediatr. 2009;46(6):464-5. 2. Khadilkar VV, Khadilkar AV, Chiplonkar SA. Growth performance of affluent Indian preschool children: a comparison with the new WHO growth standard. Indian Pediatr. 2010;47(10):869-72. 3. WHO Multicentre Growth Reference Study Group. WHO Child Growth Standards based on length/height,weight and age. Acta Paediatr Suppl. 2006;450:76-85. 4. World Health organization. Growth charts. Available from http://www.cdc.gov/growthcharts/who_charts.htm. [Accessed 30 September 2011]. 5. World Health Organization. Training Course on Child Growth Assessment. Geneva, WHO; 2008.



ibliography





In India using WHO growth charts for children under the age of 5 years is likely to overdiagnose stunting or underweight or both. In a recent multicentric study done on 1,493 affluent Indian children on all zones of India, published by the author, the mean Z scores for height, weight, BMI and weight-for-height [−0.75 (1.1), −0.59 (1.1), −0.19 (1.22) and −0.26 (1.18), respectively] were much below the WHO 2006 standards. The overall incidence of stunting was 13.6% and underweight was 8.5% amongst affluent Indian children under the age of 5 years. The same is likely to be higher in rural areas and in underprivileged urban areas of India, although, at the present time no such data is available. It may therefore be necessary to use a lower cut off of WHO standards (i.e. using the 1st rather than 3rd percentile) for referral to specialized centers in developing countries such as India.

94

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Growth and Sexual evelopment in uberty





Growth and evelopment

3.4

KN Agarwal

•

­



It occurs between 8 years and 14 years of age in girls and between 9 years and 15 years of age in boys • Girls: Breast enlargement, occasionally initially unila teral, is the first obvious sign of puberty and occurs between 10 years and 11 years of age • Boys: Testicular volume increases from 2.0 mL to more than 4.0 mL or testes length from 2.0 cm to 3.2 cm between 12 years and 13 years of age; 1 year later penile and scrotal enlargements occur.

Growth Spurt • • •

Period extends for 4 years in girls and 6 years in boys to cross “sexual maturity stages” 2–5 Height gain is 27–29 cm in boys and 24–26 cm in girls. Weight gain in both is around 25–30 kg.

D

P

E P

Initiation of uberty

D





For 2 years before puberty, there is a rise in levels of adrenal androgens (adrenarche) that can sometimes result in the early appearance of pubic hair and spots. The initial event of puberty is an increase in pulsatile release of gonadotropin hormone releasing hormone (GnRH). Therefore, the initiation of the pubertal process itself requires both changes in trans-synaptic communication and the activation of glia-to-neuron signaling pathways. While neurons that utilize excitatory and inhibitory amino acids as transmitters represent major players in the trans-synaptic control of puberty, glial cells utilize a combination of trophic factors and small cell-signaling molecules to regulate neuronal function and, thus, promote sexual development. A coordinated increase in glutamatergic transmission accompanied by a decrease in inhibitory GABAergic tone appears to initiate the trans-synaptic cascade of events leading to the pubertal increase in GnRH release. In response to GnRH stimulation, pituitary releases luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In males, LH stimulation is responsible for testosterone production, while FSH causes maturation of sperms. In females, both LH and FSH are required for production of estradiol while FSH is also required for ovulation.

ifferences between Boys and Girls

For boys, testosterone is the principal sex hormone. It induces the characterization known as virilization. A substantial product of testosterone metabolism in males is estradiol, though levels rise later and more slowly than in girls. The male “growth spurt” also begins later, accelerates more slowly and lasts longer before the epiphysis fuse. Although boys are on average similar in height or 2 cm shorter than girls before puberty begins, adult men are on average about 13 cm taller than women. The growth spurt occurs later than in girls because testosterone is a poor stimulator to GH responsiveness than estradiol in girls. Testosterone is required in relatively higher concentration to produce the same growth effect. The hormone that dominates female development is an estrogen called estradiol, which rises earlier and reaches higher levels in women than in men. It promotes growth of breasts and uterus, and is responsible for the pubertal growth spurt, epiphysis maturation and closure. Girls attain reproductive maturity about 4 years after the first physical changes of puberty appear. In contrast, boys accelerate more slowly but continue to grow for about 6 years after the first visible pubertal change.



Puberty is the growth process associated with appearance of both primary and secondary sexual characteristics in children. The changes encompass aspects of sexuality and somatic growth, together with cognitive development. Pubescent children are those in whom secondary sexual characters and early genital changes are appearing. The WHO defines adolescents as individuals in the age group of 10–19 years. The various physiological: • Adolescent growth spurt • Change in body composition (muscle/fat) • Skeletal maturity. The time of onset and the rate of sexual development have individual variability but the sequence of events remains the same. From a biological perspective, puberty is the stage of physical maturation in which, an individual becomes physiologically capable of sexual reproduction. The biological changes that occur during puberty include several neurosecretory factors and/or hormones, all of which modulate somatic growth, the development of the sex glands and their endocrine as well as exocrine secretions. The resultant increase in sex steroid production will ensure the appearance and maintenance of sexual characteristics and the capacity for reproduction. It is essentially the activation of the hypothalamic-pituitary-gonadal axis that induces and enhances the progressive ovarian and testicular sex hormone secretion that are responsible for the profound biological, morphological and psychological changes to which the adolescent is subjected.

ndocrinal Control of uberty



D

efinition

95

vip.persianss.ir

P

N

First sign of ovarian estradiol secretion is breast development “thelarche” [breast budding, B-2 or sexual maturity rating (SMR-2)] with “growth in height” (Fig. 3.4.1 and Table 3.4.1). Estradiol being a good stimulator of “growth hormone” doubles the growth velocity. The maximum height velocity [peak height velocity (PHV) = 9–10 cm/year] coincides with B-3. Thus growth spurt occurs early in female puberty, following B-2 by 1 year. Height velocity reduces to 4 cm/ year at menarche. The growth in the post enarche period is limited as girls can gain 5–6 cm in linear growth only. Puberty is associated with change in body shape like hip growth, increase in body fat from 16% to 28% and reduction in lean body mass from 80% to 72%. • Menarche follows PHV by 14–18 months or usually occurs about 2–3 years after the start of breast development (thelarche). The age of menarche is around 12–13 years (12.6 years in Indian girls). • Estradiol is the main hormone in females influencing the pubertal development, i.e. breast and genitals; and promotes uterine maturation and fat deposition in typical female contours, while androgens from adrenals and ovaries are responsible for pubic and axillary hair and the typical body odor and acne.

The first sign of puberty is testicular enlargement, which usually occurs between ages of 12 years and 13 years. The prepubertal testis is about 2 mL in volume with puberty taken to begin when a volume of around 4 mL is attained.

B-2

 



Rapid pubertal growth occurs once testes are more than 6 mL. Actually testicular growth starts as early as 10 years of age, associated with enlargement of seminiferous tubules, epididymis, seminal vesicles and prostate. Prader orchidometer (Fig. 3.4.2) is used to measure testicular volume. Penile and scrotal enlargements occur typically about a year after testicular enlargement is noticed. Pubic hair typically appears at a similar time (Fig. 3.4.3 and Table 3.4.2). • A greater and later growth spurt occurs in boys and ultimately achieves an average 12.6 cm with greater height in adult men. The growth spurt in boys is on average 2 years later than girls in SMR stages 3 and 4.

G-2

G-3

G-4

G-5

B-3

 

Figure 3.4.1 Development of breast (stages B2–B5) during puberty in girls

Figure 3.4.3 Genital development in boys in sexual maturity stages (G 2-G 5)  

B-5

B-4

96

Figure 3.4.2 Prader orchidometer



ormal uberty in Boys P

N



ics b

P

i

ext ook of ed atr T

ormal uberty in Girls

vip.persianss.ir

Breasts

Pubic hair (mean age = 13.6 years)

Growth

Other features

Undernourished rural girl

Stage 1 (B-1)

Prepubertal: elevation of papilla only

Prepubertal villus hair only

Basal level: 5–6 cm/ year

Adrenarche: ovaries grow and enlarge

Height was lower by 15.3 cm versus affluent girl

Stage 2 (B-2)

Breast bud appears under an enlarged areola. Milk ducts begin to grow (mean age 10.2 years)

Sparse hair along labia (in 22%)

Accelerated growth: about 7–8 cm/year

Breast development Clitoral enlargement delayed by 2.2 years with labial pigmentation, uterine enlargement, increase in vaginal length, menarche attained in 10%

Stage 3 (B-3)

Breast tissue grows beyond areola but without contour separation. The areola begins to darken in color. The milk ducts give rise to milk glands that also begin to grow (mean age 11.6 years)

Hair coarser and pigmented: spreads across pubes (becoming thicker, curly and darker in 92%)

Peak velocity: about 8 cm/year

Axillary hair present in majority Acne in majority Menarche attained in 20% (total 30%)

Peak height velocity not observed Height gain similar 24–2 cm; early life deficit not corrected

Stage 4 (B-4)

Projection of areola: papilla forms a secondary mound (mean age 13.6 years)

Deceleration: less Adult pattern but than 7 cm/year without spread to medial thigh, growing faster and already forming sexual pubic triangle (in 98.8%)

Menarche: mean age = 12.6 year. Regular periods (around 14 years) Menarche attained in total = 90%

Menarche delayed by 0.82 years

Stage 5 (B-5)

Adult breast contour with projection of nipple only (mean age 14.5 years)

Adult triangle is already developed. Hair is thick and often curly with spread to medial thigh but not up linea alba (100%)

Adult genitalia Menarche in all girls

Total period of growth in puberty shortened

Cessation of growth at around 16 years

D

 

Tanner stage

Growth and evelopment

Table 3.4.1 Stages of normal puberty (Tanner stages) in girls for breast, pubic hair and in relation to the peak height velocity (values in parenthesis are for Indian girls)

Source: Agarwal et al.

Body takes on a more muscular and angular shape because of testosterone. This generally begins around age 12.5 years when testosterone causes muscle mass to increase. The greatest effect can usually be seen in the upper chest and shoulder muscles. Testosterone also causes bones to lengthen, giving young men a heavier bone structure and longer arms and legs. At the end of puberty, adult men have heavier bones and nearly twice as much skeletal muscles. Some of the bone growths (e.g. shoulder width and jaw) are

Body dor and cne A

V

M

uscle Growth

disproportionately greater resulting in noticeably different male and female skeletal shapes. The average adult male has about 150% of the lean body mass of an average female, and about 50% of the body fat. Muscle growth can continue even after boys are biologically adult. The peak of the so-called “strength spurt”, the rate of muscle growth, is attained about 1 year after a male experiences his peak growth rate. O

F

ace: 25% of the total height of the mandible ramus occurs between 12 years and 20 years of age. • yes: Growth in axial diameters results in a tendency to “myopia” in adolescence. • oice: Growth of larynx, pharynx and lungs leads to typical voice. E

•

Rising levels of androgens can change the fatty acid composition of perspiration resulting in a more “adult” body odor. As in girls, another androgen effect is increased secretion of oil (sebum) from the skin and the resultant 97 variable amounts of acne. Acne cannot be prevented or diminished easily, but it fully diminishes at the end of puberty.

vip.persianss.ir

ics

Tanner stage Genitalia

Pubic hair

Growth

Other

Undernourished rural boy

Stage 1 G-1

Prepubertal: testes less than 2.5 cm or less than 2-0 mL

Villus hair only

Basal height velocity 5–6 cm/year

Adrenarche

Height at 13 years was short by 13.6 cm versus affluent Indian boy

Stage 2 G-2

Thinning and reddening of scrotal skin (mean age 11.3 years). Testes 2.5–3.2 cm or 4 mL

Sparse growth at base of penis (60%)

As above

Total body fat 16–18%

Stage 3 G-3

Growth of penis (mean age 12.8 years). Testes 3.3–4.0 cm or 6–8 mL

Thicker hair: spreads to mons pubis (97%)

Accelerated growth: 7–8 cm/year

Gynecomastia Voice break Increase in muscle mass

Genital development delayed by 1.54 years

Stage 4 G-4

Growth of penis and glans with darkening of scrotum (mean age 14.1 years) Testes 4.1–4.5 cm or 10–12 mL

Adult but no spread Peak velocity about to medial thigh 10.0 cm/year (99%)

Axillary hair Voice change Acne

Delayed appearance: axillary hair by 0.65 year; pubic hair by 0.82 year No peak height velocity noted

Stage 5 G-5

Adult genitalia (mean age Adult with spread to medial thigh but 16.4 years) Testes greater than 4.5 cm not linea alba or 12 mL (adult volume 18 mL)

Facial hair (mean age 14.8 years) Muscle mass increases further and beyond stage 5

Total weight gain only 38% as compared to affluent Indian boy

Deceleration and cessation (about 17 years)

recocious uberty P

P

No testicular enlargement by age of 14 years Pubic hair absent by age of 15 years More than 5 years between the start and completion of growth of the genitalia.



Precocious puberty is defined as the onset of secondary sexual characteristics before the age of 8 years in girls (although some sources lower this to 7 years) and 9 years in boys. It is five times more common in girls. Precocious puberty is usually a benign central process in girls but in boys a pathological peripheral cause should be excluded (found in 50%). Benign variants may manifest as breast development in girls aged less than 3 years, which spontaneously regresses, and pubic hair in both boys and girls aged less than 7 years due to adrenal androgen secretion in middle childhood (polycystic ovary syndrome—recommend follow-up). In central precocious puberty, the puberty process starts too soon. Although they begin earlier than they should, the pattern and timing of the steps in the process are otherwise normal. For the majority of children with this condition, there is no underlying medical problem and no identifiable reason for the early puberty.

• 98 • •

No breast development by 13 years No menarche by 3 years after breast development Menarche not attained by 16 years.

E

Changes under Sex ormone ffects H

Girls

P

P

D

P

ointers for elayed uberty

A

Growth attern and chievement during uberty P

•

When a boy or girl has passed the usual age of onset of puberty by 2–3 years with no physical or hormonal signs Puberty may be delayed for several years and can still occur normally—constitutional delay, a variation of healthy physical development. Delay of puberty may also occur due to undernutrition (malnutrition, cystic fibrosis and anorexia nervosa), many forms of systemic diseases (thalassemia and chronic renal failure) or defects of the reproductive system (hypogonadism and polycystic ovarian disease) or the body’s responsiveness to sex hormones. Constitutional growth delay is the most common cause in boys (> 50%). The most common cause in girls is Turner syndrome (> 80% girls have pathological cause of delayed puberty).

• • •



•

ate uberty P

L

The genetic factors account for half of the variation of pubertal timing; association of timing is strongest between mothers and daughters. The environment factors are clearly important as well; puberty occurs later in children raised at higher altitudes and in undernourished children (Tables 3.4.1 and 3.4.2). It is advanced in obese children.

•

Boys

P

actors ffecting uberty A

F

T

b

P

i

ext ook of ed atr

 

Table 3.4.2 Genital development and growth in boys during puberty (the values in parenthesis are for Indian boys)

Growth begins in distal parts like feet and hands, which also stop growing first. It is followed by growth of arms, legs, trunk and chest. The growth of trunk changes US/LS ratio

vip.persianss.ir



• •

D

P

W

P

A

ssential easurements to ssess Sexual evelopment and Growth in uberty M

At 10.5 years, boys and girls have similar height 11–12.5 years girls are taller by 2.0 cm 14 years boys are taller by 5 cm 16.0 years boys are taller by 12.5 cm The height velocity is given in relation to sexual maturity in Tables 3.4.1 and 3.4.2.

D

• • • • •

E

D

H

eight and eight Gains in uberty ( uration 4–6 Years)

Total weight gain is around 25–30 kg during puberty. The peak weight velocity follows peak height velocity. Bone growth: 50% completed during first month of life to puberty onset, 30% in puberty and 20% in late adolescence to adult. Girls mature earlier than boys, grow for a shorter time and ultimately have shorter overall bone lengths by about 7%.

Growth and evelopment

(U/S ratio), becomes 1.1 at 10–11 years, 0.98–1 at 13–14 years and 1–1.1 at completion of puberty. Pelvic inlet is wider in girls (wider hips) with more growth of acetabula. In contrast, boys have greater stature and broader shoulders.

Assess sexual maturity as per Tanner classification (Tables 3.4.1 and 3.4.2, Figs 3.4.1 and 3.4.2). The variability in time of onset and progression of puberty, which relates to somatic

Breast Development Stages Source: Agarwal KN et al. Physical growth assessment in adolescence. Indian Pediatrics. 2001;38:1217-35

99

vip.persianss.ir

ics b

P

i

ext ook of ed atr T

Genital Development Stages Source: Agarwal KN et. al. Physical growth assessment in adolescence. Indian Pediatrics. 2001;38:1217-35













1. Agarwal KN, Agarwal DK, Seth A. The growth infancy to adolescence, 2nd edition. New Delhi: CBS Publishers; 2007. pp. 35-49. 2. Agarwal KN, Agarwal DK, Upadhaya SK, et al. Physical and sexual growth pattern of affluent Indian children from 5-18 years of age. Indian Pediatr. 1992;29:1203-82. 3. Agarwal KN, Saxena A, Bansal AK, et al. Physical growth assessment in adolescence. Indian Pediatr. 2001;38:1217-35. 4. Duke PM, Litt IF, Gross RT. Adolescents’ self-assessment of sexual maturation. Pediatrics. 1980;66:918-20. 5. Tanner JM. Growth in Adolescence, 2nd edition. Oxford: Blackwell Scientific Publication; Oxford.



Bibliography



growth rather than chronological age, requires assessment of stage of sexual maturation. The necessity to undress the teenager has seriously curtailed the assessment by experts, the best approach is to give Tanner’s stages as diagram to children and they make self-assessment. • The height, weight, BMI and SFT values for age in relation to “sexual maturity” are described (see WHO Growth Curves 1 and 2). The details of measurements are given in the Chapter 3.2. • Waist/hip ratio less than 0.8 women and less than 0.9 men, indicates good health, values over and above suggest overweight/obesity). 100 • Waist-to-height ratio less than 0.5, no central obesity versus more than or equal to 0.5, central obesity present.

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ormal evelopment

N



Growth and evelopment

3.5

DK Agarwal Prefrontal cortex is not myelinated until close to adolescence.

D

•

P

D

evelopmental rofile

• • • • • • • •

Early brain stem and cord—birth: light reflex, startle reflex, Babinski reflex, reflex movement, reflex birth cry and grasp reflex Visual, auditory, tactile, mobility, language and manual competences Brain stem and early subcortical areas—2.5 months Midbrain and subcortical areas—7 months Initial cortex—12 months Early cortex—18 months Primitive cortex—36 months Sophisticated cortex—72 months



Development refers to qualitative and quantitative changes and acquisition of a variety of competencies for functioning optimally in a social milieu. Further, development is a continuous process from birth to maturity. It depends on maturation and myelination of brain. Unless that has occurred, no amount of practice can make the child learn that skill. It may be stressed that besides 10% prevalence of developmental delay, the early identification of such problems remains difficult. Although severe disorders can be recognized in infancy, it is unusual to diagnose speech impairment, hyperactivity or emotional disorders before the age of 3 or 4 years, and learning disabilities are rarely recognized before children start their schooling. If one can diagnose developmental delay in early stages of growth, the intervention can reduce long-term sequel. Developmental delay is said to exist, if the child does not reach developmental milestones at the expected age, i.e. broad variation among normal children. Although the delay may occur from a biological factor such as chromosomal disorder or an environmental factor such as maternal depression, the primary model for pathogenesis of developmental delay is a transactional one, with the process of development viewed as an interaction between the child and environment, in which each can have profound effect on other.

P

rocess of Brain Growth

•

A



The developmental history and physical findings should be compared with the achievements listed for normal children. For preterm, one must take their corrected age into account. If one finds any “warning sign”, take note of the points in history and physical examination and define the type of impairment, disability or any handicap. The children may be observed for their activities as follows:

reschool ge A

P

•



Play, climbing stairs, speech, hand (for adaptive behavior) and feeding • Posture, walking, play and manipulation with toys (tests for vision) • erformance: understanding, matching color, concent ration and visual acuity • Comprehension of language: To point to body parts, objects in books, to pick named toys and accept commands appropriate to age.

• •

Sensory and motor areas within first month to first year of life—training and practice are effective only after myelination Maximum myelination occurs by 6 years of life

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yelination

P

rocess of

M

P



–

D

ssessment of ormal evelopment

–

E

• •

In the ectoderm, notochord develops to form a neural groove—neural tube (cavity with overlying neural crest) form in 18–24 days. rror: results in spina bifida, anencephaly, etc. Few weeks after conception to cellular level through adolescence, brain continues to grow and myelinate – Cells inside the tube form central nervous system (CNS) – Cells outside and the ectoderm form autonomic nervous system (ANS).

Gross motor Fine motor Language Cognitive Self-help Social. The developmental pattern from birth to first birthday is given in Figure 3.5.1. Normal development is given in Table 3.5.1 for the developmental abilities at various ages. N

Brain growth is important to receive stimuli and take body functions. The process of brain growth and acquisition of developmental processes is summarized as:

• • • • • •

A

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Brain Growth and evelopment

Skill chievements

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ext ook of ediatri T

 

Figure 3.5.1 Growth and development in first 2 years of life

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Growth and evelopment

 

Table 3.5.1 Developmental abilities and warning signs at various ages AREAS Personal social

Language hearings and speech

Adaptive

Gross motor

Warning signs

Stills to mother's voice, startles at sudden noice

Follows face 90° stares intently

Primitive reflexes +head in line with trunk when lifted

* None is elicited *Abnormal Moro's *Persistent squint

6 month. Responds to own name. Speaks ma, da. 9 month. Mama, dada (Double syllable) Understands 'No'

6 to 7 months. Change grasp palmar to index. Transfers objects hand to mouth. 9 months Pincer grasp foot regard. Fixes pellet of paper, follows fallen object

6 months bears some wt on legs, rolling over, in prone head up. wt.of hands 7 months Crawls and pulls to stand

*Slow social responses *Absence of babble *Persistence of hand Pats regard. *Abnormal voluntary hand grasp. *Persistent primitive reflexes

Understands some words, uses 'mama, dada' with meaning 'No'

Throws objects, watches them fall, picks up crumbs from floor. Pincer grasp, shakes head, Bangs two bricks together

Shuffling gait like a bear. Cruises round holding on to furniture. Walks one hand held, pivots when sitting

*No tunefull babble *Hold objects close to eyes. *Immature gait *No sitting

Points to 3 body parts. Obeys single commands. Says 6 words. Jargons echoes, speech

Walks well, Carries toys. Neat pincer picking of threads pins. Scribbles using Climb stairs. Climbs into chair fisted grasp. Turns 2 or more pages at a time. Builds tower of 3–4 (2.5 cm) cubes

Phrases of 2–3 words, gives name, 50 words+, naming games, Has inner language

Turns one page at a time, Imitates a straight line in both vertical and horizontal and a circle, unscrews lids, makes tower of 6–8 cubes

Pushes tricycle with feet, walks downstairs 2 feet per tread. Runs, kicks ball jumps on the spot

*No speech *Unsteady on feet

Mature pen grasp, copies + and 0 Correctly matches 2 or more colors. Threads large beads. Makes tower of 9

Stands on one leg for a few seconds. Peddles tricycle, stairs adult style for ascent, jumps of bottom step

*No phrases * Persistent day-time wetting/soiling *Clumsy

Matches 4 colors, Copies cross, square and by 5 a triangle. Draws a recognizable man

4 years climbs trees and ladder, enjoys ball games. 5 years hops, skip jump off 3 steps, catches a ball

*Socially isolated. *Unintelligible or ungrammatic speech. *Unable to tell name or address

Smiles, coos responsively

D

6 weeks old

6 to 9 months old 6 month enjoys bath, playing boo and chew on items. 9 months show objects to mother, mirror image

12 months old Comes when called, finds hidden objects, waves byebye, gives toys on request

18 months old Cup: Lifts-drinks-and puts down. Self spoon feeding. Pulls at dirty nappy. Does dusting, sweeping

*Drools no words *Absent pincer grasp *Does not walk

2 to 2½ years Plays alone, tantrums, demanding. Day by day, puts on shoes, socks and pants. Turns door handles. Uses spoon and fork 3 to 3½ years Gives full name, sex. Counts Goes toilet unassisted, to 10, 3–5 word sentences dresses/undresses with minimum assistance. Knows some nursery rhymes, handles knife and fork, plays with peers 4 to 5 years Wipes own bottom. Eats using knife and fork, dresses-except for tie and laces, imaginative play, plays in groups, shares toys, obeys rules

Gives address/age/ telephone no., Counts up to 10 by 4 years, 20 by 5 years knows 3 coins, grammatical speech asks meaning of abstract words

A

School ge

•

Test for reading, arithmetic functions like +, –, ×, ÷, writing name, age, address, drawing a picture; to test application, concentration and organizational skills Test deafness and physical examination

• •

Vision by 3–5 years age of 6/6 (adult) capability Intelligence assessment.

Various tests which can be used for developmental screening are already detailed in sections 3.1 and 3.6.

•

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evelopmental elay

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tiopathogenesis

Child development is a dynamic process optimally utilizing the genetic potential of the baby, within the context of the available environment, enabling achievement of full potential. Severe forms of disability are less common and are often due to congenital, genetic, metabolic causes or intrauterine infections and need specific preventive strategies. Experience of a developmental evaluation clinic has shown that nearly 50% of babies referred for developmental evaluation had developmental delay without a specific clinical diagnosis. Delayed cry at birth, increasing age of the child, presence of feeding problems, assisted



E E B

Advances in perinatal care have improved the survival chances of low birth weight babies, adding to the burden of developmental delay. It has been shown that 40% reduction in poor performance could be achieved among neonatal nursery graduates by CDC model early stimulation. While “high-risk” newborns require periodic screening, ideally need to be determined locally. It must also be remembered that many babies not considered “high-risk” may also manifest developmental problems as they grow. These babies would obviously not be seen during “high-risk” focused follow-up screening.

evelopmental ssessment A

Statistics from different sources indicate that in India, 3.8% of the population has some form of disability, and the same was found to be more common among children of the lowest-socioeconomic class families when compared with the next-to-lowest class families. Out of the 2.5% prevalence of developmental delay/disability among under 5 years children in an integrated child development services (ICDS) block, majority had speech and language problems followed by orthopedic deformities, cerebral palsy, vision and hearing problems and mental retardation. The observed 2.5% prevalence of developmental delay in less than 2-yearold children deprived of urban settlements, the presence of risk factors for developmental delay-like low birth weight, birth asphyxia, coupled with poor environment of home and alternate child care services, highlights the need for simple cost-effective community model for promoting early child development.

Developmental screening of all babies particularly graduates of neonatal intensive care unit (ICU), including vision and hearing domain is important in identification of potentially handicapping conditions that may be prevented or ameliorated if addressed early. A screening test is only meant to identify children who might have a delay and who are in need of further developmental evaluation.

irth to ne Year O

pidemiology



Developmental delay exists when a child does not reach developmental milestones at the expected age (with the adequate provision for the broad variation among normal children). Developmental delays may occur in any or all of the major areas of child development: gross motor, fine motor, language and social. Identification of developmental delay is useful for introducing early intervention programs, with the objective of reducing childhood disability. Developmental prediction is not always possible, as we may go wrong often. By doing developmental assessment, we can only opine on present status in relation to age and average performance of other children of same age. We cannot accurately predict future intelligence, delayed maturation effects and longterm effects of emotional deprivation.

delivery and birth injury were found to be associated with increasingly abnormal developmental test. A risk factor is something that increases the likelihood of getting a disease or condition. The risk factors can be classified as follows: • stablished risk: These include medical disorders that can lead to developmental delay. It includes Down syndrome, hydrocephalus, cerebral palsy, hearing impairment, visual impairment and other congenital anomalies. • nvironmental risk: This includes limited environmental factors, which put a child at risk for developmental delay. The various factors are: a very young mother, extreme poverty, low socioeconomic status, single parent, etc. • iological risk: These include factors-like prematurity, low birth weight, neonatal hypothermia, asphyxia, hypoglycemia, hyperbilirubinemia and convulsions. These are factors which operate in the prenatal, natal and postnatal periods. • No apparent risk: Developmental delays also occur in infants without any apparent risks. In not more than 10% of cerebral palsy cases perinatal asphyxia could be attributed as the true cause.

D

efinition

B

D

MKC Nair

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3.6

Developmental Observation Card The developmental observation card (DOC) is a simple developmental card that can be used by parents to identify delay.

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ompleted 2 months: Social smile—baby smiling back in response to your smile • ompleted 4 months: Holds head steady—keeping head steady when baby is held upright • ompleted 8 months: Sits alone—baby is able to sit alone with back straight, no support • ompleted 12 months: Stands alone—baby is able to stand bearing weight on both legs with minimal support.

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C

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C

t

C

C

Grow h a d evelo me

•

IV

III

II

nt

I

Head holding grading (assessed at completed 4 months): • Grade 0: No head holding at all • Grade : Head erect and steady momentarily (Fig. 3.6.1) • Grade : Dorsal suspension—lifts head along with body (Fig. 3.6.2) • Grade : Prone position—elevates on arms, lifting chest (Fig. 3.6.3) • Grade : Holds head steady while mother moves around (Fig. 3.6.4) • Grade : Head balanced at all times (Fig. 3.6.5). Sitting grading (assessed at completed 8 months): • Grade 0: No sitting at all • Grade : Sits momentarily (Fig. 3.6.6) • Grade : Sits 30 seconds or more leaning forward (Fig. 3.6.7) • Grade : Sits with the child’s back straight (Fig. 3.6.8) • Grade : While sitting, can turn around and manipulate a toy (Fig. 3.6.9) • Grade : Raises self to sitting position (Fig. 3.6.10). Standing grading (assessed at completed 12 months): • Grade 0: Not standing well • Grade : Stands holding on to furniture momentarily (Fig. 3.6.11) • Grade : Take few steps with both hands supported (Fig. 3.6.12) • Grade : Can stand alone with legs apart (Fig. 3.6.13) • Grade : Come to standing position by throwing weight on arms (Fig. 3.6.14) • Grade : Without support takes few steps (Fig. 3.6.15). (Interpretation of CDC grading—grades III, IV, and V are normal for that age)

p

CDC Grading for Motor Milestones

 

Figure 3.6.2 Head holding grade II

B



V

IV

III

II

I

V

IV

III

II

I

V

 

Figure 3.6.1 Head holding grade I

irth to Two Years



Trivandrum Developmental Screening Chart (Fig 3.6.16 and Table 3.6.1) This is a simple developmental screening test for babies below 2 years that can be used in large scale community developmental screening programs by anganwadi workers and other health workers. The left end of each horizontal dark line represents the age at which 3% of children passed the item and the right end represents the age at which 97% of the children passed the item. A vertical line is drawn or a pencil is kept vertically, at the level of the chronological age of the child being tested. If the child fails to achieve any item

 

Figure 3.6.3 Head holding grade III

that falls short on the left side of the vertical line, the child is considered to have a developmental delay. Any obvious abnormality or asymmetry is also considered abnormal.

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Figure 3.6.5 Head holding grade V

Figure 3.6.8 Sitting grade III

Figure 3.6.6 Sitting grade I

Figure 3.6.9 Sitting grade IV

   

 

 

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Figure 3.6.7 Sitting grade II

 

Figure 3.6.4 Head holding grade IV

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Figure 3.6.10 Sitting grade V

 

Figure 3.6.13 Standing grade III

 

Figure 3.6.11 Standing grade I

 

Figure 3.6.14 Standing grade IV

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Two to our Years Developmental Assessment Tool for Anganwadis

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Developmental assessment tool for anganwadis (DATA) is a short, psychometrically strong, norm-referenced develop mental scale with partial criterion referencing to identify toddlers at anganwadi who are at risk for developing developmental delays, and differentiate those who already have developed delays at 2.5 years for appropriate interventions. In addition, it is recommended that regular developmental assessments be conducted on the bene ficiaries of anganwadis every year at three more key ages of 3.5, 4.5 and 5.5 years to institute early intervention when 107 required.

 

Figure 3.6.12 Standing grade II

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Table 3.6.1 Test items used in Trivandrum Developmental Screening Chart (Fig. 3.6.16) S. no. Test items

 

 

 

Assessment of a preschool child in a clinic setting by a developmental pediatrician or psychologist using DDST-II would help identify children with developmental delay. But in a borderline case what is more important is to understand the level of skill development in the child as compared to

 

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Nursery Evaluation Scale Trivandrum—Abridged (Table 3.6.2)

other children of the same age (percentile position), so that appropriate item based interventions can be offered.

 

 

 

 

 

 

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our to ix Years

 

Figure 3.6.15 Standing grade V

97% pass

Social smile

0.1

2.7

2.

Eyes follow pen/pencil

1.1

3.9

3.

Holds head steady

1.1

3.8

4.

Rolls from back to stomach

2.7

10.0

5.

Turns head to sound of bell/rattle

3.0

5.8

6.

Transfer object hand to hand

4.1

7.0

7.

Raises self to sitting position

5.8

11.0

8.

Standing up by furniture

6.3

11.0

9.

Fine prehension pellet

6.7

10.9

10.

Pat a cake

6.7

12.7

11.

Walk with help

7.7

13.0

12.

Throws ball

9.5

16.7

13.

Walk alone

9.9

17.4

14.

Says two words

11.2

19.1

15.

Walk backwards

11.2

19.5

16.

Walk upstairs with help

12.2

24.2

17.

Points to parts of doll

15.3

24.3

Figure 3.6.16 Trivandrum Developmental Screening Chart (TDSC) (Based on BSID Baroda norms) MKC Nair, Babu George, Elsie Philip. Indian Pediatr 1991;28:869-72  

108

3% pass

1.

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3rd, 50th and 97th percentile age placements in months 3rd percentile

50th percentile

97th percentile

61 48 64 53

68 57 69 64

72 66 72 68

50 53 63 48 50 56

56 64 66 53 57 61

59 68 72 56 65 66

55 54 53 48 46 50 57 61

64 66 63 54 52 56 65 68

66 71 69 59 65 60 70 72

56 42

63 45

68 48

49 53

52 60

57 66

51 52 51 58

59 60 57 68

63 65 62 72

n

Heel to toe walk 8 steps Stands on one foot 10 seconds Walk on 20 cm elevated balanced beam Catches a soft ball with one hand

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1. 2. 3. 4.











Gross motor development

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Paints shape Tears simple shape Copies diamond shape Prints A E F Threads 10 beads in 1 minute Draw picture with three parts (excluding draw a man)

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Fine motor development 5. 6. 7. 8. 9. 10.

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Items

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Table 3.6.2 Nursery Evaluation Scale Trivandrum (NEST)—Abridged















11. 12. 13. 14. 15. 16. 17. 18.



















Cognitive development Picks specific number of objects (5) Builds pyramid of 10 blocks Arranges objects according to width and length Puts numbers 1 to 10 in a sequence Names positions of objects Completes a simple maze Names days of a week in order Reads 10 printed words



19. Buttons and unbuttons dress 20. Washes hands and mouth when directed





Personal social development



21. Names function associated with three body parts 22. Tells materials out of which objects are made of





Expressive language development

Points to hard/soft/rough/smooth Points to middle Points to absurdities in a picture Puts together five parts picture

Nursery Evaluation Scale Trivandrum (NEST)—Abridged is such a simple tool that consists of skill-based items in the areas of gross motor, fine motor, cognitive, personal social, expressive language and receptive language, to give an overall assessment of the child.

Denver Developmental Screening Test II This instrument was designed to be a quick and simple screening tool to be used in clinical settings by persons with little training in developmental assessment. The test comprises of 125 items, divided into four categories; (1) gross motor, (2) fine motor/adaptive, (3) language and (4) personal social. The items are arranged in chronological order according to the ages at which most children pass them. The test items are represented on the form by a bar that spans the age at which 25%, 50%, 75% and 90% of the standardization sample passed that item. The child’s age is drawn as a vertical line on the chart and the examiner administers the items bisected by the line. The child’s performance is rated “pass”, “caution”, or

“delay” depending on where the age line is drawn across the bar. The total number of delays or cautions determines the rating of DDST as normal, questionable, or abnormal.

Developmental Assessment Scale for Indian Infants This is the gold standard test used for developmental evaluation, developed by Pramila Phatak, and is based on Bayley Scales of Infant Development (BSID). Developmental Assessment Scale for Indian Infants (DASII) consists of two scales, viz. mental scale and motor scale. The results of administration of mental scale are expressed as a standard score, the mental development index (MDI) and that of the motor scale as the psychomotor development index (PDI).

Neurological valuation E







23. 24. 25. 26.











Receptive language development

Although it is easy to diagnose a given case of cerebral palsy, when it comes to follow-up of high-risk babies, a 109 system of neurological examination that allows detection

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Figure 3.6.18 Heel to ear angle  

110

A

F

A

D

The examiner holds the infant’s leg straight and flexes the foot toward the leg. This is accomplished by applying pressure with the thumb to the sole of the foot. The dorsiflexion angle is formed by the dorsum of the foot and the anterior aspect of the leg (Fig. 3.6.20).

carf ign

The infant is held in a semi-reclining position, supported by the examiner’s palm. At the same time, the examiner takes the infant’s hand and pulls the arm as far as possible, across the chest towards the opposite shoulder. Four

Figure 3.6.19 Popliteal angle  

 

Figure 3.6.17 Adductor angle

orsiflexion ngle of the oot

Figure 3.6.20 Dorsiflexion angle  

With the infant lying supine, the legs are held together and pressed as far as possible, towards the ear. The pelvis must not be lifted from the table. The angle is represented by the arc extending from the infant’s heel to the table. Increased resistance on one side is an indication of asymmetry, but it might be difficult to apply equal pressure to both sides (Fig. 3.6.18).

The thighs are flexed laterally at the hip along both sides of the abdomen. While holding the infant in this position, the examiner presses the lower leg as far as possible towards the thigh. The popliteal angle, which is formed by the calf and the thigh, is estimated in both legs simultaneously. In contrast to the maneuvers described above, it is easier to apply equal pressure to both sides when examining the popliteal angle. Therefore, the estimation of asymmetry is more objective. Significant asymmetry is indicated by a difference of 10–20° between the right and left angles (Fig. 3.6.19).

S

E

eel to ar

Popliteal ngle

S

A

A

dductor ngle

With the infant lying supine, the legs are extended and gently pulled as far apart as possible. The angle formed by the legs at this point is called the adductor angle. Asymmetry between the right and the left leg should be noted (Fig. 3.6.17). H

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and recording of subtle neurological abnormalities that may disappear at the end of first year (called transient abnormalities) or persist even beyond that (persistent abnormalities) is needed. Amiel-Tison has provided us with a comprehensive system of neurological evaluation for the first five years of life that gives us a framework for instituting physical therapy program. In the Amiel-Tison method of neurological evaluation presence of hypotonia is identified by measuring the following angles (Table 3.6.1).

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ilestones

Grow h a d evelo me

Therapy ased on

Head Holding/Neck Control

•

•

 

Figure 3.6.21 Scarf sign

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Table 3.6.3 Neurological assessment

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•

Stimulating the child to hold the head by carrying the child in an upright position by supporting the infant’s head as and when possible. While playing and talking with the child, lift the child by supporting his upper arm and chest, thereby stimulating him to lift and hold his head. The child must be made to lie on his stomach and is guided on his elbow (a roll or round pillow can be used if necessary). Encourage the child to lift and hold his head by showing a colorful toy. Stimulate the child in prone position guiding on his hand on the surface, encourage the child to lift and hold his head and then rotate laterally showing a colorful toy.

nt

•

Sitting

Angles in degrees Angle

1–3 months

4–6 months

7–9 months

10–12 months

Adductor

40–80

70–110

100–150

130–150

Heel to ear

80–100

90–130

120–150

140–170

Popliteal

80–100

90–130

120–150

140–170

Dorsiflexion 45

45

45

45

Scar sign

Elbow cross midline

Elbow reaches axilla

Elbow beyond axilla

Elbow not cross midline

• • • •

D

positions are possible in describing the position of the elbow in relationship to the umbilicus (Fig. 3.6.21 and Table 3.6.3).

evelopmental Therapy

•

E

B

Therapy ased on Passive xercises

Encourage the child to sit by putting him in an arm chair in a sitting position supporting him with pillows, as and when possible. While playing and talking with the child, encourage the child in sitting position with a wide base (thighs apart), supporting at the pelvis with a downward force. During play, the child can be encouraged in side-sitting position on both sides by supporting himself on the hand to the side which he is sitting. Guide the child to support on his hand and knees (four point kneeling/quadruped position) during play. A roll or pillow can be used if necessary. Then slowly guide him to sit on one of his sides supported by the same hand. Help the child to maintain this position for a while. Then guide him again on to his hands and knees and then gradually to side sitting on the other side. Baby walker can also be used to stimulate and improve sitting.

Out of the items assessed in the Amiel-Tison method, the angles give an important clue for the therapy and stimulation part of intervention. A limitation in angles indicates hypertonia and wide angle indicates hypotonia in most cases. In such instances, stimulation becomes effective only after normalizing the muscle tone. The purpose of passive therapy is essentially to reduce these deformities by constant effort of the mother in a playful manner. Hometherapy based on Amiel-Tison passive angles is a simple concept which does not aim to hasten developmental milestones, but aims to prevent: • Mental subnormality by better mother-infant interaction • Joint stiffening by repeated passive movements • Contractures by repetitive passive movements • Muscle wasting and fibrosis • Helplessness in parents.

Standing •

• •

Guide the child on to his both knees during play. Finally support him at the pelvis. If necessary, give support to the upper part of his body. Gradually the support can be withdrawn and the child can be made to support himself by holding on to a low stool. This position can be maintained by directing the child’s attention to any play activity. From lying on the back position (supine position), stimulate the child to sit and gradually to the standing position during play time. Firstly, guide the child to his both knees supporting himself on a low stool with both hands. While directing his attention to a colorful toy through play, slowly help him to raise one leg so as to make him stand on one foot (leg straight), the other on the knee (half standing

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1. Illingworth RS. The Development of the Infant and Young Child: Normal and Abnormal, 9th edition. Haryana: Reed Elsevier Private Limited; 2010.













2. Malhi P. Screening young children for delayed development. Indian Pediatr.1999;36:569-77. 3. Nair MKC, Babu G, Sabarinathan. CDC grading for head holding sitting and standing. Indian J Pract Pediatr. 1995;3(1):53-4. 4. Nair MKC, George B. Trivandrum Developmental Screening Chart (TDSC). Indian Pediatr. 1991;28:869-72. 5. Nair MKC, Jain N, Murkhi S, et al. The High Risk Newborn. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2007. 6. Nair MKC. Early stimulation CDC Trivandrum model. Indian J Pediatr. 1992;59:663-7. 7. Nair MKC. Editorial: simplified developmental assessment. Indian Pediatr. 1991;28:837-40. 8. Indian Pediatrics. (2009). Supplement Issue on Child Development. [Online] Indian Pediatrics website. Available from http://www.indianpediatrics.net/suppl2009/supple. htm [Accessed September 2012].



ibliography

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position) help the child to maintain this position while playing and talking with him. This position can be repeated on other side. Meanwhile depending on the child’s ability, stimulate him to pull to standing position by himself, supporting on the stool. Encourage the child in standing position as and when possible, first with support then gradually withdrawing the support as per the child’s ability. A baby walker will also severe the purpose of developing standing and walking skills.

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Failure to hrive





Growth and evelopment

3.7

Madhulika Kabra

tiology

The standard classification of dividing the causes of FTT as organic and non-organic is probably not very appropriate. Whether the condition is primarily organic or non-organic in origin, all children who fail to thrive suffer the physical

D

 

Table 3.7.1 Definition of failure to thrive Attained growth •  Weight < 3rd percentile on standard growth chart •  Weight for height < 5th percentile on standard growth chart •  Weight 20% or more below ideal weight for height Rate of growth •  •  •  • 

Less than 20 g/day from birth to 3 months of age Less than 15 g/day from 3 months to 6 months of age Falloff from previously established growth curve Downward crossing of > 2 major percentiles



and psychological consequences of malnutrition and are at a significant risk for long-term physical and psychodevelopmental sequelae. Table 3.7.2 summarizes the causes of FTT. Organic diseases are responsible for less than 20% of cases with FTT. It should be recognized that environmental  

Table 3.7.2 Causes of inadequate weight gain Inadequate intake and inappropriate feeding practices •  •  •  •  •  •  •  • 

Non-availability of food Misperceptions about diet and feeding practices Errors in formula reconstitution Dysfunctional parent-child interaction, child abuse and neglect Behavioral feeding problem Mechanical problems with sucking, swallowing and feeding Primary neurological diseases Chronic systemic disease resulting in anorexia, food refusal and neurological problems 

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Failure to thrive (FTT) is a common and often perplexing concern for parents and pediatricians. Pathophysiologically, FTT is a state of caloric insufficiency without an apparent etiology. It is a descriptive term rather than a diagnosis and is used for children whose attained weight or rate of weight gain is significantly below their age, gender and ethnicity matched controls. Though primarily weight is affected, linear growth and head circumference may also get affected if the insult is prolonged and severe. By definition, FTT is sustained weight loss, failure to gain weight or a persistent fall in weight from the child’s normal centile (Fig. 3.7.1). This definition excludes transient weight loss associated with acute illness. Persistence of FTT may not only lead to long term complications related to physical growth but also development and behavior. There is lack of consensus about anthropometric criteria for FTT. Commonly used criteria are shown in Table 3.7.1. Important points to remember are: • Label of FTT should not be given, based on a single observation, i.e. failure to gain weight or weight loss should be observed over a period of time. • Usually children less than 3 years or maximum up to 5 years are included in this definition. • Small size alone is not an adequate criterion for confirming FTT, as constitutional and genetic factors may result in short stature.

Reduced absorption or digestion •  Pancreatic insufficiency—cystic fibrosis •  Damage to villus surface—celiac disease Excessive loss •  •  •  •  •  •  • 

Persistent vomiting Gastroesophageal reflux disease Gastrointestinal obstruction Increased intracranial pressure Renal losses—renal tubular acidosis Diabetes mellitus Inborn errors of metabolism

Increased caloric requirements •  •  •  •  • 

 

Figure 3.7.1 Failure to thrive: A: weight loss, B: static weight, C: Fall-off in weight gain

Congenital heart disease Chronic respiratory disease Neoplasm Hyperthyroidism Chronic or recurrent infection

Altered growth potential or regulation •  Chromosomal abnormalities •  Endocrinopathies

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Ideally, both parents should be present during the interview and parent-child and parent-parent interaction must be critically assessed.

Apart from the details of pregnancy, delivery and perinatal details, some points need special mention. • Was the child born of unplanned pregnancy? Did the parents consider medical termination of pregnancy? Children born of unplanned pregnancy tend to be emotionally deprived. • Was it a preterm delivery? If growth parameters are not corrected for gestational age, these children may be erroneously labeled as FTT. • Intrauterine growth retardation is another risk factor for FTT. Symmetrical IUGR children have a worse prognosis in this regard. • History suggestive of exposure to intrauterine infections. D

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Evaluation of growth pattern is the most important aspect of evaluation. Review child’s present and past growth parameters. This is only possible if parents have maintained a growth chart or previous growth status is known. In situations where previous record is not available, it is advisable to follow the child for weight gain.

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These are provided in earlier chapters.

Physical examination should be thorough and complete. Detailed anthropometry should include length/height, weight, head circumference, upper/lower segment ratio, skinfold thickness and mid-arm circumference. • Routine and thorough general and systemic examination is a must, as it gives clues to do specific investigations. • Detailed neuro-developmental assessment should be performed. • Specific behavior patterns should be looked for. These may give a positive clue for non-organic FTT. These include unusual watchfulness, decreased vocalization, lack of cuddliness, head banging, rocking movements and rumination. • Signs of abuse and neglect. • Signs of vitamin and nutrient deficiencies should be looked for.

aboratory nvestigations

In most instances, a detailed general and systemic examination will help in ruling out an organic cause for FTT. Detailed laboratory investigations are indicated only if the history and physical examination suggest that an organic cause is responsible for FTT and to localize the systems involved. A battery of routine investigations should be avoided because they are unproductive in most instances, expensive, may be misleading and diverting attention. The following investigations are considered adequate for initial evaluation: • Complete blood count with erythrocyte sedimentation rate (ESR) • Urine and stool examination • Urine culture and sensitivity • Tuberculin test • Blood urea and serum creatinine • Specific tests: workup for inborn errors of metabolism, karyotyping, sweat test, celiac serology, endoscopy, etc. Radiological investigations are not routinely indicated, unless the child needs evaluation for tuberculosis or physical abuse. Determination of bone age may be required in some cases. More invasive diagnostic procedures are called for, when a specific diagnosis is suspected.

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A detailed dietary history, both past and present should be elicited to evaluate caloric and protein intake.

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Lack of “support systems”: relatives and friends Financial constraints Psychiatric problems or drug abuse in family Marital problems and parental discord Serious illness or death in family.

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History and physical examination are the mainstay for diagnosis of FTT. It should be emphasized that extensive laboratory investigations have no role in the diagnosis unless assessment suggests a probable organic cause and localizes the pathology to a particular system. Before labeling an infant as FTT, one should exclude normal variants of growth. These include infant with small parents, constitutional delay and prematurely born babies.

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deprivation can coexist with and complicate organic FTT. For example, a child with cerebral palsy or multiple congenital malformations is likely to be environmentally deprived due to lack of care. Organic causes of FTT are most commonly gastrointestinal or neurologic.

A detailed social and family history provides useful clues for diagnosis of non-organic failure to thrive. Following factors need special evaluation:

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Growth and evelopment

Flow chart 3.7.1 Schematic diagram showing evaluation of FTT

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The major goals of management are nutritional rehabilitation, treating an organic cause if detected and addressing psychosocial and developmental issues involved. Individual management of these has been discussed in detail in subsequent chapters. The first decision that one has to take is, whether the child requires hospitalization or not. Indications for hospitalization are as follows: • Weight for height less than 70% of the median • Detailed evaluation for a suspected organic disorder • Suspected abuse or neglect • Non-response to outpatient management.

iet

An experienced dietician should always be involved in planning and supervising diet. Unless there is a strong suspicion of an organic cause, one should proceed directly for a two weeks trial feeding. Daily monitoring during this period is extremely important. Nutrition monitoring record includes daily weight and total calories consumed during last 24 hours against expected. Every effort should be made to feed the child orally. If oral feeding is inadequate, tube feeding may be tried for short periods.



Help of a child psychologist may be sought if indicated. Organization of a program of intensive environmental stimulation and affection is also needed. Every attempt should be made to see that parents are actively involved in the management. At the end of 2 weeks of trial feeding, the child is reassessed. A good intake during the feeding trial, and a good response in terms of weight gain, suggest that the primary problem was nutritional deprivation usually associated with emotional deprivation. Further management of a child who fails to respond to the feeding trial, is shown in Flow chart 3.7.1. It is perfectly justified to undertake detailed investigations in the child with FTT who fails to respond to a two weeks trial feeding. However, by this time, the physician usually has an idea of the diagnostic possibilities, and he/she can tailor the investigations accordingly.

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Abbreviations: GI, Gastrointestinal; GER, Gastroesophageal reflux; RTA, Renal tubular acidosis; CRF, Chronic renal failure; CNS , Central nervous system

rognosis

Most children with FTT have good growth recovery in all domain provided optimal care is taken for nutritional supplementation and emotional support. The overall prognosis for intellectual and behavioral recovery is variable and less certain.

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1. Brgman P, Graham J. An approach to failure to thrive. Aus Fam Phy. 2005;34:725-9. 2. Hank DA, Jeisel SH. Failure to thrive. Pediatr Clin North Am. 1998;35:1187-205. 3. Maggioni A, Lifshitz F. Nutritional management of failure to thrive. Pediatr Clin North Am. 1995;42:791-810.

4. Marcovitch H. Failure to thrive. Br Med J. 1994;108:35. 5. Overby KJ. Failure to thrive. In: Rudolph AM (Ed), Rudolph’s Pediatrics, 20th edition. Stamford, Connecticut: Appleton and Lange; 1996.pp.3-9. 6. Suri M, Kabra M, Aggarwal A, et al. Failure to thrive. Indian J Pediatr. 1994;8. 7. The American Board of Pediatrics. Program for renewal of certification in pediatrics. Failure of Thrive. Supplement to Pediatrics in Review 1993.

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DISCLAIMER: The views expressed by the individual authors about the Growth Curves are their own and do not reflect the official position/stand of the Editors or Indian Academy of Pediatrics.

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4 Nutrition

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Breastfeeding: Jp Dadhich Infant and Young Child Feeding: RK Anand Malnutrition: Meenakshi Mehta Water Soluble Vitamins: Dheeraj Shah Fat Soluble Vitamins: anna Choudhury Trace Elements: Ke lizabeth E



4.1 4.2 4.3 4.4 4.5 4.6















Section Editor : Dheeraj Shah

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Breastfeeding





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efinitions elated to Breastfeeding

Child health and nutrition programs all across the world (including India) conform to these guidelines based on the global recommendations. These recommendations are based on the available scientific evidence, some of which are defined as follows:

Initiation of Breastfeeding Immediately after Birth, Preferably within ne Hour Early initiation has been documented to improve neonatal survival, and protective against the infection specific mortality among newborn infants. Early initiation of breastfeeding helps to develop a bond between a mother and her baby. Early initiation is extremely important to establish successful and sustained lactation. It stimulates contractions and expulsion of placenta. The practice of delaying breastfeeding after birth and giving something else, i.e. prelacteal feeds expose the infant to infections and also lead to problems in establishing a successful lactation. Scientific evidence suggests that early is the initiation of breastfeeding, more are the chances of survival of neonate. After cesarean section, some delay in initiation of breastfeeding may be unavoidable due to the condition of the mother or infant. After cesarean section with spinal anesthesia, breastfeeding can often be initiated immediately. With general anesthesia, breastfeeding can be initiated within a few hours as soon as the mother regains consciousness.

Various definitions used in context of breastfeeding are summarized in the Table 4.1.1.

ecommendations for Breastfeeding

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Optimal infant and young child feeding (IYCF) practices are critical for child nutrition and survival. Breastfeeding is a vital component of IYCF. The “Global Strategy for Infant and Young Child Feeding” states that “breastfeeding is an unequalled way of providing ideal food for the healthy growth and development of infants; it is also an integral part of the reproductive process with important implications for the health of mothers. As a global public health recommendation, infants should be exclusively breastfed for the first 6 months of life to achieve optimal growth, development and health. Thereafter, to meet their evolving nutritional requirements, infants should receive nutritionally adequate and safe complementary foods while breastfeeding continues for up to 2 years of age or beyond”. Presently, when global efforts are on to achieve better nutritional status and survival for children enshrined in the Millennium Development Goals (MDGs), breastfeeding emerges as a very effective intervention to achieve these targets.

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”The provision has been made for infants to be fed upon their mother’s milk. They find their food and their mother at the same time. It is complete nourishment for them, body and soul. It is their first introduction to the great truth that man’s true relationship with the world is that of personal love and not that of the mechanical law of causation”. abindranath Tagore

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Table 4.1.1 Definitions related to infant feeding

Exclusive Breastfeeding for the First Six Months Exclusive breastfeeding is recommended as breast milk contains all the necessary nutrients which are sufficient to sustain appropriate growth and development of a healthy term infant for the first 6 months of life. There is sufficient evidence that a significant number of under-five-month deaths in resource poor countries could be prevented through achievement of 90% coverage with exclusive breastfeeding for 6 months. Any supplementation during the first 6 months will expose infant to infections and also decrease breast milk output.

 















•  Exclusive breastfeeding: Giving a baby no other food or drink, including water, in addition to breastfeeding with the exception of syrup/drops of vitamins, minerals and medicines (expressed breast milk is also permitted) •  Predominant breastfeeding: Giving small amounts of water or water-based drinks such as tea in addition to breastfeeding •  Partial breastfeeding: Giving a baby some breastfeeds and some artificial feeds, either milk or cereal, or other food •  Bottle feeding: Feeding a baby from a bottle, whatever is in the bottle, including expressed breast milk •  Cup feeding: Feeding a baby from cup (katori, pallad, etc.) whatever is in the cup including breast milk •  Artificial feeding: Feeding a baby on any kind of artificial milk such as animal milk, tinned milk, etc. and not breastfeeding at all •  Complementary feeding: Giving other foods and liquids in addition to breast milk or nonhuman milk • Replacement feeding: Process of feeding a child who is receiving no breast milk with a diet that provides all nutrients the infants need until the age at which they can be fully fed on family foods

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ppropriate and dequate Complementary Feeding after Six Months of ge while Continuing Breastfeeding

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Source: Adapted from Infant and young child feeding counseling—a training course, the “4 in 1 course” (integrated course on breastfeeding, complementary feeding and infant feeding and HIV). Breastfeeding Promotion Network of India (BPNI), Delhi.

Additional foods are needed at this stage to complement the breast milk to sustain the growth and development of the infant. Along with the breastfeeding, children age 6–24 months

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The breast milk contains all the macronutrients (carbo hydrates, proteins and fats), micronutrients, like vitamins and minerals, and adequate water to meet the requirements of a healthy term infant for the first 6 months of life. Apart from the nutrients, breast milk provides a variety of bioactive factors which protect the infant against infection, and also modulate the composition of the indigenous intestinal microbiota. Breast milk also contains some factors to help in digestion and absorption of nutrients.

Status of Breastfeeding Practices in India

Fats

The status of breastfeeding and complementary feeding practices is very dismal in India. According to the National Family Health Survey-3 (NFHS-3), only 24.5% of children are breastfed within the first hour of birth and about 50% initiate breastfeeding within first day of life. More than half of newborn infants receive prelacteal feeds, like milk other than breast milk, honey, sugar or glucose water, and plain water. The exclusive breastfeeding rate up to the age of 6 months is only 46.3%. Exclusive breastfeeding rapidly declines from first month to sixth month, and only about 20% children continue it by 6 months. Possible reasons for suboptimal breastfeeding are primarily due to lack of proper information to mothers, inadequate health care support, inability of the health care providers to help mothers experiencing breastfeeding difficulty, aggressive promotion of baby foods by the

The mature human breast milk contains 3.2–3.8 g/dL of fats. Fats provide 50% of the total energy content of the breast milk. Breast milk fat in immediate postpartum period contains fat needed for gray matter development and in later months, fat which is needed for myelination. Breast milk fat has steady higher level of cholesterol than animal milks and formula. Breastfed babies have significantly higher total cholesterol and low-density lipoprotein (LDL) cholesterol compared to mixed fed babies in the first 6 months of life with improving high-density lipoprotein (HDL) cholesterol/ LDL cholesterol ratio at 6 months. High cholesterol intake in infancy may have a beneficial long-term programming effect on synthesis of cholesterol by downregulation of hepatic enzymes. Human milk contains essential fatty acids and n-3 fatty acids (docosahexaenoic acid and eicosapentaenoic acid), which are needed for a baby’s growing brain and eyes and for healthy blood vessels. Human milk contains the enzyme lipase which helps to digest fat. Thus the fat in breast milk is more completely digested and more efficiently used by a baby’s body than the fat in cow’s milk or formula. The lipase in breast milk is called bile salt stimulated lipase because it starts working in the intestine in the presence of bile salts. The lipase is not active in the breast, or in the stomach before the milk mixes with bile.



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Breastfeeding along with other foods remains an important and safe source of high quality protein, energy and other nutrients like vitamin A and vitamin C between 6 months and 24 months of life. It is, therefore, crucial in preventing undernutrition and morbidities. It can provide about onethird of energy needs, half of protein and 75% of the vitamin A requirements of a child of this age (Fig. 4.1.1). Thus, breast milk helps a child to get enough energy and high quality nutrients from breastfeeding during the second year of life. These nutrients may not be easily available from the family diet. Continuing to breastfeed during the second year can help to prevent malnutrition and vitamin deficiencies.

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Continued Breastfeeding up to the ge of Two Years or Beyond

commercial industry and lack of proper support structures at the community and at work place which includes maternity entitlements and crèches. Cultural beliefs also appear to be important, e.g. breastfeeding initiation is delayed because of the belief that mother’s milk does not “come” at the time of childbirth but flows 2–3 days later.

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should be fed from three or more different food groups; two to three times a day (see more details in chapter 4.1).

Carbohydrates

 

Figure 4.1.1 Nutrition provided by breast milk in second year of life. reproduced with permission from “Infant and Young Child Feeding Counseling—a training course, the ‘4 in 1 course’ (integrated course on breastfeeding, complementary feeding and infant feeding and HIV). Breastfeeding Promotion Network of India (BPNI), Delhi”

Lactose is the main carbohydrate in human breast milk and provides about 50% of its energy content. Breast milk also contains oligosaccharides such as glucose, galactose, N-acetylglucosamine and sialic acid. These oligosaccharides attaches to the epithelial cell surface in the intestines and prevent adhesion of microorganisms thereby preventing their growth.

Proteins Proteins in breast milk provide amino acids for growth and anti-infective factors. Mature breast milk contain 0.9 g/dL of 119

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The composition of breast milk is not always the same. It varies according to the age of the baby, and from the beginning to the end of a feed. It also varies between feeds, and may be different at different times of the day.

Colostrum The milk produced during the first few days after the delivery is known as colostrum, which is a special, thick, sticky, bright lemony yellowish fluid. It is secreted in small quantities for first 3–4 days of life. Although it is in small quantities, it is sufficient to meet the needs of the newborn baby. Colostrum contains more protein than later milk. Colostrum is considered the first immunization for newborn as it is rich in the anti-infective factors that helps protect the baby against diarrhea, respiratory and other infections. Colostrum contains more epidermal growth factors in comparison to mature breast milk, which help a baby’s immature intestine to develop after birth. This helps to prevent the baby from developing allergies and intolerance to other foods. Colostrum helps to clean baby’s intestine which is important to prevent jaundice in the newborn. Colostrum is also rich in vitamin A.

Transitional Milk During the transition from colostrum to the mature milk, the amount of immunoglobulin, proteins, vitamin A and vitamin E decreases, and amount of lactose, fats, energy and water-soluble vitamins increases.

Mature milk

The benefits of breastfeeding for infant, mother and community include: • Breastfeeding provides all the nutrients a baby needs for the first 6 months of life, after which it continues to provide a major portion of the infant’s nutrition along with appropriate family foods. It provides almost half of the nutritional requirements between 6 months and 12 months of age, and up to one-third between 12 months and 24 months of age • Breast milk is easily digested by the baby • Breast milk contains antibodies and other factors which protect the baby against diarrhea and other infections • Breast milk contains enough water which is sufficient even for very dry and hot climates • Breast milk is clean, safe and cheap • Breastfeeding provides a perfect opportunity for building a close bond between mother and baby • It helps the mother by reducing the postdelivery bleeding and thus preventing anemia • Breastfed babies are less prone to have diabetes, heart disease, eczema, asthma, rheumatoid arthritis and other allergic disorders later on in life • Breastfeeding enhances brain development, visual development and visual acuity leading to learning readiness • Breastfeeding has contraceptive effect for the mother if she exclusively breastfeeds her infant for first 6 months • Mothers have a lower risk of breast and ovarian cancers • Breastfeeding costs less in terms of health care expenses as breastfed infants get ill less often • Breastfeeding protects the environment.

isks of Formula Feeding

Infant formula, which is generally used as an artificial substitute for human breast milk, is time consuming, less nutritious and expensive. It is also fraught with innumerable risks for the infants and children in comparison with the breastfeeding. Some of these risks are depicted in the Table 4.1.2.

Science of Milk Transfer Understanding the structure of breast and the process of breast milk production and transfer to the infant is useful to provide effective skilled help to the lactating mother.

natomy of the Breast



After a few days, colostrum changes into mature milk. Mature milk is in large amounts and the breasts feel full, hard and heavy. Some people call this the milk “coming in”. Foremilk is the bluish milk that is produced early in a feed. Foremilk is produced in larger amounts, and it provides plenty of protein, lactose and other nutrients. Because a baby gets large amounts of foremilk, he or she 120 gets all the water that he or she needs from it. Hindmilk is the whiter milk that is produced later in a feed. It contains

Benefits of Breastfeeding

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more fat than foremilk. This fat provides much of the energy of a breastfeed. This is why it is important not to take a baby off a breast too quickly, not until he or she leaves the breast on her/his own.

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protein while colostrum contains 2.3 g/dL. The breast milk protein contains more whey protein and less casein. Due to high whey to casein ratio, the breast milk forms softer curds which are easier to digest. In human milk, much of the whey protein consists of anti-infective proteins, which help to protect a baby against infection. The anti-infective proteins in human milk include lactoferrin (which binds iron and prevents the growth of bacteria which need iron) and lysozyme (which kills bacteria) as well as antibodies (immunoglobulin, mostly IgA). Animal milk and formula may lack the amino acid cystine, and formula may lack taurine which newborns need especially for brain growth. Human infant is ill equipped to handle phenylalanine and tyrosine, two amino acids which are in high concentration in the animal milk in comparison to breast milk.

The human breast consists of the nipple and areola, mammary tissue, the soft tissue including supporting connective tissue and fat, blood and lymphatic vessels and nerves (Fig. 4.1.2). The nipple is the area from which the milk comes out of the breast through multiple small

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Production of the breast milk is controlled by the hormone prolactin. When a baby suckles at the breast, sensory impulses go from the nipple to the brain. In response, the anterior part of the pituitary gland at the base of the brain secretes prolactin. Prolactin goes in the blood to the breast and makes the milk secreting cells produce milk. This process is known as the prolactin reflex (Fig. 4.1.3). This is evident that milk production is dependent on the suckling stimulus. If the baby suckles more, the breast will produce more milk. For the same reason if a mother has two babies, breast milk production increases accordingly. Prolactin is present in the blood for about 30 minutes after the baby finishes the feed. It makes the breast produce milk for the next feed. More prolactin is produced at night due to the inhibition of dopaminergic drive during sleep so breastfeeding at night is especially helpful for keeping up the milk supply. Prolactin suppresses ovulation so breastfeeding can help to delay a new pregnancy.

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•  Increased risk for infection from inherent and subsequent contamination of formula with microbes like Enterobacter sakazakii and Salmonella •  Increased risk of acute respiratory infections, diarrhea, otitis media and ear infections •  Increased risk of necrotizing enterocolitis •  Increased risk of asthma and other allergies •  Reduced cognitive development •  Increased risk of chronic diseases like type 1 diabetes, ulcerative colitis and Crohn’s disease •  Increased risk of cardiovascular disease, increased blood pressure, obesity, altered blood cholesterol levels and atherosclerosis in later adulthood •  Increased risk of side effects of environmental contaminants and harmful chemicals like melamine and bisphenol A (BPA)

Physiology of Lactation

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Table 4.1.2 Risks of formula feeding

Flow of Breast Milk When a baby suckles, sensory impulses go from the nipple to the brain. In response, the posterior part of the pituitary gland at the base of the brain secretes the hormone oxytocin. Oxytocin goes in the blood to the breast and makes the muscle cells around the alveoli contract. This makes the milk which has collected in the alveoli flow along the ducts toward nipple. It makes the milk in the breast flow for this feed (Fig. 4.1.4). Sometimes the milk is ejected in fine streams. This is

 

Figure 4.1.2 Anatomy of the breast. (reproduced with permission from World Health Organization. Infant and Young Child Feeding: Model Chapter for Textbooks for Medical Students and Allied Health Professionals. Geneva: WHO Press; 2009)

Figure 4.1.3 Prolactin reflex. (reproduced with permission from World Health Organization. Infant and Young Child Feeding: Model Chapter for Textbooks for Medical Students and Allied Health Professionals. Geneva: WHO Press; 2009)  

openings. This area of breast is very richly supplied with nerves. The nerve endings in the nipple are important to provide stimulus for the hormonal reflexes important for production and release of the milk from breast. The areola is the dark skin surrounding the nipple. The milk ducts beneath the areola are filled with milk and become wider during a feed. Areola is an important anatomical landmark as it is important to ensure that majority of areola is in baby’s mouth during the feed to achieve an effective suckling. The mammary tissue is composed of alveoli, which are small sacs, made up of millions of milk secreting cells. Milk produced in the alveoli is carried toward the nipple via tubular structures called ducts. These ducts open outside at the nipple area. The alveoli are surrounded by myoepithelial tissue which helps in pushing the milk present in the alveoli toward nipple.

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Positioning and ttaching the Baby at the Breast

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For effective milk transfer from mother to the infant, good breastfeeding skills including proper positioning of the baby and good attachment at the breast are required.

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the oxytocin reflex or the milk ejection reflex. Oxytocin can start working before a baby suckles, when a mother expects a feed. The oxytocin reflex is positively affected by mother’s sensations and feelings like thinking lovingly about the baby; touching, smelling or seeing the baby; or hearing the baby cry. If the oxytocin reflex does not work well, the baby may have difficulty in getting the milk. This may happen if the mother is emotionally disturbed or experiencing pain and discomfort. In such a condition, mother needs support to make her physically and/or emotionally comfortable to make the oxytocin reflex work again and let the milk flow. Signs of an active oxytocin reflex are a tingling sensation in the breast before or during a feed, milk flowing from breasts when mother thinks of the baby or hears him/her crying, milk flowing from the other breast when the baby is suckling, milk flowing from the breast in streams if suckling is interrupted, and uterine pain or a flow of blood from the uterus during the feed. However, absence of these signs does not indicate an inadequate oxytocin reflex.

The mother should be explained how to support the breast with her hand while offering it to the baby: • With her fingers and palm placed on her chest wall below the breast so that her first finger forms a support at the base of the breast • With her thumb pressing on the top of the breast so that it is easier for her baby to attach well.

Figure 4.1.4 Oxytocin reflex. (reproduced with permission from World Health Organization. Infant and Young Child Feeding: Model Chapter for Textbooks for Medical Students and Allied Health Professionals. Geneva: WHO Press; 2009)

The mother should be explained how to bring the baby to the breast: • Touch baby’s lips with her nipple • Wait until baby’s mouth is wide open • Move the baby quickly onto the breast from below.

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A woman can feed her baby in any comfortable position such as sitting, lying or even standing. If the baby suckles properly from the breast he or she will get sufficient milk. However, for a good attachment on breast, some basic principle need to be observed for relative positioning of the baby while breastfeeding. These are: • Baby turned towards mother and his or her ears, shoulder and buttock are in a straight line • His face should face the breast with nose opposite the nipple • Mother should hold the baby close to her • In a newborn, she should support his bottom with hand and not just his head and shoulders.

Attachment This is important how baby’s mouth is attached to mother’s breast for a successful suckling (Figs 4.1.5 and 4.1.6). In good suckling position, baby is suckling with nipple and a larger breast tissue having in his or her mouth. In poor suckling position, baby is suckling with nipple only or nipple with a small breast tissue in his or her mouth.

Signs of good suckling attachment are: • •

The baby’s chin touches the breast His mouth is wide open

Breast Milk Inhibitor

Figure 4.1.5 Good and poor attachment. External signs. (reproduced with permission from World Health Organization. Infant and Young Child Feeding: Model Chapter for Textbooks for Medical Students and Allied Health Professionals. Geneva: WHO Press; 2009)  

Breast milk production is also controlled within the breast itself. Sometimes one breast stops making milk, while the other breast continues to make milk although oxytocin and prolactin go equally to both breasts. There is a substance in breast milk which can reduce or inhibit milk production. If a lot of milk is left in a breast, the inhibitor stops the cells from secreting any more. If breast milk is removed by suckling 122 or expression, the inhibitor is also removed and the breast makes more milk.

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Practices for Successful Breastfeeding To ensure adequate milk production and flow for 6 months of exclusive breastfeeding and thereafter continued breastfeeding, certain practices are very important. • The infant should be fed as frequently and for as long as he or she wants to, during both day and night. The suckling should be allowed until the infant spontaneously releases the nipple. This is called demand feeding. Restricting length of the breastfeeding session may result in the baby getting less of the energy rich hindmilk. The 24-hour average intake of milk is about 800 mL per day during the first 6 months. • At the time of delivery, before breastfeeding is initiated, no prelacteal feed should be given to the infant. Apart from having the harmful effects on the infant like risk of infection, such a practice may interfere in the establishment of breastfeeding. Later on, in the first 6 months of life, no supplementary feed, like other milks, should be given to the infant. This may lead to a decreased supply of breast milk. • Sometimes, mother may have the perception that her milk is not sufficient for her infant. Adequacy of breastfeeding may be ascertained by documenting if the infant has regained the birth weight by 2 weeks of age, and the cumulative weight gain is more than 500 g in a month and the infant is passing adequate urine at least six times a day, while on the exclusive breastfeeding.

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Components of Baby-Friendly Hospital Initiative A maternity facility can be designated “baby-friendly” when it has implemented ten steps given in the Table 4.1.3 to support successful breastfeeding.

Breastfeeding the Preterm Babies The nutritional management plays a large role in the immediate survival and subsequent growth, and develop ment of the preterm infants. The optimal diet for premature infants should support growth at intrauterine rates without imposing stress on the infant’s immature metabolic and excretory functions and ensures healthy short-term and ­

His lower lip is turned outwards One can see more of the areola above his or her mouth and less below. This shows that he or she is reaching with his tongue under the lactiferous sinuses to press out the milk. Poor attachment may lead to pain and damage to mother’s nipple and she may develop sores or fissures in nipple. It may also lead to engorgement of the breast due to improper milk removal. The baby remains hungry and frustrated that leads to refusal to suck. Ultimately, it leads to production of less milk in the breast; baby is not able to feed properly, leading to weight loss. Common causes of poor attachment are use of feeding bottle, inexperience of mother and lack of skilled support.

• •

Table 4.1.3 Ten steps of baby-friendly hospital initiative  

 

Figures 4.1.6A and B (A) Good attachment and (B) poor attachment inside the infant’s mouth. (reproduced with permission from World Health Organization. Infant and Young Child Feeding: Model Chapter for Textbooks for Medical Students and Allied Health Professionals”. Geneva: WHO Press; 2009)



B

Maternity homes and health care practices should support exclusive breastfeeding during the first 6 months of life and continued breastfeeding along with appropriate complementary feeds thereafter. To ensure successful breastfeeding, the World Health Organization (WHO) and the United Nations Children’s Fund (UNICEF) launched the Baby-Friendly Hospital Initiative (BFHI) in 1991. The initiative is a global effort for improving the role of maternity services to enable mothers to breastfeed babies for the best start in life. It aims at improving the care of pregnant women, mothers and newborns at health facilities that provide maternity services for protecting, promoting and supporting breastfeeding. Since its launching, BFHI has grown with more than 20,000 designated facilities in 152 countries around the world over the last 15 years. The initiative has measurable and proven impact, increasing the likelihood of babies being exclusively breastfed for the first 6 months.

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Hospital Practices and Breastfeeding

1. Have a written breastfeeding policy that is routinely communicated to all health care staff. 2. Train all health care staff in skills necessary to implement this policy. 3. Inform all pregnant women about the benefits and management of breastfeeding. 4. Help mothers initiate breastfeeding within a half-hour of birth. 5. Show mothers how to breastfeed and maintain lactation even if they should be separated from their infants. 6. Give newborn infants no food or drink other than breast milk unless medically indicated. 7. Practice “rooming in”—allow mothers and infants to remain together 24 hours a day. 8. Encourage breastfeeding on demand. 9. Give no artificial teats or pacifiers (also called dummies or soothers) to breastfeeding infants. 10. Foster the establishment of breastfeeding support groups and refer mothers to them on discharge from the hospital or clinic.

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condition is known as inverted nipple (Fig. 4.1.7). The mother needs support in such a situation. She should be reassured that with some help she will be able to breastfeed her infant successfully. Help is most important soon after delivery when the baby starts breastfeeding. A mother with the inverted nipple may be helped with the syringe method as follows (Fig. 4.1.8): • Cut the nozzle end of a disposable syringe (10–20 mL). • Introduce the piston from the ragged cut end side. • Ask the mother to apply the smooth side of the syringe on the nipple and gently pull out the piston and let her wait for a minute. • Nipple would then protrude into the syringe. Ask the mother to slowly release the suction and put the baby to breast; at this time it helps the nipple to erect out and baby is able to suckle in the proper position.

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long-term outcomes. Breast milk produced during early postpartum period offers nutritional advantage because of its higher protein and electrolyte concentrations. Preterm infant fed preterm milk demonstrate increase in weight, length and head circumference as well as retention rates of various nutrients comparable to those for the fetus of similar postconception age. Fat absorption in preterm babies fed their own mother’s milk is significantly higher in comparison to infants fed cow’s milk formula. Long-chain polyunsaturated fatty acids (LCPUFAs), which are important for mental and visual development, are also higher in human milk. Preterm infants fed breast milk have lesser incidence of necrotizing enterocolitis in comparison to feeding with formula milk. Even if the disease occurs in infants fed with breast milk, the course of disease is less severe and the prevalence of intestinal perforation is lower. This is due to various protective factors in breast milk like immunoglobulin, erythropoietin, interleukin-10 (IL-10), epidermal growth factor, platelet activating factor, acetylhydrolase and oligosaccharides which are in greater quantity than in term milk. These factors may prevent intestinal attachment of enteropathogens by acting as receptor homologues resulting in the suppression of enteral colonization with harmful microorganisms. Breast milk also prevents a host of neonatal infections, a leading cause of neonatal mortality across the globe. Use of human milk can be adopted as an important health care intervention in neonatal units. D

Breast Conditions and ifficulties In Breastfeeding Figure 4.1.7 Flat and inverted nipple. (adapted with permission from Gupta A, Kushwaha KP, Sobti JC, Jindal T (Eds). Breastfeeding and Complementary Feeding. Delhi: BPNI; 2001)  

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There are several common breast conditions which sometimes cause difficulties with breastfeeding. Manage ment of these conditions is important both to relieve the mother and to enable successful breastfeeding. The difficulties in breastfeeding can be overcome by careful guidance, reassurance and encouragement to the mother during antenatal period to prepare for breastfeeding and by providing skilled counseling after birth.

Flat Nipple

Figure 4.1.8 Syringe method for correction of inverted nipple (adapted from Infant and Young Child Feeding Counseling—a training course, the “4 in 1 course” (integrated course on breastfeeding, complementary feeding and infant feeding, and HIV). Breastfeeding Promotion Network of India (BPNI), Delhi  

Many a times, mother becomes apprehensive that a flat nipple is a hindrance in successful breastfeeding. However, in a good suckling attachment, the infant takes the nipple and the breast tissue underlying the areola into his mouth to form a “teat”. The anatomical nipple only forms about onethird of the “teat” of breast tissue in the baby’s mouth. This is therefore evident that shape of the nipple is immaterial for successful suckling. The nipple is just a guide to show where the baby has to take the breast. A woman with flat nipples should be reassured that she has normal nipples even if they look short provided her nipples protract easily.

Inverted Nipple

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Sometimes a nipple does not protract and on attempting to pull out the nipple, it goes deeper into the breast. The

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Engorgement of the breast can be prevented by avoiding factors mentioned above. If the baby is able to suckle, he or she should feed frequently. If pain and tightness of the breast does not allow suckling, expressed milk may be given to the infant with cup/spoon. Once the mother feels comfortable, she should be advised again to breastfeed the infant on demand. Edema of the breasts may be reduced by applying cold compress. Engorged breasts may cause mild fever, which subsides spontaneously within a day or two. A

Mastitis and bscess Mastitis is inflammation of the breast which becomes red, hot, tender and swollen. The mother feels sick, has fever and severe pain in breast. Mastitis usually affects a part of the breast and usually unilateral. Mastitis may develop in an engorged breast, or it may follow a condition called blocked duct. Mastitis must be treated promptly and adequately. If treatment is delayed or incomplete, there is an increased risk of developing breast abscess. An abscess is when a collection of pus forms in part of the breast. The most important part of treatment is supportive counseling and improved drainage of milk from the affected part of the breast. The mother needs clear information and guidance about all measures needed for treatment, how to continue breastfeeding or expressing milk from the affected breast. This is important to help the mother to improve infant’s attachment at the breast with frequent unrestricted breastfeeding. If necessary express breast milk by hand or with a pump until suckling is resumed. Antibiotic should be given if laboratory tests indicate infection, symptoms are severe, or symptoms do not improve after 12–24 hours of improved milk removal. Pain should be treated with an analgesic and warm packs to the breast. Incision and drainage should be done if abscess develops.

Sore and Cracked Nipples The most common cause of sore nipples is poor attachment in which the infant pulls the nipple in and out as he or she sucks and rubs the skin of the breast against his or her mouth. If the baby continues to suckle in this way, it damages the nipple skin and causes a crack or fissure. Oral thrush in the infant’s mouth is another important cause of

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Breastfeeding and Maternal Illness Maternal illnesses can have adverse effects on lactation. A sick woman may perceive that her milk supply has gone down because of illness. She may also believe that her milk will make the baby ill. These factors may lead to discontinuation of breastfeeding. Minor illnesses such as cold and other mild viral infection, which are self-limiting, should not prevent a mother to continue breastfeeding. However, major illness requires a more careful approach. The potential role of breastfeeding in the transmission of infections must also be acknowledged and appropriate precautions should be taken. If the mother has tuberculosis, the mother-infant dyad should be treated together and breastfeeding should be continued. Similarly, in case of hepatitis (A, B and C) breastfeeding can continue normally as the risk of transmission by breastfeeding is very low. In HIV-positive mother, mother should be provided with counseling and support for appropriate infant feeding practice. With adequate and appropriate antiretroviral drugs to mother and infant, exclusive breastfeeding for first 6 months of life is now preferred recommendation in India. Certain maternal drugs may affect the breastfed infant adversely as they are secreted in the breast milk. Breastfeeding should be avoided if mother is consuming cytotoxic drugs, like cyclophosphamide, methotrexate and doxorubicin, radioactive compounds like gallium 67 (67Ga), indium 111 (111In), iodine 131 (131I) and technetium 99m (99mTc).

Infant Feeding uring Emergencies D

If breasts are not emptied, the milk gets collected in the breast leading to engorgement. The engorged breast is tight, shiny (because of edema) and painful. Also, the milk may stop flowing. The factors which cause engorgement of breasts are: • Giving prelacteal feeds to the baby • Delayed initiation of breastfeeds • Long intervals between feeds • Early removal of the baby from the breast • Bottle-feeding and any other restrictions on breastfeeding.

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Engorgement of Breasts

sore nipple but it usually develops when a baby is few weeks old. The situation is very painful for the mother. If a mother has sore or cracked nipples, improving infant’s attachment to the breast relieves the pain. Medicated creams are best avoided as they may worsen the soreness. Hindmilk, which is rich in fat, should be applied on the nipple after feeding. For oral thrush 1% gentian violet should be applied over the nipple as well as inside the baby’s mouth.



After feeding the nipple may retract back, but doing it each time before feeding over a period of few days will help to solve the problem.

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In disasters and emergencies like earthquakes, floods, typhoons and tsunami, breastfeeding is the safest, often the only reliable choice for infants and young children. It provides adequate and appropriate nutrition to the affected infants in a situation where child survival is a key issue. In disasters, infants are more likely to become ill and die from malnutrition. Uncontrolled distribution of breastmilk substitutes during disasters may lead to early and unnecessary cessation of breastfeeding. For the vast majority of infants, emphasis should be on protecting, promoting and supporting breastfeeding and ensuring timely, safe and appropriate complementary feeding.

Protecting Breastfeeding from Commercial Influence During last many decades, extensive promotion by the infant 125 food manufacturing companies through advertisements,

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meeting, conference, educational course, contests, fellowship, research work or sponsorship, etc. by the manufacturers, supplier or distributors of the products mentioned above. It prescribes standards for the infant milk substitute, infant foods and feeding bottles.



















1. American Academy of Pediatrics. Section on breastfeeding: breastfeeding and the use of human milk. Pediatrics. 2005;115:496-506. 2. Anand RK, Kumta NB, Kushwaha KP, Gupta A (Eds). The Science of Infant Feeding. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2002. 3. Breastfeeding in modern medicine. In: Lawrence RA, Lawrence RM. Breastfeeding: A Guide for the Medical Profession, 5th edition. St Louis: Mosby; 1999. 4. Breastfeeding Promotion Network of India. Infant and young child feeding counseling—a training course, the “3 in 1 course” (integrated course on breastfeeding, complementary feeding and infant feeding and HIV). New Delhi: Breastfeeding Promotion Network of India; (2010). 5. Butte NF, Lopez-Alarcon MG, Garza C. Nutrient Adequacy of Exclusive Breastfeeding for the Term Infant during the First Six Months of Life. Geneva: World Health Organization; 2002. 6. Horta BL, Bahl R, Martines JC, et al. Evidence on the LongTerm Effects of Breastfeeding: Systematic Reviews and MetaAnalysis. Geneva: World Health Organization; 2007. 7. Infant and Young Child Feeding Chapter, Indian Academy of Pediatrics, Rajeshwari K, et al. Infant and young child feeding guidelines: 2010. Indian Pediatr. 2010;47:995-1004. 8. Ministry of Women and Child Development, Food and Nutrition Board, Government of India. National Guidelines on Infant and Young Child Feeding, 2nd edition. New Delhi: 2006. 9. Ministry of Women and Child Development, Government of India. (2003). The Infant Milk Substitutes, Feeding Bottles and Infant Foods (Regulation of Production, Supply and Distribution) Amendment Act, 2003. [Online] Ministry of Women and Child Development website. Available from http://wcd.nic.in/IMSamendact2003.pdf [Accessed September 2012]. 10. World Health Organization, United Nations Children’s Fund. Global Strategy for Infant and Young Child Feeding. [online] WHO website. Available from http://www.who.int/nutrition/ publications/gs_infant_feeding_text_eng.pdf [Accessed September 2012].



Bibliography



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free samples, gifts to mothers and health workers has led to convince them that formula feeding is as good as breastfeeding. This has also made a dent in the confidence of lactating women in her capacity to optimally breastfeed and has contributed to the decline of breastfeeding rates. Recognizing this trend, the Indian Parliament enacted the “Infant Milk Substitutes, Feeding Bottles and Infant Foods (Regulation of Production, Supply and Distribution) Act 1992 (IMS Act)”. The IMS Act was further amended in the year 2003. The IMS Act controls marketing and promotion of infant milk substitutes, infant foods and feeding bottles. Some salient features of the IMS Act include: • It bans any kind of promotion or advertisement of infant milk substitutes, infant foods and feeding bottles to the public including electronic and print media. • It prohibits providing free samples of infant milk substitute, infant foods and feeding bottles and gifts to any one including pregnant women, mothers of infants and members of the families. • It prohibits donation of free or subsidized supplies of infant milk substitute, infant foods and feeding bottles for health care institutions except donations to the orphanages. • It prohibits display of posters of infant milk substitutes, infant foods and feeding bottles at health care facilities, hospitals and health centers. • It prescribes rules for information on the containers and labels of infant milk substitutes and infant foods including a specific statement in English and local languages that “Mother’s milk is best for the baby” in capital letters. • It prohibits having pictures of infants or women or phrases designed to increase the sale of the product on the labels of the products. • It prohibits any contact of employers manufacturing and distributing company with pregnant women even for providing educational material to them. • It prohibits direct or indirect financial inducement or gift to health worker or to any members of his family by the producer, supplier or distributor of the infant milk substitute, infant foods and feeding bottles. • The IMS Act also prohibits offering or giving any contribution or pecuniary benefit to a health worker or any association thereof including funding of seminar,

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RK Anand “We know that shamefully large numbers of children in both wealthy and poverty-stricken regions suffer malnutrition: the malnutrition of excess amounts of inappropriate foods and the malnutrition of insufficient nutritious foods. As adults we should feel embarrassed that so many small children are so poorly fed. We can change this situation if we want to and many people are already working to this end. Good nutrition for children harmonizes with good nutrition for adults…and it would be good for the world if we worked to this end.” Gabrielle Palmer



Complementary Feeding

T

It is the process of giving a child other food while continuing breastfeeding, when her or his nutritional demands can no longer be fulfilled by breastfeeding alone. Appropriate complementary feeding should be timely, culturally acceptable, nutritionally adequate, safe and responsive.

imely Feeding

It is recommended that all infants be exclusively breastfed for 6 months and adequate complementary foods be added after that. Complementary feeding indicators in India are far from satisfactory (Fig. 4.2.2). According to the NFHS 3, introduction of complementary feeding along with continued breastfeeding in children of 6–8 months is only about 55%. Addition of anything other than breast milk before 6 months is fraught with danger for the following reasons: • Addition of foods and other liquids (including water, soup, juice, rice water, dal water, etc.) interfere with -

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Figure 4.2.1 Optimal infant and young child feeding

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Optimal infant and young child feeding (IYCF) is an evidence based measure for improving child nutrition and child survival. The “WHO/UNICEF Global Strategy for Infant and Young Child Feeding and the National Guidelines on Infant and Young Child Feeding 2010” recommended by the IYCF subspecialty chapter of the Indian Academy of Pediatrics stress that for proper growth and development, infants should be exclusively breastfed with no other food or drink—not even water in the first 6 months of life (see Chapter 4.1). This must be followed by sequential addition of nutritionally adequate, preferably home made semisolid and solid foods to complement (not to replace) breast milk, till the child is gradually able to eat normal family food after 1 year while breastfeeding is continued up to 24 months of age or beyond (Fig. 4.2.1). Adequate nutrition for adolescent girls and pregnant and lactating mothers is also important for child nutrition.

The period after 6 months, when other foods are added is also referred to as weaning. Some wrongly interpret it as weaning the baby away from the breast. Complementary feeding is a better term than weaning.



ptimal nfant and Young Child Feeding I

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While adequate nutrition is important throughout child­ hood, it is crucial during the first 5 years of a child’s life, particularly so, in the first 2–3 years when rapid growth occurs and when the child is entirely dependent on the mother and the family for food.

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Figure 4.2.2 Complementary feeding indicators in India (National Family Health Survey-3)

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Nutritionally dequate Complementary Feeding

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To be nutritionally adequate, the complementary foods should contain all food groups—the staple, proteins, vitamins and minerals (Fig. 4.2.3, and Tables 4.2.1 and 4.2.2). After 6 months, add home made porridge or a fruit like ripe banana. Porridge can be made with the staple cereal used by the family like whole wheat flour (atta), rice, semolina (suji or rawa), broken wheat, ragi (nachni) or millet. Breast milk or any other milk can be used to make the porridge. Pieces of chapatti could also be soaked in milk, mashed properly and passed through a sieve to provide a soft semisolid food for the infant. Sugar and cream (malai) can be added to make it energy dense. Boiled or well cooked mashed vegetables (pumpkin, peas, cauliflower, carrots, leafy vegetables, sweet and 128 other potato, beet, tomato) should be added to provide vitamins and iron. Also, offer other seasonal fruits. Gradually

 

 

introduce khichdi with ghee/butter/oil, seera or halwa, upma, poha, dhokla, idli, dosa, pongal, missi roti (paratha made with a batter of wheat flour, gram flour, spices and dal). If foods of animal origin are acceptable to the family, flesh foods should be encouraged. Start with only one food at a time. Wait for a week before introducing another food so that we know whether or not the child is tolerating it. Children who do not eat at a time should be offered food, fruits or a milk feed every 2–3 hours. The child should be encouraged but not forced to eat. Some children may choke a little while learning to eat. Parents may be told not get scared but to be with the child to ward off any trouble. When children are helped to use a spoon, let it be dipped into a preparation like shrikhand or phirni. A bit will stick to the spoon and give children the joy of getting something into their mouth on their own. A child eating well around 7 months or so may suddenly become disinterested in eating. The parents should be told -

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Figure 4.2.3: Food square for the young child. Source: [Elizabeth KE. Current concepts on nutritional requirements of infants and children. Ind J Pract Pediatr. 2011;13(1):5-11]



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optimal breastfeeding. They may fill up the child’s stomach and quench the thirst, and consequently may lead to less suckling at the breast with reduced milk production. Increased risk of allergic disorders due to allergens passing through the not yet fully mature gut of the infant. It takes about 6 months after birth for the intestine to become reasonably mature. Enzymes needed to digest foods other than breast milk are also produced around 6 months. The tongue thrust reflex is active before 6 months. Infants tend to push out with the tongue anything other than liquids. Foods other than breast milk may result in more gastrointestinal and other infections and malnutrition. They may put unnecessary load on the kidney and lead to obesity, hypertension and coronary artery disease later in life. Less frequent suckling also increases the possibility of the mother becoming pregnant again.

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Table 4.2.1 Foods rich in iron Foods rich in iron (mg/100 g of edible portion) Cereals

Cauliflower leaves

40

Ragi

3.9

Chaulai

22.9

Maize flour

2.3

Muli leaves

18

Barley

1.67

Suva ni bhaji

17.4

Rawa

1.6

Pudina

15.6

Dry fruits

Arvi pan green

10

Black til

56.7

Carrot leaves

8.8

Til

9.3

Green onion

7.43

Coconut (dry)

7.8

Kothmir

1.42

Kaju

5.81

Palak

1.14

Badam

5.09

Arvi pan black

0.98

Walnut

2.64

Sargava pan

0.85

Singdana

2.5

Milk and its products

Pulses

Mawa-khoa

5.8

Soybean

10.4

Cheese

2.1

Moth

9.5

Chauli

8.6

Sugars Gud

2.64

Lentil (masoor)

7.86

Sago

1.3

Mutter (dry)

7.05

Channa dal

5.3

Meat Liver (sheep)

6.3

Rajma

5.1

Egg (hen)

2.1

Mung

4.4

Cereals Rice flakes (poha)

20

Mung bean Urad dal

3.9 3.8

Bajra

8

Tuvar dal

2.7

Rice puffed (mamra)

6.6

Wheat flour

4.9

Poppy seeds

15.9

Jowar

4.1

Vermicelli-sev (wheat sev)

2

not to panic but to try some new preparation. In any case, children should never be forced to eat more than what they want. Even if half a spoon is left in the bowl and the child is not interested to eat any more, the parents should respect the child’s appetite. Water can be given, once the child starts taking foods other than breast milk and fruits. It should be offered from an ordinary glass. Children learn to sip from the glass within a few days. Few general guidelines about the nutritive value of foods are: • To retain the nutrients, vegetables including potatoes should be scraped instead of peeling them. The water in which rice or vegetables have been boiled for cooking should be used and not thrown away. The vegetables

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Vegetables

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should not be overcooked. Children should be encouraged to get used to the taste of properly washed raw vegetables from an early age. In general, some amounts of spices are good for health. Most children can tolerate moderate amount of spices used for cooking in most homes. Dry fruits are good, but they must also be rationed, partly because they are expensive and more so because some of these, like dates, figs and raisins, can remain stuck between the teeth leading to caries. Foods that may lead to choking in children should be avoided in those below 3 years. Examples of these foods are: raw carrots, roasted grams, peanuts, other nuts, popcorn, hard candies, berries and whole grapes. 129

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Foods rich in calcium (mg/100 g of edible portion)

Foods rich in zinc (mg/100 g of edible portion)

Milk products and dry fruits

Gingelly seeds

12.2

Til

1,450

Bengal gram (desi)

6.1

Cheese

790

Cashew nut

5.99

Khoa

650

Safflower seeds

5.2

Coconut (dry)

400

Mustard seeds

4.8

Black til

300

Cow pea

4.6

Badam

230

Omum seeds

4.52

Milk (buffalo)

210

Rajma

4.5

Curd

149

Soybean black

4.4

Pista

140

Poppy seeds

4.34

Milk (cow)

120

Groundnut

3.9

Watermelon seeds

100

Samai almond

3.7

Walnut

100

Betel leaves

3.44

Soybean white

3.4

Cereal and pulses Ragi

344

Black gram (whole)

3.3

Rajma

260

Coriander seeds

3.26

Soybean

240

Bajra

3.1

Moth

202

Lentil dal

3.1

Channa

202

Red gram (whole)

3.1

Urad dal

154

Fenugreek seeds

3.08

Vlung

124

Black gram (dal)

3

Tuvar dal

73

Green gram (whole)

3

Channa dal

56

Sanwa millet

3

Cashew nut

50

Bengal gram (kabuli)

2.9

Poppy seeds

1,584

Cardamom

2.81

Almond

230

Maize (dry)

2.8

Foods like idli and parathas made from whole wheat flour should be preferred to white bread. -

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Foods that may be Avoided in the First Year of Life



In families with a strong history of allergy, peanuts and other nuts should be avoided. If any member of the family is known to react adversely to a particular food, avoid that as well. Also fried foods, foods containing too much sugar, artificial sweeteners, monosodium glutamate (MSG) (ajinomoto) and high in salt should be avoided. As recommended by the National Institute of Nutrition, the following points need to be kept in mind: • The recipes for complementary foods should be based on locally available food stuffs • The cooking methods must be simple • The cost should be minimal

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The recipes should be acceptable in taste and consistency Gradually the child should be introduced to healthy foods eaten by the rest of the family.

Consistency of Complementary Foods (Fig. 4.2.4) • To provide more calories from smaller volumes, food must be thick in consistency—thick enough to stay on the spoon without running off when the spoon is tilted. • Foods, such as nuts, which can pose choking hazard, should be avoided. Introduce lumpy or granular foods and new tastes by about 9–10 months. Missing this age may lead to fussy eating later. Avoid using mixers to make the food too smooth. • Three to four teaspoons of roasted groundnut powder can be added to the daily diet of the infant. The meal can also be made energy dense by adding ghee/butter/ oil and sugar/jaggery. -

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Table 4.2.2 Foods rich in calcium and zinc

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Method of Feeding

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When required, take suitable amounts (say 3 tablespoons) of any one of the above ready to use infant weaning food and mix with a small amount of hot water. Add more sugar or jaggery, if required, before feeding.

Amount and Frequency of Food to Be Offered (Table 4.2.3)

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This depends on the capacity or the size of the child’s stomach, which is usually 30 mL/kg of the child’s body weight. A child who weighs 8 kg will have a stomach capacity of 240 mL, about one large cup full and cannot be expected to eat more than that at one meal. Parents may not realize that a child of 1 year needs about 1,000 calories each day—almost half of what an adult may take. So some guidance to parents may be given in this respect. After that, children should be left to decide how much they want to consume. A good guide that children were having optimum quantity of food is their level of activity and weight gain. S

eady-to-use nfant Weaning Foods

afe Complementary Feeding

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Figure 4.2.4 Consistency of complementary food

The following recipes can be prepared in bulk and kept ready at hand for feeding infants.

Bajra Infant Food

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esponsive Feeding (Fig. 4.2.5)

While feeding young children, the caregivers should provide psychosocial stimulation to the child through age appropriate play and praise. Children sitting on the lap of a caregiver or eating with loved ones learn to enjoy eating. Self feeding must be encouraged even if the child makes a mess (Fig. 4.2.6). Forced feeding, threatening and punishment interfere with development of proper feeding habits. Distractions during meals and feeding in front of the television should be avoided.

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Use 45 gm of ragi prepared as given below instead of bajra in the above formula. Soak ragi in water overnight. Drain the water, spread the grains on a plate and allow them to germinate by covering with a damp cloth for one day. Dry the germinated ragi in sun and roast till it develops a malted flavor. Powder and store in an air tight tin.

 

Table 4.2.3 Amount of food to be offered Age Texture

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Ragi (Nachni) Infant Food

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Bajra (dehusked, roasted) 3 tablespoons Roasted greengram dal 1½ tablespoons (or any other dal) Roasted groundnut 3/4 tablespoon Roasted decorticated till 1 tablespoon (gingelly) seeds Sugar 2 tablespoons Powder all the roasted ingredients individually; mix them in the proportions suggested, and store in air light containers.

All utensils used for feeding must be washed thoroughly. There is no need to sterilize the utensils. Eating by hand need not be discouraged. Finger foods, which the child can hold and chew, may be given. However, the hands of the caregiver and the child must be washed thoroughly with soap and water before and after eating. Microbial contamination of complementary foods is more in hot weather. It is slower if the food is refrigerated. When that is not possible, the food should be eaten within 2 hours of its preparation. Even food kept in the refrigerator should be consumed within a day or two.

Frequency

Average amount of each meal

6–8 months

Start with thick porridge, well-mashed foods

2–3 meals per day plus frequent breastfeeding

Start with 2–3 tablespoonful

9–11 months

Finely chopped or mashed foods, and foods that baby can pick up

3–4 meals plus breastfeeding. Depending on appetite offer 1–2 snacks

1/2 of a 250 mL cup/bowl

3–4 meals plus breastfeeding. Depending on appetite offer 1–2 snacks

3/4 to one 250 mL cup/bowl

12–23 months Family-foods, chopped or mashed if necessary. As per appetite offer 1–2 snacks

If baby is not breastfed, give in addition: 1–2 cups of milk per day, and 1–2 extra meals per day. The amounts of food included in the Table are recommended when the energy density of the meals is about 0.8–1.0 kcal/g. If the energy density of the meals is about 0.6 kcal/g, recommend increasing the energy density of the meal (adding special foods) or increase the amount of food per meal. Find out what the energy content of complementary foods is in your setting and adapt the Table accordingly.

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the children get so used to them that they may not accept home made foods. Families must be equipped with means and knowledge to feed their children without the need for processed foods. All effort must be made to ensure that government policies protect public health before private profit. Tinned food/juices, cold drinks, packaged drinks and packaged wafers, health drinks, nutrition supplements promoted for “picky eaters”, bakery products, drinks with low nutrient value such as tea, coffee and sugary drinks should be avoided.

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Picky aters  

Figure 4.2.5 Responsive feeding

 

Figure 4.2.6 Self-feeding

Feeding during and after Illness The appetite during an illness may go down. However, even sick babies continue to breastfeed quite often. They should be encouraged to take enough liquids and small quantities of nutrient rich food that they like to eat. After the illness, the nutrient intake can be increased by adding one or two extra meals in the daily diet for about a month by offering nutritious snacks between meals, by giving extra amount at each meal and by continuing breastfeeding.

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Commercial ready made cereals, though convenient to use, are not preferred over home made foods. Besides high cost, the smooth consistency of such products may make

Of late, a nutritional supplement is being aggressively promoted for so called “picky eaters” for better growth and height. Before the parents start using such a product, they should be given the following information: • An infant grows rapidly in the early months of life. In the second year, the growth will be slower, the appetite may decrease and vary from day to day. Between 15 months to 3 years, the child often passes through a phase of negativism and does the opposite of what the parents want. If the child is unwell, the appetite may suffer even more though the mother’s milk is often not refused. • Keeping the above in mind, the child should not be forced to eat. Of course, various healthy food options must be offered at frequent intervals. Allow children to eat with their hands, even if it turns out to be a messy affair. Then let them learn to use the spoon. The parents may fill the spoon off and on or may offer the child some food with a separate spoon, while gradually encouraging the child to eat independently. • Parents need not get upset if the child does not eat “nourishing” foods for a few days. Children have their moods; for some days, they may eat less of certain foods, but if left to themselves, they may start eating the same again after a gap of few days. • Children, who are small at birth, may not weigh as much as their peers. The parents should be told that so long the child follows the growth curve, they should be happy. In fact, if these children are given food or products too high in calories and become obese, they become potential candidates for developing diabetes and cardiovascular diseases. • Make sure the child is not anemic and does not have urinary or any other infection responsible for anorexia. • Convey to the parents that the product promoted for “picky eaters” is expensive, not wholesome and comes in the way of the child developing healthy food habits. Also, one may get a false sense of security while the underlying causes for fussy eating mentioned above are missed.

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1. Anand RK. Health workers and the baby food industry: World Health Organization acts to end conflict of interest and promote breastfeeding. Br Med J. 1996;312:1556 7. 2. Bellad R. Complementary feeding. In: Bharadva K, Tiwari S, Chaturvedi P, Bang A, Agarwal RK (Eds). Feeding Fundamentals: A Handbook on Infant and Young Child Nutrition. 1st edition. Jaipur: Pedicon 2011; 2011. pp. 89 93. 3. Kushwaha KP. Complementary feeding of breastfed children. In: Anand RK, Kumta NB, Kushwaha KP, Gupta A (Eds). The Science of Infant Feeding. 1st edition. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2002. pp. 117 34. 4. Low Cost Nutritious Supplements, 2nd edition. Hyderabad, National Institute of Nutrition; 2000. 5. Palmer G. Complementary Feeding: Nutrition, Culture and Politics, 1st edition. London: Pinter and Martin; 2011. 6. Wiessinger D, West D, Pitman T. The Womanly Art of Breastfeeding, 8th edition. New York: Ballantine Book; 2010. 7. World Health Organization. Complementary Feeding of Young Children in Developing Countries: A Review of Current Scientific Knowledge. Geneva: World Health Organization; 1998. 8. World Health Organization. Infant and Young Child Feeding: Model Chapter for Textbooks for Medical Students and Allied Health Professionals. Geneva: World Health Organization; 2009.

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• Initiate breastfeeding as early as possible after birth, preferably within 1 hour • With the exception of any essential medicine, practice exclusive breastfeeding from birth to 6 months of age and introduce complementary foods at 6 months (180 days) • Continue frequent on-demand breastfeeding until 2 years of age or beyond • Start complementary foods at 6 months of age with small amount. Increase the quantity and frequency as the child gets older, while maintaining frequent breastfeeding • Gradually, increase food consistency and ensure that all nutrient needs of the child are met • Practice responsive feeding, applying the principles of psychosocial care • Practice good hygiene by handwashing with soap and water before preparing food, before feeding the child and after using the toilet • Increase fluid intake during illness, including more frequent breastfeeding, and encourage the child to eat soft favorite foods. After illness, encourage the child to eat more often • Ensure adequate nutrition including control of anemia in infants, young children, adolescent girls and pregnant and lactating mothers. Vitamin and mineral supplements must be given if required • Support the implementation and monitoring of IMS Act.

Nutritio

ey Messages for ptimum nfant and Young Child Feeding

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Malnutrition Meenakshi Mehta

“Underlying every other condition is malnutrition, due to both calorie and protein deficiency. Though poverty is the main contributing cause, it is greatly aggravated by lack of proper dietary knowledge.” (the orange ribbon) an awareness ribbon for malnutrition

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The World Health rganization (WH ) defines PEM as range of pathological conditions arising from coincidental lack in varying proportions of proteins and calories, occurring most frequently in infants and young children, and commonly associated with infection. The extent of weight loss and

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Eighty percent of the world’s undernourished children live in just 20 countries. of an estimated 178 million under five stunted children, most live in sub Saharan Africa and South Central Asia. Despite having economic growth, progress and largest food and nutrition program, India is home to over one third of world’s malnourished children, and for 5.6 million deaths due to malnutrition out of 10.4 million child deaths per year (Fig. 4.3.1). NFHS 3 (2005–2006)

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Magnitude of the Problem

reports a prevalence of 48% for stunting (including 24% severely stunted), 43% for underweight (including 16% severely underweight) and 20% for wasting in under five children. Prevalence of malnutrition varies state wise with highest in Madhya Pradesh (55%), and lowest in Kerala (27%). PEM has higher incidence in nutritionally vulnerable groups: young children (especially between 6 months and 2 years) and women during pregnancy and lactation as the nutritional requirements are larger relative to their size than in older children and adults. The damage caused by malnutrition in the intrauterine life or in the first 2 years of life may be irreversible due to impairment in developing brain (Fig. 4.3.2).

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Protein energy malnutrition (PEM) is one of the most widespread health and nutritional problem of the deve­ loping countries. Annually, undernutrition kills or disables millions of children. It often causes disease and disability in the survivors and prevents millions more from reaching their full intellectual and productive potential. Stunting, severe wasting and intrauterine growth restriction (IUGR) together accounted for 2.2 million deaths and 21% of disability adjusted life years (DALYs) for under five children.

Figure 4.3.2 Causes of under-five deaths  

 

Figure 4.3.1 Country-wise prevalence of malnutrition in under-five children

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Table 4.3.1 Classification of malnutrition Classification Definition Gomez Weight below % median WFA

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Grading Mild (Grade 1) Moderate (Grade 2) Severe (Grade 3) Z-scores (SD) below median WFH Mild Moderate Severe Z-scores (SD) below median WFH Moderate Severe Z-scores (SD) below median WFA Moderate Severe MUAC divided by occipitofrontal head circumference Mild Moderate Severe Z-scores of BMI for age Grade 1 Grade 2 Grade 3 Percentage of standard weight for age (50th centile of Normal Harvard standard) Grade 1 Grade 2 Grade 3 Grade 4 Mid-arm circumference Normal Mild-moderate Severe PEM Presence/absence of edema <80% Weight/age – % of expected 60–80% <60% <60%

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based on weight for age, standard weight for age measurement used was Harvard growth standard, 50th centile being 100%, many classifications have been suggested (Table 4.3.1). In 2009, WH recommended new growth standards replacing the earlier National Centre for Health Statistics (NCHS) reference charts. Table 4.3.2 presents the diagnostic criteria for severe acute malnutrition (SAM) based on WH growth standards. Moderate malnutrition is defined when the weight for



growth rate varies with severity of PEM; in early stages, there is failure to maintain weight or growth rate, but as it becomes progressive, there is loss of weight associated with loss of subcutaneous fat and muscle mass with dysfunction of many vital organs which lead to a variety of clinical features. With increasing severity, there is increasing failure in the homeostatic mechanisms of the body and damage to the immune defenses which may result in infections, shock and death. Protein energy malnutrition is a generalized syndrome complex, and it is very difficult to classify it using a single parameter. A large number of classifications using anthropometric, clinical and biochemical parameters have been proposed. Nutritional anthropometry is a valuable index of assessment of nutritional status of children and mothers. Among the most studied are weight, length/ height, arm circumference, skinfold thickness and head circumference. Since Gomez first proposed classification

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75–90% WFA 60–74% WFA <60% WFA Waterlow 80–90% WFH 70–80% WFH <70% WFH WHO (wasting) Z-score < –2 Z-score < –3 WHO (stunting) Z-score < –2 Z-score < –3 Kanawati <0.31 <0.28 <0.25 Cole BMI for age Z-score < –1 BMI for age Z-score < –2 BMI for age Z-score < –3 Jelliffe >90% 80–90% 70–79% 60–69% <60% Arnold >13.5 cm 12.5–13.4 cm <12.5 cm Welcome Edema absent (underweight) Edema present (Kwashiorkor) Edema absent (Marasmus), Edema present (Marasmic Kwashiorkor) Abbreviations: BMI, Body mass index; HFA, Height for age; MUAC, Mid and upper arm circumference; SD, Standard deviation; WFA, Weight for age; WFH, Weight for height; WHO, World Health Organization.

Table 4.3.2 Diagnostic criteria for severe acute malnutrition (SAM) in children age 6–60 months Indicator Measure Cut off Severe wasting Weight for height < –3SD Severe stunting Height/age < –3SD Severe undernutrition Weight/age < –3SD Severe wasting Mid-arm circumference < 115 mm Bilateral edema Clinical signs --

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Age Dependent Criteria • •

Weight for age expressed as percentage of the median value, Z (SD) score or as percentiles. Height for age compares child’s height with the expected height/length for a healthy child of the same age.

The Growth hart C

Age Independent Criteria

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Weight and arm circumference are affected within a short duration of inadequate nutrient intake and ill health, while height and head circumference do not change so rapidly. A slowing in the rate of growth indicated by poor gain in height would take at least 6 months to manifest itself, while a slowing of weight gain or loss can be demonstrated within a month. A child can lose weight but not height. Anthropometric parameters can be classified into two main groups, the age dependent and age independent criteria if child’s age is not known.

is taller than his circumference level on the stick, he is considered malnourished (Fig. 4.3.3). Mid-arm circumference to head circumference ratio: A ratio of 0.280–0.314 indicates mild malnutrition, 0.250–0.279 indicates moderate PEM and less than 0.249 indicates severe PEM. Mid-arm/height ratio: Less than 0.29 indicates gross malnutrition (normal 0.32–0.33). hest/head circumference ratio: Chest circumference becomes equal to head circumference at 1 year, and after 2 years, it becomes more than head circumference. In PEM, it is still smaller than head circumference beyond 2 years of age. kinfold thickness: It is an indicator of availability of caloric stores in the form of subcutaneous fat. Sites for measurements are usually the triceps and subscapular region. Its normal value is present in Tanner’s chart and measurements below 90% of the standard are considered subnormal (80–90% mild, 60–80% moderate and less than 60% severe malnutrition). Mid-thigh and calf circumference: Standards for mid thigh and calf circumference have been developed. S

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length/height is between –2SD and –3SD, or when the mid arm circumference is between 11.5 cm and 12.5 cm.

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cology and tiology of Malnutrition E

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While the reliability of a single anthropometric measurement may be suspect and difficult to interpret in terms of a child’s past growth and cannot give predictive value of future growth, measurements at regular intervals and recording on a growth chart permit systematic assessment of child’s growth. The idea of monitoring the growth of the individual which would be useful in provision of child health care, gave rise to the concept of “growth chart” pioneered by Morley in 1959. Since then various growth charts have been used (Figs 4.3.4A and B).

Protein energy malnutrition is the result of a complex interplay of interacting and related factors in the individual, family and community. Inadequate dietary intake and disease are immediate determinants of PEM. Disease may affect PEM by various mechanisms. Conversely, PEM may increase susceptibility to and severity of infections. The causes in individual are anorexia, increased losses from intestine, malabsorption and micronutrient deficiency disease, infectious diseases, inadequate intake of breast milk, early weaning from breast, late introduction of complementary feeding and inadequate access to food. The familial causes are maternal illiteracy, poor knowledge and practices of child rearing, maternal malnutrition, overcrowding, poverty, poor living and sanitary conditions, unemployment, alcoholism or debt. The community causes include national poverty, poor educational status, inadequate medical facilities, poor access to health services, cultural practices and beliefs, marginalizing of girls and women, natural and man made disasters, poor rainfall or -

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• Mid-upper arm circumference (M ) or mid-arm circumference (M ): Between 1 year and 5 years, the MUAC is relatively constant between 16.5 cm and 17.5 cm. Any child in this group whose MUAC is less than 12.5 cm is classified as undernourished. MUAC is a useful method of screening large number of children during nutritional emergencies but is less useful in long term growth monitoring programs. • Weight for height: The degree of wasting is assessed by comparing the child’s weight with the expected weight of a healthy child of same height. Combinations of these measurements have been suggested sometimes to distinguish types of malnutrition. For example, Waterlow proposed that weight/height allows one to distinguish between children who have suffered malnutrition in the past from those who are currently experiencing malnutrition. In chronic malnutrition, the child is stunted, i.e. her/his weight for age and height for age are low. In acute malnutrition, however, her/his height for age is appropriate, but she/he is wasted (low weight for height and age). Thus, weight and height measurements together are useful to understand the dynamics of malnutrition, distinguishing between current malnutrition and long term or chronic malnut­ rition. • Quack stick: Quacker’s mid arm circumference measuring stick is a height measuring rod calibrated in MUAC rather than height, values of 80% of expec­ ted MUAC for height are marked on the stick at corresponding heights levels and the child is made to stand in front of this stick. His nutritional status is easily read as 50%, 60%, 70% or 80% of the standard. If a child

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Figure 4.3.3 Quack stick: modified for Indian children



resources start appearing in the underlying and immediate causes finally manifesting as malnutrition and death (Flow chart 4.3.2) in the negative conceptual frame work. Although malnutrition is associated with lack of food and poverty, it is also seen in economically advantaged families probably because of lack of awareness in the mothers about proper infant feeding and child nutrition. In the developed nations, like USA, PEM has been reported in families who use unusual and inadequate foods to feed infants, whom the parents believe to be at risk for milk

excess rain, or poor facilities for storage and transport, and hoarding and black marketing. The community and national causes have direct impact on the family and individual child. Thus, PEM is an end result of many ecological problems (Flow chart 4.3.1, Figs 4.3.5 to 4.3.8). The United Nations Children’s Fund has suggested a conceptual framework of the causes of malnutrition (positive and negative) and three main causes: (1) basic, (3) underlying and (3) immediate. While the basic causes remain the same in either group, the lack or deficiency of

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Pathophysiology of Protein nergy Malnutrition E

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allergies, and also in families who believe in fad diets. In addition, PEM has been noted in chronically ill patients in neonatal or pediatric intensive care units as well as among patients with burns, HIV, cystic fibrosis, failure to thrive, chronic diarrhea syndromes, malignancies, bone marrow transplantation and inborn errors of metabolism.

Many of the manifestations of PEM represent adaptive responses to inadequate energy and/or protein intakes, resulting in decreased activity and energy expenditure. To meet the energy requirement, initially fat stores are

mobilized followed by protein catabolism for maintaining basal metabolism. Furthermore, micronutrients are essen­ tial in many metabolic functions as components, cofactors in enzymatic processes and immune response. In the etiopathogenesis of PEM, why and what is it that among children destined to become malnourished; some develop kwashiorkor while others develop marasmus. Amongst various theories postulated was Gopalan’s theory on adaptation/dysadaptation, Srikantia’s on antidiuretic effect of ferritin, loss of edema without change in serum albumin, noxious insults producing reactive oxidative free radicals, decreased Na, K, ATPase activity, depressed cellular protein synthesis, etc. The latest theory postulated by Golden suggests deficiency of type I (functional nutrients), like

a Figure 4.3.4A

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B Figure 4.3.4B  

Figures 4.3.4A and B Prototype of a growth chart

The clinical manifestations of malnutrition depend on the severity and duration of nutritional deprivation, the age of the undernourished subject, relative lack of different proximate principals of food and micronutrients and the associated infection. Nutritional marasmus and kwashiorkor

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are two different extreme forms of a continuous process of malnutrition. Nutritional marasmus results from predo­ minant energy deficiency whereas kwashiorkor is due to predominant protein deficiency though some energy deficiency may coexist. ccasionally, patients who are initially marasmic may develop edema due to protein loss when the individual is known as marasmic kwashiorkor. In clinical practice, such extremes account only for a small proportion of cases of malnutrition. A majority has mild to moderate deficiency with varied clinical manifestations, and this range is known as protein energy malnutrition. Malnutrition can be compared to an iceberg; while only 139 the tips of the iceberg, i.e. the severe forms are seen -

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zinc, and type II nutrients, like phosphorus, magnesium, manganese, copper and vitamins D and C, in the diets of malnourished children due to decrease in appetite. No amount of additional energy as lipids or carbohydrates would enhance convalescence of PEM, unless these specific nutrients are supplied in the balanced form.

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Flow chart 4.3.1 Ecology of PEM

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by the health workers. Those hidden in the community constitute a vast majority of children suffering from mild and moderate forms of PEM. They are not brought for any medical attention, and are at a highrisk of deterioration and progress to severe forms if uncared for prolonged period. PEM impairs resistance to infection and may present with its varied manifestations. Mild degrees of PEM lead to growth retardation; frank malnutrition if prolonged may cause mental retardation. Initial response to nutritional deprivation is of two types: (1) dynamic children, who remain active but fail to gain weight and later length, and (2) sedentary children, who 140 maintain their growth initially by limiting their activities but ultimately fail to grow. Two thirds of malnourished children

Figure 4.3.6 Mortality related to bottle feeding  

 

Figure 4.3.5 Socioeconomical and biological determinants of PEM

do not present with any clinical signs, and are diagnosed by anthropometry.

Marasmus Marasmus can develop in the first few months of life, commonly from birth to 2 years. It results if the baby is fed with diluted milk from buffalo, cow, goat or even tin milk, without offering breast milk or any other food. Marasmus is characterized by failure to gain weight and irritability, followed by weight loss and listlessness until emaciation results. It is diagnosed by gross loss of subcutaneous fat, and the infant seems to have only skin and bones, ribs become visible and costochondral junctions look prominent. There is conspicuous absence of edema. Growth retardation is

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Figure 4.3.7 Socioeconomical milieu of PEM

 

Flow chart 4.3.2 The United Nations Children’s Fund conceptual framework

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Figure 4.3.9 Marasmus

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severe and obvious. The head appears disproportionately large with very little hair. Weight is less than 60% of expected weight, muscles may be atrophied leading to hypotonia. The child is conscious, alert but apathetic and in extreme cases, is disinterested in surroundings and sits listless for long hours. The facial pads of the fat are last to go, when the child looks like a wizened old man. Anemia is moderate and may be associated with vitamin deficiencies, infections and infestations, and electrolyte imbalance. In the early stages, the child’s appetite is good and he readily accepts what is offered. However, in advanced stages, there is loss of appetite and it requires a lot of tact and patience to coax the child to eat. Infants are often constipated but may have starvation diarrhea with frequent small mucoid stools. The abdomen may be distended or flat with the intestinal pattern readily visible. As the condition progresses, the temperature usually becomes subnormal and pulse slows (Fig. 4.3.9).

washiorkor

Kwashiorkor is an African word was suggested by Dr Cicely Williams in early 1930s; meaning “the disease that occurs when the child is displaced from the breast by another

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B Figures 4.3.10A and B Dermatosis of kwashiorkor  

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child”. The age incidence is later than that of marasmus and this condition is uncommon under the age of 1 year. Kwashiorkor may initially present with vague manifestations that include lethargy, apathy and/or irritability. When advanced, there is lack of growth, lack of stamina, loss of muscle tissue, increased susceptibility to infections, vomiting, diarrhea, anorexia, flabby subcutaneous tissues and edema. The edema usually develops early and may mask the failure to gain weight. It is often present in internal organs before it is recognized in the face and limbs. Edema is characteristically pitting. It usually occurs first around the eyes, then above the ankles and above dorsum of the feet. In the latter stages, the whole face, hands and body may be edematous, but ascites is rarely due to kwashiorkor alone. Edema is mainly due to tissue wasting, together with low plasma osmotic pressure caused by low serum albumin levels. The child is listless, lethargic, apathetic and miserable, her/his moaning cry is characteristic. The hair changes are variable. Hair may be thin, dry, brittle and lusterless. These become straight and hypopigmented (grayish white or reddish brown). During recovery, the growing part of the hair gets approximately pigmented, and gives appearance of “flag”. The skin changes are not constant and manifestations are known as dermatosis (Figs 4.3.10A and B). Skin becomes darkened in irritated areas but in contrast to pellagra, it does not occur in areas exposed to sunlight. Depigmentation may occur after desquamation in these areas, or it may be generalized. The skin lesions appear as large areas of erythema, followed by hyperkeratosis. The epidermis peels off in large scales, exposing a raw area underneath which is prone to infection. It resembles old paint flaking off the surface of the wood hence called “flaky paint dermatosis”. The lesions are moist and common on areas exposed to continuous pressure and irritation. In severe cases, petechiae or ecchymoses may appear. Alternate areas of hypopigmentation and hyper­ pigmentation give a resemblance to pavement, and this is known as “pavement dermatosis” or when skin changes are seen in a particular mosaic form, as “mosaic dermatosis”.

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evident. The usual differentiating features of marasmus and kwashiorkor are summarized in Table 4.3.3. D

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Liver may be enlarged and fatty. There may be associated infections in the form of diarrhea, respiratory infections, urinary tract infections and vitamin deficiencies, especially vitamin A, thiamine, riboflavin and niacin. Eventually there is stupor, coma and death. K

Marasmic washiorkor Children with severe muscle and fat wasting, but with presence of edema are called marasmic kwashiorkor. This syndrome is seen in children who have marasmus, but suddenly develop edema due to increased deficiency of protein than before. Thus the clinical features are those of both marasmus and kwashiorkor (Fig. 4.3.11). Anemia may be moderate, and one or more vitamin deficiencies may be

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Figure 4.3.11 Marasmic kwashiorkor

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The nutritional deficiencies are generally multiple and anemia due to deficiencies of iron, vitamin B12 or folate may be associated. Anemia may be hypochromic microcytic, macrocytic or normocytic normochromic. Deficiencies of vitamin B complex factors, especially ariboflavinosis, vitamin A (manifesting as keratomalacia and xerophthalmia) and vitamin C occur commonly. Since growth gets arrested in severe PEM, rickets may become manifest only when the child starts growing with nutritional rehabilitation.

Potassium The total body potassium may be markedly decreased in PEM. The loss is due partly to the cellular breakdown but more so by the loss in diarrheal stools.

Other Electrolytes There is also deficit of total body sodium, calcium, phosphorus, magnesium and chloride. The body sodium is 93% of the expected values. There is significant loss of

 

Table 4.3.3 Differences between marasmus and kwashiorkor

 

A.

1–3 years

None

* Lower legs, sometimes face or generalized

2.

Wasting

*Gross loss of subcutaneous fat “All skin and bone”

Sometimes hidden, sometimes fat blubbery

3.

Muscle wasting

Obvious

Sometimes hidden

4.

Growth retardation

Obvious

Sometimes hidden

5.

Mental changes

Usually apathetic quiet

Usually irritable moaning, also apathetic.

 

Edema

     

Variable features Appetite

Usually good

Usually poor

2.

Diarrhea

Often (past or present)

Often (past or present)

3.

Skin changes

Seldom

Often—diffuse depigmentation occasional flaky paint or enamel dermatosis

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Hair changes

Seldom

Often sparse, straight silky, dyspigmentation, gray or reddish

Usually normal (or low)

* Low

2. Urinary urea per g creatinine

Usually normal (or low)

* Low

3.

Urinary hydroxyproline per g creatinine

* Low

* Low

4.

Serum essential amino acid index

* Low

* Low

5.

Anemia

Uncommon

* Common

6.

Liver biopsy

* Normal or atrophic

* Fatty changes

 

 

 

 

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Biochemistry/pathology Serum albumin

 

 

 

 

 

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0–3 years

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Kwashiorkor

Essential features

 

B.

Usual age

Marasmus

*These are the most characteristic or useful distinguishing features.

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Long-Term onsequences Malnourished children are more susceptible to disease,

144 have a reduced capacity to learn, have deficits in cognitive function, less likely to perform well in school and are likely

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This is recommended for mild to moderate PEM, and those uncomplicated severe PEM, who have fairly good appetite, normal body temperature, who are conscious and active, and without evidence of serious infection. These children are managed at home by parents under observation and supervision. They are monitored through weekly visits by paramedicals or visits to the hospital or at a nutritional rehabilitation center every week. The main goal of treatment -

The complications of PEM are usually seen with severe malnutrition. They are dehydration, hypothermia, hypo­ glycemia, infections, anemia, xerophthalmia, congestive heart failure, hypomagnesemia, hypocalcemia, zinc, copper, chromium and manganese deficiency and deficiencies of vitamins.

The management of PEM depends on nutritional status, degree of hypermetabolism, expected duration of illness and associated complications. The goals are to minimize weight loss, to maintain body mass and to encourage body mass repletion or growth. The principles of management are as follows: • The patient is evaluated for the severity, presence of systemic infections, other nutritional, micronutrients deficits, anemia, and fluid and electrolyte disturbances • The intake of food is promoted by all available means. Locally available, culturally acceptable, and affordable foods are advised • Complications of malnutrition and sequelae are prevented by careful surveillance and prompt remedial action • Possible epidemiological factors for malnutrition are considered and attempt is made to eliminate these as far as possible. Mild to moderate PEM is best managed at home. Majority of cases of severe PEM are associated with some of the complications listed above and hence are best managed in hospital. -

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Infectious disease worsens when malnutrition is present and conversely malnutrition usually weakens resistance to various infections which are more serious in a malnourished host than in a well nourished child. Malnourished children with PEM have recurrent episodes of acute infections or chronic insidious infections which may go undetected unless carefully looked for. Thus recurrent diarrheal diseases, lower respiratory tract infections and occult urinary tract infection are common, and have high mortality. Measles is usually a preceding illness. Tuberculosis and malaria must be always ruled out, and intestinal parasitosis, like ascariasis, hookworm, and giardiasis, must be treated. Septicemia, especially in infants and toddlers, may be life threatening. Regarding humoral immunity, IgG, IgM and secretory IgA, blood concentrations are not significantly affected in mild and moderate forms of PEM and show a good response when challenged with bacterial and viral vaccines, but is depressed in severe forms of PEM with infections. The cell mediated immunity (CMI) is impaired in all grades of malnutrition except in Grade I. It is severely impaired in grades III and IV, PEM and kwashiorkor. This explains a high incidence of Gram negative bacterial infections and serious morbidity and high mortality to viral infection like herpes simplex and measles. Due to depressed CMI, the tuberculin skin test is often negative in marasmus and kwashiorkor in spite of active tuberculosis. Following dietary treatment of four to six weeks, the CMI might improve and the skin test may become positive. Serum C reactive protein and C3 complement levels are depressed in severe malnutrition but rise in presence of infections and thus behave as acute phase reactants.



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to drop out. The evidence suggests that undernutrition has pervasive effects on immediate health and survival as well as on subsequent performance. These include not only acute effects on morbidity and mortality but also long term effects on cognitive and social development, physical work capacity, productivity and economic growth. The magnitude of both the acute and the long term effects is considerable. Survivors of undernutrition have deficits in height and weight that persist beyond adolescence into adulthood. These may be accompanied by deficit in frame size as well as muscle circumference and strength. The implications of these deficits with respect to the work capacity of both men and women and to women’s reproductive performance are obvious. nce in the job market, their productivity is low. For the economy as a whole, this translates into losses of nearly 3% of gross domestic product. All this places India’s large population, the basis of its much awaited demographic dividend, at a growing disadvantage in today’s globalizing world. These deficits are related to the severity of PEM and can be decreased probably by a combination of dietary and behavioral interventions, coupled with improvements to the overall quality of home and/or school environment. Such interventions appear to be much more effective if instituted in early life.

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Growth hormone, plasma cortisol levels, thyroid stimulating hormone (TSH) and T4 levels may be raised in PEM, while insulin levels and T3 levels are reduced both in marasmus and kwashiorkor.

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magnesium from the cells, levels being significantly low in children with moderate and severe malnutrition, and in children with marked linear growth retardation.

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decades. Infections, including diarrheal dehydration and electrolyte disturbances are common in severely malnourished children, and found to be the poor prognostic factors. According to the WH , a death rate of more than 20% is considered unacceptable in the management of severely malnourished children, 11–20% is poor, 5–10% is moderate, 1–4% is good and less than 1% is excellent. Appropriate feeding, micronutrient supplementation, broad spectrum antibiotic therapy, less use of intravenous fluids for rehydration, and careful management of complications are factors that can reduce death, morbidity and cost of treating these children. Based on these factors, WH have prepared guidelines for the inpatient case management of severe malnutrition. Not all severely malnourished children need hospitalization (Table 4.3.4). Majority of children usually have some complications; they need hospitalization for critical care and intense monitoring. The management of SAM can be achieved by three ways and in three phases (Fig. 4.3.12):

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is to provide adequate calories to replace losses, to build up nutrition, and to promote growth. Caution must be taken to gradually build up the calories and proteins. The expected calories and proteins are calculated on the present weight. nce this is achieved, then over next 7 days, calories and proteins are calculated of the average weight. After that, over 2 weeks, the diet (calories and proteins) are increased for the expected weight for that age. It takes about 6 months to achieve this target. The examples are cereal pulse combinations—double or triple mixes, like dal rice, khichdi, with seasonal green leafy and yellow orange vegetables, root vegetables with sugar, jaggery; thick butter milk based diets, milk based diets, either of them supplemented with proteins like ground nut, soya, and amylase based food formulations. Emphasis must be laid on adding enough oil/ghee/butter to the diet to increase calories and palatability. The energy recommended is 80–100 kcal/kg/day and protein 0.70–1.0 g/kg/day, stepped up gradually to 120–150 kcal/kg/day and protein 2–3 g/kg/day of high biological value. Basically these should be from locally available, seasonal and affordable food sources, commonly consumed by the family. The diet should be liquid, semisolid or solid depending on the child’s acceptability and appetite. Frequent small feeds are encouraged, increased gradually rather than one or two major bulky meals. Non vegetarian articles like egg, fish, chicken, meat, etc. are recommended for those whose cultural, religious practices permit them. Zinc is added when child improves weight. Parents are educated about proper cooking, clean drinking water, sanitation and personal hygiene. Some basic advice is also given for management of common problems like diarrhea by oral rehydration solution ( RS), of anemia with oral iron and folic acid, vitamin deficiencies, infestations and infection as well as immunization.

evere Malnutrition

 

•  •  •  •  •  •  •  •  •  •  •  •  •  •  •  •  • 

Hypothermia Infection Fluid and electrolyte imbalance Convulsions Unconsciousness Jaundice, purpura Raised liver enzymes Severe anemia and congestive cardiac failure Xerophthalmia Severe dermatosis Extreme weight deficit Bleeding Marked hepatomegaly Persistent vomiting Severe anorexia Distended tender abdomen Age less than 1 year





The management of uncomplicated SAM using simple, ready to use therapeutic foods—RUTF (fortified with all essential nutrients like zinc, potassium, magnesium, and phosphate with low levels of sodium, protein and iron), with community based care is encouraging and worthwhile. With these diets children recover their appetite. Home based management has the advantage of easier access by rural population, promoting early intervention in the disease, improving coverage rates and preventing nosocomial infections. The limited hospital staff can focus on inpatient complicated cases. The risk of death rises progressively with worsening nutritional status. However, over 80% malnutrition deaths occur in mild to moderately malnourished children as these greatly outnumber children with severe malnutrition. Hence, for better child survival, intervention is necessary for management of mild and moderately malnourished children in addition to that of severely malnourished children. Hence, there is an urgent need to identify these malnourished children timely and plan the treatment based on the need of an individual child. Case fatality rates in children with severe malnutrition have remained unchanged at 20–30% over the past five

Table 4.3.4 Indications for hospitalization in severe malnutrition

145

 

Figure 4.3.12 Stepwise management of severe malnutrition (Source: The World Health Organization)

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Phase II: Restoration After the initial phase of resuscitation, there is improvement in child’s condition with return of appetite, beginning of loss of edema and return of smile. During this phase the aim is to make the child gain weight and restore weight for height. Dietary management of severe protein energy malnutrition: In the initial stabilization phase, because of child’s fragile physiological and metabolic state, great caution is required in dietary intervention of SAM children. The rule of “go slow, rather than hurry” is appropriate. Feeding is designed to provide 75–80 cal/kg/day and proteins 0.7 g/kg/day. Each feed should be small, gradually increased, of low osmolality and lactose, offered at frequent intervals, according to the child’s tolerance (Table 4.3.5). Breastfeeding should be continued and Starter formulas like F 75 (milk based containing 75 cal/100 mL and 0.9 g/100 mL protein and fluid volume 130 mL/kg) are satisfactory for most children (Table 4.3.6). Very weak children or those with anorexia may be fed with spoon, dropper, or nasogastric tube. As per the child’s progress and response to the treatment of complications by the end of 1 week, the calories and proteins may be stepped up to 100 cal/kg and proteins 1–1.5 g/kg/day. Minerals and vitamins are also added. In the phase of restoration, the principle is to increase weight and catch up growth as the child’s appetite has regained. The calories and proteins (preferably 50% should have high biological value, e.g. milk, chicken, meat or egg) are stepped up gradually, approximately 25 cal/kg/day on every other day, to 100–120 cal/kg/day and proteins 1–2 g/ kg/day based on patient’s changing weight. F 100 formulas (skimmed milk/fresh egg based) are used in inpatients only (Table 4.3.7). Diets/RUTF based on -









Hypoglycemia: • Ten percent glucose 1–2 mL/kg intravenously bolus followed by 10% dextrose in N/5 saline as maintenance for 24 hours. If 10% intravenous glucose not available, give 10% sucrose (one full teaspoonful sugar in 3.5 tablespoonful of water) orally/by nasogastric tube then every 30 minutes for 2 hours • Early and frequent feeding. Hypothermia: Warm bed and room, keep the baby with mother, double clothing, and cover head and feet. Treat hypoglycemia and sepsis. Start feeds early. Septicemia: Intravenous ampicillin 50 mg/kg, 6 hourly for 2 days, gentamicin 7.5 mg/kg intramuscularly/intravenously. If no improvement, add chloramphenicol/cephalosporin. If anorexia persists, continue antibiotics for 10 days. Give metronidazole 7.5 mg/kg 8 hourly for 7 days for potential anaerobic infections. Congestive heart failure: This mostly occurs due to fluid overload (e.g. overuse of intravenous fluids, unmonitored blood transfusion) or due to severe anemia. When congestive heart failure is due to fluid overload, administer frusemide 1–2 mg/kg, and reduce/stop fluid infusion. Avoid 146 digitalis. Diuretics should never be used to correct edema in



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Electrolyte imbalance: • Potassium: 2–5 mmol/kg/day • Magnesium: 0.3–0.6 mmol/kg/day or 50% MgS intramuscularly 0.3 mL/kg (2 mL maximum) D • Sodium: Restrict salt, no diuretics.

Micronutrients: • Iron: ral ferrous sulfate or fumarate syrup 4 mg (elemental)/kg • Calcium gluconate IV: 1–2 mL/kg or ral calcium lactate powder: 3 g/day • Zinc: 2 mg/kg/day • Copper: 20 µg/kg/day • Chromium: 0.2 µg/kg/day • Manganese: 10 µg/kg/day • Vitamin A: 100,000 IU for age less than 1 year and 50,000 IU for age less than 6 months • Vitamin D: Rickets—oral vitamin D • ther vitamins: B complex, vitamin K (5 mg weekly). O

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Phase 1: Resuscitation or Stabilization and Treatment of Complications Dehydration: Cautious management to avoid overhydration. • Severe/shock: Intravenous Ringer lactate 20–30 mL/kg in 1 hour, followed by 70 mL/kg over next 2 hours, followed by 0.45% glucose saline/Isolyte P as maintenance fluid. Total fluid and sodium not to exceed 75% of allowance. • Mild: ral rehydration solution—hypo osmolar/pref­ erably ReSoMal 5 mL/kg every 30 minutes—orally/by nasogastric tube (ReSoMal: 45 mmol sodium, 40 mmol potassium and 3 mmol magnesium).

case of edematous malnutrition. Anemia: If hemoglobin is less than 5 g/dL, give packed cells transfusion 5–10 mL/kg. Iron should be started only after resolution of infection (2–3 weeks).



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• Three ways: 1. Traditional nutrition therapy (community based management of SAM). 2. Hospital based therapy using F 75 and F 100 diets. 3. Initial stabilization in hospital using F 75 diet, and rehabilitation at home using RUTF. • Three phases: 1. Phase 1: Phase of resuscitation. The initial or acute phase (0–7 days) when the child is being treated for complications, dietary therapy is started simul­ taneously. 2. Phase 2: Phase of restoration or recovery (1–2 weeks) when the child will increase dietary intake and gain weight. 3. Phase 3: Phase of rehabilitation and follow up (2–26 weeks) which may be after discharge.

 

Table 4.3.5 Feeding schedule Days Frequency Volume/kg/feed 1–2 2 hourly 11 mL 3–5 3 hourly 16 mL 6–7+ 4 hourly 22 mL

Volume/kg/day 130 mL 130 mL 130 mL

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Table 4.3.6 Composition of F-75 Starter Formula Sugar (g)

Oil (g)

Cereal powder (g)*

CMV** (red scoop = 6 g)

Water (ml)

Dry skim milk

25

0

70

27

35

2

Up to 1000

Dry whole milk

35

0

70

20

35

2

Up to 1000

Fresh cow milk

280

0

65

20

35

2

Up to 1000

Fresh goat milk

280

0

65

20

40

2

Up to 1000

Whole eggs

0

80

70

20

40

2

Up to 1000

Egg yolks

0

50

70

15

40

2

Up to 1000

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Eggs (g)

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Milk (g)

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F-75 Type of milk

* Cereal powder should be cooked for around 10 minutes and then the other ingredients be added ** CMV Special mineral and vitamin mix adapted to severe acute malnutrition treatment Table 4.3.7 Composition of F-100 catch-up formula F 100 Type of milk

Milk (g)

Eggs (g)

Sugar (g)

Oil (g)

CMV** (red scoop = 6 g)

Water (ml)

Dry skim milk

80

0

50

60

2

Up to 1000

Dry whole milk

110

0

50

30

2

Up to 1000

Fresh cow milk

900

0

50

25

2

Up to 1000

Fresh goat milk

900

0

50

25

2

Up to 1000

Whole eggs

0

220

90

35

2

Up to 1000

Egg yolks

0

170

90

10

2

Up to 1000

** CMV Special Mineral mix adapted to severe acute malnutrition

Phase III: High Energy Feeding By now the child has progressed well with return of appetite, tolerance to high energy and protein feeds. In this phase, emphasis is on intensive feeding to restore lost weight, catch up growth and recover emotionally and physically. The calories are gradually increased from 150 cal/kg/day to 180 cal/kg/day and proteins 1.5–2.5/3 g/kg/day. Milk is gradually withdrawn; semisolids and solids are introduced. Ideally this phase extends from 6 weeks to 26 weeks to give the child his/her immune system, the best chance to recover before being challenged to home environment if the child

 

Table 4.3.8 Composition of peanut butter based RUTF Ingredients

Contents% by weight

Full fat milk powder

30

Sugar

28

Vegetable oil

15

Peanut butter

25

Fortified with micro nutrients (sodium, 1.6 potassium, calcium, phosphorous, mag nesium, iron, zinc, copper, selenium, iodine, vitamin A, vitamin D, vitamin E, vitamin K, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, folic acid, niacin, pantothenic acid, biotin) ­

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cereal pulse, (rice, moong dal) combinations, fortified with oil, jaggery and seasonal vegetables, or buttermilk based diets added with whey soy/casein, fine roasted powdered groundnut protein and sugar, and oil are recommended and can be prepared and fed as RUTF. A typical recipe RUTF (peanut based) (Table 4.3.8) can also be given. ccasionally children with secondary lactose intolerance do not tolerate milk based feeds. Depending on the severity, either the amount of milk may be diminished in the diet, by replacing with other articles like rice, egg, curds, etc. In severe lactose intolerance, milk will have to be temporarily completely omitted and replaced by cereals, pulses—rice, dal, soya, rice gruel, egg, soy milk, chicken gruel/rice, curds and rice, etc, (Table 4.3.9).

Energy

520–550 kcal/100 g

Proteins

10–12% of total energy

Fat

45–60% of total energy

is in hospital (if not already discharged) or a nutritional rehabilitation unit.

Phase IV: Transfer to Family Diet or Phase of Rehabilitation By now as the child is accustomed to semisolid or solid diet. The child and parents are encouraged and taught to make the child share family diet. Additional supplements can be

147

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Calories

Proteins

1. Dried skimmed milk Skimmed milk (60 g) Sucrose (12 g) Vegetable oil (15 g)

400

20

2. Milk and rice

Milk (75 mL) Rice (5 g) Sugar (25 g) Water (100 mL)

79

3

1. Rice and egg

Rice (50 g) Glucose (45 g) Egg (one) Oil (30 g)

710

10

2. Cereal pulse

715 Rice (50 g) Green gram pulse (25 g) Jaggery (50 g) Oil (25 g)

9.2

3. Soya rice gruel

Rice (25 g) Soybean (25 g) Glucose (50 g) Oil (35 g)

715

12.5

4. Chicken gruel

Chicken (100 g) Glucose (40 g), Oil (50 g) Water (1 L)

720

26

Low lactose diet

Prevention requires a coordinated approach of many disci­ plines: nutrition, agriculture, food technology, education, health administration, social services, non governmental organizations, community and religion. A strong political commitment is must for tackling malnutrition in the country. Nutrition should be a priority at national and sub national levels as it is central for human, social and economic development. As the World Bank advocates nutrition needs to be repositioned in national development if the MDGs are to be achieved. Achieving the MDG target halving the proportion of underweight children between 1990 and 2015 will involve effort at micro, meso, macro, and global levels (Fig. 4.3.13) as well as partnerships among all sectors of society. -

Lactose free diet

Prevention of Protein nergy Malnutrition

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Constituents

Physical activity should be encouraged as soon as possible. Mother should be involved in caring for the baby as far as possible (e.g. comforting, feeding, bathing and play). E

 

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Table 4.3.9 Diet for lactose intolerance (of varying severity)

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offered as shown in Table 4.3.10. The discharge criteria of severely malnourished child may vary and are summarized in Table 4.3.11. During recovery and follow up, tender loving care should be provided. Provide a cheerful stimulating environment in form of structured play therapy 15–30 minutes/day.

 

Figure 4.3.13 Action from micro to global level

 

Table 4.3.10 Energy rich foods Name

Calories/100 g

Proteins/100 g

Besan Mix/ladoo Panjiri

Bengal gram flour Wheat flour Jaggery, ghee (1 part of each)

500

9

2.

Sooji (Rawa) Kheer

Toned milk (750 mL), Sugar (100 g), Sooji (25 g), Oil (5 g)

1432

28.4

3.

Hyderabad Mix

Whole wheat (40 g) Bengal gram (16 g) Groundnuts (10 g) Jaggery (20 g)

330/86

11.3/86

4.

Shakti Ahar

Roasted peanut (10 g) Roasted wheat (40 g) Roasted gram (20 g) Jaggery (30 g)

390

11.4

 

 

1.

 

 

148

Ingredients

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1. Bhatnagar S, Lodha R, Choudhary P, et al. IAP guidelines 2006 on hospital based management of severely malnourished children (adapted from WH guidelines). Indian Pediatr. 2007;44:443 61. 2. Bhutta ZA, Ahmed T, Black RE, et al. Maternal and child undernutrition 3. What works? Interventions for maternal

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and child under nutrition and survival. Lancet. 2008;371:417 40. Black RE, Lindsey A, Bhutta ZA, et al. Maternal and child nutrition: global and regional exposures and health consequences. Maternal and child undernutrition. Lancet. 2008;371:243 60. Bryce J, Coitinho D, Darton Hill I, et al. Maternal child undernutrition 4. Maternal and child undernutrition: effective action at national level. Lancet. 2008;371: 510 26. International Institute for Population Sciences and Macro International. National Family Health Survey (NFHS 3), 2005 06: India, vol. I. Mumbai: International Institute for Population Sciences; 2007. Mehta MN, Rangnekar J. Assessment of growth and growth charts. In: Agarwal KN (Ed). Update Growth: Varanasi; 1988. pp. 101 7. Mehta MN. Nutritional management of diarrheal diseases. Indian Pediatr. 1996;32:149 57. Morris SS, Cogill B, Uauy R. Maternal and child undernutrition 5. Effective international action against undernutrition: why has it proven so difficult and what can be done to accelerate progress. Lancet. 2008;371:608 21. Protocol for the management of severe malnutrition. Addis Ababa Ethiopian Federal Ministry of Health, 2007. World Bank. Repositioning nutrition as central to deve­ lopment: a strategy for large scale action, directions in development. The International Bank for Reconstruction and Development. Washington DC: The World Bank, 2006. World Health rganization. The WH Child Growth Charts. [online] WH website. Available from http://www.who.int/ childgrowth/standards/en [Accessed September 2012].

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Table 4.3.11 Discharge from hospital 1. No definite guidelines •  Criteria vary from hospital to hospital: Of weight/age Attainment of 75%, 80–90% •  Difficult to attain and associated with high morbidity and mortality 2. General guidelines •  Acute problems are over •  Appetite has returned •  Oral dietary intake adequate •  Weight gain has started 3. Prolonged hospitalization •  Risks of acquiring nosocomial infection •  Cost of hospital therapy increases •  Inconvenience to family and loss of daily wages 4. Premature discharge •  Incomplete recovery, morbidity, recurrence of illness, rarely death 10–30% 5. Follow-up after discharge •  Continued supervision is vital for sustained and complete recovery •  Prevent recurrence Note: Along with medical and nutritional management providing care and stimulation is vital.

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Water oluble Vitamins Dheeraj Shah

Vitamin

C

Water-soluble vitamins include all vitamins in B-complex group [thiamine (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3), pyridoxine (vitamin B6), cobalamin (vitamin B12), folate, biotin, pantothenic acid, choline, inositol], and ascorbic acid (vitamin C). These vitamins act as coenzymes in many interrelated metabolic pathways. As these vitamins are water soluble and heat-labile, large amounts are lost from the ingredients if they are repeatedly washed, and when the cooking water is discarded. These vitamins are not stored for prolonged period in the body; significant toxicities at therapeutic doses are uncommon. B

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4.4

omplex

Thiamine Active form of this vitamin acts as a cofactor for enzymes involved in carbohydrate catabolism, nucleic acid synthesis and nerve conduction.

Dietary Sources Rice, wheat, legumes, fortified flours, fish and meat are good sources of thiamine. Polished rice is depleted of thiamine. It can be retained in rice by steaming the rice in the husk before milling (parboiling).

Deficiency State ­

Malnutrition, gastrointestinal disorders such as mala bsorption, blind loops and short bowel, and chronic debilitation conditions such as malignancies are common causes of deficiency. Fatigue, irritability, poor mental concentration, anorexia and nausea are early manifestations of deficiency. A full-fledged deficiency state (beri beri) manifests as peripheral neuropathy resulting in tingling, paresthesias, leg cramps, hyporeflexia, ataxia and lack of coordination. Cardiac manifestations include cardiomegaly and congestive heart failure. Central nervous system (CNS) involvement occurs late in disease, and is characterized by psychic disturbances, optic atrophy, hoarseness, raised intracranial pressure and coma.

Treatment Oral administration of thiamine is sufficient in mild-tomoderate deficiency states. Children with cardiac and CNS manifestations should be given 10 mg of thiamine intramuscularly or intravenously daily for the first week, followed by 3–5 mg/day orally for 6–12 weeks. Most children show dramatic improvement to oral or parenteral thiamine. R

iboflavin 150 Majority of this vitamin in tissues is found in the form of coenzyme flavin adenine dinucleotide (FAD), which

participates in oxidation-reduction reactions in numerous metabolic pathways and in energy production via the respiratory chain.

Dietary Sources This included milk and its products, eggs, fortified cereals and grains and liver. Vegan diets are poor sources.

Deficiency State Ariboflavinosis is characterized by glossitis, angular cheilosis, keratitis, conjunctivitis, photophobia, corneal vascularization and seborrheic dermatitis. Malnutrition, malabsorption and gastrointestinal infections commonly precipitate the deficiency.

Treatment Oral administration of riboflavin (3–10 mg/day) as a part of vitamin B complex mix rapidly corrects the deficiency and controls the associated symptoms.

Niacin Niacin is a component of the coenzymes NAD and NADP, which are important for many redox reactions involved in carbohydrate metabolism, fatty acid synthesis and steroid synthesis.

Dietary Sources Niacin is rapidly absorbed from the stomach or the intestine. Good sources are fish, meat, cereals, legumes, milk and green leafy vegetables. Predominantly maize eating populations suffer from niacin deficiency.

Deficiency State The classical triad of niacin deficiency (pellagra) is diarrhea, dermatitis and dementia. Certain inborn errors of tryptophan metabolism (carcinoid syndrome, Hartnup’s disease) are also associated with niacin deficiency. Skin lesions of pellagra start as symmetric erythematous areas, resembling sunburn. These lesions are distributed on hands and feet in a “glove and stocking” pattern, and are sometimes present over the neck (Casal necklace). Infants and young children often do not develop classical deficiency signs, and present with irritability, fatigue, anorexia and scaly skin.

Treatment Oral administration of niacin (50–200 mg/day) as a part of vitamin B complex mix is indicated for pellagra. Severe cases may require intravenous administration. Sun exposure should be avoided during active skin lesions, and soothing agents are applied.

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Poultry, meat, fish, fortified cereals and bananas are good sources of pyridoxine. Drugs inhibiting pyridoxine activity (e.g. isoniazid, oral contraceptives, penicillamine, and phenytoin) may precipitate the deficiency.

Deficiency State

O

Dietary Sources

Biotin (found in a variety of vegetarian and non-vegetarian foodstuffs) deficiency causes scaly periorificial dermatitis, alopecia, hypotonia and apathy.

Treatment

Choline and Inositol

Oral administration of 10–100 mg/day is sufficient for correcting the deficiency and dependency. Intramuscular or intravenous administration of 100 mg pyridoxine is administered in case of seizures. Treatment should be followed by ensuring adequate dietary consumption.

Though important for normal body functions, these are not known to be associated with any specific deficiency syndromes.

Folate and Vitamin B12

Vitamin C has important roles in collagen synthesis and synthesis of steroid hormones, neurotransmitters and bile acids. Vitamin C increases the gastrointestinal absorption of iron, and also has important antioxidant activity.

Pantothenic acid (found in seafood, organ meats, egg yolk, legumes and milk) deficiency causes muscle cramps and burning feet syndrome; clinical deficiency is extremely rare.

Deficiency State Megaloblastic anemia results from either (or combined) folate or vitamin B12 deficiency. Maternal folate deficiency increases the risk of neural tube defects in the fetus. Vitamin B12 also may result in neurological manifestations such as irritability, poor attention span, hypotonia, abnormal movements and peripheral neuropathy progressing to subacute combined degeneration. Hyperpigmentation of knuckles is another commonly observed sign of vitamin B12 deficiency.

Treatment Megaloblastic anemia due to folate deficiency requires oral administration of 0.5–1 mg/day of folic acid

A

A

ietary ources S

D

C

Vitamin ( scorbic cid)

Citrus fruits, tomatoes, capsicum and green leafy vegetables are good sources of vitamin C. Breast milk is a good source of vitamin C, and children consuming animal milk are at risk of deficiency.

eficiency tate S

D

Legumes, fortified cereals, citrus fruits and leafy vegetables are good sources of folate. On the other hand, vitamin B12 is found only in foods from animal sources. Organ meats, sea foods, egg yolk, fish and poultry are rich sources of vitamin B12. Vegetarians get their requirements mainly from fortified cereals and milk.

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Biotin

Pantothenic Acid

Dietary Sources

t

thers

Early symptoms/signs are electroencephalography (EEG) abnormalities, irritability and vomiting. Seizures, failure to thrive, skin lesions and microcytic anemia may occur in severe deficiency states.

Folate is involved in a variety of reactions involved in amino acid and nucleotide metabolism. Vitamin B12 (cobalamin) is required as a cofactor for methyl group transfer from a folic acid cofactor to form methionine. The unmethylated folate cofactor then participates in single carbon reactions for nucleic acid synthesis. Thus some B12 and folic deficiency symptoms are similar.

n

Pyridoxine (vitamin B6) is a component of pyridoxine hydrochloride, pyridoxal and pyridoxamine cofactors in metabolism of carbohydrates, amino acids, steroids and nucleic acids.

until a definite hematologic response has occurred. Intramuscular or intravenous administration of single dose of 1,000 µg of vitamin B12 is adequate for achieving hematological response in vitamin B12 deficiencies. A combined treatment is required if the blood levels for both are not available.

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Pyridoxine

Scurvy, resulting from severe vitamin C deficiency, manifests as gum bleeding, petechial hemorrhages, painful and swollen bones, and poor wound healing. Children having scurvy often have other nutrient deficiencies including severe malnutrition, anemia and vitamin B complex deficiency. The diagnosis of scurvy is usually made by radiographs; the changes being most prominent at the knee (Fig. 4.4.1). The shafts of the long bones have a typical ground-glass appearance with thin and dense cortex (pencil thinning). Metaphyseal changes are characterized by thickened bands (white line of Frankel) with a zone of destruction underneath (Trumerfeld’s zone). Ends of the white lines often end abruptly into a spur (Pelkan’s spur). Epiphyses are also outlined by dense line giving the appearance of a ring (Wimberger’s ring). Subperiosteal hemorrhages may complicate the disease causing periosteal elevation and underlying calcifications.

151

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Oral administration of vitamin C (100–200 mg/day) results in complete recovery. Resolution of clinical symptoms is rapid





 

Treatment

1. Allen LH. Causes of vitamin B12 and folate deficiency. Food Nutr Bull. 2008;29(2 Suppl):S20-34. 2. Black MM. Effects of vitamin B12 and folate deficiency on brain development in children. Food Nutr Bull. 2008;29(2 Suppl):S126-31. 3. Brickley M, Ives R. Skeletal manifestations of infantile scurvy. Am J Phys Anthropol. 2006;129:163-72. 4. Kauffman G, Coats D, Seab S, et al. Thiamine deficiency in ill children. Am J Clin Nutr. 2011;94:616-7. 5. Rasmussen SA, Fernhoff PM, Scanlon KS. Vitamin B12 deficiency in children and adolescents. J Pediatr. 2001;138:107. 6. Sachdev HPS, Shah D. Vitamin B complex deficiency and excess. In: Kliegman RM, Stanton B, Geme JS, Schor N, Behrman RE (Eds). Nelson Textbook of Pediatrics, 19th edition. United States: Saunders (Elsevier Inc.); 2011. 7. Shah D, Sachdev HPS. Vitamin C (Ascorbic acid) In: Kliegman RM, Stanton B, Geme JS, Schor N, Behrman RE (Eds). Nelson Textbook of Pediatrics, 19th edition. United States: Saunders (Elsevier Inc.); 2011. 8. Suskind DL. Nutritional deficiencies during normal growth. Pediatr Clin North Am. 2009;56:1035-53.

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Figure 4.4.1 Bony changes of scurvy at knee Abbreviations: WL, White line; TZ, Trumerfeld’s zone; PS, Pelkan’s spur

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whereas bony changes and subperiosteal hemorrhages take more time to recover. Treatment must be followed by ensuring adequate dietary vitamin C to prevent recurrence.

152

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Fat Soluble Vitamins

n

Panna Choudhury

Nutritio

4.5

Retinol is the predominant circulating form of vitamin A in the blood. In response to tissue demand, it is released from the liver in a 1:1 ratio with RBP. In the blood, this complex combines with transthyretin. Specific receptors on target cell surfaces or nuclei bind this complex or its active metabolites, thereby regulating many critical functions in the body, including vision, growth and hematopoiesis. It is often termed as anti-infective vitamin for its role in maintaining epithelial tissue integrity and immune competence. However, the key to most of these functions is the role of vitamin A in regulating the expression of several hundred genes and cell differentiation practically for every cell in the body. The importance of vitamin A in functioning of the retina for vision has been well established. Visual pigment in rods is called rhodopsin, which is composed of a protein called opsin and a pigment, 11-cis retinine (vitamin A). Rhodopsin is light sensitive and when light falls on eyes, rhodopsin splits and 11-cis retinine is converted to 11-trans retinine. This initiates an electrochemical signal to be carried to the brain where visual images are constructed. In vitamin A deficiency, the threshold for stimulating rods is raised, thus, affecting the vision under dim light.

Dietary Sources Rich sources of vitamin A include fish liver oils, whole milk and milk products like butter, cheese and egg yolk. Carotenoids are plentiful in fruits and vegetables that are green or deep yellow/orange in color, such as green leafy vegetables, carrots, tomatoes, sweet potatoes, papaya and mango. Food fortified with vitamin A is an important source. Breastfeeding protects children during infancy. Quantification of vitamin A is expressed in various



Ocular Lesions These affect the posterior segment of eye initially with impairment of dark adaptation and night blindness. Often the mother of the infant notices that he or she takes considerable time to adjust to dim light or darkness (twilight blindness). Xerosis of conjunctiva is usually the first sign that can be seen on examination. The conjunctiva becomes dry, lusterless, wrinkled and dirty brown in color. These changes are most obvious in the interpalpebral bulbar conjunctiva. Conjunctival xerosis may lead to formation of the so called “Bitot’s spot,” which consists of almost a triangular area, usually about the temporal aspect of the limbus covered by a fine, white foamy or greasy substance. It is composed of heaped up sloughed-off keratinized cells and saprophytic bacilli, which collect on conjunctival surface (Fig. 4.5.1A). Corneal xerosis reflects more advanced deficiency (Fig. 4.5.1B). Keratomalacia is seen in the late stage and consists of softening, necrosis and ulceration of the cornea. Once cornea gets involved, photophobia accompanies the clinical profile. WHO has proposed a classification for xerophthalmia (Table 4.5.1). ­

Physiology

Clinical Features of Deficiency State

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Vitamin A is a generic descriptor of retinoids that exhibit qualitatively the activity of alltrans-retinol compounds. Retinol signifies vitamin A alcohol and is found in foods of animal origin only. Some carotenoids, which are found in plants, bacteria, algae and fungi, can be converted into retinol and are called provitamin A. The carotenoid with the highest vitamin A activity is beta carotene. Beta carotene yields two molecules of retinol. Retinol is esterified in the mucosal cell with palmitic acid. Retinyl palmitate is stored in the liver. Being fat soluble, retinol mobilized from the liver must be bound in serum to retinol binding protein (RBP), which is synthesized in the liver. Retinol binding protein also protects retinol from oxidation and releases it to specific receptor sites on the surface of the target cell. It has been suggested that RBP synthesis may be affected in zinc deficiency.

ways. One international unit (IU) equals 0.3 µg retinol. Daily intake of vitamin A as retinol equivalent has been recommended as 350 µg for infants, 400 µg for preschool children, and 600 µg for school children and adolescents by Indian Council of Medical Research. Daily intake of 100 g of leafy vegetables is an efficient way to meet the requirement of vitamin A. Deficiency of vitamin A can occur from deficient diet, decreased absorption due to chronic intestinal disorders or reduced storage in liver diseases. There could be an increased requirement of vitamin A in presence of infections. Vitamin A deficiency in general is associated with higher morbidity and mortality in children.

Extraocular Lesions These include dry, scaly skin, especially over the outer aspect of the limbs, called follicular hyperkeratosis, toad skin or phrynoderma. Increased susceptibility to infections due to squamous metaplasia of respiratory, urinary and vaginal tract epithelium; renal and vesical calculus may occur more often in such subjects. It is heartening that prevalence of clinical signs of vitamin A deficiency is declining. Survey of the Indian National Nutrition Monitoring Bureau showed that prevalence of Bitot’s spots had declined in 1988–90 compared with 1975– 79 from 1.8% to 0.7%. Severe deficiency, causing corneal 153 xerophthalmia or keratomalacia and eventual blindness in children, is now uncommon. However, subclinical vitamin

Vitamin A

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is a noninvasive technique that assesses vitamin A status by detecting early losses of vitamin A-dependent, mucus secreting goblet cells and early metaplasia of the epithelium.

reatment of Vitamin A Deficiency

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f

Prevention of vitamin A deficiency can be achieved by making available the recommended daily allowances of vitamin A to all children. According to the National Program for Prevention of Blindness, children in the age group of 6–11 months should receive 100,000 IU of vitamin A orally (preferably during measles immunization), and other children between 1 year and 5 years should receive 200,000 IU vitamin A every 6 months in the target areas. Use of vitamin A and beta carotene rich food should be encouraged. Fortification of commonly eaten foods with vitamin A can be an effective prophylactic measure. For treatment of xerophthalmia, according to WHO guidelines, 200,000 IU vitamin should be given orally on presentation, the following day and whenever possible, 1–4 weeks later. Infants aged between 6 months and 12 months should receive a half dose, and infants less than 6 months should receive one-quarter the dose, following the same schedule. Children with severe malnutrition, recurrent diarrhea, pneumonia and severe infections should also receive full treatment course of vitamin A. Cochrane review showed that vitamin A megadoses (200,000 IUs on each day for two days) lowered the number of deaths from measles in hospitalized children under the age of 2 years.

a

Hypervitaminosis A

Table 4.5.1 WHO classification for xerophthalmia Classification

Primary signs

X1A

Conjunctival xerosis

X1B

Bitot’s spots

X2

Corneal xerosis

X3A

Corneal ulceration

X3B

Keratomalacia Secondary signs

XN

Night blindness

XF

Fundal changes

XS

Corneal scarring

A deficiency continues to be a significant problem and is reported to be as high as 55% in rural preschool children of Maharashtra.

Diagnosis of Vitamin A Deficiency In the presence of clinical manifestations, diagnosis is not difficult. In vitamin A deficiency state serum retinol level is 154 usually below 20 µg/dL. Conjunctival impression cytology

Signs of toxicity may appear with massive doses or with large doses over a large time period. Child may have nausea, vomiting, drowsiness, papilledema and symptoms suggestive of raised intracranial tension (pseudotumor cerebri). In chronic cases, marked anorexia, failure to thrive, alopecia, seborrheic dermatitis, hepatomegaly and tender bone swelling may develop. Radiographic examination may show hyperosteosis of the shafts of long bones. However, beta carotene ingestion is seemingly without toxicity. With chronic high consumption, the skin but not the sclerae is stained yellow-orange, which is benign and reversible.

Vitamin D Antirachitic properties of vitamin D are the result of small structural changes, under the influence of ultraviolet irradiation in a number of steroids related to cholesterol. However, only ergosterol and 7-dehydrocholesterol have practical importance. Ergosterol is of plant origin, and on irradiation, it transforms to Vitamin D2 (calciferol). The 7-dehydrocholesterol is normally present under the skin, and on exposure to ultraviolet rays of the sunlight, it converts to vitamin D3 or cholecalciferol. The latter is converted to 25-hydroxycalciferol in the liver and is further converted to 1,25-dihydroxycholecalciferol, which is specifically helpful in promoting synthesis of “calcium transport protein” in ­

 

Figures 4.5.1A and B (A) Bitot’s spot; (B) Corneal xerosis

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Vitamin D Deficiency Vitamin D deficiency causes decreased absorption of calcium from gut. The resulting hypocalcemia leads to increase in parathormone secretion. This helps in release of calcium from bone. Parathormone also reduces the excretion of calcium by kidneys and renal tubular reabsorption of phosphate. As a result, the serum calcium level tends to become normal, while the serum phosphate level falls. After sometime, this compensatory mechanism fails and both calcium and phosphorus levels fall. Since calcium phosphate is necessary for deposition of calcium in growing bones, decrease in blood levels of calcium, phosphorus or both interfere with the calcification of the osteoid tissue. Serum alkaline phosphatase level also gets increased due to increase in osteoblastic activity.

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Vitamin D, unlike other vitamins is not abundantly available in foodstuffs. Rich source of vitamin D is fish liver oil and to some extent it is available in butter and egg. Thus, infants are more prone to vitamin D deficiency, as natural diet of infants like milk, cereals, vegetables and fruits are deficient in vitamin D. This gets aggravated if there is also lack of access to sunlight. In a study from Delhi, clinical vitamin D deficiency was noted in 11.5% apparently healthy school girls, whereas biochemical hypovitaminosis D (serum 25-hydroxyvitamin D < 50 nmol/L) was seen in 90.8% of girls. Vitamin D deficiency also occurs in presence of malabsorption, liver and kidney diseases. Rickets, a metabolic disorder of growing bone leading to bony deformities, when results from vitamin D deficiency are known as nutritional rickets. The normal daily requirements of vitamin D for infants and children are 200 IU (5 µg) and 400 IU (10 µg) respectively. It has been estimated that only 5 minutes of exposure to sunlight may be sufficient to meet the daily requirement of vitamin D. However, it should be remembered that the effective ultraviolet rays in sunlight are cut-off by haze, windowpane, etc.

Clinical Features Rickets is a disease of growing bones and its incidence is particularly high between 4 months and 18 months. Skeletal deformities are the most striking feature of rickets. One of the early signs of rickets is craniotabes. In this condition, on pressing occipital or posterior part of parietal bone, a sensation like pressing a ping-pong ball can be felt. It results from the thinning out of inner table of the skull due to absorption of noncalcified osteoid tissue. Fontanel may remain wider than normal and close late. Other early evidences of osseous changes are palpable enlargement of costochondral junctions, i.e. rachitic rosary and widening of the wrists (Fig. 4.5.2) and ankles. Signs of advanced rickets can be easily recognized. Bossing of skull generally starts after the age of 6 months. It occurs due to heaping up of osteoid tissue in the frontal and parietal regions so that the skull appears squarish or box-like shape. In thorax, the sternum is pushed forward producing a “pigeon chest.” A horizontal depression known as Harrison’s groove, corresponding to costal insertion of the diaphragm develops. The chest deformities decrease the lung resilience and predispose the child to intercurrent infections. Bending of the spine backwards (kyphosis) and laterally (scoliosis) may occur. Pelvis may become softened, and the promontory of the sacrum is pushed anteriorly and the acetabulae inwards, resulting in a narrowed pelvic inlet. This is helped by lax ligaments. Deformity of the pelvis in a female results

Sources

end of long bones. There is also defective mineralization in the subperiosteal bone. In longstanding cases, the bones under stress may become deformed or even have pathological fractures. Supplementation of vitamin D restores the normal development of bone with calcification starting at the zone of preparatory calcification, which in radiography would be seen as a thin dense line near the epiphysis.

Nutritio

the intestinal wall. Parathormone controls the production of 1,25-dihydroxycholecalciferol, the metabolically active form of vitamin D.

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Pathology of ickets

Figure 4.5.2 Case of rickets showing widening of wrists and beading of ribs on chest  

The epiphyseal plate is a narrow well-defined strip from where cartilage cells grow in parallel column towards the metaphysis. After initial proliferation, the old cartilage cells degenerate and disappear, leaving spaces into which the blood vessels and osteoblasts of the shaft can penetrate. Calcium is deposited in the zone of degenerating cartilage, which is then called “zone of preparatory calcification.” In rickets, the cartilage cells go on multiplying giving rise to a broad, irregular cartilaginous zone. The process of degeneration and calcification becomes incomplete, leading to softness of the bone. Rapidly growing cartilage cells particularly affect the costochondral junctions and the

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in difficulty during labor at a later stage. Long bones of the legs get deformed when the child starts bearing weight and is thus, usually seen after the age of 1 year. Bending of the femur, tibia and fibula results in “bow-legs” or “knock-knees.” Coxa vara and green stick fractures may also occur. All deformities of bones result in rachitic dwarfism. Dentition may be delayed and disordered eruption of temporary teeth occurs. In children between 8 months and 18 months, permanent teeth, which are undergoing calcification, may be affected. Besides skeletal deformities, there is a generalized hypotonia with delay in motor development. The abdomen is protuberant, and generalized flabbiness of muscles may result into visceroptosis with downward displacement of spleen and liver.

Diagnosis The diagnosis of rickets is based on the clinical features, biochemical findings and characteristic radiological picture. The serum calcium level may be normal or low, the serum phosphorus level is below 4 mg/dL, and the serum alkaline phosphatase is usually elevated. Radiological changes are best seen in the lower end of radius and ulna. Skiagram of the wrist shows widening, cupping and fraying of the epiphyses in contrast to the normally sharply demarcated and slightly convex epiphyseal line (Figs 4.5.3A and B). The density of shafts decreases with prominent trabeculae. There is an increase in distance between concave epiphyseal line and the ends of metacarpals. Green stick fractures, expansion of bone ends and bending of bones may be evident on radiographs. Periosteum may be raised due to excess of osteoid lying under the periosteum.

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Differential Diagnosis of ickets

 

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Vitamin E is a group of closely related, naturally occurring fat-soluble compound of which tocopherol is functionally the most potent. It is active as an antioxidant and, probably involved in the metabolism of nucleic acids. It is widely present in most foods. One milligram of alpha-tocopherol provides 1.5 IU activity of vitamin E. The deficiency of vitamin E is rare. The most common causes are diarrhea and poor intake of food. Deficiency may result in areflexia, ataxia, muscle weakness and dysarthria. In premature infant, low levels of vitamin E are associated with hemolytic anemia, hyperbilirubinemia and intraventricular hemor ­

High dose of vitamin D given over a long period may cause anorexia, vomiting, hypotonia, irritability, polydipsia 156 and polyuria. There is hypercalcemia and hypercalciuria.

Vitamin

­

Hypervitaminosis D

Radiological examination reveals evidence of metastatic calcification and osteoporosis of long bones.

­

Vitamin D is given in a dose of 15,000 µg (or 600,000 IU) orally or intramuscularly. If there is no sign of healing line in skiagram taken 3–4 weeks after therapy, the same dose can be repeated. If there is no response within 3–4 weeks of the second dose, investigations for refractory rickets should be initiated. Rickets can also be treated with a dose of 50–125 µg (2,000–5,000 IU) daily for 4 weeks. After the healing of rickets, normal daily requirement of vitamin D should be continued. Deformities of bones are corrected by orthopedic measures.

Figures 4.5.3A and B Florid rickets showing cupping, fraying and widening of metaphysis of distal end of radius and ulna; (B) Healing rickets showing zone of calcification at the distal end of radius and ulna; also seen at the periosteal calcification of metaphysis

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Management

B

E

Nutritional rickets should be differentiated from other types of rickets and chondrodystrophy. Other conditions producing bony deformities may, sometimes, need consideration. Craniotabes and a large head apart from rickets occurs in hydrocephalus, congenital syphilis and osteogenesis imperfecta. Enlargement of costochondral junctions may also be seen in scurvy and chondrodystrophy.

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1. Arlappa N, Laxmaiah A, Balakrishna N, et al. Clinical and subclinical vitamin A deficiency among rural pre-school children of Maharashtra, India. Ann Hum Biol. 2008;35:606-14. 2. Dietary Guidelines for Indians. Indian Council of Medical Research, New Delhi; 2010. 3. Huiming Y, Chaomin W, Meng M. Vitamin A for treating measles in children. Coch Database Syst Rev. 2005;(4):CD001479. 4. Indicators for assessing vitamin A deficiency and their application in monitoring and evaluating intervention programs. WHO/NUT/96.10. Geneva, WHO; 1996. 5. Nutrition Monitoring Bureau. Report of Repeat Survey (1989– 1990). Hyderabad: National Institute of Nutrition; 1991. 6. Puri R, Marwaha RK, Agarwal N, et al. Vitamin D status of apparently healthy school girls from two different socioeconomic strata in Delhi: relation to nutrition and lifestyle. Br J Nutr. 2008;99:876-82.

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ibliography



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Vitamin K is a naphthoquinone derivative. Absence or failure of its absorption from the intestine leads to hypo prothrombinemia and decreased synthesis of some coagulation factors (VII, IX and X). The normal requirement of vitamin K is met by bacterial synthesis in the intestine. In addition, it is also found in high concentration in a wide variety of foods and vegetables like spinach, cabbage, peas, tomatoes, soybean and liver. The deficiency of vitamin K can occur in malabsorp tion states, biliary obstruction, after oral antibiotic therapy or in newborn before colonization of the guts. In general, vitamin K deficiency or hypoprothrombinemia should be considered in all patients with hemorrhagic disturbances. Hemorrhagic disease of the newborn is one of the most common manifestations. The bleeding is variable and can occur anywhere, though, most common

B

K

Vitamin

is gastrointestinal bleeding. A daily dose of 1–2 mg of vitamin K orally is sufficient for treatment. In severe deficiency state, 5 mg of aqueous vitamin K can be given parenterally.

Nutritio

rhage. This responds quickly to 5–25 mg of vitamin E therapy. Generally, infants should receive 3 mg of alphatocopherol daily.

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Trace lements

E

• •

• •

pidemiology

A balanced diet that includes all the food groups can supply all the TE. Infant and young child feeding practices, especially in the first 1,000 days of life, are crucial in preventing deficiency and ensuring enough stores of TE. Trace elements deficiencies occur usually in those with PEM, picky eaters, low birth weight (LBW) babies, and in those on exclusion diets and total parenteral nutrition (TPN). Trace element deficiencies noted with TPN are given in Table 4.6.1. Excess intake of dietary fiber, phytates and oxalates reduce trace element absorption. Both deficiency/ excess and current trace element status can be detected from hair with accuracy. The various aspects related to TEs are summarized in Table 4.6.2.

•

Table 4.6.1 Common trace element deficiencies noted with parenteral nutrition Element Deficiency state Zinc Periorificial crusting dermatitis, bullae in hands and feet, alopecia, diarrhea and growth retardation Copper Refractory hypochromic anemia, neutropenia, subperiosteal hematoma, soft tissue calcification and osteoporosis Selenium Cardiomyopathy, myopathy and myalgia Chromium Hyperglycemia, glycosuria, peripheral neuropathy and encephalopathy Manganese Reddening of hair, weight loss and hypocholesterolemia Molybdenum Tachycardia, irritability, coma and central scotoma

•

•

• •

Boron is recognized essential for healthy bones and utilization of vitamin D and calcium in the body. Cobalt is an essential component of vitamin B12, and increases iron absorption and iodine utilization. Deficiency produces anemia and goiter and excess can lead to goiter and cardiomyopathy. Germanium is said to be the secret behind the health benefits of garlic, ginseng and mushrooms. Molybdenum deficiency can lead to tachycardia, central scotoma, irritability, coma and probably increased incidence of mouth and esophageal cancers. Excess may unmask hyperuricemia, gout and genu valgum. Abnormally high level leads to copper deficiency. Fluorine is not considered an essential mineral by some as humans do not require it for growth or to sustain life. However, it prevents dental caries and primary action occurs topically. Strontium is involved in utilization of calcium. It promotes calcium uptake into bone at moderate dietary levels, but has rachitogenic action at higher dietary levels. Arsenic, bromine, cadmium, silicon, tungsten and vanadium have biochemical roles as structural/ functional cofactors in other organisms. Arsenic is thought to promote nail and hair growth. Excess residue found in cow’s milk may be toxic to skin, CNS and respiratory tract. Mercury is toxic to enzymes and RNA. Excess leads to Minamata disease in fetus and acrodynia in others.

Practice Guidelines and Tips I

 

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D

thers

ron eficiency nemia A

efinition

Except in a few minerals like iron, iodine, zinc and selenium, specific features of deficiency may not occur. A high index of suspicion and therapeutic response to supplementation help in clinching the diagnosis. Levels of TE in the blood can be estimated by colorimetry, atomic absorption spectrophotometry (ASS) and neutron activation analysis (NAA).

D

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Several elements of the 109 well-characterized elements are essential for human growth, development and function. These include trace elements (TEs), also known as mineral nutrients, microminerals, bionutrients or bioelements. The essential TEs are iron, iodine, zinc, copper, chromium, sele nium, manganese, cobalt, molybdenum, nickel, vanadium and silicon.

Trace elements are those minerals present only in minute amounts in a particular sample or environment (usually < 10 parts/million) or those required only in minute amounts by living organisms for normal growth. By definition, TEs are those present in concentration less than 0.01% body dry weight, i.e. less than 0.1 mg/g or less than 100 µg/g, previously denoted as detected in trace quantities. Ultra TEs occur in smaller quantities less than 0.0001% by weight, less than 1000 ng or 1 µg/g.

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KE Elizabeth

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4.6

Iron insufficiency leads to iron depletion, iron deficiency and iron deficiency anemia (IDA) with microcytic hypochromic RBCs with increased red cell distribution width (RDW), reduced physical stamina, lack of concentration and learning ability, pica and koilonychia. Pica includes eating disorders like geophagia (mud), amylophagia (eating raw rice) and pagophagia (ice cubes). Even mild-to-moderate anemia in

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Liver, beef, oyster, cereals, nuts, grapes

Yeast, liver cereals, nuts, cocoa, pepper

Chromium

Liver, fish, meat, oyster, legumes. Competes with Zn and Mo for absorption

Copper

Zinc

Sea foods, drinking water (two-thirds requirement), iodized salts

Iodine

 

Facilitates insulin action and weight loss, help to prevent diabetes

Constituent of thyroxine, for metabolic control, modulation of estrogen and fetal health

PEM, TPN

Low content in water, especially mountainous areas, excessive intake of brassica species; cabbage, cauliflower

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Contd...

Phytates reduce absorption. Excess reduces iron and copper levels Used as adjuvant in Wilson disease. Toxicity: Gl upset, Cu deficiency 5–15 mg/day Treatment: Zinc deficiency 1–2 mg/kg/day up to 150 mg elemental zinc. During diarrhea - 2–6 Mo: 10 mg/day; more than 6 Mo: 20 mg/day for 2 weeks

1–2 mg/day

Toxicity: Renal failure, dermatitis

Heme iron better absorbed than nonheme iron. Oxalate, phytates, Zn, coffee/ tea inhibit absorption. Vitamin C, cobalt, lime juice and acid medium increase absorption. Toxicity: Chronichemosiderosis, hemochromatosis. Acute - Gl upset and hepatic failure Iodized salt to contain 15 µg/g (15 ppm); up to 30 ppm added to tackle loss. Excess can cause iodism, reversible dermatitis and goiter Toxicity: Indian childhood cirrhosis, hepatitis, cirrhosis, hemolytic anemia, Zn deficiency Prophylaxis: 1–2 mg/kg/ day, Children 10–20 mg/ day, pregnancy and lactation 30–40 mg/day, Treatment: Oral: 3–6 mg/kg/day for 3–4 months. Inj -weight in kg × deficit in g/dL × 2.5 + 25%, iron sucrose IV/IM. Packed red cell transfusion: 5–10 mL/kg. Always treat the cause

50–150 µg/day

Remarks and toxicity

Requirement

Hyperglycemia, 10 µg/day encephalopathy. Treatment: Single dose 180 Investigation: S. Cr 0.02 µg/dL µg in hyperglycemia

Endemic goiter, hypothyroidism, stillbirth, CNS defects Investigation: urinary iodine, PBI, T3, T4 TSH, iodine uptake study LBW, preterm TPN, PEM, Hypochromic anemia, Constituents of enzymes, neutropenia, hypopigmented ceruloplasmin and hormone nephrotic syndrome hair, bony defects function, role in hemopoiesis, Investigation: S. Cu 75–150 essential for Zn, iron and µg/dL, serum ceruloplasmin vitamin C function, bone 10–50 µg/dL metabolism Constituents of enzymes, role PEM, TPN, hepatitis, nephrotic Growth retardation, anorexia, gonadal atrophy, alopecia, in protein and nucleic acid syndrome, acrodermatitis synthesis enteropathica especially as a dermatitis, diarrhea, reduced taste sensation Investigation: genetic defect Zn level in hair, S. Zn 60–150 µg/dL

Table 4.6.2 Sources, functions, deficiencies, clinical features, requirements and toxicity of the various trace elements Trace Sources Functions Deficiency Clinical features element LBW, excess cow’s milk, blood Pallor, dyspnea, CHF, Iron Fish, meat, liver, 3 Gs: grams, Constituent of hemoglobin and enzymes, role in oxygen loss, hook worm, whip worm, irritability, lack of grains, greens concentration, pica, malabsorption poor intake, jaggery/molasses, asafoetida, transport koilonychia increased demand turmeric, dates, watermelon Investigations: serum cooking in iron vessels iron (50–150 µg/dL), iron binding capacity (100–400 µg/dL) Serum ferritin (50–250 ng/mL), blood smear hypochromic microcytic anemia

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Deficiency

Chocolate

Nickel

l

Cereals, legumes, greens, tea

Manganese

Component of urease, and nickel plasmin, stabilizes membranes Cross-linkage of collagen

Component of superoxide dismutase, role in oxidative phosphorylation

Antioxidant, co-factor of enzyme function, maintains liver integrity

i

TPN

TPN

TPN

i

PEM, TPN, poor soil content

Keshan cardiomyopathy, arthritis, myalgia, growth retardation, liver necrosis, risk of liver cancer. Investigation: S. Se 13 µg/dL Growth retardation, reddening of hair, increased prothrombin time Investigation: S. Mn 0.06 µg/ dL Investigation: S. nickel 0.02 µg/dL

Dental caries

Clinical features

Not known

Excess: Dermatitis, liver necrosis, nasal and lung cancers Excess: Granuloma and fibrosis of lung

Iron decreases Mn absorption. Toxicity: Encephalitis, goiter, cardiomyopathy, cholestasis

1–5 mg/d

100 µg/day

Toxicity: Dental and skeletal fluorosis, genu valgum with excess in drinking water and sorghum intake, more than 2–3 ppm in drinking water needs defluoridation by alum and lime Dental caries, alopecia, garlic odor in breath

Remarks and toxicity

t

1–5 mg/day. Drinking water up to 1 ppm

Requirement

t

Tex book of Pedia rics

Growth retardation, defective Not known bone growth Vanadium Protein rich food TPN PEM Associated with nutritional Not known edema Abbreviations: LBW, ow birth weight; CHF, Congestive heart failure, IV, ntravenous; IM, ntramuscular; CNS, Central nervous system; PBI, Protein bound iodine; TSH, Thyroid stimulating hormone; TPN, Total parenteral nutrition; PEM, Protein energy malnutrition

Meat groups, green, garlic

Silicon

Functions

Drinking water, sea foods, tea, Constituent of bone and teeth Poor water content cheese

Sources

Selenium

Trace element Fluorine

Contd...

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ibliography 1. Elizabeth KE. Vitamins, minerals and micronutrients. In: Elizabeth KE (ED). Nutrition and Child Development, 4th edition. Hyderabad: Paras Medical Publisher; 2010. pp. 98120. 2. Gupta P, Shah D, Ghai OP. Micronutrients in health and disease. In: Ghai OP, Gupta P, Paul VK (Eds). Ghai Essential Pediatrics, 6th edition. New Delhi: CBS Publishers and Distributors; 2004. pp. 119-35.



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Subclinical zinc deficiency is not uncommon. It is useful in treatment of Wilson disease. Zinc supplementation results in better catch up growth in LBW and PEM. In field settings, oral rehydration solution and Zn are promoted in diarrhea for control and also prevention as Zn results in repair of mucosa, replenishment of brush border enzymes and fluid regulation. The 20 mg zinc sulphate tablets are made available in reproductive and child health programme RCH kit, ½ tablet in 2–6 months old and one tablet more than 6 months for 14 days is to be given during each episode of acute diarrhea. In those less than 2-month-old, it can be prescribed if indicated, but not given as routine.



About two-thirds of iodine requirement is generally derived from the drinking water and one-third from diet. Universal iodization of salt ensuring potassium iodate 15 ppm (15 µg/g) is recommended in India. Salt testing kits are made available to ensure optimum iodization. In commercial iodized salt, up to 30–50 ppm is added to cover losses. Double fortified salt contains potassium iodate and ferrous sulphate to tackle IDA and iodine deficiency disorders (IDD). Urinary iodine excretion is reduced in deficiency. Urinary iodine can be tested using dipstick/ laboratory method. Excretion more than 100 µg/L indicates

Zinc eficiency



D

D

I

odine eficiency isorders

iodine sufficiency, 50–100 mg mild, 20–50 mg moderate and less than 20 mg indicates severe deficiency. Goiter is an indication of previous deficiency state and rates more than 5% in prepubertal children indicate endemic IDD (Grade 0, goiter not visible or palpable; Grade 1, goiter palpable; Grade 2, both visible and palpable).

Nu ri io

infancy and childhood may lead to permanent changes in the brain. Iron deficiency anemia is an added risk factor for breath holding spell, febrile fit and hypercyanotic blue spell. For prophylaxis, iron folic acid (IFA) pediatric tablets with 20 mg elemental iron and 100 µg FA are given to children for 100 days/year. Iron folic acid adult tablet has five times more concentration, and 1 mL IFA syrup is equivalent to one IFA pediatric tablet and 5 mL is equivalent to one IFA adult tablet. Weekly Iron Folic Acid Supplementation (WIFS) is found beneficial in children and adolescents and is integrated with School Health Program and adolescent clinics in some states of India. Normal hemoglobin (Hb, g/dL) levels vary in different age groups (WHO 1968): Newborn: more than 13; 2–6 months: more than 9; 6 months to 6 years: 11; 6–12 years: 12; adolescent male: more than 13, female: more than 12 and pregnancy: more than 11 g/dL. In severe deficiency Hb less than 4–5 g/dL, packed red cell transfusion is advised initially followed by iron.

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Section

5

Immunity, Immunization and Infectious Diseases



5.1 5.2 5.3 5.4

































5.5 5.6 5.7 5.8 5.9 5.10 5.11 5.12 5.13 5.14 5.15 5.16 5.17 5.18 5.19 5.20 5.21 5.22















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Section Editor : Ritabrata Kundu

Basics of Immune System: Naveen Thacker Primary Immunodeficiency Disorders: Tanu Singhal The Principles and Practice of Immunization: T Jacob John Rationale of Selection of Vaccines in National Immunization Program and IAP Immunization Time Table: Vijay Yewale The Universal Immunization Program (UIP) in India: Tanmay Amladi Non UIP Vaccines in India: Anju Aggarwal Vaccine Storage and Handling: Digant D Shastri Adverse Events Following Immunization and Their Management: M Indrashekhar Rao Future Vaccines, Adjuvants and Immunization Techniques: AJ Chitkara Fever and Fever of Unknown Origin: PP Maiya An Approach to a Child with Fever and Skin Rash: Jayakar Thomas Malaria: Ritabrata Kundu Kala-azar (Visceral Leishmaniasis): Utpal Kant Singh Dengue Illnesses: Ashok Kapse Chikungunya Fever: Rajniti Prasad Poliomyelitis: AK Dutta Chickenpox (Varicella): Lalitha Kailas Measles: AP Dubey Mumps: Jaydeep Choudhury Rubella: Nupur Ganguly Rabies: Ritabrata Kundu Pediatric Human Immunodeficiency Virus (HIV) Infection or Acquired Immunodeficiency Syndrome (AIDS): Milind S Tullu Leptospirosis in Children: S Ramesh Tuberculosis in Children: Vimlesh Seth Diphtheria: Monjori Mitra Pertussis: Sailesh Gupta Tetanus: Raju C Shah Rickettsial Diseases in India: Narendra Rathi Leprosy: Rajeshwar Dayal Pandemic Influenza: Nitin Shah

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Basics of Immune System Naveen Thacker

It is “not antigen-specific”

It is “antigen-specific”

Exposure does not result in indu ction of memory cells

Exposure results in induction of memory cells

Some of its cellular components or their products may aid “specific immunity”

Some of its products may aid “non-specific immunity”

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Acquired Immunity



Acquired immunity has two components: Humoral immunity and cellular immunity. 1. Humoral immunity is mediated by circulating immuno­ globulin antibodies in the blood. Immunoglobulin is produced by B lymphocytes, and they activate the complement system and attack and neutralize antigens. Humoral immunity is the major defense system against bacterial infections.



Components of the Immune System The immune system consists of T lymphocytes, B lymphocytes, natural killer (NK) cells, dendritic and phagocytic cells, and complement proteins (Fig. 5.1.1)

T Lymphocytes



Cellular immunity is mediated by T lymphocytes which are derived from the thymus. In the blood, T cells constitute 60– 70% of the peripheral lymphocytes. Each T cell can recognize a specific cell-bound antigen by an antigen-specific T cell receptor called as TCR. Subpopulations of lymphocytes may be identified by surface markers as well as by functional abilities. Markers on the surface of the lymphocytes are assigned CD (clusters of differentiation) numbers on the basis of their reactions to a panel of monoclonal antibodies. There are three major types of T cells: cytotoxic T cells, helper T cells and memory T cells. Most cytotoxic T cells display the glycoprotein CD8, and the helper T cells display the glycoprotein CD4. These proteins are closely associated with the T cell receptors and may function as co-receptors. CD4 is expressed on approximately 60% of the mature T cells, whereas CD8 is expressed on about 30% of T cells. Thus in a normal healthy person, the CD4 to CD8 ratio is about 2:1. There are two subtypes of helper T cells depending on the cytokines they produce on activation. T helper 1 (TH1) cells secrete interleukin-2 (IL-2) and gamma interferon 163







There are three levels of defense mechanisms for protection against pathogens: 1. The first line of defense mechanism (non-specific) is the physical barrier (skin and mucous membrane). 2. If a pathogen breaches these barriers, the innate immune system provides an immediate, but nonspecific response (Table 5.1.1). 3. However, if pathogens successfully evade the innate response, vertebrates possess a third layer of protection, the adaptive immune system, which is activated by the innate response. Here, the immune system adapts its response during an infection to improve its recognition of the pathogen. This improved response is then retained after the pathogen has been eliminated, in the form of an immunological memory, and allows the adaptive immune system to mount faster and stronger attacks each time the same pathogen is encountered (Table 5.1.1).

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2. Cellular immunity is mediated by T lymphocytes. It is responsible for delayed allergic reactions and rejection of foreign tissue transplants. It constitutes a major defense against infections due to viruses, fungi and a few bacteria such as the tubercle Bacillus. It also plays an important role in protection against tumors.

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There is a “lag time” between exposure and maximal response

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There is “immediate” response

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Its response is “antigen-depen dent”

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Specific immunity (adaptive)

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Non-specific immunity (innate)

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Our environment contains a huge range of pathogenic microbes and toxic substances that challenges the host by a very broad selection of pathogenic mechanisms. It requires a vigorous and vigilant immune system to keep the body free from pathogens. Immune system is a collection of mechanisms within an organism that protects against disease by eliminating pathological microbes and toxic or allergenic proteins. The immune system consists of major lymphoid organs like spleen and lymph nodes as well as smaller lymphoid tissues lining the mucosal entry points of the body like the airway (adenoids and tonsils) and gut associated lymphoid tissue (GALT). The immune cells are found in the reticuloendothelial system of many organs and in circulation. There is constant traffic of these cells from one point to other in the body which helps disseminate immune message throughout the body.

Table 5.1.1 Comparison of innate and adaptive immunity

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which promote cytotoxic T cell or delayed hypersensitivity types of responses. T helper 2 (TH2) cells secrete interleukin-4 (IL-4) and IL-5 and interact primarily with B cells in relation to humoral immunity and allergic sensitization. Cytotoxic T cells recognize foreign or self-altered antigen on the surface and destroy them. This mechanism may play a role in rejection of transplanted tissues, detection of virus-infected cells and surveillance against malignancy.

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B Lymphocytes B cells are derived from Bursa of Fabricius in birds (hence the name B cells). But in mammals, as there is no bursa, the transformation occurs in bursal equivalents, i.e. fetal liver and, after birth, the bone marrow. B lymphocytes constitute 10–20% of the circulating peripheral lymphocyte population. B cells can bind to antigens directly, but they 164 must contact helper T cells to produce full activation and

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Clinical Significance ­

• Patients with immune deficiency syndromes involving B lymphocytes, viz. X-linked agammaglobulinemia, suffer from recurrent pyogenic infections primarily involving the sinopulmonary tract. These defects usually manifest after 6 months of life when the passively transferred maternal IgG antibodies level begin to decline. • The capacity to produce specific antibodies to protein antigens is intact at the time of birth. However, normal infants cannot produce antibodies to polysaccharide antigens until usually after two years of life. But if the polysaccharide antigen is conjugated to a protein carrier, as in the conjugate Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae vaccines, the child less than 2 years of age can produce the immune response. ­

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Normal newborn infants are also capable of mounting antigen-specific T cell responses at birth, as evidenced by the vigorous tuberculin reactivity a few weeks after BCG vaccination even on the first day of life. Patients with severe defects of T lymphocyte number and/or function, such as severe combined immune deficiency and thymic aplasia (DiGeorge syndrome), show an increased susceptibility to infections due to Candida, cytomegalovirus and Pneumocystis carinii. They also have higher incidence of malignancies if they survive infections. HIV selectively binds to the cells expressing CD4 molecules on their surface, primarily helper T cells (CD4 cells) leading to progressive depletion of these cells.

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Clinical Significance



 

Figure 5.1.1 Origin of immune cells







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antibody production. It is the TH2 subtype that is mainly involved. The activated B cells proliferate and transform into plasma cells. The plasma cells secrete large quantities of antibodies into the general circulation. Circulating antibodies protect their host by binding to and neutralizing some protein toxins, by blocking the attachment of some viruses and bacteria to cells, by opsonizing bacteria, and by activating complement. As with T cells, each B cell receptor has unique antigen specificity, derived in part from somatic rearrangements of immunoglobulin genes. Thus the presence of rearranged immunoglobulin genes in a lymphoid cell is used as a molecular marker of B-lineage cells. B cells also possess several other molecules that are essential for B cell function. These include complement receptors, Fc receptors and CD19. B lymphocytes produce five different classes of immuno globulins called IgG, IgA, IgM, IgE and IgD. 1. IgG is the most abundant of all immunoglobulins found in plasma and plays a major role in the prevention of infections. It crosses the placenta and thus is the primary defense against infections in the first few weeks of life in the neonate. 2. IgM is the first antibody to be produced after an antigenic stimulation and is especially important in the initial period of primary immune response. The fetus can synthesize IgM in utero starting from 20 weeks of gestation. 3. IgA is the secretory immunoglobulin which is secreted by the B cells and protects the mucosal surfaces of the gastrointestinal, respiratory and genitourinary tracts and the breast. 4. IgE is found in low concentrations in the serum. The normal biological role of the IgE antibody is not clear. It is probably important in defense against parasitic infestations. Generally, an elevated level of IgE is found in the patients suffering from atopic diseases. 5. IgD is found in small amounts in serum and also on the surface of the lymphocytes.

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The Sequence of Events on Exposure to an Antigen (Fig. 5.1.2)

helper cell binds directly to the MHC class II molecules on APCs; whereas the CD8 molecules on the cytotoxic T cells bind to the MHC class I molecule on the target cell. Thus, both CD4 and CD8 molecules are directly involved in the T cell regulation. This antigen binding signals the T cell to produce cytokines that ultimately result in T cell activation and proliferation. The activated T cells secrete lymphokines which aggregate and activate macrophages and induce them to phagocytose and destroy the foreign antigen. They also attract polymorphs and monocytes to the site of infection. The helper T cells stimulate B cells to induce humoral immune response. In the primary immune response, native antigen is carried to a lymph node and taken up by specialized cells called follicular dendritic cells (FDC). Virgin B cells, bearing surface Ig, specific for that antigen then bind to this antigen. This antigenic adherence stimulates the B cells to differentiate into antibody producing plasma cells. Initially, these plasma cells produce IgM. Later, a

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The ability to recognize the antigen is innate and develops without exposure to the antigen. Stem cells differentiate into many million different T and B lymphocytes, each with the ability to respond to particular antigen. In case of T cells, the antigen is taken up by an antigen presenting cell (APC), processed and presented to the T lymphocytes by major histocompatibility complex (MHC) molecules present on the APC. For the high affinity binding, specific molecules are required to be present on the T cells and APCs. For example, the CD4 molecule present on the T



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Complement receptor 2 (CD21) is also the receptor for the Ebstein-Barr virus (EBV) and hence B cells are readily infected by EBV. CD19, a signal-transducing molecule, is B cell restricted and appears early in B cell differentiation. It is therefore useful in identification of B cell tumors.

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Figure 5.1.2 Cellular and humoral immunity

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Antigen Presenting Cells and Dendritic Cells



Antigen presenting cells are the cells that capture antigens by endo- or phagocytosis, process them into small peptides, display them at their surface through MHC molecules and provide co-stimulation signals that act synergistically to activate antigen-specific T cells. Antigen presenting cells include B cells, macrophages and dendritic cells, although only dendritic cells are capable of activating naïve T cells. Dendritic cells are major APCs in the body in addition to the B cells and the macrophages. The major role of these cells is to identify dangers, which is done by the special receptors on the APC named toll-like receptors (TLRs). Antigens are taken up by immature dendritic cells (DCs) activated by the local inflammation, which provides the signals required for their migration to draining lymph nodes. During this migration, DCs mature and their surface expression of molecules changes. DCs sense ‘danger signals’ through their toll-like receptors and respond by a modulation of their surface or secreted molecules. Simultaneously, antigens are processed into small frag ments and displayed at the cell surface in the grooves of major histocompatibility complex human leukocyte antigen (MHC HLA) molecules in humans. As a rule, MHC class I molecules present peptides from antigens that are produced within infected cells, whereas phagocytosed antigens are displayed on MHC class II molecules. Thus, mature DCs reaching the T cell zone of lymph nodes display MHC-peptide complexes and high levels of co-stimulation molecules at their surface. CD4+ T cells recognize antigenic peptides displayed by class II MHC molecules, whereas CD8+ T cells bind to class I MHC peptide complexes. Antigen-specific T cell receptors may only bind to specific MHC molecules (e.g. HLA-A2), which differ among individuals and populations. Consequently, T cell responses are highly variable within a population.

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Cytokines These are the substances that regulate the immunologic, inflammatory and reparative host responses and comprise of previously designated lymphokines (lymphocyte derived); monokines (monocyte derived); and several other polypeptides.

The Complement System The cell killing effects of innate and acquired immunity are mediated in part by a system of plasma enzymes originally 166 named the complement system. Complement activation

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Approximately 10–15% of the peripheral blood lymphocytes do not bear TCR or cell-surface immunoglobulins. These cells are endowed with an innate ability to lyse a variety of tumor cells and virally infected cells without prior sensitization. Hence they are called as natural killer cells. Two cell surface molecules, CD16 and CD56, are widely used to identify NK cells.



Natural Killer (NK) Cells

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Macrophages are a part of mononuclear phagocyte system. The functions carried out by macrophages in the immune response are as follows: 1. They are required to process and present antigen to immunocompetent T cells. 2. They produce a variety of cytokines such as IL-1 and tumor necrosis factor (TNF) and thus exert modulatory effect on inflammatory response. 3. They are the effector cells of some forms of cell-mediated immunity, e.g. delayed hypersensitivity reaction. The enzymes in macrophages include lysozymes, cathepsins, acid hydrolases and neutral proteases. They can secrete digestive enzymes, complement component, arachidonic acid metabolites, enzyme inhibitors, interferons and chemotactic factors in its environment. Clinically, the deficiency of phagocyte function is acquired secondary to systemic illnesses, viz. diabetes mellitus, malnutrition and neoplasia, in which defects of chemotaxis may contribute to susceptibility to infections. The most common congenital deficiency is chronic granulomatous disease (CGD). Staphylococcus, Gram-negative rods and fungi are troublesome for these individuals who suffer from skin, periorificial and deep organ infections.





Macrophages

occurs in two phases, viz. activation of C3 component followed by activation of the attack or lytic sequence. The critical event is cleavage of C3 by complement derived enzymes termed C3 convertases. The major fragment (C3b) of activated C3 mediates a number of vital biological activities. Two different pathways or enzyme cascades activate the system: the classic pathway, triggered by immune complexes and the alternative or properdin pathway, triggered by contact with various viruses, bacteria, fungi and tumor cells. These proteins have two functions: 1. They help killing invading organisms by opsonization, chemotaxis and eventual lysis of the cells. 2. They serve in part as a bridge between innate to acquired immunity by activating B cells.

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switchover in the production of immunoglobulins takes place and plasma cells start producing IgG class of immuno globulins. When the stimulus is removed, the B cell division and differentiation stops, but the circulating pool of B lymphocytes still contains a large population of memory cells. During re-exposure to the same antigen (secondary immune response), immediate and extensive divisions of the B cells with IgG receptors take place and large quantity of IgG antibodies are produced. These antibodies combine with the antigen.

Immune Response The response mounted by the body is called as immune response and it consists of producing either proteins called as antibodies as in humoral response or specific cells as

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T Cell Dependent Immune Response Certain antigens, mainly proteins, induce both B cell and T cell stimulation leading to what is called T cell dependent immune response; whereas large molecular antigens like polysaccharides induce only B cell response as they are incapable of inducing T cell response on their own. The T cell dependent response is usually prompt with higher titers, IgG type, and longer lasting. It also shows booster effects with repeated exposure. Infants of 6 weeks of age onwards are capable of T cell dependent responses. Lastly IgA antibodies are also produced in such response which probably helps in providing mucosal protection and eradicating the carrier state. As compared to this T cell independent response being only B cell mediated. It is predominantly IgM type with low titers. The response is short lived, does not lead to boosting and such vaccines are actually revaccination rather than boosters when given repeatedly which produces the same type of response every time the antigen is introduced. Lastly IgA is not produced and hence there is no local mucosal protection with this 167 type of antigens.



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This arm is mediated by the production of antibodies against the specific antigens on the microbes. The anti bodies consist of heavy chains and light chains. There are two types of light chains: lambda and kappa chains whereas there are five different types of heavy chains which identifies the five types of immunoglobulins IgG, IgM, IgA, IgD and IgE. Of this IgG, IgM and IgA are protective against pathogens. IgE may play a role against parasites and is also involved in allergies. During acute infection, IgM antibodies appear within a few days, peak at around 7–10 days and disappear in next few months to undetected levels. Hence presence of IgM indicates recent infection. Similarly, IgM being a large molecule is not transferred transplacentally in a newborn. Hence presence of IgM antibodies indicates congenital infection in the newborn. The IgM response is usually seen

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Humoral Immune Response

When the antigen is introduced for the first time the immune system responds primarily after a lag phase of up to 10 days. On re-introduction of the same antigen there is no lag phase and the immune system responds by producing antibodies immediately and this is called as secondary response. There are some basic differences in both these response. Primary response has lag phase, is of predominantly IgM type, is short lived and the titers are low. As compared, the secondary response is almost immediate, is of IgG type, is long lasting and the titers are very high. These differences are more with the antigens stimulating both B cells and T cells. Sometimes there is a negative phase where there is transient drop in the antibody levels immediately after the infection. The significance of this negative phase is not well known. Repeated exposure of the same antigen leads to more maturation of the immune response with better affinity and avidity of the antibodies and a longer time till anamnestic response occurs. Affinity is the force with which the antigen binding site on the antibody bonds with the epitopes and the combined such forces lead to avidity. High affinity and avidity antibodies are very useful in controlling infections.

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This is the most important arm of immune system as proved by the fact that defects in this pathway are often lifethreatening in nature. Except for the transplacental transfer of immunoglobulin, which offers protection to the newborn for a temporary period of time, it is not fully active at birth and develops gradually after birth on repeated exposure to the microbes in the surrounding. It can be divided into natural versus acquired, passive versus active and humoral versus cellular. The most important cells of this arm include the B lymphocytes, T lymphocytes and their various subsets. On activation by an antigen the B cells proliferate and get converted to plasma cells, which in turn produce the antibodies. Approximately 10% of the lymphocytes in the blood consist of B cells and they reside mostly in the peripheral lymphoid organs. For effective production of antibodies, B cells need help from T helper cells. On the other hand, T cells lead to cellular response and mature in thymus. The cellular response involves the T cells, macrophages and lymphokines, which are secreted by the lymphocytes and act as signal for communication between many of these immune cells.

Primary versus Secondary Immune Response

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Specific Immunity

in primary response. It is short lived and the titers of the antibodies are lower. IgG response usually picks up along with IgM or after a few days, peaks it around 2–3 weeks and lasts for a very long time. It is usually seen best during the secondary response, classically seen on re-exposure and the titers are very high. IgA response depends upon the route and the type of infection. Serum IgA is seen in organisms that invade from mucosa whereas surface IgA is classically seen with localized mucosal infections like in cholera, RSV infection, etc.

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in cellular response. Both these with the help from other cells like neutrophils, monocytes, macrophages as well as chemicals like complements and other cytokines elaborated by immune cells leads to ultimate clearance of the invading organism. The immune response is both specific and highly effective, e.g. anti-measles antibodies do not react with varicella virus and vice versa. Antigen has specific site to which the antibody binds is called epitope. There are multiple epitopes on the same antigen and there are multiple antigens on the same organism. Accordingly the immune system mounts multiple antibodies to the same organism. Only some of these antibodies are actually protective in nature and rest are not useful in this sense. In general viruses contain lesser number of antigens than bacteria, fungi or parasites.

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Cell Mediated Immunity This type of immunity is transferable by the lymphocytes and not by antibodies and is mediated via T cells. T cell lymphocyte is a very important cell in the immune response. It has many subsets, which carry out different functions. These cells are in circulation and in the lymphatic vessels. There are three essential subsets, helper T cells, suppressor T cells and cytotoxic T cells. T helper cells are CD4 positive and help the B lymphocytes proliferate and produce antibodies. T suppressor cells suppress various immune response and cytotoxic T cells lead to lysis of the infected macrophages and cancer cells. Both the suppressor and cytotoxic T cells are CD8 positive. T cell response is very important for T cell dependant humoral response as discussed before and for immunity against certain organisms which are essentially intercellular pathogens like M. tuberculosis, M. leprae, fungal infections, etc. They are also important in surveillance against malignant cells. The patients with T cell deficiency suffer from opportunistic infections, which are intracellular like tuberculosis and fungal infection as well as peculiar cancers like Kaposi’s sarcoma in an HIV infected person. T cells communicate with one another and with other types of cells through production and release of substances called lymphokines.

Passive Immunity ­

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Passive immunity is specific immunity which is transferred passively to the recipient. It gives readymade immuno globulins, which helps to fight infection immediately. However it is for a temporary period and it wanes after few weeks to few months depending upon the half-life of the transferred immunoglobulins. Besides the natural transplacental passive transfer of the immunoglobulins in the newborn, the other examples of the passive immunity are infusing immunoglobulins in the person to protect him for a specific disease.

Transplacental Passive Immunity The most common form of passive immunity is that given to the newborn from the mother. Immunoglobulins are transferred predominantly in the last trimester and are mainly of IgG type. This means that at birth the child will have similar type of antibody pattern as the mother. This 168 protects the child for first few months till the time she/he

develops her/his own immunity after repeated exposure to various antigens after birth. The protection offered by transplacental passive immunity depends on the half-life of the specific antibody, e.g. the antibody against poliomyelitis does not protect child for more than 4–6 weeks (the time of starting the polio vaccination in the baby) whereas the antimeasles antibody protects the child till 6–9 months (the reason for delaying the measles vaccine till 9 months). Not only does the passive immunity protect the child against the specific diseases, it also interferes with the immune response to the concerned vaccine if given in the presence of maternal antibody like for measles as discussed before.

Acquired Passive Immunity Immunoglobulins can be passively transferred by giving immunoglobulin preparation intramuscularly or intravenously. It can also be done inadvertently by infusing blood and blood products which will also infuse immunoglobulins which may interfere with some live vaccines like measles vaccine. There are three types of preparations, which will lead to passive transfer of the immunoglobulins. They are: 1) pooled human immunoglobulin preparation; 2) homologous hyperimmune globulin and 3) heterologous hyperimmune immunoglobulin preparation. ­



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A T cell independent antigen like polysaccharide can be converted to T cell dependent antigen by the technique of conjugation where a carrier protein is conjugated with the polysaccharide. When this conjugated moiety is presented to the T cell, it recognizes the protein carrier as an antigen and leads to internalization of the whole complex, which leads to the T cell now responding even to the carbohydrate antigen of the complex, producing T cell response to the polysaccharide. This technique is very useful in producing vaccines like conjugated Hib, pneumococcal, typhoid and meningococcal vaccines.

Human Immunoglobulins This is prepared by pooled plasma from more than 100 healthy donors and fractionation of this plasma to produce the final product, which is available as IM as well as IV preparation. As it contains a variety of antibodies it is ideally suitable for replacement therapy in congenital and acquired immune deficiency with antibody deficiency. It is also used in many autoimmune disorders. It is also used for passive prophylaxis for measles or hepatitis A infection.

Homologous Human Hyperimmune Globulins This is obtained by pooling plasma from specific donors who have high titers of a specific antibody either due to repeated past natural exposure or due to vaccination. This preparation serves to protect against a specific disease. Of course it will also have other types of antibodies too, albeit to a lesser extent. They are used for prophylaxis of diseases like hepatitis B, tetanus, varicella or rabies.

Heterologous Hyperimmune Globulins These were used in past to prevent diseases like rabies or tetanus. It is obtained from animals mainly horse or rabbit who are hyperimmunized by repeated vaccination against the concerned disease and then collecting plasma which is fractionated to obtain pure product. Being an animal product it can lead to severe allergic reactions including anaphylaxis, anaphylactoid reactions or serum sickness.

Active Immunity Active immunity is developed by stimulating the immune system by antigens which can lead to specific humoral or

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1. Chaplin DD. Overview of the Immune Response. J Allergy Clin Immunol. 2010;125(Suppl 2):S3-23. 2. Lahiri KR, Taori RN. Basics of immune system in children. In: Parthasarathy A, Menon PSN, Nair MKC (Eds). IAP Textbook of Pediatrics, 4th edition. New Delhi: Jaypee Brothers Medical Publishers; 2009.pp.1080-84. 3. Paul Y, Vashishtha VM. Immunology of vaccines: basics and beyond. In: Vashishtha VM, Kalra A, Thacker N (Eds). FAQs on Immunization, 1st edition. New Delhi: Jaypee Brothers Medical Publishers; 2011.pp.3-23. 4. Shah NK, Thacker N. General principles of vaccination. In: Thacker N, Shah NK (Eds). Immunization in Clinical Practice. New Delhi: Jaypee Brothers Medical Publishers; 2005.pp. 1-5.

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Parts of this chapter including the figures are adapted from the Chapter 20.1 ‘Basics of Immune System in Children’ by

Bibliography

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Acknowledgments

Keya R Lahiri and Roshani N Taori from the 4th edition of the IAP Textbook of Pediatrics.

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cellular immune response or both. It can happen in two ways, either by exposure to the wild pathogen naturally where the immunity develops after the person suffers from the disease which has chances of morbidity and even mortality; or by exposure to the antigens given as vaccines where the person has least morbidity and the person becomes immune without much suffering. Not all the natural diseases lead to protective immunity like in natural tetanus or typhoid where repeated clinical courses are known unless vaccination is done. Most of the time natural disease leads to strong protective immunity which probably lasts lifelong, e.g. in measles or varicella. Vaccination on the other hand is introduction of antigens with the purpose of inducing immune response without leading to clinical disease.

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tract, chronic diarrhea, hematological malignancies and endocrine growth problems. Transient hypogammaglobulinemia of infancy is charac terized by delay in production of immunoglobulins after disappearance of maternal immunoglobulins. Many cases are asymptomatic; others may have recurrent airway infections, severe sepsis, meningitis, recurrent diarrhea, oral candidiasis and severe varicella infection. Antibody levels normalize by 2 years in most. Treatment consists mainly of antibiotic prophylaxis and immunoglobulin replacement only in those with severe infections. Selective IgA deficiency, specific IgG2 subclass deficiency and specific anti-polysaccharide deficiency (SPAD) are the most common immunodeficiency disorders and usually occur in combination. SPAD is diagnosed by impaired response to pneumococcal polysaccharide vaccine in children above 2 years and should be suspected in the setting of repeated infections when all other immunodeficiencies are ruled out. These disorders may be asymptomatic or present with recurrent airway infections and in IgA deficiency with chronic diarrhea due to giardiasis.





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These are the most common PIDs and account for half of all cases. The earliest recognized immunodeficiency disorder, Bruton’s agammaglobulinemia (X linked inheritance) is characterized by severe depletion of circulating B cells and very low levels of IgG, IgM and IgA. A more severe variant is inherited autosomal recessively. Most children present by late infancy with severe and recurrent ear nose throat (ENT) and airway infections and susceptibility to severe enteroviral meningitis. Treatment consists of lifelong immunoglobulin replacement therapy and antibiotic therapy. Oral polio vaccine is absolutely contraindicated in these children and their close contacts. Class switch immunoglobulin deficiencies (earlier known as hyper IgM syndromes and now reclassified as combined immunodeficiencies) are characterized by low levels of IgG and IgA and normal or high levels of IgM. There is associated T cell deficiency and neutropenia and propensity for severe pneumocystis infections in addition to respiratory bacterial infections. Common variable immunodeficiency (CVID) is characterized by levels of IgG below 2SD of normal, in the presence of decreased IgA and/or IgM levels, recurrent infections, impaired response to immunization, exclusion of defined causes of hypogammaglobulinemia, and an age above 2 years. These patients present in late childhood or young adulthood with recurrent ENT and airway infections, granulomatous inflammation of the lungs and gastrointestinal

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Disorder of IFN-γ or IL-12 axis present with disseminated infections due to BCG, poorly pathogenic mycobacteria, disseminated tuberculosis, Salmonella typhi, nontyphoidal Salmonella or severe herpes virus infections. All the screening tests for B and T cell functions are normal. Markedly elevated serum IFN-γ levels may be used as a screening test. Treatment is by subcutaneous (SC) IFN-γ or in some with bone marrow transplant (BMT). Chronic mucocutaneous candidiasis is characterized by recurrent candidiasis of skin, nails and mucous membranes (systemic or invasive candidiasis is rare) and in some with autoimmune endocrinopathy. Treatment is with prolonged administration of antifungal agents. NK cell defects are characterized by severe susceptibility to herpes viral infections (cytomegalovirus, Ebstein-Barr virus, Varicella zoster virus and Herpes simplex virus). These patients benefit with chemoprophylaxis with antiviral drugs. Idiopathic CD4 lymphocytopenia is an illness with AIDSlike opportunistic infections in patients with a CD4 count less than 300 cells/µl and absence of HIV by serologic and molecular tests. Management is by antimicrobial prophylaxis.

Humoral immunodeficiencies Cellular immunodeficiencies Combined humoral and cellular immunodeficiencies Disorders of phagocyte function Disorders of the complement system













1. 2. 3. 4. 5.



Primary immunodeficiency disorders (PIDs) are inheritable genetic disorders that disrupt immune cells either quantitatively or qualitatively in the performance of their functions. They occur at an incidence of 1 in 2000 live births and are often under-diagnosed or diagnosed late. Early diagnosis, correct classification and appropriate treatment are essential to reduce morbidity and mortality. More than 150 PIDs have been described; this section gives a bird’s eye view of the common ones. PIDs are broadly classified as:



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Primary immunodeficiencies should be suspected in the setting of infections that are: Recurrent, or Of unusual severity, or Are due to uncommon organisms, or At unusual sites.



There is associated failure to thrive. Autoimmune diseases and malignancies are also common in many PIDs. Children less than 5 years of age who get recurrent upper respiratory tract infections is the most common setting when immunodeficiency is suspected but rarely established. Secondary causes such as malnutrition, HIV, treatment with steroids and immunosuppressive drugs should always be excluded. Clinical presentation varies with the type of immune defect. Antibody deficiencies present with sinopulmonary bacterial infections and chronic lung disease particularly bronchiectasis. Cellular immunodeficiencies present with infection with intracellular organisms such as mycobacteria, Salmonella, fungi, pneumocystis and viruses. Patients with suspected severe combined immunodeficiency disorder (SCID) should be immediately referred for possible stem cell transplant. In case of NK cell dysfunction, recurrent severe herpes virus infection may be observed. Terminal complement component deficiencies are suggested by neisserial infections. Phagocytic disorders are suggested by recurrent skin, soft tissue and dental infections with catalase-positive organisms, such as S. aureus. An algorithmic 171 approach to diagnosis of PIDs is depicted in Flow chart 5.2.1.

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The most prominent defect of phagocyte function is chronic granulomatous disease occurring at a rate of 1:200,000 births, mostly inherited as XR (X linked recessive) inheritance is due to defect in the neutrophil oxidative burst. It is characterized by recurrent skin, soft tissue and lymph node infections and granulomatous abscesses in internal organs. Commonly implicated organisms are Staphylococcus aureus, Aspergillus, Serratia, Nocardia, Candida and Burkholderia. In India it is commonly misdiagnosed as tuberculosis due to presence of granulomas on histopathology. Diagnosis is by estimation of neutrophil oxidase activity and treatment includes cotri moxazole prophylaxis, itraconazole prophylaxis, use of interferon-γ and finally BMT. Chediak Higashi syndrome presents with recurrent infections of skin, respiratory tract with oculocutaneous albinism, neurologic defects and propensity to develop an immunoproliferative disease. Leukocyte adhesion deficiency (LAD 1 and 2) present with delayed separation of umbilical cord (LAD 1), recurrent cellulitis and abscesses with absence of pus formation, severe periodontitis and characteristic facies (LAD 2). There is significant neutrophilia even in the absence of infection and counts may reach up to 100,000/mm3. Persistent (Kostmann) and cyclic neutropenia are characterized by recurrent skin, soft tissue, respiratory tract

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Complement deficiencies present variably as recurrent urticaria or angioedema, autoimmune disease, recurrent bacterial/neisserial infections depending on the component which is deficient. Complement deficiencies should be suspected in patients with recurrent bacterial infections if all antibody defects have been ruled out. Treatment consists of antibiotic prophylaxis and immunization (especially meningococcal vaccine).







Severe combined immunodeficiency (SCID) is a group of syndromes of differing genetic basis characterized by complete lack of specific lymphocyte dependent adaptive immunity. These children present in the first few months of life with recurrent, persistent, severe and disseminated bacterial, viral, or fungal infections and failure to thrive, diarrhea, and rashes. There is absence of lymphoid tissue and no thymic shadow on the radiograph. There is severe lymphopenia and depletion of all lymphocyte subpopulations with pan-hypogammaglobulinemia. SCID is a medical emergency and patients need to be referred for BMT to a specialist center as soon as possible. Wiskott Aldrich syndrome is characterized by eczema, bleeding complications due to thrombocytopenia and small platelet size, recurrent and severe infections, autoimmune disease and tendency for EBV related lymphoma. Treatment options include gammaglobulin replacement, antibiotic prophylaxis, splenectomy and finally BMT. Ataxia telangiectasia related disorders are characterized by ocular telangiectasia, ataxia and recurrent severe bacterial respiratory infections. There is an increased tendency for malignancy owing to chromosomal fragility. Presence of acanthocytes in the peripheral smear is a diagnostic pointer. DiGeorge syndrome is characterized by thymic hypoplasia, hypoparathyroidism and structural cardiac defects. The immune deficiency is variable and very severe lymphopenia is rare.

and rectal infections. The nadir in cyclic neutropenia is usually 21 days but may range from 14-36 days. Treatment is with G-CSF and stem cell transplantation in unresponsive cases. Hyper IgE syndrome or Job syndrome is characterized by chronic eczematous dermatitis, recurrent skin and respiratory infections, and in an autosomal dominant variant skeletal or bony abnormalities with delayed shedding of teeth and facial abnormalities. Common organisms are S. aureus and Aspergillus. The eosinophil count and IgE levels are high. Transplant is not curative.

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Flow chart 5.2.1 General approach for the diagnosis of primary immunodeficiency and severe combined immunodeficiency (SCID)

The most crucial investigation is a complete blood count with peripheral smear. The absolute lymphocyte count should be calculated; a count of less than 4500 in infants and less than 1500 in older children is lymphopenia. The absolute neutrophil count is low in the congenital neutrophil deficiencies and very high in leukocyte adhesion deficiencies. The platelet count is low and platelet size

small in Wiskott Aldrich syndrome and presence of Howell Jolly bodies in the red blood cells raises the possibility of asplenia. Screening tests for PIDs are detailed in Table 5.2.1. The molecular basis for many of the common PIDs have been identified. Diagnosis at the genetic or molecular level is always desirable to establish unequivocal diagnosis, to permit accurate genetic counseling, to define better the genotype-phenotype associations, and for the best therapy of specific disorders now and in the future.

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Table 5.2.1 Screening tests for immune function Immune function Enumeration/Flow cytometry Cellular function CBC with differential Enumeration of T cells (CD3) Enumeration of NK cells (CD16 and CD56)

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Functional tests Cutaneous delayed hypersensitivity Enzyme assays (ADA, PNP) FISH for 22q11 and 10p11 deletion NK cell cytolysis assay Humoral function Enumeration of B cells IgG, IgA, IgM levels CD19 or CD20 Antibody response to immunization (diphtheria and tetanus toxoids, pneumococcal polysaccharide) IgG sub class levels Phagocytes CBC with differential Oxidase function (NBT, DHR, chemiluminescence) LFA-1 Enzyme assays (MPO, G6PD) Phagocyte function Complement AH 50 (alternative pathway) CH 50 (classical pathway) Abbreviations: ADA, Adenosine deaminase; CBC, Complete blood count; DHR, Dihydrorhodamine; FISH, Fluorescence in situ hybridization; G6PD, Glucose-6-phosphate dehydrogenase; LFA-1, ymphocyte function antigen 1; MPO, Myeloperoxidase; NK, Natural killer; NPT, Nitroblue tetrazolium; PNP, Purine nucleoside 3-phosphorylase.

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1. Bonilla FA, Bernstein IL, Khan DA, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. Ann Allergy Asthma Immunol. 2005;94(Suppl 1):S1-63. 2. Desai M, Currimbhoy Z. Primary Immunodeficiency Disorders in India. Electronic publication. Available at URL: http://sites. google.com/site/mmdesai007/ 3. Driessen G, Van der Burg M. Primary antibody deficiencies. Eur J Pediatr. 2011;170:693-702. 4. Morimoto Y, Routes JM. Immunodeficiency overview. Prim Care Clin Office Pract. 2008;35:159-73.



PIDs are rare but often missed serious disorders. Diagnosis and treatment is complicated, expensive and not readily available. It is crucial to develop regional referral centers

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The largest series of PIDs from India has been reported from Bai Jerbai Wadia Hospital for children, Mumbai. Phagocytic dysfunction was the most common (72%) followed by NK cell defects (14%) and then B and T cell immunodeficiencies (13%) and finally complement defects (1%).

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Antisera prepared in horses against tetanus toxin, diphtheria toxin, rabies virus and snake venom are widely used in India. Horse serum may cause hypersensitivity reactions including anaphylaxis and serum sickness. The active principle is immunoglobulins; hence unwanted components such as albumin may be removed and more concentrated “hyperimmune” equine immunoglobulins may be prepared. Even with such preparations hypersensitivity remains a problem. The Fc part of immunoglobulins are responsible for such responses and removing Fc portion while preserving the antigen-binding Fab portion has become the standard practice in presenting equine hyperimmune immunoglobulins against rabies and hepatitis B antigens. Homologous products prepared from pooled human plasma are safer and more potent, but also more expensive. Human immune globulins against tetanus, rabies and HBV are available in India; elsewhere other preparations are available, for example, varicella-zoster immune globulin. Apart from these antigen-specific products, human gamma globulin preparations are available for intramuscular and intravenous injection either as replacement in hypo gammaglobulinemia or for therapeutic purposes in certain specific autoimmune disorders.



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The injection of pre-formed antibodies to a specific antigen, in the form of “antiserum” or “immune globulin” is termed as passive immunization. The term “gammaglobulin” is used to denote that the product is not “hyperimmune” to any specific antigen, but contains antibodies to all common antigens encountered by adults from whom plasma had been collected for its extraction. The physiological transfer of immunoglobulins across the placenta to the fetus from the mother provides natural but passive immunity to the infant.

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The induction of immune response by the deliberate inoculation of appropriate immunogen(s) in the form of a vaccine is termed as active immunization or simply immunization or vaccination. In practice, this term applies to the inoculation of vaccine, regardless of the success or failure of inducing the desired immune response.

(lymph nodes, spleen, thymus, bone marrow and several submucosal tissues), constitute the immune system. These cells include dendritic cells and macrophages that recognize and interact with pathogen-associated molecular patterns (PAMP) or detect and ingest microbes and process and present the immunogenic epitopes to T and B lymphocytes; T and B cells that are thus stimulated to respond; and a set of non-T/non-B lymphocytes called natural killer (NK) cells. T cells have subsets. CD4 positive T helper (Th) cells of Th-1 pathway regulate cell-mediated immunity (CMI) through cytotoxic lymphocytes, which are CD8 positive. Th-2 pathway regulates antibody production by B cells. Th-17 cells modulate autoimmunity (antibody-related). Humoral immunity is mediated through immunoglobulins (antibodies) which belong to class IgM, IgG, IgA, IgD and IgE. When stimulated, B cells transform into plasma cells and secrete antibodies. After adequate stimulation of the regulatory (T cells) and effector cells (T and B cells), memory cells (T and B cells) survive for very long periods, ready to respond rapidly to the same immunogens if re-introduced (anamnestic response). Microbial infection is the prototype of immune stimu lation; many vaccines contain infectious organisms. Intra cellular pathogens are strong inducers of CMI. To nonreplicating antigens (killed microbes/subunits containing PAMP) the initial response is weak and slow (mainly IgM) but the immune system gets “primed”, ready for anamnestic (booster) responses (mainly IgG) that are greater and brisker than primary response. Such vaccines require one or two priming doses and one or more boosting doses (primeboost principle). Protein antigens stimulate T cells to regulate immune responses resulting in sequential secretion of IgM, IgA and IgG by plasma cells and in development of memory cells. Polysaccharide antigens are T-cell-independent, directly stimulate B cells and induce only IgM secretion and fail to induce memory cells. B cells mature to directly respond in this manner only after the child is about 2 years old. Mucosal immunization (with live attenuated viruses or bacteria) induces mucosal (secretory) IgA responses in addition to systemic immunity. Mucosal protection from infection is mediated through several factors and local/ secretory IgA is only one of them. Humoral IgG, IgM and IgA do reach mucosal surfaces by passive transport (or spill over) and mediate microbial binding or viral neutralization. Most immune responses (natural and vaccine-induced) are not necessarily protective against infection, but prevent disease when exposed. When re-infected, immune persons shed less quantum of pathogen for shorter duration than in the non-immune, resulting in less transmission and epidemiological herd effect (less disease even in the unvaccinated); this is the basis of vaccination in public health. ­

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Every pediatrician must familiarize oneself with the descriptive leaflet supplied by the vaccine manufacturer and also with the techniques of inoculation, side effects and contraindications, if any. When OPV is given, the nose of the infant should not be pinched in order to make the infant open the mouth. Instead, a slight pressure may be applied on both the cheeks, between upper and lower jaws, using the thumb and a finger. There is no need to withhold breastfeeding for long periods before or after giving OPV; in practice a gap of 10–15 minutes is usually observed to breastfeed after OPV. BCG must be given intradermally; the preferred site is the lateral aspect of the convex region of the left shoulder. In infancy, intramuscular (IM) injections are given in the anterolateral aspect of the thigh. Subcutaneous (SC) injections may be given into the tissue targeted by pinching the posterior skin fold of triceps muscle. HBV, or indeed any vaccine, should not be given in the gluteus. In older children, the deltoid muscle is often chosen for IM injections and the triceps region for SC injections. There is no need to warm the vaccine vial in the hands before it is drawn in the syringe, or given in the mouth. Frozen OPV needs to be just thawed before giving. C

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All licensed vaccines except OPV are virtually/completely safe products. However, all vaccines do cause some adverse reactions, most of which are temporary, self-limited and 175 inconsequential. Specific contraindications are also very few. ­

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Vaccines are allowed to be marketed in India, only after licensing by the drugs controller. Every batch of vaccine manufactured in India or imported, is checked for quality assurance by the Central Research Institute (CRI, at Kasauli) of the Directorate General of Health Services. All UIP vaccines are centrally purchased by the Department of Family Welfare and distributed to the governments of all states and union territories. Pediatricians are allowed to collect all UIP vaccines from the local area health authority without any charge, to be given to children according to the national schedule. Vaccine utilization must be accounted for by returning the list of beneficiaries. Vaccines outside the UIP list are available for purchase from various vaccine distributors.



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Pediatricians immunize children in healthcare setting, choosing vaccines after risk assessment and with con currence of parents, with cost borne by parents. The IAP immunization schedule illustrates the choice of vaccines in preventive medicine mode. The Immunization Division under Ministry of Health provides a selected subset of licensed vaccines and provide them free of charge, under Universal Immunization Program (UIP). The purpose of UIP is to control target diseases, in many cases taking advantage of herd effect (reduced incidence in unvaccinated segment of population).



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All vaccines are susceptible to loss of potency, when exposed to warm temperatures, but are very stable at 2–8°C. Lyophilized vaccines (BCG, measles, and MMR) and unadjuvanted liquid vaccines (OPV) are also stable when frozen. Adjuvanted vaccines (DPT and HBV) lose potency when frozen. If they accidentally freeze, they should be rejected. Vaccines should be used within their date of expiry. The system of transporting, distributing and storing vaccines from the manufacturer right up to the point of use under refrigeration is referred to as the cold chain. In clinics, vaccines must be stored in a refrigerator which maintains the inside temperature between 4 degrees and 8 degrees. If temperature falls below 3, there is a chance for some vaccines to freeze solid. Where vaccines are maintained in the cold chain in clinics, multidose vials can be used to reduce cost. Partially used vials must be maintained under cold conditions for subsequent use. However, care should be taken to disinfect the top, before puncturing the vial. Reconstituted lyophilized vaccines (BCG, measles, MMR, varicella and Hib) should be used immediately after recon stitution. Multidose BCG or measles vaccine may be used over a few hours, preferably 4 but maximum 6 hours; during the interim they should not be frozen, but kept cold and not exposed to bright light. Any left-over contents must be dis carded after 6 hours.

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The vaccines licensed in India include live attenuated bacteria (Bacillus calmette Guerin or BCG; Salmonella typhi Ty21a), live attenuated viruses (oral polio vaccine or OPV, trivalent, monovalent types 1 and 3 and bivalent 1 and 3; measles, mumps, rubella, varicella, Japanese encephalitis, rotavirus and hepatitis A), killed bacteria (Bordetella pertussis, killed Vibrio cholerae), polysaccharides (pneumococcal capsular antigens with 23 serotypes; S. typhi Vi; meningococcal capsular antigens), protein-conjugated polysaccharides (Haemophilus influenzae b antigens conjugated with different proteins; pneumococcal conjugated antigens of 10 or 13 serotypes, conjugate meningococcal vaccine), killed viruses (rabies, polioviruses, hepatitis A, Japanese encephalitis, influenza and Kyasanur forest disease), structural subunits (hepatitis B, papilloma virus) or antigen components (acellular pertussis). Many are presented in combinations such as diphtheria pertussis tetanus (DPT), measles, mumps and rubella (MMR), DPT-HBV, DPT-Hib, and DPT-HBV-Hib.

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ibliography 1. Indian Academy of Pediatrics. Available at http://www. iapindia.org/immunization/immunization-schedule 2. John TJ, Samuel R. Herd immunity and herd effect: New insights and definitions. Euro J Epidemiol. 2000;16:601-6. 3. World Health Organization. Available at http://www.who.int/ immunization_safety/publications/aefi/en/ 4. World Health Organization South East Asia Region. http:// whoindia.org/en/Section6/Section284/Section286_508.htm.





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An epidemic of an infectious disease reaches a peak and declines rapidly because of the very high community immunity consequent upon the epidemic spread of the agent. The transmission may be interrupted soon after an epidemic. Only when sufficient numbers of susceptible children accumulate over time, the agent will re-establish itself in the community. This principle is applied in pulse immunization. When a large proportion of susceptible children are vaccinated in a short period of time, an epidemic is simulated. The consequent “herd effect” may result in break of transmission of the agent. For epidemic-prone diseases with more than 1 year of interepidemic intervals such as poliomyelitis and measles, the pulsing of the vaccine at annual intervals has been shown to be effective in disease control. The term pulse immunization is given to denote the repetitive campaigns at annual intervals. The term is loosely applied for repetitive vaccination campaigns. The herd effect of pulse immunization would be higher than the same volume of vaccine is given routinely throughout the year. In other words, better herd effect for the same herd immunity is achieved with annual pulse immunization. In developing countries where the transmission of polio viruses is not interrupted in spite of high coverage with the routine use of OPV, pulse method can be applied to interrupt it. Since measles virus is very contagious, it will be virtually impossible to interrupt its transmission without resorting to pulsing of vaccine at intervals that are shorter than the regional interepidemic intervals.

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proportions of children in a community are immunized against a specific disease, the transmission/circulation of the infectious agent may be retarded; hence, the incidence of disease may decline even in the unimmunized segment of the childhood population. This phenomenon is called the herd effect. Immunization in public health mode takes advantage of herd effect for disease control. The term herd immunity refers to the proportion of individuals in the population that have immunity due to immunization. As immunization coverage increases, herd immunity increases and herd effect may become manifest. Herd effect can be recognized, only if the incidence of disease is measured before, during and after the immunization activities.



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Minor illnesses are not a contraindication to giving any vaccine. However, if the nature of illness is not clear, caution must be exercised in order to avoid the vaccine from being blamed for the worsening of an illness. Immunization is better postponed when there is any illness that requires treatment, unless access to the infant is difficult later or there is an outbreak of illness, e.g. measles. Every clinic or hospital visit or admission must be used as an opportunity to assess the immunization needs of the child and to offer any pending doses. No gastrointestinal or systemic reactions occur after giving OPV and oral typhoid fever vaccines. Mild diarrhea may occur after feeding rotavirus vaccine. On rare occasions vaccine-associated paralytic polio (VAPP) has been docu mented, either in the vaccinee or in contacts in the vicinity. Its frequency in India appears to be more common than previously thought; adults are not at risk in India, since virtually all the adults are immune due to prior asymptomatic infections. Since hypogammaglobulinemia has been noted as a risk factor for VAPP, the recommendation is to give the non-infectious injectable killed polio vaccine to immuno deficient children and any family members. OPV is usually given to infants born to HIV-infected mothers whether or not themselves HIV-infected without problems. DPT vaccine causes local inflammation and fever in a proportion of vaccines. Paracetamol is advised only after fever develops but not prophylactically, as it may reduce immune response. If any neurological reactions other than febrile convulsions are observed within days after DPT, the infant must be carefully assessed for any pre-existing disease process. There is no evidence that DPT per se causes any neurological illness; in specific instances of difficulty, expert opinion must be obtained and discussed with the family before continuing or discontinuing further doses of DPT. The immunization clinic staff must be trained to recognize vasovagal syncopal attacks and anaphylaxis in vaccinated infants/children. While it is true that rural health workers vaccinate at convenient places in the villages where there are no facilities for resuscitation, the immunization clinic must be equipped to handle such events. Any serious event, not recognized as the usual side reaction of the vaccine, must be reported to the local area health authority. Any illness occurring within a month after vaccination is to be considered adverse event following immunization (AEFI). Serious AEFI include illness with hospitalization, any resulting in chronic disability or death. In UIP, serious AEFI must be reported to the district immunization officer; AEFI following non-UIP vaccines should be reported to the Drugs Controller General.

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The National Immunization Schedule is designed on the five criteria: epidemiological relevance, immunological appropriateness, technical feasibility, economic viability and sociocultural acceptability (Table 5.4.1).

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The National Family Health Survey III (NFHS III), conducted in 2005-2006, showed that there was a marginal improvement of fully immunized children from 42% to 44% nationally. There has been some improvement in comparison to NFHS II conducted in 1998-1999. Improvement from NFHS II to NFHS III in the state of Uttar Pradesh is from 20.2% to 22.9%, Bihar from 11.62% to 32.8%, Jharkhand from 8.8% to 34.5%, and in Rajasthan from 17.3% to 26.5%. However, in some of the good performing states like Tamil Nadu, Maharashtra, Karnataka, Kerala, and Punjab, the coverage of fully immunized children has gone down. T

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The following factors are considered in selection of a vaccination schedule: • Age-specific burden of disease. • Age-specific immunologic response to vaccines. • Potential interference with the immune response by passively transferred maternal antibodies. • Age-specific risks of vaccine-associated complications. • Programmatic feasibility. The basic schedule of 6-10-14 weeks for the primary doses of DTP and polio is followed by some developing countries including India due to high burden of disease from pertussis in very young infants. Most developed countries like US use schedules (2-4-6 months) that start later in infancy and have longer intervals between doses. For killed vaccines such as DPT, Haemophilus influenzae type B (Hib), pneumococcus (PCV) and hepatitis B (HepB) which are administered as early as birth/6 weeks, the first dose acts only as a priming dose while subsequent doses provide an immune response even in presence of maternal antibodies. Booster dose at 18 months is required for sustaining the immunity. As the age of commencement of vaccination advances, the number of doses reduces for some antigens (e.g. two doses at 6–12 months followed by a booster dose and 1–2 doses between 12 months and 23 months for Hib and pneumococcal vaccines). Live vaccines are even more susceptible to maternal antibodies as compared to killed vaccines. However, BCG may be given at birth as the maternal antibodies actually enhance T cell responses. OPV may be given at birth as there are no maternal IgA in the gut to neutralize the virus. Furthermore, measles vaccine if given at the age of 6 months (in an outbreak situation) may work by inducing T cell immunity. The WHO encourages countries to select vaccination schedules that are epidemiologically relevant, immuno logically effective, operationally feasible, and socially acceptable. The EPI against six most common, preventable childhood diseases, viz. diphtheria, pertussis, tetanus, polio, tuberculosis and measles was launched by the WHO in

The National Immunization Schedule is prepared by the Ministry of Health and Family Welfare; it makes vaccines available free of cost and delivered through various central/state government agencies, health workers, and private practitioners. The National Technical Advisory Group on Immunization (NTAGI) is a group of experts from the Government of India, state governments, academic institutions, development partners and professional organizations, who meet on an annual basis to discuss the technical and policy issues pertaining to the program and advice on the introduction of newer vaccines, based on the available disease burden data. Any major immunization decision is first discussed by the NTAGI and the recommendations given are then considered by the Program Division within the Ministry. IAP is also represented through its national president who is an important member of this committee. The vaccines licensing authority in India, i.e. the National Regulatory Authority (NRA) is the Drugs Controller General of India (DCGI) approved by the WHO. N

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Immunization is a powerful tool to help achieve the Millennium Development Goal 4, which calls for a reduction by two-thirds of the under-5 mortality by 2015. Scaling up the delivery and coverage with traditional Expanded Program on Immunization (EPI) vaccines will reduce 13% of child deaths and the introduction of new vaccines will help to prevent further 10% (1.1 million) child deaths that are due to meningococcal, pneumococcal and rotavirus diseases.

1974. The WHO recommendations are usually followed by the national governments who are member states of the United Nations.

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Rationale of election of Vaccines in ational Immunization Program and I P Immunization ime able

The Indian Academy of Pediatrics (IAP) is an independent 177 body which is committed to provide unbiased, rational, ethical, practical yet balanced guidelines to its members on the various issues related to immunization in India. The

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Rationale of ero and ultiple oses of PV Oral polio vaccine (OPV) is recommended at birth, for routine immunization at 6, 10 and 14 weeks, 18–24 months 178 and at 5 years and on all National Immunization Days (NID) and Sub-National Immunization Days (SNID). Data from the composite of Vellore studies in 1970s and 1980s suggest that seroconversion rates after three doses of OPV average 65%,

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Rationale of G at irth Childhood tuberculosis in India is believed to constitute 15–20% of all tuberculosis cases. BCG vaccine is the only effective vaccine available against tuberculosis. BCG has an efficacy of 50–80% for prevention of miliary and meningeal forms of the disease. Protective efficacy for pulmonary tuberculosis is 50%. For programmatic convenience and to capture all those delivered in the institutions or health care facilities, Bacillus Calmette-Guerin (BCG) is advised at birth and the maternal antibodies actually enhance T cell responses.

Rationale behind PV and IPV ombination The Indian Academy of Pediatrics Committee on Immu nization (IAPCOI) also recommends offering additional dose of inactivated polio vaccine (IPV) with oral polio vaccine (OPV) in all children. The recommendation for combined use of OPV and IPV is for the following reasons: • Excellent and highly predictable immunogenicity, efficacy and safety of IPV. The seroconversion rates of IPV are 90–100% after two doses given after the age of 2 months and at 2 months interval or in the EPI schedule of three doses at 6, 10 and 14 weeks and can be used in combination with DTwP/DTaP, Hib and HepB vaccines without compromising seroconversion or increasing side effects. • Better mucosal immunity of OPV and IPV combination schedule as compared to IPV alone. • The incidence of VAPP has been estimated at four cases per million (1/1,000,000) birth cohort per year in countries using OPV. The risk of VAPP with the combined OPV and IPV schedule is extremely low as the child is receiving OPV at the time when he/she is already protected against VAPP by maternal antibodies. Subsequent protection from VAPP is by IPV. Even if we adopt an all IPV schedule, the child may still be at a small risk for VAPP through exposure to the oral polio vaccine virus through contacts or environment before the child receives its first dose of IPV. • OPV and IPV used simultaneously in combination in the trials in Gambia, Oman, Thailand and Pakistan have shown higher levels of seropositivity as compared to all OPV or IPV alone schedules. In the Gaza strip combined IPV-OPV use reduced the incidence of paralytic polio from 10 to less than 2 cases per 100,000 persons in the first 3 years and it further reduced to 0.16 per 100,000 cases in the next 5 years. Furthermore, the concurrent use of OPV may compensate for somewhat inferior seroresponse (particularly against types 1 and 2 serotypes) of IPV when used in accelerated 6, 10, and 14 weeks schedule. Refer Chapter 5.4.1. DT

 

recommendations made by the IAP are the ‘best individual practice schedule’ for a given child, while the National Immunization Schedule of the Government of India is meant for the public at large. Therefore these recommendations go beyond the national immunization program and cater primarily to pediatricians in office practice (Tables 5.4.2 to 5.4.4).

96% and 63% for types I, II and III, respectively. Therefore multiple doses of OPV are necessary before 90–95% of children develop immune responses to all three poliovirus types. The zero dose of OPV is given at birth to initiate early immunization against polio as there are no maternal IgA in the gut, the vaccine virus is not neutralized and the risk of vaccine-associated paralytic poliomyelitis (VAPP) is minimized due to the presence of maternal antibodies. O

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Table 5.4.1 National immunization schedule (UIP Schedule 2009) Age Vaccines Birth BCG, OPV0 (for institutional deliveries) 6 weeks DTwP-1, OPV-1, HepB-1, Hib-1* (BCG if not given at birth) 10 weeks DTwP-2, OPV-2, HepB-2, Hib-2 14 weeks DTwP-3, OPV-3, HepB-3, Hib-3 9–12 months Measles 16–24 months DTwP B-1, OPV-4, MMR** 5–6 years DTwP*** 10 years TT**** 16 years TT**** Pregnant women TT-1 (early in pregnancy) TT-2 (1 month later) TT booster (if vaccinated in past 3 years) Vitamin A 9, 18, 24, 30 and 36 months Abbreviations: BCG, Bacillus Calmette Guerin Vaccine against Tuberculosis; OPV, Oral Polio Vaccine; DTwP, Diphtheria, Tetanus and whole-cell Pertussis vaccine; HepB, Hepatitis B virus vaccine; Hib, Haemophilus influenzae type b vaccine; MMR, Mumps, Measles and Rubella vaccine; TT, Tetanus toxoid. Note: * Haemophilus influenzae type b (Hib) is being introduced in two states to begin with. ** MMR is available in some states only. *** A second dose of Tetanus toxoid (TT) vaccine should be given at an interval of 1 month if there is no clear history or documented evidence of previous immunization with DTwP, Diphtheria tetanus toxoid (DT) or TT vaccines. **** A second dose of TT vaccine should be given at an interval of one month if there is no clear history or documented evidence of previous immunization with DTwP, DT or TT vaccines.

aP

The IAPCOI unequivocally endorses the continued use of diphtheria and tetanus toxoids combined with whole-cell pertussis (DTwP) vaccine in EPI because of its proven efficacy and safety. DT with acellular pertussis (DTaP) vaccine is not more efficacious than DTwP vaccine, but has fewer adverse effects. Serious adverse effects are rare phenomena even with the whole cell vaccine unlike popular belief. The parents should be made aware of these facts and be asked to decide on the choice of the DTP vaccine they wish to immunize their child with. The DTaP vaccines may be preferred to DTwP vaccines in those children with history of

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Table 5.4.2 IAP Immunization Time Table 2012 I. IAP Recommended Vaccines for Routine Use Vaccines

Comments

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Age (completed weeks/months/ years) Birth

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* High-Risk Category of Children •  Congenital or acquired immunodeficiency (including HIV infection) •  Chronic cardiac, pulmonary (including asthma if treated with prolonged high-dose oral corticosteroids), hematologic, renal (including nephrotic syndrome), liver disease and diabetes mellitus •  Children on long term steroids, salicylates, immunosuppressive or radiation therapy •  Diabetes mellitus, cerebrospinal fluid leak, cochlear implant, malignancies •  Children with functional/ anatomic asplenia/hyposplenia •  During disease outbreaks •  Laboratory personnel and healthcare workers

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BCG HepB: Administer HepB vaccine to all newborns before hospital discharge. OPV 0 HepB 1 IPV: Two doses instead of three can be used for primary series if started at 8 and 16 weeks. 6 weeks DTwP 1/DTaP 1 Rotavirus vaccine: Only two doses of RV-1 and three doses of RV-5. IPV 1 HepB 2 Hib 1 Rotavirus 1 PCV 1 Polio: Additional doses of OPV on all NIDs/SNIDs. 10 weeks DTwP 2/DTaP 2 IPV 2 Hib 2 Rotavirus 2 PCV 2 Polio: Additional doses of OPV on all NIDs/SNIDs 14 weeks DTwP 3/DTaP 3 Only two doses of RV1 are needed. IPV 3 Hib 3 Rotavirus 3 PCV 3 6 months OPV 1 HepB: The final (third or fourth) dose in the HepB vaccine series should be administered no earlier than age HepB 3 24 weeks and at least 16 weeks after the first dose. 9 months OPV 2 Measles 12 months HepA 1 15 months MMR 1 Varicella: The risk of breakthrough varicella is lower if given 15 months onwards. Varicella 1 PCV booster 16–18 months DTwP B1/ DTaP B1 The first booster (4th dose) may be administered as early as age 12 months, provided at least 6 months have IPV B1 elapsed since the third dose. Hib B1 18 months HepA 2 HepA: Two doses of both killed and live hepatitis-A vaccines. 2 years Typhoid 1 Typhoid revaccination every 3 years, if Vi-polysaccharide vaccine is used. 5 years DTwP B2/DTaP B2 MMR: The 2nd dose can be given at any time 4–8 weeks after the 1st dose. OPV 3 Varicella: The 2nd dose can be given at any time 3 months after the 1st dose. MMR 2 Varicella 2 Typhoid 2 10–12 years Tdap/Td Tdap: is preferred to Td followed by Td every 10 years. HPV HPV: only for females, three doses at 0, 1–2 (depending on brands) and 6 months. II. IAP Recommended Vaccines for High-Risk* Children (Vaccines under Special Circumstances) •  Influenza vaccine •  Meningococcal vaccine •  Japanese encephalitis vaccine •  Cholera vaccine •  Rabies vaccine •  Yellow fever vaccine •  Pneumococcal polysaccharide vaccine (PPSV 23)

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RV 1

Rotavirus*

10 wk

RV* 3

PCV 3

Hib 3

DTP 3

14 wk

IPV3

18 wk

OPV1

6 mo

OPV2

9 mo

DTP B1 Hib-booster

18 mo

Hep A 1

JE

Cholera 1 and 2

Influenza (yearly)

Varicella 1

MMR 1

PCV -booster

Hep B3

15 mo

 Range of recommended ages for certain high-risk groups

Measles

IPV B1

12 mo

Hep A 2

2-3 Yr

Varicella 2

MMR 2

DTP B2

Meningococcal

Typhoid

PPSV

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1.     2.          

 

 

 

 

 

 

 

 







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BCG vaccine: •  Should be given at birth or at first contact •  Catch up may be given up to 5 years Hepatitis B (HepB) vaccine •  Minimum age: irth •  Administer monovalent HepB vaccine to all newborns before hospital discharge. •  The second dose should be administered at age 4–8 weeks. •  Monovalent HepB vaccine should be used for doses administered before age 6 weeks. •  Administration of a total of 4 doses of HepB vaccine is permissible when a combination vaccine containing HepB is administered after the birth dose. •  Infants who did not receive a birth dose should receive 3 doses of a HepB containing vaccine starting as soon as feasible. •  The ideal minimum interval between dose 1 and dose 2 is 4 weeks, and between dose 2 and 3 is 8 weeks.

 

 

 

 

 

 

 

 

 

 

 

 

 







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•  Ideally, the final (third or fourth) dose in the HepB vaccine series should be administered, no earlier than age 24 weeks and at least 16 weeks after the first dose.   •  Hep B vaccine may also be given in any of the following schedules: Birth, 1 and 6 months, Birth, 6 and 14 weeks; 6, 10 and 14 weeks; Birth, 6 weeks, 10 weeks, 14 weeks, etc. 3. Poliovirus vaccines   •  Additional doses of OPV on all NIDs/SNIDs   •  IPV: Minimum age is 6 weeks   •  IPV: wo doses instead of three can be used for primary series if started at 8 and 16 weeks   •  IPV catch-up schedule: Two doses at 2 months apart followed by a booster after 6 months 4. Diphtheria and tetanus toxoids and pertussis (DTP) vaccine   •  Minimum age: 6 weeks   •  The first booster (4th dose) may be administered as early as age 12 months, provided at least 6 months have elapsed since the third dose.   •  DTwP/DTaP/Tdap/Td: Catch up below 7 years: DTwP/DTaP at 0, 1 and 6 months   •  Catch up above 7 years: Tdap, Td, Td at 0, 1 and 6 months

 

(This schedule includes recommendations in effect as of April 2012. Any dose not administered at the recommended age should be administered at a subsequent visit, when indicated and feasible. The use of a combination vaccine generally is preferred over separate injections of its equivalent component vaccines).

RV 2

PCV 2

Hib 2

DTP 2

IPV2

Hep B2

  Range of recommended ages for all children

JE

Cholera

Meningococcal

Influenza

Typhoid

Hep A

Varicella

MMR

Measles

PCV 1

Pneumococcal

IPV1 Hib 1

OPV0

Polio vaccines

Hib

Hep B1

Hep B DTP 1

BCG

BCG

6 wk

DTP

Birth

Age  Vaccine 

Table 5.4.3 IAP Recommended immunization schedule for children aged 0–6 years, 2012

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•  The second dose may be administered before age 4 years, provided at least 3 months have elapsed since the first dose.   •  For children aged 12 months through 12 years, the recommended minimum interval between doses is 3 months. However, if the second dose was administered at least 4 weeks after the first dose, it can be accepted as valid. 11. Hepatitis A (HepA) vaccine   •  Minimum age: 12 months   •  Two doses of both killed and live HepA vaccines.   •  Administer the second (final) dose 6–18 months after the first. 12. Typhoid vaccine   •  Only Vi-PS (polysaccharide) vaccine is recommended   •  Vi-PS conjugate vaccine: Data not sufficient to recommend for routine use   •  Minimum age: 2 years   •  Revaccination every 3 years. 13. Influenza vaccine   •  Minimum age: 6 months for trivalent inactivated influenza vaccine   •  First time vaccination: 6 months to below 9 years: two doses 1 month apart; 9 years and above single dose; Annual revaccination with single dose.   •  For children aged 6 months to below 9 years: For the 2012 season, administer 2 doses (separated by at least 4 weeks) to those who did not receive at least 1 dose of the 2010-11 vaccine. Those who received at least 1 dose of the 2010-11 vaccine require 1 dose for the 2011-12 season   •  Best time to vaccinate: As soon as the new vaccine is released and available in the market   •  Follow vaccine strain recommendations issued for southern hemisphere 14. Meningococcal vaccine   •  Only meningococcal polysaccharide vaccine (MPSV) is available   •  Minimum age: 2 years   •  Revaccination only once after 3 years in those at continued high-risk 15. Cholera vaccine   •  Minimum age: One year (killed whole cell vibrio cholera (Shanchol)   •  Two doses 2 weeks apart for >1-year-old 16. Japanese encephalitis (JE) vaccine   •  Currently no type of JE vaccine available in private Indian market   •  Cell culture derived SA-14-14-2 vaccine should be preferred   •  Minimum age: 8 months; can be co-administered with measles vaccine at 9 months   •  Catch-up vaccination: All susceptible children up to 15 years should be administered. During disease outbreaks.

 

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5. Haemophilus influenzae type b (Hib) conjugate vaccine   •  Minimum age: 6 weeks   •  Catch up in 6–12 months; 2 doses 1 month apart and 1 booster; 12–15 months: 1 primary and 1 booster; above 15 months single dose. 6. Pneumococcal vaccines   •  Minimum age: 6 weeks for pneumococcal conjugate vaccine (PCV); 2 years for pneumococcal polysaccharide vaccine (PPSV)   •  Administer 1 dose of PCV to all healthy children aged 24 through 59 months who are not completely vaccinated for their age   •  For children who have received an age-appropriate series of 7-valent PCV (PCV7), a single supplemental dose of 13-valent PCV (PCV13) is recommended for: – All children aged 14 through 59 months       – Children aged 60 through 71 months with underlying medical conditions.   •  Administer PPSV at least 8 weeks after last dose of PCV to children aged 2 years or older with certain underlying medical conditions (certain high-risk groups)   •  PCV: Catch up in 6–12 months: 2 doses 1 month apart and 1 booster; 12–23 months: 2 doses 2 months apart   •  PPSV: Revaccination only once after 3–5 years only in certain high-risk patients. 7.  Rotavirus (RV) vaccines*   •  Minimum age: 6 weeks for both RV-1 (Rotarix) and RV-5 (Rota Teq)   •  Only two doses of RV-1 are required.   •  The maximum age for the first dose in the series is 14 weeks, 6 days; and 8 months, 0 days for the final dose in the series.   •  Vaccination should not be initiated for infants aged 15 weeks, 0 days or older. 8. Measles   •  Minimum age: At completed months/270 completed days   •  Catch up vaccination beyond 12 months should be MMR   •  Measles vaccine can be administered to infants aged 6 through 11 months during outbreaks. These children should be revaccinated with 2 doses of measles containing vaccines, the first at ages 12 through 15 months and at least 4 weeks after the previous dose, and the second at ages 4 through 6 years. 9. Measles, mumps, and rubella (MMR) vaccine   •  Minimum age: 12 months   •  The second dose may be administered before age 4 years, provided at least 4 weeks have elapsed since the first dose. 10. Varicella vaccine   •  Minimum age: 12 months   •  The risk of breakthrough varicella is lower if given 15 months onwards.

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Table 5.4.4 IAPCOI recommended immunization schedule for persons aged 7 through 18 years, 2012 Age  Vaccine 

7–10 years

Tdap1

1 dose (if indicated)

HPV

See footnote 2

2

11–12 years

13–18 years 1 dose

1 dose (if indicated)

3 doses

Complete 3-dose series

MMR3

Complete 2-dose series

Varicella4

Complete 2-dose series

Hepatitis B5

Complete 3-dose series

Hepatitis A

Complete 2-dose series

6

Typhoid

1 dose every 3 years

7

One dose every year

Influenza Vaccine

8

Catch-up up to 15 years

Japanese Encephalitis Vaccine

9

See footnote 10

Pneumococcal Vaccine10

2 doses 4–8 weeks apart

Meningococcal Vaccine

11

 

 Range of recommended ages for all children

 Range of recommended ages for catch-up immunization

Range of recommended ages for certain high-risk groups Any dose not administered at the recommended age should be administered at a subsequent visit, when indicated and feasible. The use of a combination vaccine generally is preferred over separate injections of its equivalent component vaccines.

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5. Hepatitis B (HepB) vaccine   •  Administer the 3-dose series to those not previously vaccinated.   •  For those with incomplete vaccination, the recommended minimum interval between dose 1 and dose 2 is 4 weeks, and between dose 2 and 3 is 8 weeks. The final (third or fourth) dose in the HepB vaccine series should be administered at least 16 weeks after the first dose. 6. Hepatitis A (HepA) vaccine   •  Administer 2 doses at least 6 months apart to unvaccinated persons.   •  For catch-up vaccination, prevaccination screening for Hepatitis A antibody is recommended in children older than 10 years as at this age the estimated sero-positive rates exceed 50%.   •  Combination of Hep B and Hep A may be used in 0, 1, 6 schedule. 7.  Typhoid vaccine   •  Only Vi-PS (polysaccharide) vaccine is recommended   •  Vi-PS conjugate vaccine: Data not sufficient to recommend for routine use A minimum interval of 3 years should be observed between 2 doses of typhoid vaccine. 8. Influenza vaccine   •  Administer 1 dose to persons aged 9 years and older   •  For children aged 6 months through 8 years   •  For the 2012 season, administer 2 doses (separated by at least 4 weeks) to those who did not receive at least 1 dose of the 2010–11 vaccine. Those who received at least 1 dose of the 2010–11 vaccine require 1 dose for the 2011–12 season   •  Annual revaccination with single dose   •  Best time to vaccinate: As soon as the new vaccine is released and available in the market   •  Follow vaccine strain recommendations issued for southern hemisphere. 9.  Japanese encephalitis vaccine   •  Only in endemic area as catch-up   •  Currently no type of JE vaccine available in private Indian market   •  Cell culture derived SA-14-14-2 JE vaccine should be preferred.



 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1. Tetanus and diphtheria toxoids and acellular pertussis (Tdap) vaccine   •  Minimum age: 10 years for Boostrix and 11 years for Adacel   •  Persons aged 11 through 18 years who have not received Tdap vaccine should receive a dose followed by tetanus and diphtheria toxoids (Td) booster doses every 10 years thereafter.   •  Tdap vaccine should be substituted for a single dose of Td in the catch-up series for children aged 7 through 10 years.   •  Tdap vaccine can be administered regardless of the interval since the last tetanus and diphtheria toxoid-containing vaccine.   •  Catch-up above 7 years: Tdap, Td, Td at 0, 1 and 6 months.   •  Tdap can also be administered safely to pregnant women. 2. Human papillomavirus (HPV) vaccine   •  HPV4 [Gardasil] and HPV2 [Cervarix]   •  Minimum age: 9 years   •  Either HPV4 (0, 2, 6 months) or HPV2 (0, 1, 6 months) is recommended in a 3-dose series for females aged 11 or 12 years.   •  HPV4 can also be given in a 3-dose series for males aged 11 or 12 years.   •  The vaccine series can be started beginning at age 9 years.   •  Administer the second dose 1 to 2 months after the first dose and the third dose 6 months after the first dose (at least 24 weeks after the first dose). 3. Measles, mumps, and rubella (MMR) vaccine   •  The minimum interval between the 2 doses of MMR vaccine is 4 weeks.   •  One dose if previously vaccinated with one dose. 4. Varicella (VAR) vaccine   •  For persons without evidence of immunity, administer two doses if not previously vaccinated or the second dose if only 1 dose has been administered.   •  For persons aged 7 through 12 years, the recommended minimum interval between doses is 3 months. However, if the second dose was administered at least 4 weeks after the first dose, it can be accepted as valid.   •  For persons aged 13 years and older, the minimum interval between doses is 4 weeks.

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Rationale of Recommendation for Introduction of Hib in IP The IAPCOI recommends offering the Haemophilus influenzae type b (Hib) vaccine to all children. In April 2008, the Hib and Pneumococcal Subcommittee of NTAGI 183 in India reviewed the existing Indian, regional and global data on H. influenzae type b disease epidemiology, vaccine safety, efficacy and cost effectiveness. It concluded that vip.persianss.ir N

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Rationale of easles Vaccine at 9 onths The immunogenicity and efficacy are best when the measles vaccine is administered beyond the age of 12 months. However, in India, a significant proportion of measles cases occur below the age of 12 months. Hence in order to achieve the best balance between early protection and high seroconversion, completed 9 months of age has been recommended as the appropriate age for measles vaccination in India. In case of an outbreak, however, the vaccine can be given to infants as young as completed 6 months. Administration of the vaccine within 2 days of exposure protects and/or modifies the severity of clinical disease. For reducing measles mortality in the country, NTAGI reviewed data on measles epidemiology and case fatality rate, and has recommended the following: • A second dose of measles vaccine should be introduced in the Universal Immunization Program (UIP) at the time of DPT booster dose (at 18 months of age) in states with >80% evaluated coverage with the first dose of measles vaccine. Second dose of measles containing vaccine can be either a combination of measles and rubella (MR as used in the EPI in some states), or measles mumps and rubella (MMR). Haphazard use of MR or MMR may shift the epidemiology of rubella upwards and make the women in childbearing age susceptible for rubella

Rationale of wo oses of R IAPCOI endorses the above NTAGI recommendations. For the purposes of universal immunization, the vaccine should be introduced in those areas where immunization coverage is at least 80% and can be sustained on a long-term basis, failing which an epidemiologic shift and increase in congenital rubella syndrome (CRS) may occur. For this reason MMR vaccine has been introduced in those Indian states where measles coverage is at least 70%. Simultaneously, a system for surveillance for CRS and catch-up immunization for all adolescent girls should also be instituted. For office practice the IAPCOI recommends offering MMR vaccine to all children. This use of MMR in the private sector is unlikely to impact the epidemiology of rubella at present but must be carefully monitored. Two doses are recommended one at the age of 12–15 months and second at school entry (4–6 years) or at any time 8 weeks after the first dose. The second dose of MMR vaccine is to protect children failing to seroconvert against primarily mumps and less commonly against rubella (primary vaccine failures). In a child aged 12 months or older, who has not received measles vaccine, two doses of MMR at 8 weeks interval suffices; monovalent measles vaccine is not required. Catch-up vaccination with two doses of the vaccine should be given to all those not previously immunized (with no upward age limit) and especially to healthcare workers, adolescent girls and students traveling for studies overseas.

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Rationale of dap at 10 ears Tdap is the acronym for the collective vaccine preventing tetanus, diphtheria, and pertussis recommended for adolescents and adults with reduced concentration of diphtheria and pertussis toxoids to prevent adverse effects. There is no data on the incidence of adolescent and adult pertussis in India but is perceived to be significant, especially in those states where childhood immunization coverage is good and reduced natural circulation of pertussis has led to infrequent adolescent boosting. A safe and efficacious vaccine is available. The IAPCOI therefore recommends offering Tdap vaccine instead of Td/TT vaccine in all children and adolescents who can afford to use the vaccine at 10 years.

•

infection during pregnancy resulting in increased incidence of congenital rubella syndrome (CRS). This is the reason why MMR is included in the EPI only in those states where vaccination coverage can be sustained at a high level of 80–85%. Catch-up measles vaccination campaigns should be implemented for children up to age 10 years in states with <80% evaluated coverage with the first dose of measles vaccine and that detailed action plans for the Supplementary Immunization Activity (SIA) should be finalized immediately in states with low coverage and high measles mortality burden. T

severe adverse effects following DTwP vaccines or children with neurologic disorders, if resources permit. The schedule is same as with DTwP vaccines. Like DTwP vaccines, DTaP vaccines must not be used in children 7 years or older because of increased reactogenicity. All licensed DTaP vaccines are of similar efficacy and safety as of currently available data and any one of them may be used.

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•  A single re-vaccination (with PPSV) should be administered after 5 years to children with anatomic/functional asplenia or an immunocompromising condition. 11. Meningococcal vaccine   •  Only meningococcal polysaccharide vaccine (MPSV) is available   •  Minimum age: 2 years   •  Recommended only for certain high-risk group of children, during outbreaks, travelers to endemic areas, and students going for study abroad   •  Revaccination only once after 3 years in those at continued high-risk.  

 

 







 

 

 

 

10. Pneumococcal vaccine   •  Pneumococcal conjugate vaccine (PCV) and pneumococcal polysaccharide vaccine (PPSV) both are used in certain high-risk group of children.   •  A single dose of PCV may be administered to children aged 6 through 18 years who have anatomic/functional asplenia, HIV infection or other immunocompromising condition, cochlear implant, or cerebral spinal fluid leak.   •  Administer PPSV at least 8 weeks after the last dose of PCV to children aged 2 years or older with certain underlying medical conditions, including a cochlear implant.

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The varicella vaccines are licensed for age 12 months and above. However the risk of breakthrough varicella is lower if given 15 months onwards. Hence the IAPCOI recommends administration of varicella vaccine in children aged 15 months or older. After a single dose of varicella vaccine, approximately 15% of vaccinees remain at risk of developing a breakthrough varicella disease. These varicella infections in immunized population may raise concern regarding vaccine efficacy and a misunderstanding by physicians or parents who may lose faith in vaccination. Because immunized children who experience breakthrough disease are coinfected with both wild and vaccine strains of varicella virus, they may be at increased risk of zoster from the reactivated wild-type strain later in life, compared with vaccine recipients who do not experience breakthrough disease. Two doses of varicella vaccine offer superior individual protection as compared to a single dose. The risk of breakthrough disease is 3.3 fold less when two doses are administered. The IAPCOI now recommends two doses of varicella vaccine for children of all age groups. For primary immunization, the first dose should be given at the age of 15 months and the second dose at 4–6 years. However the immune response to the vaccine when given at 3 months interval is same as that when given at a longer interval of 4–6 years. M

A

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Rationale of irst ose of Hepatitis and wo oses of Hepatitis T

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Rationale of Recommendation of yphoid Vaccine in IP The public health burden of enteric fever in India is huge. Improvements in hygiene and sanitation are still a distant dream. The Vi polysaccharide vaccine has been demonstrated to have reasonable efficacy in the Indian setting and is available. The IAPCOI therefore recommends the immediate inclusion of the Vi polysaccharide vaccines in the national immunization schedule. Cost effectiveness studies demonstrate that administration of a single dose of the polysaccharide vaccine in the age group of 2–15 years will be highly cost-effective. For office practice, the IAPCOI recommends the administration of the currently available Vi polysaccharide vaccine 0.5 ml IM every three years beginning at the age of 2 years. A child with history of suspected/confirmed 184 enteric fever may be vaccinated 4 weeks after recovery if there is no history of vaccine administration in the past 3 years. The available typhoid vaccine is a polysaccharide

Rationale of wo oses for Varicella Vaccine





Rationale of the Hepatitis Vaccine chedule Immunologically 0-1-6 month’s schedule of hepatitis B immunization has been most widely used and proven to be ideal with high antibody titers at the end of the vaccination. However hepatitis B vaccine is a T-cell dependent vaccine and the titers at the end of immunization schedule may not be important so far as it is well above the protective level. There would occur anamnestic response with the titers going up, should there occur contact with the virus again in future. Also now that hepatitis B vaccination is integrated into the existing immunization program in India, due to operational issues at a national level one has to piggy back on the available contacts for routine immunization, i.e. DTP which is given at 6, 10 and 14 weeks of age. At the same time, birth dose has to be given to cover for the vertical route. Hence IAPCOI recommends 0-6-14 weeks schedule for public health. In case birth dose has been missed, 6–10–14 weeks schedule can be followed. In office practice, one can still use 0 to 4/6weeks to 6 months schedule. As of now, from the data available, none of the above schedules needs a booster.

and hence, unlike a protein antigen, is not capable of inducing T cell dependent immune response and cannot be used below the age of 2 years. The immunity wanes over 3 years due to the lack of T cell dependent memory response with the polysaccharide antigen. However the phenomenon of hyporesponsiveness following repeated doses of a polysaccharide antigen is not observed with the typhoid polysaccharide antigen and hence revaccination is recommended every 3 years starting at 2 years of age.

All hepatitis A vaccines are licensed for use in children aged 1 year or older. In its earlier publications, the committee had recommended initiation of hepatitis A vaccination at the age of 18 months, so that interference with maternal antibodies is minimized. However new data suggests decline in the adult seropositivity rates especially in those belonging to the high socioeconomic status. Consequently babies may be born with no maternal antibodies. Immunogenicity studies also show that antibody titers achieved with vaccination at 12 months are comparable to those achieved at 18 months to 2 years. In light of these facts, the committee now recommends initiating hepatitis A vaccine at the age of 12 months. For catch-up vaccination, pre-vaccination screening for hepatitis A antibody is recommended in children older than 10 years as at this age the estimated seropositive rates exceed 50%. Two doses of hepatitis A vaccine at 6 months apart are recommended. The manufacturers of the live attenuated vaccine claim that a single dose is sufficient for long term

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the disease burden of Hib is sufficiently high in India to warrant prevention by vaccination, the vaccine is safe and efficacious. It strongly recommended its immediate introduction in India’s UIP. The decision of Government of India (GoI) to introduce Hib vaccine in EPI in a phased manner was challenged in the court of laws in a public interest litigation (PIL) on the grounds that India does not have significant Hib disease burden to warrant use of Hib vaccine in the EPI. However, after hearing the NTAGI’s stand on the issue, initially the GoI chose 10 districts for the pilot project but subsequently introduction of Hib vaccine in combo formulation ‘Pentavac’ will be in two states to begin with and gradually use it in the remaining states before the National roll out. Since a protein conjugate polysaccharide vaccine is available to prevent Hib disease, it can be given as early as 6 weeks of life along with the DTP. A combination vaccine with DTP and/or hepatitis B further would help improve the compliance. A booster dose at 15–18 months is a must to maintain the protective antibody titer at the required level.

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Streptococcus pneumoniae is responsible for 15–50% of all episodes of community acquired pneumonia, 30–50% of all cases of acute otitis media and a significant proportion of bacterial meningitis and bacteremia. It is estimated that 50% of the 2 million deaths due to pneumonia globally every year are attributable to S. pneumoniae. According to a recent publication, seven serotypes (1, 5, 6A, 6B, 14, 19F, and 23F) were the most common globally. WHO in 2007 recommended pneumococcal conjugate vaccine (PCV) in the NIP of any country with under-five mortality rate (U5MR) of more than 50/1000 live births or absolute child deaths of >50,000 per year. With U5MR of 72/1000 live birth and nearly 2 million under-five deaths per year, India merits to include PCV in NIP with high priority. Following three priming doses of PCV at 6, 10 and 14 weeks, it is important to give a single booster dose between

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Infection with human papilloma virus (HPV) is the obligatory cause of cervical cancer. In India, high-risk HPV types were found in 97% of cervical cancers. Types 16 and 18 account for 70% of the cases of invasive cervical cancer, globally. A meta-analysis of HPV type distribution from India showed that in invasive cervical carcinoma (ICC), HPV16 was the predominant type (64.8%), followed by HPV18, 45, 33, 35, 58, 59 and 31. The estimated HPV 16/18 positive fraction was 78.9% in women with ICC (87.7% in North and 77.2% in South India), 61.5% with high squamous intra-epithelial lesion, 30.8% with low squamous intra-epithelial lesion and 3.9% in women with normal cytology/histology. It is estimated that HPV16/18 vaccines will provide over 75% protection against ICC in South Asia. Oncogenic HPV serotypes have also been implicated in causation of anal, vulvar, vaginal, penile and oropharyngeal cancers. Additionally, non-oncogenic HPV serotypes 6 and 11 are responsible for more than 90% of anogenital warts and most recurrent respiratory papillomatosis. Clinical trials of the two HPV vaccines conducted in India prior to licensure, demonstrated high immunogenicity and a good safety profile, confirming the findings reported in other countries. These have been approved by the Drug Controller General of India (DCGI) for general use. The IAPCOI recommends offering HPV vaccine to all women in the above mentioned schedule. Since protection is seen only when the vaccine is given before infection with HPV, the vaccine should preferably be given prior to sexual debut. The vaccine should preferably be introduced to parents as a cervical cancer preventing vaccine and not as a vaccine against a sexually transmitted infection (STI). Though HPV vaccines are of public health importance, cervical cancer prevention is not a public health priority and the programmatic feasibility and economic sustainability need to be given due consideration before including the 185 HPV vaccine in NIP.

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Diarrhea is the second leading cause of deaths in under-five children. About 25–40% of hospitalized diarrhea is caused by rotavirus. In India alone, rotavirus causes more than 120,000 deaths annually; 450,000 hospitalizations; 5 million clinic visits and 25 million diarrheal episodes in under-five children. A study from India showed that the rotavirus detection rates were greatest among children aged 6–23 months, and 13.3% of rotavirus infections involved children aged <6 months. The study also documents the early incidence of rotavirus disease in India. The most common types of strains were G2P[4] (25.7% of strains), G1P[8] (22.1%), and G9P[8] (8.5%); G12 strains were seen in combination with types P[4], P[6], and P[8] and together comprised 6.5% of strains. Human monovalent live vaccine and bovine human pentavalent live vaccine are now available in India and administered orally in a two- or three-dose schedule. Both the vaccines have demonstrated, though less as compared to the developed nations, acceptable efficacy and significant impact on reduction in rotavirus diarrhea episodes in developing countries of Africa and Asia. The IAPCOI acknowledges the morbidity and mortality burden of rotavirus and need for a rotavirus vaccine. Such a vaccine would be most needed in the National Immunization Program (NIP) as the disease consequences are the most serious in the underprivileged. Given the minimal impact that water and sanitation measures have had on the burden of rotavirus in developing areas, there is wide agreement that effective vaccination represents the most promising prevention strategy against the disease.

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12 months and 15 months to maintain the antibody titers above the minimum required for protection against the invasive pneumococcal disease. Generally PCV is not recommended routinely in a healthy child above 2 years, as most of the invasive pneumococcal disease is seen below the age of 2 years. There is another type of pneumococcal vaccine, the nonconjugate polysaccharide pneumococcal vaccine (PPSV) which is recommended for the high-risk group (HRG) children in addition to routine PCV doses. Since PPSV does not elicit a good immune response below the age of 2 years it is not recommended for children below 2 years of age for routine immunization. PPSV is reserved for the high risk group children above 2 years in addition to routine PCV vaccination. Because of the hyporesponsiveness phenomenon associated with repeated doses of the polysaccharide vaccines, not more than two doses are recommended at any time in life and the vaccine is recommended for use only in children at risk for pneumococcal disease.

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protection. Since controlled studies from China demonstrate superiority of two dose schedule vs. single dose schedule and since long term serologic data from India with single dose of the live vaccine is still not available, the IAPCOI recommends two doses of even the live attenuated vaccine.

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In India, Japanese encephalitis (JE) is believed to be responsible for approximately 2,000-3,000 clinical cases and 500–600 deaths every year. Highly endemic states include West Bengal, Bihar, Karnataka, Tamil Nadu, Andhra Pradesh, Assam, Uttar Pradesh, Manipur, and Goa. IAPCOI recommends that the government should implement universal immunization with this vaccine in all children in JE endemic states. The SA-14-14-2 vaccine appears best suited for this purpose. A recent study from Philippines showed acceptable efficacy and safety of this vaccine when co-administered with the measles vaccine at 9 months. Along with all infants, all susceptible children up to the age of 15 years should be administered catch-up vaccination. C

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Rabies Vaccine Rabies is a fatal disease and vaccination is the only effective tool to reduce the burden. The currently available vaccines are the modern tissue culture vaccines (MTCV) and include purified chick embryo cell (PCEC) vaccine, human diploid cell vaccine (HDCV), purified Vero cell rabies vaccine (PVRV) and purified duck embryo vaccine (PDEV). Rabies vaccine is recommended as post-prophylaxis in any significant contact with a warm blooded animal and as pre-prophylaxis in those with high-risk of rabies exposure.



Cholera cases are reported from almost all states, the predominant strain being Vibrio cholerae 01, and V. cholerae O139 is an emerging strain. The variant WC-rBS vaccine first developed and licensed in Vietnam comprises only of killed whole cell V. cholerae O1 (classical and El Tor) and V. cholerae O139. This inexpensive oral vaccine without buffer and cold chain requirements administered as two doses 2 weeks apart has been demonstrated to have 50% efficacy for up to 3 years after vaccination. This vaccine is now manufactured and licensed in India for children above the age of 1 year. The inclusion of new killed whole cell oral cholera vaccine in the national immunization schedule is being considered by the policy makers in those areas where cholera is highly endemic, particularly the states of West Bengal and Orissa. For office practice purposes, the cholera vaccine remains a vaccine to be used in special circumstances. These include travel to or residence in a highly endemic area and circumstances where there is risk of an outbreak such as during pilgrimages like Kumbh Mela, etc. Protection starts 2 weeks after receipt of the second dose.

In a comprehensive study of epidemiology of meningococcal disease in India, prevalence of meningitis was 1.5–3.3% of all acute hospital admissions in children. Contribution of meningococcus to this is just 1.9%. Unconjugated meningococcal polysaccharide vaccine (MPSV) is either bivalent (A and C) or quadrivalent (A, C, Y, and W135) and contain 50 μg of each of the individual polysaccharides, available in lyophilized form, reconstituted with sterile water and stored at 2–8°C. These ‘T cell independent’ vaccines do not induce immunological memory, and the response in children younger than 2 years is poor; hence these are indicated for adults and children older than 2 years (only under special circumstances in children 3 months to 2 years of age). The conjugate vaccines are preferred but currently unavailable in India. At present only the quadrivalent and bivalent polysaccharide vaccines are available.

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1. Bhatla N, Lal N, Bao YP, et al. A meta-analysis of human papillomavirus type-distribution in women from South Asia: implications for vaccination. Vaccine. 2008;26(23):2811-7. 2. Hadler SC, Dietz V, Okwo-Bele JM, et al. Immunization in developing countries. In: Plotkin SA, Orenstein WA (Eds). Vaccines, 5th edition. Philadelphia: Saunders; 2008. pp. 467-517.

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Till the 2009 pandemic, data on morbidity and mortality of influenza in India was very limited. A handful of studies showed that influenza contributed to 5–10% of all acute respiratory tract infections (ARI). The course of influenza is mild and self-limited. However serious complications leading to morbidity and death occur, especially in those with underlying chronic illnesses. The H1N1 2009 virus caused deaths in young children, adolescents and nearly 25–30% of the deaths occurred in those without any underlying risk factors. In the current scenario wherein we are in the postpandemic phase, the IAPCOI recommends using the influenza vaccine in all children with risk factors and also wherein the vaccine is desired/requested by parents (discussing with them the benefits and limitations of the vaccine).

There are several factors that determine introduction of a new vaccine in NIP for public use that include burden of disease, cost-effectiveness of a vaccination program, suitability of vaccine product available in the world market, safety and efficacy of the vaccine and programmatic issues. Although inclusion of a new vaccine in national schedule adds the cost of vaccine and logistics to the health budget of a country, it also results in savings by reduction of the disease burden. Still, the decision to include a new vaccine in national schedule is not straight-forward as there are numerous issues in prioritizing investments of a NIP. These issues need to be tackled systematically, providing best possible immunization schedule as per the needs and resources of the country.



Influenza Vaccine

Introduction of a ew Vaccine in ational Immunization Program

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8. Sinclair D, Preziosi MP, John TJ, et al. The epidemiology of meningococcal disease in India. Tropical Medicine and International Health. 2010;15(12):1421-35. 9. UNICEF/WHO. Pneumonia: The forgotten killer of children, 2006, Available from URL: http://whqlibdoc.who.int/ publications/2006/9280640489_eng.pdf 10. World Health Organization: 2005 Global Immunization data, Geneva, Switzerland, World Health Organization, 2006. Available at 11. http://www.who.int/immunization_monitoring/data/ SlidesGlobalImmunization.pdf 12. World Health Organization. Pneumococcal Conjugate Vaccine for Childhood Immunization: WHO Position Paper. Wkly Epidemiol Rev. 2007;82:93-104. 13. Yewale V, Choudhury P, Thacker N. In: IAP Guide Book on Immunization 2011. Available at http://www.indg.in/ health/child-health/IAP %20GUIDE %20BOOK %20ON %20 IMMUNIZATION %202009-2011.pdf.

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3. Johnson HL, Deloria-Knoll M, Levine OS, et al. Systematic evaluation of serotypes causing invasive pneumococcal disease among children under five: the pneumococcal global serotype project. PLoS Med. 2010;7(10). pii: e1000348. 4. Kang G, Arora R, Chitambar SD, et al. Indian Rotavirus Strain Surveillance Network. Multicenter, hospital-based surveillance of rotavirus disease and strains among Indian children aged <5 years. J Infect Dis. 2009;200(Suppl 1):S147-53. 5. Mathur P, Arora NK. Epidemiological transition of hepatitis A in India: issues for vaccination in developing countries. Indian J Med Res. 2008;128(6):699-704. 6. Pradhan SK. Time to revamp the universal immunization program in India. Indian Journal of Public Health. 2010;54(2):71-4. 7. Sharma V, Verma PK, Gupta S, et al. Mortality from Influenza A/H1N1 in a tertiary care teaching institution in North India. J Infect Dev Countries. 2010;4(8):468-71.

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Polio nd Game: Global and National Perspective K Surendran Migration of people is a major risk factor for spread of polio virus transmission, both globally and nationally. The last global WPV type II occurred in October, 1999 in India. Continued use of OPV at global level poses two known risks, viz. • Vaccine derived polio virus (VDPV) • Vaccine associated paralytic poliomyelitis (VAPP)

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Smallpox was successfully eradicated and certified in 1980. Subsequent to this historical success, the 41st World Health Assembly (WHA), in May 1988, passed a resolution calling for the Global Polio Eradication by the year 2000. Tremendous progress has been made since then. There were 125 countries endemic for polio in 1988 which had been reduced to three endemic countries, viz. Pakistan, Afghanistan and Nigeria. It was estimated that nearly 3,50,000 children were crippled due to polio in the year 1988. Currently, there are 213 wild polio virus (WPV) cases globally (as on 11th Dec, 2012). Of these, 191 were P1 serotype cases and 22 were P3 serotype cases reported from four countries. Global Polio Eradication Initiatives (GPEI) envisaged the following strategies: • At least 90% routine immunization (RI) coverage • Mass campaign (NID and SNID) • Acute flaccid paralysis (AFP) surveillance • Mop-up immunization response



Figure 5.4.1.1.1 633 circulating vaccine-derived polioviruses, (2000-2012) 19 countries, 24 oubreaks data as of 11th Dec. 2012 (Source: WHO HQ)  

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During the period 2000–2012, there were 24 outbreaks of circulating VDPV (cVDPV) occurring in 19 countries with 633 cases (as on 11th Dec, 2012) (Fig. 5.4.1.1.1). The other polio eradication challenges will include: • Maintaining population immunity • Sustaining AFP surveillance • Readiness to respond to importation • Minimizing risk. WHO Executive Board passed resolution in January, 2012 endorsing eventual replacement of trivalent oral polio vaccine (tOPV) with bivalent oral polio vaccine (bOPV) globally and member states should start preparing

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Government of India (GOI) initiated mass oral polio vaccine (OPV) campaign popularly called Pulse Polio Immunization (PPI) program during 1995-1996 targeting children in the age group 0–3 years. Subsequently, the target age group was revised to include 0–5 years in the year 1996–1997 onwards. WHO in collaboration with GOI had initiated National Polio Surveillance Project (NPSP) in 1997 with network of Surveillance Medical Officers (SMOs) to establish and strengthen AFP surveillance system across the country. This syndromic AFP surveillance enabled to map WPV transmission accurately. India Expert Advisory Group (IEAG) on poliomyelitis comprising both National and International experts periodically review polio data. IEAG recommends on strategies for stopping polio transmission and polio certification process including NIDs and SNIDs for the country. It was estimated that approximately 2,00,000 paralytic poliomyelitis cases occurred before OPV introduction in RI during 1978 (Fig. 5.4.1.2.1)

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Figure 5.4.1.2.1 History of polio in India 1978-2012 (14th Dec. 2012)

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Based on evident information, Monovalent OPV Type-I (mOPV1) elicited better immune response than trivalent Oral-Polio Vaccine (tOPV). mOPV1 was introduced in India during April, 2005 to control polio transmission. Subsequently, mOPV3 was introduced to improve serotype specific herd immunity in P3 serotype transmission areas. bOPV was introduced in selected states in India during the year 2010. Migration of people was identified as one of the major risk factors for polio virus spread. GOI in collaboration with WHO-NPSP initiated Migrant Sites and High Risk Areas (HRAs) with settled population mapping since December, 2008. These low population immunity areas were targeted during supplementary immunization activities (SIAs). Hard to reach Kosi riverine areas and 107 high risk blocks in Uttar Pradesh and Bihar were identified and targeted for quality SIA coverage. After aggressive initiation of polio eradication strategies, polio incidence dramatically declined over the years 1995–2011. Environmental surveillance for polio is carried out through sewage sampling in Mumbai since 2001. This supplementary surveillance was expanded to New Delhi, Patna and Kolkata and is under expansion to other major cities.

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appropriate policies, potentially as early as April, 2014. Cessation of bOPV use globally is planned during 2017– 2018.

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of Inactivated Polio Vaccine (IPV) to boost population immunity prior to tOPV-bOPV switch to minimize risk of type 2 cVDPV emergence. In India, the evaluated routine immunization coverage (Central Evaluation Survey: CES 2009) showed that only 61% were fully immunized against all six vaccinepreventable diseases. Sustaining high levels of population immunity against polio is critical to prevent emergence of cVDPV. India expert advisory group (IEAG) had proposed the following polio end-game actions in India (Fig. 5.4.1.2.3): • To sustain certification standard AFP surveillance • High routine immunization coverage • tOPV to bOPV switch in early 2014 • Introduction of IPV in late 2013 • Two rounds of tOPV NIDs will be conducted during 2013 and 2014.



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Any wild polio virus (in a case or in the environment) from any source will be considered a public health emergency and responded to with urgent mop-ups. All states in India have developed Emergency Preparedness and Response Plan (EPRP) for polio virus importation. Aggressive and emergency mop-up immunization response will target 3–5 million children of 0–5 years age group. The immunization Response will be carried out within 10 days of wild polio virus case confirmation. India reported the last wild polio type I case in Howrah (West Bengal) on 13/01/2011 (onset of paralysis). During the Polio Summit (25–26 February, 2012) in New Delhi, WHO declared that India is no longer Polio endemic country. This was a remarkable success of India’s polio eradication initiative. India had reported VDPV cases during the year 2010 (5 cases), 2011 (7 cases) 2012 (1 case) respectively (Fig. 5.4.1.2.2). IEAG in March, 2012 recommended for 1 dose

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Figure 5.4.1.2.2 Location of wild poliovirus and VDPV cases by type, India (Source: GOI-WHO [NPSP]  

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focused hard work were critical for the phenomenal polio eradication success in India.

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Polio eradication in India was accomplished by sheer professionalism involving all categories of staff of Government, Volunteers of Private sector and International Service Organizations, viz. WHO, UNICEF, CDC, Rotary International and Professional Organizations like Indian Academy of Pediatrics (IAP), Indian Medical Association (IMA), etc. The most geographically inaccessible terrains were reached by the committed polio vaccination team particularly in Bihar and UP. Special micro-plans were evolved for these hard-to-reach areas and implementation was closely monitored. The intelligent strategy of replacing tOPV by mOPV and bOPV 1 and 3 in SNID and mop-ups had succeeded in interrupting polio transmission in India. Routine immunization was strengthened in all poor coverage states. The quality AFP surveillance system with timely polio laboratory results was guiding India’s polio eradication efforts. All the above factors coupled with

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Comprehensive polio end-game strategy will involve the following: • tOPV to bOPV switch • Eventual cessation OPV use • Introduction of IPV in all countries • Sustaining high levels of herd immunity and AFP surveillance • High RI coverage with focus on migrant sites and HRAs • Protect population against WPV and circulating VDPV • Immunization of travelers at border areas during SIA and RI The South East Asian Region (SEAR) of WHO is on right track towards polio free certification by early 2014.

 

Figure 5.4.1.2.3 Polio endgame strategy-India, potential timeline (Source: IEAG March, 2012)

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The immunization coverage has seen an improvement over the years. However, there is further need for improvement especially in DPT3 and OPV3 coverage and reducing drop outs (refer to chapter 5.6). To strengthen routine immunization, some newer initiatives have been introduced as part of the State Program Implementation Plan (PIP). These initiatives are provision of auto-disable (AD) syringe to ensure injection safety; support for alternate vaccine delivery from primary health center (PHC) to sub-centers and outreach sessions; provision for deploying additional manpower to carry out immunization activities in urban slums and under-served areas where services are deficient; and support for mobilization of children to immunization session sites by Accredited Social Health Activist (ASHA), Women Self Help Groups, etc. The NTAGI has made the following recommendations subsequent to introduction of new vaccines like hepatitis B since 2002-2003: 1. Introduction of at birth dose of hepatitis B vaccine. 2. Introduction of 2nd dose for measles at 15–18 months of age. 3. Introduction of DTwP-HB-Hib vaccine—a combination of diphtheria and tetanus toxoids, whole cell pertussis vaccine, and vaccines against hepatitis and Haemophilus influenzae type b—(Penta-combo-vaccine, Pentavac) in pilot project areas of the country where the routine DTwP coverage is more than 85%. 4. Initially 10 such states were selected for Pentavac introduction and the Union Cabinet nod was also obtained. Due to logistic reasons, currently the Pentavac introduction is restricted to the states of Kerala and Tamil Nadu from October 2011, which strategy will be expanded to the other eight states in a phased manner aiming at national roll out in future. 5. The second DTwP booster at 5 years in place of DT vaccine. 6. NTAGI has also discussed and recommended in principle the introduction of pneumococcal conjugate vaccine (PCV), rotavirus and human papilloma virus (HPV) vaccines in the NIP with aid from Global Alliance for Vaccines and Immunization (GAVI) in future in a phased manner. However the recommendations and strategies on polio vaccines are exclusively made by Indian Advisory Group on

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Delivering effective and safe vaccines through an efficient system is one of the most cost-effective public health interventions. Immunization programs aim to reduce mortality and morbidity due to vaccine preventable diseases (VPDs), particularly for children. Following the WHO recommendation, India introduced six vaccines under the Expanded Program on Immunization (EPI) in 1978 to reduce child mortality. These included Bacillus Calmette-Guerin (BCG), tetanus toxoid (TT), diphtheriapertussis-tetanus vaccine (DPT), diphtheria-tetanus vaccine (DT), poliomyelitis, and typhoid vaccines. Subsequently, in 1985 the Government of India included measles vaccine in the National Immunization Schedule (NIS) and launched the Universal Immunization Program (UIP) and the National Technology Mission on Immunization to achieve more than 85% immunization coverage of all infants and pregnant women by the year 1990. India’s immunization program is one of the largest in the world in terms of quantities of vaccines used, numbers of beneficiaries, number of immunization sessions organized and the geographical area covered. In India, in the NIP, since 1985, the target populations are infants under 1 year of age and pregnant women. Infants receive vaccines against six killer diseases, viz. tuberculosis, poliomyelitis, diphtheria, pertussis, tetanus and measles; and pregnant women and the newborn are protected with tetanus toxoid, respectively. The National Technical Advisory Group on Immunization (NTAGI) recommends from time to time on issues like addition of newer vaccines and allied issues in the NIP. Since 1997, the single disease surveillance viz. acute flaccid paralysis (AFP) surveillance as part of Indian Polio Eradication Initiative (IPEI) by National Polio Surveillance Project (NPSP) has been carried out to find the impact of Pulse Polio Immunization (PPI) on polio eradication. The Indian Experts Advisory Group (IEAG) in collaboration with NPSP makes recommendations on the strategies for Pulse Polio Immunization through National Immunization Days (NIDS) and Sub-National Immunization Days (SNIDs) in polio hyperendemic regions and for the whole country during PPI. Subsequently since 2001–2002, the Integrated Disease Surveillance Project (IDSP) has also been introduced to focus attention on vaccine preventable diseases (VPDs) and other notifiable infectious diseases from remote reporting sites, private health facilities and the sentinel centers throughout the country in the specially designed ‘reporting format’ to enable the Government of India to make evidence based, recommendations on introduction of newer vaccines based on epidemiological data available.

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Thus UIP in India and the IPEI have achieved remarkable success in eliminating the 6 killer diseases which were targeted in 1985 with the launch of UIP. However reemergence of vaccine preventable diseases (VPDs) like diphtheria and pertussis in certain regions of the country is causing concern. There is re-emergence of certain eliminated VPDs and NTAGI is looking forward strengthening the UIP coverage of routine vaccines and to the introduction of newer vaccines in the NIP with aid from Global Alliance for Vaccines and Immunization (GAVI) funded and supported by Melinda and Gates Foundation, USAID, Rockefeller Foundation, Global vaccine manufacturers, etc. The laudable objective of GAVI—“ALL vaccines for ALL children of the world”—will be the future achievement of the Global Immunization Program which will become a reality rather than a dream ensuing equity of the affluent as well as the downtrodden children and pregnant women of the international society.

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1. Annual Report of the Ministry of Health and family Welfare, Govt. of India, PDF file http://mohfw.nic.in/showfile. php?lid=767 2. http://india.gov.in/citizen/health/immunization.php 3. Immunization Schedules, individual Vaccines In: IAP Guide book on Immunization 2011; Yewale V, Choudhury P, Thacker N; Mumbai (Eds); Indian Academy of Pediatrics; 2011.pp. 47-50. 4. National Polio Surveillance Project www.npsp.com 5. www.polio eradication .org.



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Japanese B encephalitis (JE) vaccination was started in 2006 in a campaign approach in JE hyper-endemic areas to cover 109 endemic districts in phased manner, using SA 14-14-2 vaccine, imported from China. Single dose of JE vaccine was given to all children between 1 year and 15 years of age through campaigns followed by one dose at 16–24 months under routine immunization to cover the newer cohort. By the end of 2009-2010, 90 districts have

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Measles immunization directly contributes to the reduction of under-five child mortality and hence to the achievement of Millennium Development Goal number 4. In order to accelerate the reduction of measles related morbidity and mortality, second opportunity for measles vaccination is being implemented. The NTAGI has recommended the introduction of another dose of measles vaccine through Measles Supplementary Immunization Activity (SIA) for states where evaluated coverage for measles vaccine is less than 80%. For the remaining states where coverage is more than 80%, NTAGI recommended a second dose through routine immunization. The 14 states with measles coverage of less than or equal to 80%, viz. Arunachal Pradesh, Assam, Bihar, Chhattisgarh, Gujarat, Haryana, Jharkhand, Madhya Pradesh, Manipur, Meghalaya, Nagaland, Rajasthan, Tripura and Uttar Pradesh are being covered through, in a phased manner followed by introduction of second dose at 16–24 months in routine immunization.

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Hepatitis B vaccination was introduced in UIP in the financial year 2002-2003 as a pilot in 33 districts and 15 cities and was further expanded to all the districts of 10 states namely Andhra Pradesh, Himachal Pradesh, Jammu and Kashmir, Karnataka, Kerala, Madhya Pradesh, Maharashtra, Punjab, Tamil Nadu and West Bengal. Following the recommendation of NTAGI, it has been decided to provide hepatitis B vaccination all over the country.

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been covered under the JE vaccination program; and remaining 19 districts are being covered in 2010-2011. In addition, in 2010-2011 re-campaign has been planned in 9 districts; 7 in Uttar Pradesh and 2 in Assam, in view of their low coverage as per the coverage evaluation survey conducted in 2008. The JE vaccine is being integrated into routine immunization in the districts where campaign had already been conducted to immunize the new cohort of children by vaccinating with single doses at 16–24 months.

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same as DPT at 6, 10, and 14 weeks with a booster at 15–18 months. After 6 months, two doses are required. Single dose is required after 2 years. PCV7 has been replaced by PCV13.

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Vaccines are included in the immunization schedule of a country based on the WHO recommendations which takes into consideration the epidemiology, cost effectiveness and availability of the vaccines in that country. In the last decade, several new vaccines have been developed and are available in India apart from the basic vaccines included in the National Immunization Schedule (NIS) under Universal Immunization Program (UIP). Indian Academy of Pediatrics Committee on Immunization (IAPCOI) periodically reviews the need for these vaccines and recommends their use. Physician should be able to counsel the parents regarding the efficacy and importance of these vaccines in the present health situation. This chapter includes a brief description of these vaccines. In fact, almost all these vaccines are included in the Expanded Program on Immunization (EPI) national schedules of several developed countries. In India too, almost all these vaccines find a place in the IAP Immunization Time Table 2011 for routine use.

13-Valent Conjugate Pneumococcal Vaccine (PCV13) A 13-valent conjugate vaccine is now available which covers about 70% of strains worldwide and India. It has 1, 5, 7F, 3, 6A and 19A in addition to the 7-valent vaccine. Schedule of immunization is the same. This is recommended over the 7-valent vaccine as it has better serotype coverage. Routine use is not recommended in children above 5 years. Details of the schedule to be followed in various ages and situations should be as per recommendation of Indian Academy of Pediatrics (IAP) and American Academy of Pediatrics (AAP).

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Immunity following primary/booster DTP/DTaP vaccination wanes over 5–10 years. Standard strength DTP and DTaP vaccines cannot be used in children above 7 years due to increased reactogenicity. Tdap vaccine contains lower doses of diphtheria and acellular pertussis components; hence can be used in children above 7 years. Systemic side effects are rarely seen. A dose of this vaccine can be given at 10–11 years of age. A single dose is recommended after 7 years if the child has not received vaccine before. This vaccine is now routinely recommended as a single booster to be followed by boosters of Td vaccine at intervals of 10 years by the IAPCOI in view of re-emerging pertussis and diphtheria in certain regions of the country.

Typhoid Vaccine



A 23-valent non-conjugate capsular polysaccharide vaccine (PPSV23) is available for use in children above 2 years of age who belong to the “high-risk group” and for use in older children, adolescents and adults routinely. This vaccine covers most of the prevalent strains of pneumococcus causing disease. It is given as a single dose of 0.5 ml subcutaneously or intramuscularly in children, more than 2 years of age. The vaccine being a capsular polysaccharide is not immunogenic in children of less than 2 years of age. At present, the vaccine is recommended in children with sickle cell disease, functional and anatomic asplenia, nephrotic syndrome, patients with cerebrospinal fluid leak and children with malignancies and HIV infection. Polysaccharide vaccine fails to elicit a protective immune response in children less than 2 years, even though 80% of the pneumococcal disease occurs in children less than 2 years of age. Hence the use of conjugated vaccines is preferred.

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This 10-valent pneumococcal vaccine has 1, 5 and 7F strains in addition to the 7-valent strains. This vaccine has been proved to be immunogenic when used in the EPI schedule in European countries and covers up to 70% of the prevalent strains in a given geographical area. The vaccine is expected to be licensed in India in the near future.

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Pneumococcal Vaccine Currently two types of pneumococcal vaccines are marketed in India: conjugate (PCV13) and non-conjugate (PPSV23) pneumococcal vaccines.

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7-Valent Conjugate Vaccine (PCV7) ­

This vaccine contains seven purified capsular polysac charides of S. pneumoniae coupled with a nontoxic variant of diphtheria to CRM197. It has serotypes 4, 6B, 9V, 14, 18C, 19F, 23F, responsible for 85% of invasive disease and 65% 194 of otitis media in western countries. It covers only 50% of the prevalent strains in India. Dose is 0.5 ml IM. Schedule is

Typhoid vaccine was included in the National Immunization Schedule till 1987; but discontinued because the vaccine had lot of side effects. Now typhoid is occurring in younger age groups and there is emergence of multiple drug resistance. Hence there is a need for typhoid vaccines. Two types of typhoid vaccines are now available.

Vi Polysaccharide Typhoid Vaccine The Vi antigen of Salmonella typhi is a capsular antigen with known virulence property of the organism and is available as injectable vaccine containing 25 mg purified Vi capsular

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Quadrivalent Vaccine

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Hepatitis

There are two types of hepatitis A vaccines now available: inactivated and live attenuated formulations.

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The live attenuated varicella ( AV) vaccine contains OKA or DKA/Merck strain. Dose is 0.5 ml given subcutaneously. First dose should be given at 15 months and second at 4–6 years. IAPCOI now recommends the second dose of varicella vaccine at 5 years along with second dose of MMR vaccine, in view of reported ‘breakthrough’ infection in approximately 30% of children who received a single dose. A combined MMR-V vaccine is also expected to be licensed in India in the near future. It has an efficacy of 95–100%. Varicella like rash and fever may manifest in few vaccines one week after vaccination. It is specially indicated in immunocompromised children and a group of high-risk children like those suffering from leukemia and malignant tumors, AIDS, chronic kidney disease, nephrotic syndrome and children on long-term steroids.

ocal minor adverse reactions include pain, swelling and erythema which are self-limiting.

Vaccine

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Human papilloma virus (HPV) serotypes 16 and 18 are implicated in 70% of cervical cancers globally. Types 6 and 11 are known to cause 90% of anogenital warts. Two types of HPV vaccines are now available in India: bivalent formulation aimed at prevention of cervical cancer and a quadrivalent formulation aimed at prevention of cervical cancer, warts and dystocia.

Adverse Effects

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Three doses of 0.5 ml IM or SC along with DPT vaccine, can be given according to the DPT schedule (6, 10, and 14 weeks or 2, 3, and 4 months or 2, 4, and 6 months) of the country. The booster dose is recommended along with DPT at 18 months. As a catch-up vaccine in children less than 5 years of age completing the primary immunization with OPV, two doses of IPV 1 month apart may be given. The efficacy of the enhanced potency IPV is over 90%–100% in various studies. The IAPCOI recommends IPV at 6, 10 and 14 weeks followed by a single booster at 18 months and OPV at 6, 9 and 12 months and the annual PPI doses in addition. For booster dose, combined DTaP-eIPV vaccine now licensed in India can also be used for children of affordable parents as a single booster.

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This has been manufactured from the H2 strain in China. The vaccine has been widely used in China. It should preferably be given subcutaneously in a prime-boost two doses schedule at 0 and 6 months and not in a single dose of 1 ml in children aged 1 year or older as recommended by the manufacturer. ong-term follow-up studies are not currently available.

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Live Attenuated Hepatitis A Vaccine

nactivated Polio Vaccine ( PV)

This vaccine is prepared from the virus of the original Salk strain grown in monkey’s kidney, human diploid or Vero cell line and is inactivated by formalin. Presently, it is available as an enhanced inactivated potency vaccine (eIPV) containing 40, 8 and 32 D antigen units against types I, II and III polio viruses respectively in 0.5 ml of the vaccine.

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Vi antigen is conjugated with nontoxic recombinant Pseudomonas aeruginosa exotoxin, A(rEPA). This vaccine has been found to be effective in Vietnam, in a schedule of two doses, 6 weeks apart. Efficacy is about 89%. The available conjugate typhoid vaccine in India lacks large scale epidemiological studies on efficacy and hence is not recommended by IAPCOI. It can be administered to children below 1 year and will be helpful in endemic regions.

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This contains formaldehyde inactivated hepatitis A virus derived from HM175/GBM strain adsorbed onto aluminum hydroxide. A combined HepA-HepB vaccine formulation is also available for use in older children, adolescents and adults. Dose and schedule: Hepatitis A vaccine is given in a prime boost schedule viz. the priming dose on elected date ‘0’ followed by a single booster at 6 months interval. IAPCOI now recommends the vaccine to be given at 12 months of age routinely for optimal protection in view of waning maternal antibodies in infants. Dose is 0.5 ml IM containing 720 E U in children. Adverse effects: Adverse reactions are minimal and include self-limiting local reactions at injection site. It can be given after 1 year in children as a routine vaccine.

Conjugated Typhoid Vaccine

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polysaccharide per dose. The dose is 0.5 ml intramuscularly in the deltoid region above the age of two years with revaccination every three years. The efficacy of the vaccine varies from 64% to 72% in various studies. Adverse reactions include pain, erythema and induration at the local site and rarely fever. All the reactions are of mild nature and selflimiting. A Vi antigen vaccine conjugated with tetanus toxoid is available in India but is not recommended because no reliable immunogenicity or efficacy trial of the vaccine is available.

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This contains HPV serotype 16 and 18. Dose is 0.5 ml at 0, 1, and 6 months. Recommended age of starting is 9 years. Both the vaccine formulations are now recommended in women up to 45 years of age. Pregnancy is a contrain dication. Preferably the vaccine should be administered in naïve adolescent girls and young women where microabrasions following sexual activity facilitating invasion of the virus in the vaginal epithelium have occurred preferably in cervical intraepithelial neoplasia (CIN) stages 1 and 2 only. CIN 3 is considered to be precancerous and the vaccine is contraindicated at this stage. Hence a prevaccination screening for evidence of precancerous stage is ideal and recommended in married women prior to administration of HPV vaccine.

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All tissue culture vaccines are given in 5 doses on 0, 3, 7, 14 and 30 days. The vaccine is given IM in the deltoid region or in anterolateral aspect of thigh in infants. The vaccine is not given in gluteal region. The dose is same irrespective of age, viz. 2.5 IU per dose in 1 ml or 0.5 ml as recommended by the manufacturer. Intradermal schedules have been recommended at government centres.

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This is indicated in persons at high-risk of exposure, e.g. laboratory staff working with rabies virus, veterinarians, animal handlers and wildlife officers. Even children who are exposed to stray dogs are candidates for preexposure prophylaxis. Three doses on 0, 7, and 28 days are recommended with reinforcing doses given if the antirabies antibody titer falls below 0.5 IU/ml. If persons who have received full course of pre- or post-exposure prophylaxis get an animal bite at any point of time, two doses on day 0 and 3 is recommended.

nfluenza Vaccine

Inactivated Influenza Vaccine This is available as a whole cell or split virus vaccine or subunit surface antigen formulations. Whole cell vaccines are currently not in use due to side effects. The trivalent vaccine contains the WHO recommended two strains of influenza A (H1N1, and H3N2) and one influenza B strain. Monovalent vaccine has a novel H1N1 2009 strain. The strains of influenza virus used in the vaccine have to be changed every year according to the prevailing strains in the geographical area. Dose and Schedule: Two doses 1 month apart are given for the first time for children from 6 months to less than 9 years with revaccination every year. Dose is 0.25 ml for 6–35 months and 0.5 ml for 3–8 years. After 9 years, only a single dose of 0.5 ml is given followed by a single revaccination every year. It is recommended in high-risk groups, e.g. immunocompromised children and children with cardiopulmonary diseases. It should also be given to children whose parents ask for the vaccine.



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Four types of tissue culture vaccines are available: human diploid cell vaccine (HDCV), purified chick embryo vaccine (PCEV), purified Vero cell vaccine (PVRV) and purified duck embryo vaccine (PDEV).

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Vaccines ecommended under pecial ircumstances

otavirus Vaccines

Currently two live attenuated oral vaccines are available. 1. onovalent vaccine: Monovalent vaccine is an attenuated human rotavirus vaccine derived from human rotavirus strain 89-12 that contains GIPI [8] strain. It is available as a lyophilized vaccine to be reconstituted with a diluent. First dose can be given at 6 weeks (not later than 12 weeks). Second dose is given 4 weeks later. The two dose schedule should be completed by 16 weeks and not later than 32 weeks. 2. Pentavalent human bovine reassortant vaccine: Pentavalent human bovine reassortant vaccine contains five reassortants between the bovine WC 23 strain and human G1, G2, G3, G4 and P1A8 rotavirus strain. Recommended schedule is three oral doses at 2, 4, and 6 months. First dose is to be started at 6–12 weeks with subsequent doses at interval of 4–8 weeks and all the recommended doses should be completed before 32 weeks. It is available as a liquid formulation and should not be frozen or injected. Both vaccines have an efficacy of 85–98% against severe rotavirus gastroenteritis and 42–60% against hospitalization from diarrhea of any cause. These vaccines have been recommended by the WHO to be included in the routine schedule in countries where more than 10% of under-five deaths are due to diarrhea. It is a public health vaccine. NTAGI has recommended inclusion of this vaccine in the NIP with Global Alliance for Vaccines and Immunization (GAVI) aid.

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at 12–15 months of age. IAPCOI recommends a second dose anytime 8 weeks after the first dose of MMR or at 4–6 years (school entry). It is a very safe vaccine. Minor allergic reactions, febrile seizure, rash, pruritus and encephalopathy have been reported.

Bivalent Vaccine

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DNA technology. Dose is 0.5 ml at 0, 2, and 6 months. Recommended age of starting the schedule is 10–12 years.

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This is available for use in 2–49 years as a nasal spray. It is efficacious but is not licensed for use in immuno compromised and pregnant; and should be avoided in children less than 5 years of age with reactive airway disease.

The vaccine is given as 0.5 ml single dose after the age of 2 years subcutaneously. The vaccine is not recommended for routine use and is to be given in epidemic situations and in children with functional asplenia and complement deficiencies. It is also recommended for travelers to endemic countries and mandatory for Haj pilgrimage.

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A capsular polysaccharide meningococcal vaccine is now available. Available vaccines are monovalent group A or C, bivalent A and C and a tetravalent vaccine containing group A, C, Y and W-135. Each dose contains 0.5 ml containing 50 µg of each polysaccharide available as lyophilized powder.

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This vaccine contains neuro-attenuated strains of JE virus (SA 14-14-2). Dose is 0.5 ml subcutaneously as a single dose in a campaign mode to children aged 1–15 years in certain hyperendemic districts of India.

1. Centers for Disease Control and Prevention (CDC). Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccine from the Advisory Committee on Immunization Practices, 2010. Morb Mortal Wkly Rep (MMWR). 2011;60:13-5. 2. Committee of Infectious Diseases American Academy of Pediatrics. Report of Committee of Infectious diseases. Red Book, 28th edition; 2009. 3. Garland SM, Smith JS. Human papillomavirus vaccines: current status and future prospects. Drugs. 2010;70: 1079-98. 4. ucero MG, Dulalia VE, Nillos T, et al. Pneumococcal conjugate vaccines for preventing vaccine-type invasive pneumococcal disease and X-ray defined pneumonia in children less than two years of age. Cochrane Database Syst Rev. 2009;(4):CD004977. 5. Mittal SK, Dutta AK, Agarwal V. Immunization update. New Delhi: CBS Publishers and Distributors; 1994. 6. Rodrigo C, Salman N, Tatochenko V, et al. Recommendations for rotavirus vaccination: A worldwide perspective. Vaccine. 2010;28:5100-8. 7. Yewale V, Choudhary P, Thacker N. IAP Guide Book on Immunization. IAP Committee on Immunization; 2011.

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Cell Cultured Live SA 14-14-2 Vaccine

ibliography

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An inactivated vaccine derived from infected mouse brain is recommended for travellers to endemic areas. Vaccine is given in a dose of 1 ml subcutaneously on days 0, 7 and 30 for travellers planning to spend more than 30 days in endemic area at least 10 days before travel. It is also recommended for persons residing in areas where Japanese B encephalitis is endemic or epidemic. Dose in children from 1 year to 3 years of age is 0.5 ml and 1 ml in older children.

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Vaccine torage and Handling

can cause degradation and consequently total or partial loss of potency (Table 5.7.1).



Deep freezers have top opening lid. The cabinet temperature is maintained between –15°C and –25°C. At PHC level, it is used to prepare icepacks and should not be used to store UIP vaccines.



 

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There are several cold chain maintenance equipment of different capacity for storage of vaccines at different levels. Storage equipment could be electrical as well as nonelectrical (Table 5.7.2).

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Table 5.7.1 Heat, light and freeze sensitivity of vaccines Vaccine Exposure to heat/light Heat and Light-Sensitive Vaccines BCG Relatively heat stable, but sensitive to light OPV Heat sensitive Measles Sensitive to heat and light Freeze-Sensitive Vaccines DPT Relatively heat stable HepB Relatively heat stable DT Relatively heat stable TT Relatively heat stable

ifferent Vaccine torage quipment for mmunization Program S

An effective logistics system and a well-maintained cold chain are essential for safe and effective immunization service delivery. An improperly functioning cold chain can lead to wasted vaccines, missed opportunities to immunize due to lack of vaccines, and children receiving vaccines that do not protect them as intended or that actually make them sick. The cold-chain is the system of storing and transporting vaccines at recommended temperature from the point of manufacture to the point of use. It has three main components: 1. Personnel to manage vaccine storage and distribution 2. Equipment to store and transport vaccines and to monitor the temperature 3. Procedures to ensure that vaccines are stored and transported at appropriate temperature. All three elements must combine to ensure safe vaccine transport and storage. Evaluations in many developing countries have shown weak points in cold chain performance. The vaccines which are not stored in the recommended temperature range get degraded. In addition to higher temperature, freezing of vaccines also

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These types of refrigerators have top opening. It can keep vaccine safe with, as little as, 8 hours continuous electricity supply in a 24-hour period. Hence they are suitable for use in the area with poor power supply. ILR has two sections: the top

Exposure to cold

Not damaged by freezing Not damaged by freezing Not damaged by freezing

+2°C to +8°C +2°C to +8°C +2°C to +8°C

Freezes at –3°C Freezes at –0.5°C Freezes at –3°C Freezes at –0.5°C

+2°C to +8°C +2°C to +8°C +2°C to +8°C +2°C to +8°C

 

Table 5.7.2 Types of cold chain equipment Equipment Temperature Storage capacity

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Deep Freezer

-15°C to -25°C

Electrical 200 icepacks or OPV stock for 3 months

ILR

+2°C to +8°C

BCG, DPT, DT, TT, Measles, Hepatitis B vaccine stock for 3 months

Cold Box ( large)

+2°C to +8°C

Non-Electrical All vaccines stored for transport or in case of power failure

Vaccine Carrier

+2°C to +8°C

All vaccines carried for 12 hours

Holdover time 43°C for 18 hours 32°C for 22 hours 43°C for 18 hours 32°C for 22 hours 43°C for 6.5 days 32°C for 10 hours 43°C for 34 hours 32°C for 51 hours

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afe Vaccine torage and Transport

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Temperature varies significantly every time the door is opened. Temperature rises during defrosting in cycle in cyclic defrost and frost-free refrigerators. Cabinet temperature is easily affected by ambient temperature. Temperature setting using dial is crude and inaccurate.

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Majority of the private vaccination service providers use domestic refrigerators to store the vaccines. They are not designed for the special temperature needs of vaccines and the safety of vaccines is at risk. For vaccine storage, the domestic refrigerator has following drawbacks:

 

Figure 5.7.1 Ice lined refrigerator (ILR)

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Safe vaccine storage is possible in most refrigerators if following points are observed:

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• Placement of refrigerator: Refrigerator should be placed away from exposure to direct sunlight and away from heat and with restricted accessibility so as to minimize unnecessary door opening. • tabilize the temperature of the refrigerator before stocking: The refrigerator temperature needs to be stabilized before start using for vaccine storage. • onitor temperatures inside the refrigerators: Monitor internal temperature regularly with thermometer, preferably Celsius digital minimum-maximum ther-

It is used by health workers for carrying vaccines (16–20 vials) from PHC to session sites. They maintain the cold chain during transport from the PHC for one day use in the field. With four conditioned ice packs inside, temperature is maintained between +2°C and +8°C for one day.

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Cold boxes are insulated boxes with ice packs (Fig. 5.7.2). They are mainly used for transportation of vaccines from district store to the PHC. In emergency, they can also be used to store vaccines and frozen ice packs. Before placing vaccines in the cold boxes, first place conditioned ice packs at the bottom and sides of the cold box and load the vaccines in cartons or polythene bags.

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Store vaccine in a dedicated refrigerator; do not store food or drink in vaccine refrigerators. The refrigerator compartment temperature is maintained between 2°C and 8°C and freezer compartment temperatures maintained at or below 5°F (–15°C). The door seals are in good condition and are sealing tightly. The door closes properly automatically on leaving it free. The refrigerator has separate freezer compartment.

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• and the bottom (Fig. 5.7.1). The bottom of the refrigerator is the coldest place. OPV and measles vaccine can be placed at the bottom of the ILR. DPT, DT, TT and HepB vaccines should be stored in a basket and never be kept directly on the floor of the refrigerator as they can freeze.

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Figure 5.7.2 Cold box

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Power Failure In the event of power failure, first record the time and refrigerator temperature (Table 5.7.4) (Fig. 5.7.3). R

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Purpose- uilt Vaccine efrigerator Purpose-built vaccine refrigerator is preferred refrigerator for vaccine storage. It is used by hospitals, pharmacies and larger general practices. In contrast to domestic refrigerator (Fig. 5.7.4): • They are programmed to maintain an internal temperature between 2°C and 8°C. • Cabinet temperature is not affected by ambient temperature and is stable and uniform. • They have external temperature reading display, maximum/minimum temperature continuous display and an out of range temperature alarm. • Good temperature recovery—when the fridge is open to access the vaccines.

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In every vaccine storage equipment the temperature should be monitored. Temperature should be recorded at least two times in a day and plotted on a chart to show high/low excursions. To measure the temperature during storage different type of thermometers are used.

Minimum/Maximum Thermometer (Fig. 5.7.5) It shows the current temperature and the minimum and maximum temperatures achieved. Temperature fluctuations outside the recommended range can also be detected. Available in fluid-filled and digital forms of which digital type with a probe is most effective type. Place the probe directly in contact with a vaccine vial or package.











 

Table 5.7.3 Periodic maintenance plan for vaccine refrigerator Daily Weekly Every fortnight •  Clean the coils and •  Check to make •  Check for ice the motor sure the doors are build-up in the closed and sealed freezer and defrost •  Defrost and clean the refrigerator if >0.5 cm frost has and freezer accumulated compartments •  Adjust the thermostat if necessary

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mometer. Place the thermometer in a central location within the storage compartment. • afeguard the power source: Ensure the power source is marked clearly in a way to prevent the refrigerator from being accidentally unplugged or turned off. • ncrease cool mass: Place water bottles and ice packs or gel packs in the refrigerator to increase the cool mass. These will assist in stabilizing the temperature in refrigerator compartment, reduce warming periods when the refrigerator is opened and are useful during short time power cuts or refrigerator failure. • deal storage method in domestic refrigerator ( ig. 5.7.3): – If a domestic refrigerator is used for storing vaccines in office room practice, it is mandatory that it should be used exclusively for storing vaccines only. A label may be affixed on the door of the refrigerators titled “VACCINES ONLY”. – In the domestic refrigerator, vaccines must be stored in labeled plastic containers or baskets. This will allow easy identification of vaccines and minimize time spent with the door opened searching for vaccines. – Vaccines should be stored in original packing. It provides some protection from very short-term power fluctuations. – The vaccines should not be overcrowded by overfilling the shelves. Space should be allowed between containers and a gap of at least 4 cm from all refrigerator walls to allow free air circulation. – Any vaccine in the door must never be stored. – Freeze-tolerant vaccines (Measles, Mumps, Rubella, OPV and BCG) should be placed in the top shelf. Freeze-sensitive vaccines (DTwP, DTaP, DT, TT, Tdap combination vaccines, HPV, typhoid, rotavirus, pneumococcal, influenza, hepatitis vaccines and IPV) should be stored in the middle shelf. – The door should be kept closed as much as possible. Reducing door opening helps to keep internal temperature stable. – A sticker on the door should be placed to remind staff of avoiding unnecessary door opening. – A basic map of vaccine locations outside of the refrigerator door should be sticked so that staff can go ‘straight’ to the vaccine when the door is opened. – The door should not be opened fully; it should be opened just to minimum as per need. – Training and assigning staff: Good vaccine storage and handling depends on knowledge and habits of the staff. – Everyone handling vaccines should know how to handle them and for consistency assign one person the responsibility for adjusting refrigerator thermostat and for cold chain management.

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aintenance of the Vaccine efrigerator (Table 5.7.3) Refrigerator Failure •

If it is found that the refrigerator is not working properly, do not open it unless the vaccine must be retrieved.

 

Table 5.7.4 Action plan for power failure situation Power failure duration Action Power failure of ≤4 hours Keep vaccines in the refrigerator and keep the door closed Power failure of >4 hours Identify an available unit and shift the vaccines If power failure of >4 hours and no Store vaccines in an insulated back-up generator/fridge container with icepacks and store in fridge

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Figure 5.7.3 Storing of vaccines in a refrigerator

igital thermometer: These are the most accurate constant monitors and also offer alarm to safeguard against damage from refrigerator malfunction. To get accurate reading, place the temperature probe in proper location.

 

Figure 5.7.4 Purpose built vaccine refrigerator

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ial thermometer: They are the most common but not the most accurate. They only indicate the temperature at the time they are read. Temperature fluctuations outside the recommended range may not be detected. • tem ( lcohol) thermometer: It is more sensitive and accurate compared to dial thermometer as it records temperature from –50°C to +50°C. It can be used in ILR and deep freezers. S

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A vaccine vial monitor (VVM) is a label containing a heat sensitive material, which is placed on a vaccine vial to register cumulative heat exposure over time (Fig. 5.7.6). A VVM enables the health worker to know whether vaccine has been damaged by exposure to heat. The VVM is a circle with a small square inside it which is lighter in color than surroundings. The inner square of VVM is made of heat sensitive material that is lighter in color at the starting point. The combined effect of time and temperature cause the inner square of the VVM to darken gradually. The color change is irreversible. A direct relationship exists between rate of color change and temperature. Thus, lower the temperature, slower the color change; and higher the temperature, faster the color change. Thus VVM gives information about the heat exposure over a period of time that affects vaccine potency. It does not give information about other factors responsible for vaccine degradation like light. VVMs are not substitutes for expiry dates. If the inner square is lighter than the outer ring, the vaccine can be used, whereas if inner-square matches or has darker color than outer ring the vaccine should be discarded (Fig. 201 5.7.7).

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Figure 5.7.5 Minimum/maximum thermometer

























1. Australian Government Department of Health, National Vaccine Storage Guidelines. Strive for 5; 2005. 2. Galazka A, Milstien J, Zaffran M. Thermostability of Vaccines. WHO (Global Program for Vaccines and Immunization); 1998. 3. Getting started with VVMs. VVM for all, Technical Session on Vaccine Vial Monitors. WHO publication 27/3/2002. Geneva. 4. Immunization Handbook for Medical Officers, Dept of Health and Family Welfare, Govt. of India; 2007. 5. Nelson C, Froes P, Dyck AM, et al. Monitoring temperatures in the vaccine cold chain in Bolivia. Vaccine. 2007;25:433-7. 6. Safety of vaccines affected by a power outage Quick Clinical Notes, Disaster management and response. 2004;2:62-3 CDC. 7. Target-5, Guide to vaccine storage and Handling. Surat: IAP Surat Publication; 2006. 8. UK Guidance on Best Practice in Vaccine Administration, Department of Health; November 2005. 9. Vaccine Management, Handling and Storage Details for vaccines. Utah VFC program. 10. Vaccine Management, Recommendations for handling and storage of selected biologicals. Department of Health and Human Services, CDC. Atlanta.



 

Figure 5.7.6 Vaccine vial monitor

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Figure 5.7.7 Decision to use vaccine/s based on VVM sensitivity

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Immun ty, Immun zat on and Infect ous

dverse vents ollowing Immunization and heir anagement

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Introduction

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Table 5.8.2 Common, minor vaccine reactions and treatment* Vaccine Local reaction (pain, swelling, redness) BCG 90–95% Hib 5–15% Hepatitis B Adults: 15% Children: 5% Measles/MMR/MR 10% Oral polio vaccine — Tetanus/DT/Td 10% Pertussis (DTwP) Up to 50% Treatment Cold sponging at injection site Oral paracetamol

shock or induction of active disease following measles or OPV vaccine respectively. Hypothetical type of reaction may be related to vaccine scares, which has causal relationship relating to the issues, which are of controversial nature occurring in vaccinated children. The common vaccine reactions are due to the immune response of the host and sometimes due to vaccine components (e.g. aluminum adjuvant and preservatives). A successful vaccine reduces these reactions to a minimum while inducing the best possible immunity. These anticipated reactions occur within a day or two of immunization and are listed in Table 5.8.2. The vaccine scare-related adverse events have a very casual link and are most often hypothetical as listed in Table 5.8.3.

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Immunization is a major contributor to the success story of child health in the last century, which has enhanced and improved the child survival all over the world. Vaccines used in national immunization programs are extremely safe and effective. Several scientific, ethical and statutory obligations are fulfilled by the manufacturers and elaborate field trials regarding safety and protection offered by individual vaccines are established before they are recommended for routine use. However, no vaccine is perfectly safe and adverse events can occur following immunization. In addition, vaccines being products of biological nature, the process of immunization is a potential source for adverse events. An adverse event following immunization (AEFI) is one that is believed to be caused by immunization. A reported adverse event can be true adverse event or an event coincidental to the immunization. AEFIs are classified into five categories (Table 5.8.1). Immunization can cause adverse events from the inherent properties of vaccine (vaccine reaction) or some error in immunization process (program error). The event may be unrelated to the immunization but have temporal association (coincidental event). Anxiety-related reactions can arise from fear or pain of the injection rather than the vaccine itself. In some cases, the cause of AEFI remains unknown. The adverse event following the immunization may be anticipated and not severe enough to cause discomfort for a long duration of time (e.g. pain or fever after DTP vaccination); whereas a severe or a rare event following the vaccine may be in the form of unexpected anaphylactic

Table 5.8.1 Classification of adverse events following immunization (AEFI)* Type of AEFI Definition and characteristics Vaccine reactions Event caused or precipitated by the vaccine when given correctly, caused by the inherent properties of the vaccine Program error Event caused by an error in vaccine preparation, handling, or administration Coincidental event Event that happens after immunization but not caused by the vaccine—a chance association Injection reaction Event from anxiety about, or pain from the injection itself rather than the vaccine Unknown Event’s cause cannot be determined *Source: Immunization Safety Surveillance. WHO; 1999. p. 9(2)

*Source: Immunization Safety Surveillance, WHO; 1999.p.10(2).

Fever >38°C — 2–10% 1–6% 5–15% <1% 10% Up to 50% Give extra fluids Wear cool clothing Tepid sponge or bath Oral paracetamol

Irritability, malaise and systemic symptoms — — — 5% (Rash) <1 % 25% Up to 50% • Give extra fluids • Oral paracetamol

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Table 5.8.3 Vaccination scares Vaccine Hepatitis B Whole cell pertussis Diphtheria, tetanus and pertussis Inactivated polio vaccine Influenza Haemophilus influenzae type b Measles, mumps and rubella: Rubella Thiomersol-containing vaccines Aluminum-containing vaccines Various vaccines

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nticipated reactions: Nodule formation at the site of vaccination (3–6 weeks) which discharges, ulcerates and heals by tiny scar (10–12 weeks). Local adverse reactions: • Persistent discharging sinus at the site of vaccination. • Regional axillary adenitis: – Below 2 cm—no treatment – Fluctuant, more than 2 cm—treatment with INH for 3–6 months/excision • BCG complex (local lymphadenitis + positive Mantoux reaction + paratracheal lymph node): treat with RHZ (2 months) + RH (4 months). ystemic reactions: Disseminated infection, tuberculous osteomyelitis, scrofuloderma—treat these like tuberculosis.

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dverse reactions: • Incessant cry (more than 3 hours) • Febrile convulsions • Hyperpyrexia • Hypotonic hyporesponsive episode (shock-like state) • Acute encephalopathy • Anaphylactic shock. DT

 

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Adverse events like pain or swelling are minimal with above vaccine. Clinical features of anaphylaxis: These involve multiple body systems (skin, respiration and circulation). • Itchy urticarial rash and facial flushing. • Progressive edema involving face, mouth and body parts.

         

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nticipated reactions: Pain, discomfort, fever and indu ration—treatment with analgesics and antipyretics; para cetamol 15 mg/kg/dose.

 

 

 

 

 

 

 

 

 

 

 

Table 5.8.4 Program errors leading to adverse events* Nonsterile injections • Reuse of disposable syringe or needles • Improperly sterilized syringe or needles • Contaminated vaccine or diluents • Reuse of reconstituted vaccine at subsequent session Vaccine prepared incorrectly • Vaccine reconstituted with incorrect diluent • Drugs substituted for vaccine or diluent Immunization injected at wrong site • Subcutaneous instead of intradermal for BCG • Too superficial for toxoid vaccine (DTP, DT, TT) • Buttocks Vaccine transported/stored incorrectly Contraindications ignored Infection • Local suppuration at injection site, abscess, cellulitis • Systemic infection, sepsis, toxic shock syndrome • Transmission of blood-borne virus (HIV, hepatitis B or C) Local reaction or abscess • From inadequate shaking effect of drug (e.g. muscle relaxant) • Local reaction or injection site abscess • Sciatic nerve damage (+ ineffective vaccine—hepatitis B and rabies) • Increased local reaction from frozen vaccine (and ineffective vaccine) Avoidable severe vaccine reaction *Source: Immunization Safety Surveillance, WHO. 1999; p. 30(2)

Vaccination omplications and heir anagement

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Another notable component of adverse events following immunization is due to program errors that would result from errors and accidents in vaccine preparation, handling or administration (Table 5.8.4). The identification and correction of these errors are of great importance, which would otherwise lead to a cluster of other events associated with immunization. The most common program error is iatrogenic infection as a result of nonsterile injection, e.g. sterile abscess, which may have a systemic effect or blood-borne infection (e.g. HIV and hepatitis B). Each vaccine administered in the immunization program has specific complications most of which are anticipated and mild. Some of them are serious adverse reactions, which always have to be expected, and immediate remedial measures have to be given as described below.

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Vaccine scare related adverse event Multiple sclerosis, lupus, diabetes mellitus Encephalopathy, epilepsy, learning disorders Cot death/sudden infant death syndrome (SIDS), HIV infection Diabetes mellitus Diabetes mellitus Autistic spectrum disorder, inflammatory bowel disease, childhood arthropathy Ethical concerns because grown in cells from an aborted fetus, neurodevelopmental disorder, autism, muscular fibrosclerosis Diseases of unknown or partially understood etiology, e.g. asthma, autism Inflammatory bowel disease, cot death, chronic fatigue syndrome, immune deficiency, leukemia, autoimmune diseases, learning disorders, increase in violent crime, etc. *Source: Vaccines—Children and Practice 2003, Vol. 5 No. 2 (3).

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nticipated reactions: Mild fever, rash and coryza (up to 4–7 days following vaccination). reatment: Paracetamol.

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• Local reactions: Erythema and induration; if the patient is sensitive to streptomycin/neomycin she/he might develop hypersensitive reactions as IPV contains these as preservatives. • ystemic reactions: Transient arthralgia, rarely agitation, somnolence and convulsions.

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Hib Vaccine Local reactions: Mild redness, pain and swelling.

Varicella Vaccine Local reactions: Papular vesicular eruption in less than 4% of vaccinees. ystemic reactions: Mild fever, headache, pneumonitis, arthropathy and breakthrough varicella. S

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Respiratory symptoms: Sneezing, coughing, wheezing and airway obstruction. Hypotension and shock. Emergency management of anaphylaxis: Place the patient in recumbent position and elevate the feet. Clear the airway, establish breathing (O2 supplementation and bag mask application) and maintain circulation. Injection adrenaline (1:1000) 0.01 ml/kg SC/IM (in severe cases). Repeat dose at 20 minutes intervals till response. Volume expanders (20 ml/kg normal saline or Ringer lactate (R ) over 20 minutes); repeat till response. Dopamine (5–10 µg/kg/min) or dobutamine (5–40 µg/ kg/min). Monitor vital signs. Other measures to reduce the absorption of vaccine from injection site: – Placing a tourniquet above vaccination site. – ocal adrenaline to reduce vaccine absorption (only if vaccines given through SC route).

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ystemic reactions: Headache, fever, anaphylaxis and rarely transient neuroparalytic illness (Guillain-Barre type).

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Local reactions: Inflammation.

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ystemic reactions: Anaphylaxis rarely.

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Local reactions: Soreness.

oxic shock syndrome: It occurs due to contamination of measles vaccine with S. aureus due to usage of unsterile syringes, needles/and using a vaccine vial beyond 4 hours after reconstitution.

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dverse reactions: • Toxic shock syndrome • Exaggeration of tuberculosis • Encephalitis.

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ystemic reactions: Mild undesirable side effects like fever, vomiting, irritability and rash may occur. The risk of intussusception with rotavirus is not increased as with placebo group.

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Guidelines for afe Vaccination Always ensure safe injection practices for safe health by using disposable syringes. • Select proper vaccine and follow manufacturer’s instructions (dose/route/administration). • Maintain cold chain. • Inform the parents regarding vaccine benefits and their anticipated reactions. • Obtain written or at least oral consent before vaccination. • Keep the child under observation for 15 minutes after vaccination. Be equipped and geared up to treat any untoward reactions. • Have always resuscitation kit ready. • Use desired injection procedure, i.e. load the vaccine

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It is mandatory for the person administering the vaccine to have sufficient knowledge regarding vaccines and expected side effects and to inform parents thoroughly regarding such adverse effects, which may however occur very rarely. It is also essential to be prepared and to always have a ‘kit’ with lifesaving drugs and equipment at each place of vaccination. Advice on managing the common reactions as well as the instructions, to return to the clinic if there are more serious symptoms, should be given to parents. This will help to reassure parents about immunization and prepare them for common reactions. Program errors are easily preventable. Identification and correction of these errors are of great importance. WHO guidelines to avoid program errors are as follows: • Vaccines must be reconstituted only with the diluent supplied by the manufacturer. • Reconstituted vaccines must be discarded at the end of each immunization session and never retained. • No other drugs or substances should be stored in the refrigerator of the immunization center. • Immunization workers must be adequately trained and closely supervised to ensure that proper procedures are being followed. • Careful epidemiological investigation of an AFEI is needed to pinpoint the cause and to correct immunization practices.

 

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The reportable AEFI must include any death or serious event believed by the public or health worker to be caused by immunization (Table 5.8.6). The minor common reactions such as local reactions, fever, and self-limiting systemic symptoms need not be reported. It is important for the persons administering the vaccine to advise the parent/patient at the time of immunization that these reactions are expected and advise them how to manage these common reactions (e.g. vip.persianss.ir

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 5.8.5 Vaccines and contraindications* Avoid: Live vaccine • Immunodeficient individuals • Immunosuppressant therapy • Chronic debilitating illness (till recovery) Avoid: DTP (1st dose) • Progressive neurological disease • Uncontrolled seizure disorder (postpone till control) Avoid: Rubella vaccine • During pregnancy Avoid: Measles vaccine/ • If person is sensitive to egg protein should not be given Delay: Live vaccine • Measles/MMR for 6 weeks following immunoglobulin therapy • Severe febrile illness Discontinue DTP • In case of severe post-vaccinal reactions Do not stop vaccination in • Malnutrition • Moderate fever • Respiratory infections • Mild diarrhea • Any benign ailment *Source: Bhatia R, Ichhpujani RL. Immunization against infectious disease; 1996.pp.20-60.

Prevention and reatment of Vaccine eaction



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It is often difficult to prove definite cause-effect relationship between the act of vaccination and subsequent compli cation. The following guidelines as well as the list of contraindications for vaccinations will help in deciding vaccine administration (Table 5.8.5).

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ystemic reactions: Fever and headache.

into appropriate syringe size. Discard the needle used for drawing and use a fresh needle for injection (one syringe and two needles for each vaccination). Do not mix vaccines in single syringe unless approved for such use. Use different syringes for different vaccines. Use different sites for injection. Always use anterolateral aspect of thigh in young children and deltoid area for older children for injections. Never use gluteal region in children. Avoid fomentation/vigorous rubbing after vaccination. Firm pressure for a few minutes is sufficient. Document every vaccination procedure in the immuni zation card and keep a copy of it. Complete the vaccination schedule as per immunization calendar. Remind the parents regarding next date. There is no need to restart immunization of multi-dose vaccine, e.g. Hib, DTP, etc. if the child is not brought for immunization on suggested date. Instead just continue and complete the schedule. ­

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When to Report? Who Should Report? • Minor AEFI are to be reported by the auxiliary-nursemidwife (ANM) to the medical officer of primary health venter (MO PHC) in the monthly reports who will include the report from all ANMs in the monthly report to the District headquarters authority. • Pediatricians can report any AEFI case to the PHC/CHC medical officers (in rural area) or may directly report to District Immunization Officer (DIO) (Flow chart 5.8.1). • The DIO reports this in the monthly report to the state and the state to the Govt. of India as per the timeline for monthly report. The report should contain the following details at a minimum as per standard operating procedure: • Description of the event • Timing of the event in relation to immunization • Vaccines given • Patients identifying details. This is called as first information report (FIR). The routine vaccination program should continue while awaiting the completion of the reporting and investigation.

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attention, hence there is tendency to dramatize and personalize the event. It is easy for the media to create sense of panic and outrage about the events, which are unrelated to immunization (coincidental). The guiding principle while dealing with media must be that one should show empathy and caring, honesty and openness, dedication and commitment, whenever possible positive terms like immunization safety or vaccine safety should be used. Key messages have to be prepared before media contact and they should include some of these facts: • That benefit of immunization in preventing disease is well proven. • It is very risky not to immunize (risk of disease and complications). • Vaccine-preventable diseases (VPD) caused millions of deaths and/or disability before the introduction of vaccines, and that situation would return without continued use of vaccines. • Vaccines do cause reactions, but these are rarely serious and hardly ever cause long-term problems. • Immunization safety is of paramount importance, and any suspicion of a problem is investigated (advantage of well-established immunization safety surveillance). • The AEFI is currently being investigated but is likely to be coincidental/due to a local problem (depending on type of event), and the immunization program must continue to keep the population safe from disease.

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paracetamol to treat fever). For more serious problems, the patient should be advised to return or to seek medical attention and to allow detection of AEFI. More importantly, they should be advised not to delay treatment of a coincidental illness falsely attributed as vaccine reaction. Severe local reactions, especially if occurring in clusters, should be reported, as they can be markers for program errors or for problems with specific vaccine lots.

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Type of adverse effects Anaphylactoid reaction (acute hypersensitivity reaction) Anaphylaxis Persistent (more than 3 hours) inconsolable screaming and crying Hypotonic hyporesponsive episode (HHE) Occurring within 5 days of immunization Toxic shock syndrome (TSS) Severe local reaction Sepsis Injection site abscess (bacterial/sterile) Occurring within 15 days of immunization Seizures, including febrile seizures (6–12 days for measles/MMR; 0–2 days for DTP) Encephalopathy (6–12 days for measles/MMR; 0–2 days for DTP) Occurring within 3 months of immunization Acute flaccid paralysis (4–30 days for OPV recipient; 4–75 days for contact) Brachial neuritis (2–28 days after tetanus containing vaccine) Occurring within 1 and 12 months after BCG Thrombocytopenia (15–35 days after measles/MMR) immunization Lymphadenitis Disseminated BCG infection Osteitis/osteomyelitis No time limit Any death, hospitalization, or other severe and unusual events that are thought by health workers or the public to be related to immunization *Source: Immunization Safety Surveillance, WHO; 1999.p.23(2).

Immun ty, Immun zat on and Infect ous

Table 5.8.6 List of reportable AEFI* Time period Occurring within 24 hours of immunization

Over the past decade there has been tremendous controversy on the relationship between vaccines particularly MMR and autism/autistic spectrum disorder. 207 Review of all currently available evidence does not support any causal relationship between MMR vaccine and autism.

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A system for reporting VAERS is crucial in any immunization program so as to pick up previously unrecognized adverse effects and generate further data on vaccine safety. A robust system for reporting VAERS exists in most developed countries including the US. However such a system is currently not available in India. Pediatricians are encouraged to report VAERS to the IAP immunization website www.iapcoi.com. Events that should be reported include all serious adverse effects, irrespective of causal association, non-serious adverse events that are unexpected in nature, severity, frequency or outcome, vaccine failures, and all usage in pregnancy.

1. Adverse events following immunization. In: Parthasarathy A, okeshwar MR, Shah NK (Eds). Immunization Digest, 1st edition. New Delhi: Jaypee Brothers Medical Publishers Pvt. td; 2004. pp. 59-62. 2. Bhatia R, Ichhpujani R . Immunization against infectious disease. 1996;20-60. Reference incomplete. or Immunisation against infectious disease--1996 Edward Jenner Bicentenary Edition. Commun Dis Rep CDR Wkly. 1996;6(39):339. 3. Immunization Safety Surveillance. Guidelines for managers of immunization programmes on reporting and investigation adverse events following immunization. Manila: World Health Organization; 1999. 4. Rao MIS. Immunisation in Clinical Practice. New Delhi: Jaypee Brothers Medical Publishers Pvt. td; 2005. pp. 37-46. 5. Rao I. Vaccination complications, their management and contraindications. Paediatric Clinics of India. 2001;36:30-35. 6. Vaccines—Children and Practice, 2003; vol. 5(2) Reference incomplete. 7. IAP Guide Book on Immunization, 2009-2011. Mumbai: Indian Academy of Pediatrics; 2011. pp. 43-46. L

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preventable diseases through the development of strong, sustainable National Immunization Programs, capable of delivering high quality vaccines in a safe and effective way to all children.’ Safe and efficient immunization practices with thorough knowledge of the vaccines, well-maintained cold chain, proper parent education and efficient resuscitation equipment are vital components essential to make immuni zation most cost-effective public health tool in child survival programs.



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afety of hiomersol Thiomersol (50% ethyl mercury) is a preservative in inactivated vaccines particularly in multidose vials which has been linked in the past to autistic spectrum disorders and neurodevelopmental disorders. Consequently most of the vaccine preparations available in the developed nations are thiomersol free. Systematic review of evidence however has not supported any causal association between thiomersol and neurotoxic effects. Therefore in developing nations, where multi-dose vials significantly bring down vaccine costs and cold chain space requirement, the benefits of thiomersol far outweigh any possible risks.

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The empirical approach of selecting a vaccine antigen had an inherent problem of longer gestation period till it could be available for mass usage and was associated with a high failure rate as well as safety concerns. Genomics have changed the concept of antigen selection by the reverse vaccinology. The genomic details of a pathogen help identify the potential vaccine antigen that can be protective and further enhanced using an adjuvant to steer the immune response in the desired direction. Meningococcal B protection which has eluded the researchers till now has become feasible. The rapid development of influenza vaccine is another example of reverse vaccinology. The detailed atomic configuration of an antigen by structural biology shall further help identify the specific epitopes determining viral entry into the cell or the virulence and can be used as vaccine antigen. Such efforts are being made for a new measles vaccine. Systems biology is another emerging discipline which based on cytokine and immunological responses that can

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Anecdotal evidence of vaccination does exist since the eleventh century, but it was the landmark observation of Edward Jenner and Louis Pasteur about 200 years ago which started the success story of vaccination. Though attenuation and inactivation still remain the cornerstones of modern vaccinology, the rapid advancements in the field of immunology, structural biology, systems biology and bioinformatics have led to the development of newer, effective and highly safe vaccines. The synthetic microbial antigens, expression of protective antigens in live vectors and plants, antigen sparing adjuvants that manipulate the desired immune response in the host, alternate modes of delivery, high productivity and thermostability are some of the exciting developments which shall revolutionize the prevention of not only infectious diseases but also target the noninfectious ailments like malignancy and degenerative diseases. Translational research shall further expedite the development of safe vaccines. The realm of endless possibilities has led all the stakeholders to adopt “Call to action for the new decade of vaccines” emphasizing the need of intensified research and funding, advocacy at all levels for not only equity in distribution and access to vaccines but ensure its consumption. The argument that vaccines create wealth and prevent unnecessary deaths has to be percolated at all levels to ensure global health.

identify markers which can predict safety and efficacy of a vaccine using modelling techniques. These developments have helped identify numerous potential vaccine antigens but complicated the issue of selecting the best. The antigens being targeted today are not only the virulence factors but those having a crucial role in pathogenesis of disease and the survival of bacteria and viruses in the host. Pneumococcal adhesin antigen is being looked upon as a potential candidate for a multi-serotype protection with a high herd effect. Glyco-conjugation of polysaccharide antigen has already revolutionized protection against Hib, meningococcal and pneumococcal organisms and is being further exploited for group A and B Streptococcus and S. aureus. The first marvel of genetic engineering in vaccinology has been the Hep-B vaccine made from yeast carrying the surface antigen gene. Subsequently, recombinant proteins as effective immunizing agents have been enabled by gene insertion in yeast, E. coli and Chinese hamster ovary cells for Lyme disease, CMV and pertussis. Vectored vaccines are live recombinants using apathogenic viruses or bacteria to deliver vaccine antigens which have met with reasonable success for diseases like JE, dengue (yellow fever virus vector) and RSV (human parainfluenza virus 3). The vectors serve as a carrier for the pathogenic gene and have the advantage of simulating a natural infection and stimulating both humoral and cell-mediated immunity (CMI) effectively. The vectored approach has also the potential for therapeutic vaccines for cancer, e.g. fowl poxvirus encoding prostate specific antigen for prostatic cancer. The preferred vector candidates are poxviruses, adenovirus, yellow fever and BCG. The strategy is being used for much work on HIV and malaria vaccines. Viruslike particles (VLP) produced in vitro by assembly of viral proteins are highly immunogenic and the basis for the HPV vaccines available today. SARS vaccine is being developed on the same premise. Cell culture techniques in use since 1950 are being further refined and offer the advantage of attenuation (many live viral vaccines), cold adaptation live attenuated influenza vaccine (LAIV), single clone selection with highest efficacy and lowest virulence, rapid and high productivity and re-assortment, i.e. mixing RNA segments of attenuated strain with the protective antigen from the wild strain (pandemic influenza and rotavirus vaccines). DNA

Introduction

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uture Vaccines, djuvants and Immunization echniques

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DNA vaccines are bacterial plasmids containing viral or non-viral genes that get integrated with the host cell DNA 209 and encode for the surface proteins of the pathogen which are carried to the cell surface and incite immune response

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The euphoria of developing edible vaccines in the form of locally available fruits or other plant parts for oral use, providing mucosal immunity about two decades back was short-lived. The difficulties of standardization, regulatory affairs and the potential risk of contaminating food chain halted further progress. However, there has been a renewed interest in plant-made vaccines utilizing plants like tobacco which are not staple foods and using recombinant protein synthesis as used in yeast, bacteria and mammalian cells. The proteins are highly purified and used as vaccine antigen. The two closest products have been a veterinary vaccine for Newcastle disease virus and the most recent attempts to express protective antigens of various influenza viruses including H5N1 in tobacco plant N. benthamiana using an agrobacterium-mediated transient expression system yielding a purified vaccine within 3 weeks of viral sequence

release and have completed phase II human trials in USA. However regulatory permissions would be delayed for such novel products.

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Live vaccines mimic a natural infection and induce strong immunological response without unacceptable adverse events. However the inactivated vaccines, be it subunits, peptides, polysaccharides or DNA plasmids, need adjuvants to enhance immunogenicity. The conventional alum adju vant though safe had its limitations of reactogenicity, incompatibility with certain antigens and a narrow spectrum of only TH2 stimulation (humoral). Newer adjuvants like MF59, ASO4, lipidated peptides and the most recent lecithin nanoparticles appear to be promising to overcome these limitations (Table 5.9.1). ­

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in the body. The first generation DNA vaccines though safe and well tolerated, failed miserably because of erratic immunogenicity. The second generation DNA vaccines formulated with plasmids encoded with carefully designed antigens, delivered effectively by needle free approaches like electroporation, particle bombardment, dermal patches and simultaneous incorporation of genes encoding for molecular adjuvants like cytokines, chemokines or costimulatory factors like GM-CSF have renewed interest in this platform. The second generation DNA vaccines lead to a high antigen expression and a directed and predictable immune response. Currently there are 43 ongoing clinical trials, majority being for HIV and cancer. The other targets being evaluated are influenza, HBV, HCV, malaria and HPV. Safe, stable, cheaper and unaffected by maternal antibodies, there are concerns about genomic integration and anti-DNA immune responses; but these have not been substantiated in many non-human primate studies till now. RNA vaccines prepared with tumor antigens are highly immunogenic and have potential use in cancer immunotherapy.

Immunology and Vaccinology Immunology and vaccinology have a long intertwined relationship. Both have had a different pace of development and often vaccinology has lagged behind. The success of vaccines till now has rested on high avidity, long lasting protective antibodies. The role of cell-mediated immunity especially for chronic diseases like HIV, tuberculosis, hepatitis C virus (HCV), hepatitis B virus (HBV), malaria and cancer; mucosal immunity and interaction between mucosal and systemic immunity (many respiratory and enteric pathogens) has given the necessary fillip to development of vaccines regulating these pathways for a higher efficacy. RSV disease can worsen with a vaccine that only enhances humoral response without adequately stimulating T cell responses. The most recent studies on toll-like receptors (TLRs) mediated stimulation of innate immunity and neuro-regulation of host defenses, newer adjuvants capable of inducing CMI, availability of laboratory assessment of CMI by enzyme-linked immunosorbent spot (ELISPOT) tests and tetramer staining, systems biology techniques to study innate immunity,

 

Table 5.9.1 Newer adjuvants and the immunological characteristics Adjuvant Immunological characteristics Alum (aluminum salt) Depot and proinflammatory effects MF-59 oil-in-water emulsion Local proinflammatory effects, immune-cell activation AS03 oil-in water emulsion Local proinflammatory effects, immune-cell activation AS02 oil-in water emulsion Induces antibody and cell-mediated immune containing MPL and Q-21 response AS04 (combination of aluminum salts Strong antibody and cell-mediated-immune and MPL) response, toll-like receptor 4 dependent CpG oligonucleotides Toll-like receptor 9 agonist IC31 (oligonucleotides plus KLKL5 Toll-like receptor 9 agonist bacterial peptide) GLA synthetic lipid A Activates toll-like receptor 4 receptors, induces Th1 CD4 helper cells with broad humoral response Source: Rappuoli R et al. Lancet 2011

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Usage in vaccines Many vaccines (e.g. DTaP-Hepatitis B) Influenza and pandemic influenza Influenza and pandemic influenza Malaria vaccine candidate HPV vaccine Hepatitis B, cancer, malaria Influenza, tuberculosis Tuberculosis, leishmaniasis, malaria

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New vaccine development is highly cost intensive and has a long gestation period till licensing. The stringent regulatory approach to guard against the remotest adverse event puts the industry on the back foot. Translational studies can help identify the early predictors of success by assessment of early events after vaccination like inflammatory biomarkers and innate immunity activation within 1–5 days of vaccination. The safety concerns in the preclinical stage can be addressed using bioinformatics and systems biology to avoid vaccine antigens that can mimic human antigens (proteins and polysaccharide) and cause autoimmunity. Microarray technology can effectively demonstrate immunostimulation at the site of injection within hours of administration. 211 ­

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The ever-increasing list of not only available but desirable vaccines for children will result in babies becoming pin cushions. Introduction of new vaccines shall become challenging in such a scenario. To simplify the immunization schedule, it is imperative that age appropriate combination vaccines are made available to simplify schedule, better compliance and coverage with feasible costs and logistics. However there are multiple technical challenges in main taining immunogenicity and safety of different antigens in combination vaccines. The need to combine pneumococcal and meningococcal vaccines to existing DTP combinations is being explored. To address these immunogenicity and safety issues, different carrier proteins like protein D, DT, CRM 197, peptides containing T-helper cell epitopes, novel

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Conventionally vaccines have been primarily used for infants and children but the future needs demand universal immunization of adolescents and adult population especially targeted for DPT because of the changing epidemiology of HSV, HPV, CMV and influenza. A structured vaccination schedule may be desirable. The concerns of an aging population will merit a similar program for elderly, e.g. zoster, influenza, pneumococcal, cancer and degenerative diseases like Alzheimer disease. Vaccination during pregnancy is done to prevent vertical transmission of infections (GBS and HIV), ensure high levels of protective antibodies in neonate especially for RSV, pneumococcal, pertussis and protect the pregnant women against diseases like influenza, compounded by various ethical issues merits consideration in future. Protection against nosocomial infections and bioterrorism are areas where lot of new vaccines are being targeted.

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Since most pathogens invade through the epithelia (skin, mucosa) or blood (cuts and abrasions, insect bites), same routes have been conventionally used for vaccination guided by the fact that most of the immune system is within or close to these entry portals. Because of the physical and chemical barriers posed by the skin and mucosa, the mainstay has been the parenteral route which is painful and poses a big challenge to mass vaccination. It is now an established fact that mucosal immunity is highly important for protection against many pathogens. Recent developments in immunology, biotechnology, pharmacology, microbiology and biomedical engineering have opened new vistas in alternative routes of immunization chiefly the nasal and painless cutaneous administration. Nasal administration has been found effective for LAIV, RSV, group-B meningococcal and human parainfluenza 3. The nasal associated lymphoid tissue elicits a strong mucosal secretory IgA and systemic IgG response. The secretory IgA can also be detected in other mucosal sites following nasal administration. Attempts are in progress to develop highly safe and immunogenic nasal vaccines by optimizing antigenic formulation and novel adjuvants and mass administration by inhalational devices. Painless cutaneous administration by microneedles containing transdermal patches shall soon revolutionize the vaccination practices. The microneedles just pierce the stratum corneum without reaching the pain receptors in the dermis. The breach in skin helps deliver antigen and/or the adjuvant to the abundant dendritic cells and Langerhans cells in the dermis. Several studies using various formulations of influenza vaccine have demonstrated a dose sparing, stable formulation, early and directed immune response better than the IM administration. Electroporation, jet propulsion and ultrasonic (sonophoresis) are other methods being evaluated but are cost-intensive. Oral administration of inactivated vaccines and rectal or vaginal administration are other areas of future research.

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Though vaccines against 24 infectious diseases have been licensed, the future vaccine list is gradually expanding. The vaccine candidates are in varying stages of development. HIV, malaria and tuberculosis remain elusive while JE and dengue appear close by. Many novel antigens from cancer cells and autoimmune disorders are being targeted for specific immune responses to prevent/treat disease and improve survival.

argeting ewer Routes of dministration



Vaccines in Pipeline

adjuvants and developing in vitro assays for potency are being researched.

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have further opened exciting opportunities in vaccinology. The impact of T regulatory cells on pathogens evading immune response has been another recent development. One can foresee vectored, DNA and RNA vaccines, synthetic peptides using adjuvants like lecithin nanoparticles, lipid in water emulsions, TLR agonists, liposomes and cytokines to selectively guide host TH1 and/or TH2 for effective protection against many infectious and non-infectious diseases. Therapeutic vaccines for chronic infections by inducing cell mediated immune (CMI) responses that will decrease viral load for HCV, HPV (E6, E7 oncogenes) and HIV (gag and tat genes) appear feasible in the near future.

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1. Bachmann MF, Jennings GT. Vaccine delivery: a matter of size, geometry, kinetics and molecular patterns. Nature reviews. Immunology. 2010;10:787-96. 2. Bitter C, Zimmermann KS, Surber C. Nasal drug delivery in Humans. Curr Probl Dermatol. 2011;40:20-35. 3. Douek DC, et al. Vaccines. Immunological reviews. 2011;239:5-7. 4. Ferraro B, Morrow MP, Hutnic NA, et al. Clinical applications of DNA vaccines: Current progress. Clinical infectious diseases. 2011;53(3):296-302. 5. Hegde NR, et al. Recent advances in administration of vaccine for infectious diseases: Microneedles as painless delivery device for mass vaccination. Drug Discov Today. 2011. 6. Moxon ER, Das P, et al. A call to action for the new decade of vaccines. Lancet. 2011;378:298-302. 7. Pires A, Fortuna A, Alves G, et al. Intranasal drug delivery: How, Why and What for? J Pharm Pharmaceut Sci. 2009;12(3):288-311. 8. Plotkin SA. Vaccines past, present and future. Nature Medicine Supplement. 2005;11:S5-11. 9. Poland GA, Jacobson RM, Ovsyannikova IG. Trends affecting the future of vaccine development and delivery: The role of demographics, regulatory science, the anti vaccine movement and vaccinomics. Vaccine. 2009;27(25-26):3240-4. 10. Rappudi R, Black S, Lambert PH. Vaccine delivery and translation of new vaccine technology. Lancet. 2011;378:360-8.



Vaccines are perfect interventions that prevent morbidity and mortality, yet its introduction into public health is a herculean task especially in a developing country. The availability, cost, its sustainability, safety and efficacy concerns, regulatory constraints, logistics of access and political will are the major impediments. In countries with a high disease burden some trade off for safety may be acceptable but it may erode the already meagre public confidence in the vaccination program. This decade shall clearly witness unprecedented development in vaccines and a highly consistent advocacy by all the stakeholders is necessary to promote a simple idea ‘vaccines save lives, prevent suffering and create wealth’.

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The vaccine formulations with extensive non-specific immunostimulation are best avoided. Identification of specific genetic risk factors for adverse events is being studied to further ensure safety. This ‘bench to bedside’ methodology can expedite rapid development of safe and effective vaccines in the near future. The challenges of postlicensure assessment of vaccine safety and effectiveness are also likely to be addressed by availability of large computer databases, comprehensive surveillance networks and genomic information of the population.

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PP Maiya Humanity has but three great enemies: Fever, war and famine. Of these by far the greatest, by far the most terrible is fever

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Fever results from a series of cellular events that begin peripherally and ends centrally with resetting of body’s temperature set point. Unlike hyperthermia, fever does not represent a failure of temperature control, but rather an upward shift of the regulated temperature as a result of body’s exposure to infecting microorganisms, immune complexes and other sources of inflammation. Various mediators like cytokines, tumor necrosis factor (TNF) as well as interleukins 1 and 6 (IL-1 and IL-6) stimulate prostaglandin (PGE2) production in the anterior hypothalamus, which brings about rise in the temperature set point by a variety of physiological mechanisms including activation of cAMP. This sends signals to various efferent nerves innervating peripheral blood vessels to conserve heat. The vasoconstriction causes the feeling of chills which may lead to rigors with sudden elevation of body temperature. Also the thermoregulatory center sends signal to cerebral cortex to initiate behavioral changes like seeking warm environment, extra clothing and flexed

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This term refers to fever of acute onset and short duration (<1 week) without any localizing symptoms or any clinical signs on physical examination. It is a cause for concern as young children often shows limited signs of infection making it difficult to distinguish between serious bacterial infections from self-limiting viral infections. Table 5.10.1 summarizes the clinical differentiation between viral and bacterial infections. O

ever of nknown rigin

Fever of unknown origin (FUO) in children remains one of the most challenging clinical situations for the pediatrician. Evaluation of FUO in children benefits from an understanding of the historic definition of this entity and how its definition has changed over time. FUO is defined as a single illness that has lasted for 3 or more weeks with temperature greater than 38.3°C on most days and with Flow chart 5.10.1 Pathogenesis of fever  

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The narrow body temperature is maintained between a range of 36.8 ± 0.4°C (98.2 ± 0.7°F) with a circadian rhythm of lowest temperature at 6:00 AM (37.2°C or 98.9°F) and highest temperature of 37.7°C or 99.9°F at 4:00 PM. In general fever is considered to be present if temperature in rectum is above 38.3°C, in oral cavity above 37.8°C or in axilla above 37°C.

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Fever in children is one of the most common manifestations of an illness, which makes the parents seek medical attention early. Fever occurs when various infectious and non-infectious processes interact with the host’s defense mechanism. It is important that all children with fever are carefully assessed to find the cause. Nevertheless cause remains undetermined in a significant percentage of cases, leading to the designation of fever without focus (FWF) and fever of unknown origin (FUO). But even with the etiology being determined, fever remains the overriding source of anxiety.

posture. All these mechanisms act to elevate the core body temperature so that the blood bathing neurons in the anterior hypothalamus is warm and matches with the new temperature set point (Flow chart 5.10.1).

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Infectious auses The most common infections implicated in FUO are tuberculosis, infectious mononucleosis, rickettsial infections, hepatitis, leptospirosis, Salmonella and brucellosis. The common localized infections that may present as FUO are sinusitis, tonsillitis, urinary tract infections (UTI), osteomyelitis



































 

Table 5.10.2 Possible etiology of fever of unknown origin Infectious Causes 1. Specific infection: a. Bacteria: Salmonella, Tuberculosis, Brucellosis, Meningococcemia, Actinomycosis, Mycoplasma pneumoniae b. Spirochetes: Borrelia burgdorferi, relapsing fever, leptospirosis, syphilis c. Parasites: Amoebiasis, babesiosis, giardiasis, malaria, toxoplasmosis d. Fungi: Blastomycosis, coccidioidomycosis, histoplasmosis e. Chlamydia: Psittacosis f. Rickettsia: Q fever, rocky mountain spotted fever, tick born typhus g. Viruses: Cytomegalovirus (CMV), hepatitis, HIV, infectious mononucleosis 2. Local septic infections: Dental abscess, hepatic abscess, subphrenic abscess, bronchiectasis, sinusitis, mastoditis, tonsillitis 3. Local infection without pus formation: UTI, phlebitis, ulcerative enteritis, diverticulitis Noninfectious Causes 1. Collagen vascular disorder: Juvenile rheumatoid arthritis (JRA), Behcet’s disease, juvenile dermatomyositis, systemic lupus erythematosus (SLE) 2. Neoplastic: Leukemia, lymphoma, neuroblastoma, Wilms tumor 3. Metabolic : Gout, porphyria 4. Endocrine: Thyrotoxicosis, Addison disease 5. Hypersensitive reaction: Serum sickness, drug fever 6. Miscellaneous: Cirrhosis of liver, sarcoidosis, familial mediterranean fever, poisoning, factitious fever, malingering





There are a good number of causes for FUO. Incidence of disease causing FUO varies depending upon the age of the child. In children less than 6 years of age, most common are infectious causes accounting for 65% followed by neoplastic (8%) and autoimmune (8%) causes. In the age group between 7 years and 12 years, infective causes accounts for 38%, neoplastic 4% and autoimmune 23%.



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lassic : The child has temperature >38.3°C for a duration of more than 3 weeks and has been evaluated on at least 3 OPD visits or 3 days of inpatient stay. • osocomial : Temperature of more than 38.3°C developing on several occasions in a hospitalized patient who is receiving acute care and in whom infection was not manifest at admission. Three days of investigations, including at least 2 days incubation of cultures is the minimum requirement for this diagnosis. • eutropenic : Temperature of 38.3°C on several occasions in a patient whose neutrophil count is less than 500/cells/mm3. The diagnosis of neutropenic FUO is invoked if a specific cause is not identified after 3 days of investigations including at least 2 days incubation of culture. • HIV ssociated : Temperature of 38.0°C on several occasions over a period of more than 4 weeks for outpatient or 3 days for hospitalized patient with HIV infection. The diagnosis is invoked if appropriate investigations over 3 days including 2 days incubation of culture reveal no organism. N

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uncertain diagnosis after 1 week of intense evaluation which includes hospitalization and CT of the abdomen. FUO can be further categorized into four types.

All these are identified by history, physical examination or simple laboratory studies. Tuberculosis is common and diagnosis can be established by appropriate investigations. The second most common causes include autoimmune dis eases such as juvenile rheumatoid arthritis or inflammatory bowel disease. Relatively small numbers are due to malignancies, the most common being leukemia and lymphoma. Etiology of FUO can be classified into infective causes and non-infective causes. Table 5.10.2 lists the possible etiology of FUO. Most children presenting with fever have either an identifiable entity at presentation that directs further evaluation or more likely have a self-limited viral illness that will run its course. Often children presenting initially with fever without focus may progress to meet FUO criteria if the cause is not identified early and fever persists. Serial evaluation is critical for these children.



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Table 5.10.1 Clinical differentiation between viral and bacterial infections Viral infections Bacterial infections Abrupt onset Insidious onset Duration usually 3–5 days May last for more than 7 days Prodrome usually present No prodrome Presence of rash almost always Very few bacterial conditions suggests viral etiology produce rash No localizing findings May have systemic localization and organomegaly Seasonal incidence No seasonal variation Many members in the family may Isolated cases be affected simultaneously Investigations usually normal Elevated WBC counts, CRP positive, culture positivity, X-rays suggestive in pneumonia Majority self-limiting Majority require antibiotic therapy

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pelvic, rectal examinations are important. Confirm abscess by CT or USG abdomen.

Brucellosis

Connective Tissue Diseases

If the patient is an infant or young child, parent or caretaker is the one who is fabricating. In most cases, factitious fever is excluded by recording of temperature by healthcare worker. Occasionally temperature is recorded rectally or measuring temperature of freshly voided urine.

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Non-specificity of signs and symptoms accounts for association of salmonellosis with FUO. Children with salmonellosis presents with moderate grade fever, abdo minal pain and severe watery diarrhea. Serological tests are generally not useful. Repetitive blood and stool cultures are useful to establish diagnosis.

They are the third most frequent cause of FUO in children. Most cases are caused by leukemia or lymphoma. Rarely neuroblastoma, hepatoma, atrial myxoma and rhabdo myosarcoma can present as FUO.

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Transmission of infection from animals to humans may follow direct contact with the blood, urine, or organs of infected animals. The clinical manifestations are non-specific. Some patients present with classical features such as fever, jaundice, hepatosplenomegaly, renal manifestations and, bleeding tendencies. In many cases a definite diagnosis cannot be established because of negative cultures and failure to demonstrate serological titers.

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They form the second leading cause of FUO in children and juvenile rheumatoid arthritis (JRA) accounts for most of the cases. The systemic form of JRA most commonly presents as FUO. The classic fever has one or two spikes daily. Serology may be negative in children rendering diagnosis difficult. The diagnosis is made clinically by observation over a prolonged period. Classical fever in association with evanescent rash with objective arthritis is highly suggestive of systemic JRA.

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The presentation of brucellosis as FUO is explained by the non-specificity of its symptoms and chronicity of untreated infection. Classic triad of undulant fever, arthralgia, arthritis and hepatosplenomegaly can be demonstrated in most of the patients. Enquire carefully for the exposure to animals or animal products such as cheese made from unpasteurized animal milk. Enzyme immunoassay is sensitive to detect Brucella antibodies.

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and occult abscesses which include subphrenic, hepatic or pelvic. Some cardinal features of selected diseases are given below.

Tuberculosis

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It is considered if patient is taking any drugs. The tempera ture tends to remain elevated at a relative constant level. Withdrawal of the drug is associated with resolution of fever within 72 hours. Drugs commonly implicated include penicillin and phenytoin.

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It is an important cause of FUO in children. Non-pulmonary tuberculosis (disseminated, peritoneal, hepatic, or geni tourinary) presents as FUO more commonly than pulmonary tuberculosis. Active disseminated tuberculosis has been documented in children with normal chest X-ray and negative Mantoux test.

Drug Fever

Infections of bones and joints can present as FUO. Infection of pelvic bone is commonly implicated. Bone scanning is required to locate the site of infection.

Liver Abscess Pyogenic liver abscesses are encountered most frequently in immunocompromised patients but can occur in normal children. Blood cultures are usually sterile and liver function tests (LFT) are usually within normal limits. Diagnosis is established by CT scan or ultrasound (USG) of abdomen.

Intra-abdominal Abscesses The combination of history of intra-abdominal disease, recent abdominal surgery, and abdominal pain heightens the suspicion of accumulation of pus. Careful abdominal,

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The diagnostic approach for each child has to be indi vidualized. It has to be kept in mind that in most cases, the cause of FUO is a common disease with an uncommon presentation, rather than a rare disease. For most patients diagnostic evaluation may be initiated on an outpatient basis. However young infants and children who appear toxic or chronically ill and children who have been febrile for a prolonged period should be hospitalized for evaluation. Hospitalization helps in documenting the fever, exploring the history further, repeating the physical examination and maintaining constant observation along with laboratory evaluation.

History A detailed carefully taken history is the most important tool in the diagnosis of FUO. Some helpful hints are given below. • Age: Neonates and young children are susceptible to specific organisms like Listeria monocytogenes and Group B Streptococcus. Adolescents are susceptible 215

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Careful and meticulous physical examination is mandatory in all children with FUO. Repetitive examinations, preferable daily examination is important to pick-up subtle or new signs which appear during the course of illness and help in identifying the etiology. Following are some of the clinical parameters which give clues to the diagnosis. • emperature: Temperature pattern during hospitali zation may give clues to the diagnosis – Intermittent: Malaria or acute pyelonephritis. – Continuous: Typhoid, miliary tuberculosis, subacute bacterial endocarditis (SBE), or pneumonia. – Periodic/undulating: Hodgkin’s lymphoma or bru cellosis. • Pulse rate: Relative bradycardia is seen in typhoid, meningitis, dengue, and Weil’s disease. • nemia: Malaria, kala-azar, SBE, acute leukemia, and chronic diseases. • Lymph nodes: All lymph nodes should be described and recorded. – Generalized lymphadenopathy: Hodgkin’s disease or tuberculosis. – Localized lymphadenopathy: Glandular fever.

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Table 5.10.3 Investigations in FUO Routine investigations Advanced investigations •  Serum for virological studies •  Complete blood counts •  Autoimmune work-up (RA and •  ESR, CRP ANA factors) •  Chest X-ray •  ECG /ECHO •  Peripheral smear including •  CT/MRI night smears for filaria •  Barium studies •  Mantoux test •  Isotope scans •  Urine analysis •  Lymphangiography to localize •  Blood and Urine cultures retroperitoneal, aortic and iliac •  Stool examination including lymph nodes occult blood •  Exploratory laparotomy •  Liver function tests •  CSF analysis •  Ultrasonography (USG) •  Bone marrow aspiration and biopsy •  Lymph node biopsy •  Liver biopsy 

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Investigations should be appropriate and based on clinical history and physical findings. Table 5.10.3 lists the investigations which are routinely done for patients with FUO. Further investigations depend on the child’s presentation and are listed as advanced investigations. Routine investigations should include total and differential blood counts, peripheral blood smear, ESR, urine analysis, blood culture. Total WBC count greater than 11,000/mm3 have a high likelihood of bacterial infection. Conversely, absolute neutrophil count of less than 5,000/mm3 is against indolent bacterial infection except typhoid fever. Peripheral eosinophilia provides clue to parasitic infestation, immunodeficiency disorder or occult malignancies. Direct blood smear examination with Giemsa or Wright stain reveals organisms of malaria, toxoplasma and relapsing fever. ESR exceeding 30 mm/hour indicates inflammation and need for further evaluation. ESR greater than 100 mm/hour may suggest autoimmune disorders, tuberculosis, Kawasaki’s disease  

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• Jaundice: Infectious hepatitis, Weil’s disease, tuber culosis, acute lymphatic leukemia, malaria, liver abscess. • kin rash: Viral exanthematous illnesses like measles and varicella, meningococcemia, dengue, septicemia, rickettsial illness. • lubbing: Lung abscess, bronchiectasis, SBE and liver abscess. • rthritis: Rheumatic fever, SBE, meningococcemia, and leukemia. • ony tenderness: Septic arthritis and leukemia. • undus: Choroid tubercles in tuberculosis. • ardiovascular system should be examined for murmurs daily.



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for Neisseria gonorrhoeae infection. Connective tissue disorders are four times more common in children who are more than 6 years old. Gender: Chronic granulomatous disease and Bruton’s agammaglobulinemia are X-linked disorders restricted to boys. Pelvic inflammatory disease occurs more often in girls. History of fever in the family members or neighbors may point towards infectious cause of fever. Contact with tuberculosis and past history of exanthe matous illness may suggest the possibility of tuber culosis. Pets in the house raise the possibility of toxoplasmosis, visceral larva migrans and cat scratch disease. History of pica or ingestion of dirt provides clue for toxocara or toxoplasma infections. Note should be made about the presence of epidemics in the community like dengue, enteroviral, leptospiral infections for considering appropriate diagnostic tests. Take details regarding travel to areas with endemic illnesses. Recent history of surgery suggests possibility of occult infection. A history of abdominal pain may suggest intra-abdominal abscess. Medication history should be looked into and should include over the counter preparation and topical agents including atropine (atropine induced fever). Genetic background of the patient is important for conditions like Riley-Day syndrome.

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1. Chandra J. Antipyretics in children. Indian Journal of Pediatrics. 2002;69:69-74. 2. Cunha BA. Fever of unknown origin: focused diagnostic approach based on clinical clues from the history, physical examination, and laboratory tests. Infect Dis Clin N Am. 2007;21(4):1137-87. 3. Long SS. Distinguishing among prolonged, recurrent and periodic fever syndromes. Pediatr Clin N Am. 2005;52:811-35. 4. Lorin MI. Fever of unknown origin. In: McMillan JA, DeAngelis CD, Feigin RD, Warshaw JB (Eds). Oski’s Pediatrics: Principles and Practice, 3rd edition. Lippincott Williams and Wilkins. 1999. pp. 844-48. 5. Lorin MI. Pathogenesis of fever and its treatment. In: McMillan JA, DeAngelis CD, Feigin RD, Warshaw JB (Eds). Oski’s Pediatrics: Principles and Practice, 3rd edition. Lippincott Williams and Wilkins; 1999. pp.848-50. 6. Powell KR. Fever of unknown origin. In: Kliegman RM, Jenson HB, Behrman RE, Stanton BF (Eds). Nelson Text Book of Pediatrics, 16th edition. Philadelphia: Elsevier; 2000. pp. 142-7. 7. Singh M. Fever of acute onset. A practical approach. IAP J Pract Ped. 2002;4:85-90. 8. Singh M. Symptomatic management of fever in children: A rational approach. IAP J Pract Ped. 1999;1:75-80.



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Serial history taking and careful systematic physical examination with judicious and focused laboratory tests are the most useful tools in evaluating children with FUO.

reatment

As far as possible any treatment for FUO should be started only when sufficient grounds for diagnosis are available. Mild antipyretics are given for the patient comfort. Empirical trial with antibiotics may mask the diagnosis of infective endocarditis, osteomyelitis or meningitis. In general observation of the temperature pattern, repeated clinical examination, careful laboratory evaluation and interpretation of the results might throw a light on the diagnosis. Specific treatment depends on the diagnosis.

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or malignancy. Blood culture should include aerobic and anaerobic cultures. Chest X-ray should be initial investigation. X-ray of the sinuses, mastoids or GI tract may be indicated by specific history or physical findings. Other investigations like ultrasonography, CT scan, bone marrow examination must proceed step-wise. Lumbar puncture is necessary in young infant or child with meningeal signs and altered mental status. Isotope scans with technetium-99m, gallium citrate and indium-111 labeled leukocytes help in localizing inflammatory processes. Bronchoscopy, laparoscopy, gastrointestinal endoscopy and mediastinoscopy may be warranted on individual merits of the case. Lymphangiography is resorted to localize aortic, iliac and retroperitoneal lymph nodes. Exploratory laparotomy is performed when all the other diagnostic procedures fail.

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Skin rash in a child with fever is always a cause for great concern. They can be caused by a drug reaction, an infection, or an allergic reaction (Table 5.11.1). The skin can only react to injury in a few ways, and many different agents can cause rashes that look the same. Often, the symptoms in addition to the rash help make the diagnosis, such as a history of insect bites, exposure to other ill children or adults, recent use of medication, environmental exposure, or prior immunizations. Most rashes caused by viruses  do not harm the child and  go away over time without any treatment.  However, some childhood rashes have serious or even life-threatening causes. A physician should be familiar with these rashes. Many rashes can look the same, making it difficult to know the exact diagnosis. About 10% of all febrile children have a dermatological problem. The approach to such a situation is a challenge and in clinical practice, physicians “lean” on their eyes in no other situation more than they do when confronted by an acutely ill child with fever and a skin eruption. The morphology of the skin lesions may contribute reasonably to its cause in relation to the fever. It is common to see more than one type of morphology at a given point of time. Drug reactions are classical examples of such presentation. At times the lesions go through stages, and in such cases the presenting lesion along with relevant evidence from the history on evolution will help clinch the diagnosis. Yet others may start in a particular form and continue the same morphology, as in measles and rubella. Therefore it is mandatory that the physician familiarizes himself with a sound knowledge of the morphology of skin lesions in the different disorders. Definitions of these patterns are given in the chapter on skin diseases in children. Some examples are shown in Table 5.11.2. These are only guidelines and should not be considered as complete and comprehensive. Laboratory work-up, in terms of essential investigations, include: • Complete hemogram • Urine microbiology • Blood biochemistry • Smear examination from skin lesion • Gram/Leishman/AFB staining • Dark field microscopy • LE cell test • Blood serology • Skin biopsy. Many childhood diseases have bacterial or viral causes 218 and include a rash of some type. As study continues and

Table 5.11.1 Some examples of skin rashes in a febrile child  

ntroduction

Allergy •  Urticaria •  Drug rash •  Allergic vasculitis Infection •  Measles •  Varicella •  Dengue fever •  Typhoid •  Rubella •  Herpes zoster (disseminated) •  Scarlet fever •  Meningococcemia Other illnesses •  Kawasaki’s disease (KD) •  Systemic lupus erythematosus (SLE) •  Erythema multiforme •  Toxic epidermal necrolysis (TEN) •  Staphylococcal scalded skin syndrome (SSSS) •  Erythema marginatum (EM) •  Erythema infectiosum •  Dermatomyositis •  Hand foot and mouth disease (HFMD) An algorithmic or stereotyped approach to a child with fever and skin rash would not sound meaningful. Prudence, however, demands a systematic approach. It will comprise of: •  Careful history taking •  Astute clinical examination •  Relevant laboratory work-up In history taking with regard to the fever, the points to be considered include: •  Duration of fever •  Variation with time of day •  Drug intake •  Itching/burning/pain •  Other symptoms With regard to the skin rash, the points to be considered include: •  Distribution of rash •  Morphology or pattern of skin rash •  Evolution •  Prodrome, if any Clinical examination will include: •  Grade of fever •  Pattern of fever •  Type of skin lesions •  Configuration •  Arrangement •  Distribution •  Site of first appearance •  Evolution •  Tenderness •  Mucosal involvement •  Involvement of palms/soles/ hair/ nails •  Other systems

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Table 5.11.2 Examples of various types of rashes and their possible etiology Macules, papules, and blisters Macules and blisters •  Erythema multiforme •  Drug rash •  Toxic epidermal necrolysis (TEN) •  HFMD •  Staphylococcal scalded skin syndrome (SSSS) •  Systemic lupus erythematosus (SLE) •  Varicella •  Erysipelas •  Meningococcemia •  Bacterial endocarditis

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The process seems to be immune-complex mediated. Septicemia, GI hemorrhage, leukopenia, pneumonia, fluid and/or electrolyte imbalance, and renal insufficiency are the major complications that contribute to a mortality rate of approximately 15–40%. Physical examination may show the following: – Pyrexia may be present. – Skin lesions may begin as hot, tender, erythematous morbilliform or discrete macules that rapidly coalesce and become patches of loose skin. These patches may wrinkle, slide laterally, and separate with slight pressure (Nikolsky sign). –

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Life-threatening rashes are uncommon, and the child usually appears quite ill if he or she has a life-threatening rash. Fever and petechiae are the common symptoms. These two symptoms are present with many rashes and are often signs of a more serious condition. Children can develop petechiae from a number of causes. It is not unusual for forceful coughing or vomiting to cause petechiae on the face and chest. Petechiae with fever are more concerning, although most of these children  have a viral illness that does not require any therapy. A small percentage (2–7%) may have diseases that need immediate evaluation. Petechiae are red dots on the skin that do not fade when pressure is applied. The dots represent bleeding from the capillaries leaving a small, temporary blood blister in the skin. Examples include toxic epidermal necrolysis (TEN), erythema multiforme (EM) and staphylococcal scalded skin syndrome (SSSS). These are briefly discussed below.

The oral mucosa especially is susceptible to inflammation, blistering, and erosion. The vaginal tract epithelium also may be involved. – Eye involvement may result in bilateral purulent conjunctivitis, which manifests as edema, crusting, and ulceration with pain and photophobia. – Pulmonary involvement leads to bronchopneu monia in approximately 30% of all cases. Many patients require ventilator support because of respiratory failure. Differential diagnosis: SJS, SSSS No definitive or specific emergent laboratory tests are indicated. Basic laboratory tests may be helpful in planning symptomatic or supportive therapy. No specific definitive therapies for TEN exist; therefore, intensive care is supportive. Care is given to minimize fluid and electrolyte loss and prevent secondary infection. Discontinuation of the offending agent (if identified) should be immediate. Intensive care or critical care specialists should be consulted, depending on severity of disease. Ophthal mologists may manage ocular manifestations and help to prevent sequelae. Further inpatient care includes continuance of supportive care and meticulous wound care to prevent secondary infection. Transfer to intensive care unit or burn unit may be necessary for those patients with involvement of a large body surface area or with hemodynamic instability. Numerous complications appear to be unfavorable prognostic signs. –



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more vaccines become available, these diseases become less of a threat to the child’s long-term health. A rash of any kind should be taken seriously, however, and may require a laboratory work-up for evaluation. Since the viral and bacterial disorders are described elsewhere, this chapter will deal with the more serious lifethreatening and vascular drug rashes.

Macules only •  Dermatomyositis •  Urticaria •  Allergic vasculitis •  Scarlet fever •  Kawasaki’s disease •  Erythema infectiosum •  Measles •  Rubella •  Erythema marginatum •  Typhoid

ultiforme

A reaction of the skin to different causes, such as viral infections (commonly herpes simplex), bacterial, mycotic or parasitic infections drugs or systemic diseases (rheumatic fever, systemic lupus erythematosus, etc.). Exhibited clinically as characteristic erythematous irisshaped papules. The characteristic lesions are also known as target lesions. The eruption begins rapidly with varying degrees of constitutional symptoms.

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Staphylococcal scalded skin syndrome (SSSS) is a toxinmediated epidermolytic disease characterized by erythema and widespread detachment of the superficial layers of the epidermis, resembling the effects of scalding. Nikolsky sign is positive. Mucous membranes are usually uninvolved. Investigations include Gram staining.

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ullous impetigo: findings include pus in bullae and clumps of Gram-positive cocci within PMNL. – Generalized : Gram-positive cocci are only observed at colonized site, not in areas of epider molysis. Bacterial culture may be yielding. For a newborn, hospitalization and treatment with IV cloxacillin, 200 mg per kg body weight per day in divided every 4 hours, are preferable. Hospitalize infants with extensive sloughing of skin or if parental compliance to treatment is questioned. With reliable home care and mild involvement, cloxacillin, 30–50 mg per kg body weight per day, can be given orally. Topical care includes baths or compresses, and sisomicin/mupirocin ointment. –

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The reader is reminded that the above description is narrated only as guidelines and is advised to refer to other standard books of dermatology for more comprehensive information.

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The mucous membranes are severely involved and there are severe general constitutional symptoms. Skin lesions may be pruritic or painful. Mouth lesions are painful and tender. All attempts must be made to rule out occult viral, fungal, and bacterial infections. Systemic corticosteroids are usually given (prednisolone 50 to 80 mg daily in divided doses, quickly tapered), but their effectiveness has not been established by controlled studies. S

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ight microscopy of well stained thick and thin films by a skilled microscopist has remained the ‘gold standard’ for diagnosis. Thick films are nearly 10 times more sensitive for diagnosis of malaria as larger amount of blood is there in a given area compared to thin films. Species identification is better with thin films as morphology of the parasite and RBCs is well preserved. Sample collection should be done as soon as malaria is suspected. It can be collected any time irrespective of fever and not necessarily only at the height of fever. Collection should be before administration of antimalarials which causes detection of parasites difficult due to its morphologic alteration. DT

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Fever is the most important feature of malaria. The symptom complex is non-specific and may mimic other diseases with fever. Fever is often accompanied by headache, nausea, vomiting, aches and pains in muscles and joints, chills and lassitude. In endemic areas diagnosis of malaria on the basis of symptoms alone invariably leads to over-diagnosis due to their non-specificity. If not diagnosed in time the parasite burden, particularly in falciparum malaria, may increase leading to severe malaria often in a few hours. Severe malaria if left untreated has mortality nearly up to 100%, but timely adequate supportive care and specific antimalarial therapy can reduce around 80% of deaths. Severe malaria is characterized by one or more of the following clinical or laboratory features: • Impaired consciousness or non-arousable coma • Prostration so that the patient is unable to walk or sit up without assistance • Failure to feed • Multiple convulsions, more than two episodes in 24 hours • Deep breathing, respiratory distress (acidotic breathing) • Circulatory collapse or shock, systolic blood pressure <50 mm Hg in children • Clinical jaundice plus evidence of other vital organ dysfunction • Hemoglobinuria

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Malaria is caused by the protozoan parasite of the genus Plasmodium through bite of female anopheles mosquito. The four Plasmodium species that infect humans are P. falciparum, P. vivax, P. ovale and P. malariae of which the first two are the main causative agents in our country.

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Abnormal spontaneous bleeding Pulmonary edema (radiological) The laboratory features include: • Hypoglycemia (blood glucose <40 mg/dl) • Metabolic acidosis (plasma bicarbonate <15 mmol/ ) • Severe normocytic anemia (Hemoglobin <5 g/dl, PCV <15%) • Hyperparasitemia (>2% or 100,000/m ) • Renal impairment (serum creatinine >3 mg/dl) • Hyperlactemia (lactate >5 mmol/ ) Though all manifestations of severe malaria may be seen in children, the most common are cerebral malaria, severe anemia, respiratory distress due to acidosis and hypoglycemia. Convulsions are common in children and symptoms preceding coma are very brief, i.e. 1–2 days. Generalized seizures are the most common features of cerebral malaria in children. Repeated seizures more than two in a 24 hoursperiod may occur. The most common neurological feature is symmetrical upper motor neuron lesions. Severe anemia with hepatomegaly, gallop rhythm and heart failure is common. Indrawing of lower chest wall without any localizing sign in the chest suggests metabolic acidosis and is seen in malaria with severe anemia and dehydration. Hypoglycemia often presents with convulsions or coma.



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Malaria is a major public health problem of developing countries. About 1.5 million cases of malaria are reported annually of which nearly 50% is due to Plasmodium falciparum which is rising in recent years. The magnitude of the problem is further enhanced by resistance of P. falciparum to standard antimalarial drugs particularly chloroquine. The important contributing factors to drug resistance are population movement, infrastructure deficiency, deforestation, unplanned development, drug pressure and haphazard use of drugs. Drug pressure is the single most important factor in the development of resistance followed by presumptive antimalarial treatment.

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to report resistance. So to counter the threat of resistance of falciparum to monotherapy, the WHO recommends combinations of antimalarials for the treatment of falci parum malaria. D

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WHO recommends combination of antimalarials for the treatment of falciparum malaria to improve treatment outcome and halt the threat of resistance to monotherapy. Antimalarial combination therapy is the simultaneous use of two or more blood schizonticidal drugs with independent mode of action and unrelated biochemical target in the parasite. If a mutant parasite arises de novo during the course of infection to one drug it will be killed by the other drug. However, to reap the benefit of combination therapy the partners in the combination should be individually effective. This mutual protection will prevent or at least delay emergence of resistance to individual drugs. The only disadvantage of combination therapy is increased risk of adverse effects and increased cost of therapy. According to WHO, one of the partners in combination therapy will be artemisinin and its derivatives, hence known as artemisinin based combination therapy (ACT). The reason for choosing artemisinin is its rapid clearance of parasitemia and resolution of symptoms. They reduce the parasite number by approximately 10,000 fold (104) in each asexual cycle. The second important reason is its rapid elimination from the body so that the residual concentration of the drug does not provide a selective filter for resistant parasites. The other reasons include its lack of serious adverse effects and absence of significant resistance till date. It has also the advantage of reducing gametocyte carriage and thus transmission of malaria which is particularly important in malaria control. If artemisinin is combined with other rapidly eliminated antimalarials like tetracycline or clindamycin, a seven days course of treatment is required. This long course invariably results in poor adherence but when combined with slowly eliminated antimalarials like SP, mefloquine (MQ) or lumefantrine shorter courses of treatment (3 days) will be effective and also ensure adherence. Slowly eliminated partner drug persists at parasiticidal concentration until all the infecting parasites have been killed. The following ACTs are currently, available in our country: • Artesunate (AS) + SP • Artesunate + MQ • Artemether- umefantrine L



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Malaria in children has some unique features. Young children below 5 years of age, whose passive immunity wanes and have not developed sufficient immunity of their own, are most vulnerable. Falciparum malaria can be rapidly progressive leading to rapid clinical deterioration; hence this group needs constant monitoring. Children can tolerate antimalarial drugs better than adults and their symptoms resolve more quickly following successful treatment. Malaria parasite develops resistance to drugs randomly due to de novo genetic mutations. Non-immune patients of our country are infected with large number of parasites and if they receive inadequate treatment, they become potent sources of de novo resistance. Here lies the importance of prescribing highly effective treatment regimen in hyper parasitemic patients and ensuring good adherence to prescribed drugs. It has been noted that monotherapy in case of resistant falciparum malaria invariably results in failure. Sulfadoxinepyrimethamine (SP) introduced following chloroquine 222 (CQ) resistance was ineffective in the early 1980s. Similarly mefloquine introduced as monotherapy took only 4–5 years

In India first reports of resistance of P. falciparum to CQ came from Diphu of Karbi Anglong district in Assam. Thereafter it started spreading throughout the country. There are reports of resistance to SP at various levels in districts of seven north eastern states. Though few reports of emergence of chloroquine resistant P. vivax are there, the drug still retains its effectivity against vivax malaria in our country.



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Other diagnostic methods namely microscopy using fluorochromes on centrifuged blood specimens, molecular probes, polymerase chain reaction (PCR) and serology are available. Unfortunately they are not suitable for routine disease management and do not have wide field application. Their use is currently for only research and epidemiological purposes.

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antigens. In our country, where falciparum and vivax malaria parasites co-circulate, typically occurring as a single species infection, a RDT which can detect both falciparum and vivax malaria and distinguish between them is warranted. aboratory confirmation of malaria is an essential component of disease management. Expert microscopic diagnosis is available in central levels of health care system like metro cities but is often unreliable or unavailable in areas with poor health facilities. So RDT will be useful in following situations in our country: • In faraway communities with poor health care facilities where microscopic diagnosis is not available. Also in areas where laboratory service is inadequate, of an unacceptable standard or not available at odd hours. • In places where quality microscopy is available, RDT and microscopy can run in parallel. RDT will provide rapid or screening diagnosis whereas microscopy is reserved for resolution of confusing cases, confirmation of negative result in RDT with high clinical suspicion of malaria. • In some cases of severe and complicated malaria, peripheral parasitemia may be negative due to sequest ration but RDT is expected to provide evidence of anti genemia.

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be fatal. Confirmation of the diagnosis is preferable but one should not delay the treatment if it needs more than 1 hour. Further in cases of strong clinical suspicion, prompt antimalarial therapy is needed even if parasites are not found in the initial blood examination. Effective therapy in children with severe malaria includes antimalarial chemotherapy, supportive management and management of complications. All these three interventions are equally important and to be taken care of simultaneously.



Ideally, antimalarial drug should be given initially by intravenous infusion, which should be replaced by oral administration as soon as condition permits. After weighing the patient antimalarials should be given according to the body weight. According to the National Anti-Malarial Program (NAMP) drug policy in all cases of severe malaria either IV quinine or parenteral artemisinin derivatives are to be given irrespective of chloroquine resistance status. A single dose of primaquine (0.75 mg/kg) is to be given for gametocytocidal action irrespective of the drug given. • oading dose of quinine should not be used if the 223 patient has received quinine, quinidine or mefloquine L

 

 

 

Table 5.12.1 Recommended treatment in chloroquine sensitive malaria Drug sensitivity Recommended treatment P. vivax and Chloroquine Chloroquine 10 mg base/kg stat orally followed sensitive P. falciparum by 5 mg/kg at 6, 24 and 48 hours (total dose 25 mg/kg) OR Chloroquine 10 mg base/kg stat orally followed by 10 mg/kg at 24 hours and 5 mg/kg at 48 hours (total dose 25 mg base/kg) In case of vivax malaria to prevent relapse primaquine should be given in a dose of 0.25 mg/kg once daily for 14 days In case of falciparum malaria a single dose of primaquine (0.75 mg/kg) is given for gametocytocidal action Note: 1. Chloroquine should not be given in empty stomach and in high fever. Temperature should be brought down first. If vomiting occurs within 45 minutes of a dose of chloroquine that particular dose is to be repeated after taking care of vomiting by using antiemetic (Domperidone/Ondansetron). 2. As primaquine can cause hemolytic anemia in children with G6PD deficiency, they should preferably be screened for the same prior to starting treatment. As infants are relatively G6PD deficient, it is not recommended in this age group. In cases of borderline G6PD deficiency, once weekly dose of primaquine, 0.6–0.8 mg/kg, is given for 6 weeks.

 

Severe life-threatening malaria is nearly always due to P. falciparum. All cases with severe manifestations are to be treated in the same line of complicated malaria with injectable antimalarials irrespective of the species. High degree of suspicion of severe malaria is of utmost importance and any delay in initiation of treatment can

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Treatment regimens are to be tailored specifically according to the resistance pattern of the region under consideration. According to the National Vector Borne Disease Control Program, ACT in falciparum malaria is being implemented in 117 districts (i.e. 50 highly endemic districts of states, viz. Andhra Pradesh, Chhattisgarh, Jharkhand, Madhya Pradesh and Orissa + 67 in North Eastern States) in addition to 256 PHCs of 48 districts included on the basis of chloroquine resistance status (www.nvbdcp.gov.in/malaria-new.html). However, in view of gradually increasing resistance, it has been suggested that all falciparum cases may be treated with ACT both in public or private health care system to win the war against ongoing drug resistance. Different treatment regimens according to the status of drug resistance pattern are shown in Tables 5.12.1 to 5.12.3.

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Table 5.12.2 Recommended treatment in chloroquine resistant P. falciparum malaria Drug sensitivity Recommended treatment Chloroquine resistant P. Artesunate 4 mg/kg of body weight orally once falciparum daily for 3 days and a single administration of SP as 25 mg/kg of sulfadoxine and 1.25 mg/kg of pyrimethamine on day 1 OR Artesunate as above and mefloquine 25 mg/kg of body weight in two divided doses (15 mg/kg and 10 mg/kg) on day 2 and day 3 OR Co-formulated tablets containing 20 mg of artemether and 120 mg of lumefantrine can be used as a six-dose regimen orally twice a day for 3 days. For 5–14 kg body weight one tablet twice daily. For 15–24 kg body weight same schedule with two tablets. For 25–35 kg body weight and above same schedule with three and four tablets, respectively A single dose of primaquine (0.75 mg/kg) is given for gametocytocidal action Note: 1. Currently there are insufficient safety and tolerability data on mefloquine at its recommended dosage of 25 mg/kg body weight in children. Mefloquine shares cross resistance with quinine which is still an effective drug in our country. Health planners of our country do not advocate use of mefloquine. 2. Advantage of artemether lumefantrine combination is that lumefantrine is not available as monotherapy and has never been used alone for the treatment of malaria. Lumefantrine absorption is enhanced by co-administration with fatty food like milk.

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Of these artemether-lumefantrine is available as coformulated tablets and lumefantrine is not available as monotherapy. Other combinations are available separately.

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within the preceding 12 hours. Alternatively loading dose can be administered as 7 mg salt/kg by IV infusion pump over 30 minutes, followed immediately by 10 mg salt/kg diluted in 10 ml isotonic fluid/kg by IV infusion over 4 hours. Quinine should not be given by bolus or push injection. Infusion rate should not exceed 5 mg salt/kg/hour. If there is no clinical improvement after 48 hours of parenteral therapy the maintenance dose of quinine should be reduced by one-third to one half, i.e. 5–7 mg salt/kg. Quinine should not be given subcutaneously as this may cause skin necrosis. Artesunate, 60 mg per ampoule is dissolved in 0.6 ml of 5% sodium bicarbonate diluted to 3–5 ml with 5% dextrose and given immediately by IV bolus (push injection). Artemether is dispensed in 1 ml ampoule containing 80 mg of artemether in peanut oil.

Table 5.12.4 Recommended treatment of complicated and severe malaria Drug Dosage Artesunate 2.4 mg/kg IV stat then at 12 and 24 hours, then once a day. Parenteral antimalarials should be used for a minimum of 24 hours, once started irrespective of the patients ability to swallow oral medication, and, thereafter, complete the treatment by giving a course of: Artemether plus lumefantrine OR Artesunate plus sulfadoxine-pyrimethamine as shown in Table 5.12.2 Artemether 3.2 mg/kg (loading dose) IM stat, should only be used if none of the other alternative are available as its absorption may be erratic. Followed by 1.6 mg/kg daily. Parenteral antimalarials should be used for a minimum of 24 hours, once started irrespective of the patients ability to swallow oral medication, and, thereafter, complete the treatment by giving a course of : Artemether plus lumefantrine OR Artesunate plus sulfadoxine-pyrimethamine as shown in Table 5.12.2. Quinine salt 20 mg salt/kg (loading dose) diluted in 10 m of isotonic fluid/kg by infusion over 4 hours. Then 12 hours after the start of loading dose give a maintenance dose of 10 mg salt/kg over 2 hours. This maintenance dose should be repeated every 8 hours, calculated from beginning of previous infusion, until the patient can swallow, then quinine tablets, 10 mg salt/kg 8 hourly to complete a 7-day course of treatment (including both parenteral and oral). Tetracycline or doxycycline or clindamycin is added to quinine as soon as the patient is able to swallow and should be continued for 7 days as shown in Table 5.12.3. If controlled IV infusion cannot be administered, quinine salt can be given in the same dosages by IM injection in the anterior thigh (not in buttocks). The dose of quinine should be divided between two sites, half the dose in each anterior thigh. If possible IM quinine should be diluted in normal saline to a concentration of 60–100 mg salt/m (Quinine is usually available as 300 mg salt/m ). Tetracycline or doxycycline or clindamycin should be added as above. l

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Table 5.12.3 Recommended treatment of multidrug resistant P. falciparum (Both to CQ and SP) Drug sensitivity Recommended treatment Multidrug resistant P. Artemether lumefantrine combination orally as falciparum, i.e. both to in Table 5.12.2 CQ and SP OR Artemether mefloquine combination orally as in Table 5.12.2 OR Quinine, 10 mg salt/kg/dose orally 3 times daily for 7 days + Tetracycline (above 8 years) 4 mg/ kg/dose 4 times daily for 7 days OR Doxycycline (above 8 years) 3.5 mg/kg daily for 7 days OR Clindamycin 20 mg/kg/day in 2 divided doses for 7 days In case of developing cinchonism, Quinine, 10 mg salt/kg/dose orally 3 times daily for 3–5 days + Tetracycline (above 8 years) 4 mg/kg/dose 4 times daily for 7 days OR Doxycycline (above 8 years) 3.5 mg/kg daily for 7 days OR Clindamycin 20 mg/kg/day in 2 divided doses for 7 days OR A single dose of primaquine above 1 year age (0.75 mg/kg) is given for gametocytocidal action Note: 1. Doxycycline is preferred to tetracycline as it can be given once daily and does not accumulate in renal failure. 2. One of the drawbacks of quinine therapy is its long course. Unsupervised and ambulatory setting may decrease patient’s compliance and many patients might not complete the full course of prescribed therapy. 3. Fortunately children tolerate quinine better than adults.

Quinine or Artemisinin—Which One to Use? Artemisinin are the most rapidly acting of all known antimalarial drugs, they often produce a 10,000 fold reduction of parasites per asexual cycle. They have the broadest time window of antimalarial effects from ring forms to early schizonts. Thus they can stop parasite maturation, particularly from the less pathogenic circulating ring stages to the more pathogenic cytoadherent stages. Artemisinin also has an excellent safety profile and the cost of therapy as compared to quinine is almost similar. There are no reports of resistance to artemisinin at present but declining sensitivity to quinine has been reported from some South East Asian countries like Thailand. Moreover, the WHO GRADE panel

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Deep breathing with indrawing of lower chest wall without any localizing chest signs suggest lactic acidosis. It usually accompanies cerebral malaria, anemia or dehydration. Correct hypovolemia, treat anemia and prevent seizures. Monitor acid base status, blood glucose and urea and electrolyte level.

Hypoglycemia It is common in children below 3 years especially with hyperparasitemia or with convulsion. It also occurs in patients treated with quinine. Manifestations are similar to those of cerebral malaria so it can be easily overlooked. Monitor blood sugar every 4–6 hours. If facilities to monitor blood glucose are not available assume hypoglycemia in symptomatic patient and treat accordingly. Correct hypoglycemia with IV dextrose (25% dextrose 2–4 ml/kg by bolus) and it should be followed by slow infusion of 5% dextrose containing fluid to prevent recurrence. B

Of the various complications of falciparum malaria the common and important ones in children are as follows: • Cerebral malaria • Severe anemia • Respiratory distress (acidosis) • Hypoglycemia

Lactic cidosis

ibliography 1. Guidelines for the Treatment of Malaria, 2nd edition. World Health Organization; 2010. 2. Guidelines for Diagnosis and Treatment of Malaria in India 2009. Published by Director, National Institute of Malaria Research. New Delhi.

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Children with hyperparasitemia due to acute destruction of red cells may develop severe anemia. Packed red cell transfusion should be given cautiously when PCV is 12% or less, or hemoglobin is below 4 g%. Transfusion should also be considered in patients with less severe anemia in the presence of respiratory distress (acidosis), impaired consciousness or hyperparasitemia (>20% of RBCs infected).



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Rapid clinical assessment with respect to level of consciousness (Use Blantyre coma scale), blood pressure, rate and depth of respiration, anemia, state of hydration and temperature. • Good nursing care with proper positioning, meticulous attention to airways, eyes, mucosa and skin should be done. • For unconscious child nasogastric tube is to be inserted to reduce the risk of aspiration. • Oxygen therapy and respiratory support should be given if necessary. • In case of shock resuscitate with Normal saline or Ringer lactate by bolus infusion. Avoid under or over-hydration. • Hyperpyrexia should be treated with tepid sponging, fanning and paracetamol. • Close monitoring of the vital signs preferably every 4 hours to be done till the patient is out of danger. Also maintain intake output chart and watch for hemoglobinuria. • Monitoring of the response to treatment is essential. Blood smear examination every 6–12 hours for parasitemia for first 48 hours is needed. • In case of artemisinin derivatives parasite count usually comes down within 5–6 hours of starting therapy. Asexual parasitemia generally disappears after 72 hours of therapy. • In case of quinine parasite count may remain unchanged or even rise in first 18–24 hours which should not be taken as an indicator of quinine resistance. However, parasite count should fall after 24 hours of quinine therapy and should disappear within 5 days. M

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Initial presentation is usually fever followed by inability to eat or drink. The progression to coma or convulsion is usually very rapid within 1 or 2 days. Convulsions may be very subtle with nystagmus, salivation or twitching of an isolated part of the body. Effort should be given to exclude other treatable causes of coma (e.g. bacterial meningitis, hypoglycemia). Patients should be given good nursing care, convulsions should be treated with diazepam/midazolam and avoid harmful adjuvant treatment like corticosteroids, mannitol, adrenaline and phenobarbitone.



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Laboratory iagnosis The diagnosis of kala-azar is substantiated by direct demonstration of amastigote form of parasites in blood, bone marrow, spleen, liver and lymph node aspirates or promastigote forms in culture of aspirated materials in NNN media and modified USMARAO media. The splenic aspiration and smear examination is the most sensitive (95–98%) method. Prior assessment of coagulation profile including platelet count and INR are essential as this procedure may lead to splenic hemorrhage and if massive may lead to death. The contraindications of splenic aspiration are INR more than 2.5 and platelet count less than 40,000/cu mm. Bone marrow aspiration is usually without any risk and positive in 75–85% of cases. Lymph node aspiration and liver biopsy are positive in 60% and 50% of cases, respectively. The peripheral smear in kala-azar usually shows anemia, thrombocytopenia, leukopenia with neutropenia, marked eosinopenia and relative lymphocytosis and monocytosis. The ratio of WBC to RBC may be altered from 1:750 to 1:2,000-1:10,000. ­

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erological Tests ldehyde test (Napier test): It is simple and non-specific test for kala-azar. The increase in immunoglobulin is the basis of this test. The sensitivity of this test is 35–94% with poor specificity. False positive reactions may occur in children with cirrhosis, malaria and multiple myeloma. In this test, 1 or 2 drops of formalin (40%) are added to 1–2 m of patient’s serum in a test tube. The egg white jellification of serum with opacification within 2–20 minutes indicates strongly positive reaction, and within 24 hours weakly positive. ­

The incubation period is 2–6 months but there may be wide variations between 2 weeks and 2 years. A large majority of the cases have insidious onset though acute onset may rarely be seen with high fever and rapidly enlarging spleen. Persistent, mild to moderate, intermittent pyrexia with enlargement of spleen in 2–4 weeks’ time is the characteristic feature. Liver enlargement occurs rather slowly. Fever, hepatosplenomegaly and pallor are seen in more than 95% of cases. Malnutrition in association with pigmentation of skin, polymorphic waxy non-ulcerating nodules and sparse, falling and brittle hairs are the additional manifestations. Appetite is however good. Rarely it may present as bleeding; epistaxis, hematemesis, melena and retinal hemorrhage. The serious complications may occur in kala-azar and include pneumonia, dysentery, severe hemorrhage, agranulocytosis, acute glomerulonephritis, amyloidosis, 226 papilledema, jaundice and cancrum oris. Cancrum oris, also

The diagnosis of kala-azar is usually clear from clinical manifestations. However chronic cases need to be differentiated from tropical splenomegaly, malaria, Hodgkin disease, leukemia, tuberculosis and hemolytic anemia. At times, cirrhosis and storage diseases also warrant exclusion. When the onset is typhoid-like, kala-azar should be differentiated from enteric fever, septicemia, miliary tuberculosis, brucellosis and hepatic amebiasis. Kala-azar with malaria-like onset needs differentiation from malaria, urinary tract infection and tuberculosis.

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Kala-azar is distributed worldwide with about 12 million people infected and about 1.5 million new cases each year (WHO). Fifty percent of these cases are children. In India, it is endemic in Bihar, West Bengal, Orissa, Assam, Sikkim and eastern Uttar Pradesh but sporadic cases have been reported from different parts of the country. Furthermore Leishmania donovani has emerged as opportunistic pathogen of HIV-infected children. Human beings are the only reservoir of infection in India. Kala-azar does not usually occur above 600 meter altitude. The disease is more or less confined to rural areas, especially those along rivers (Ganga-Brahmaputra) and lakes. Its epidemic is known to follow famine and war. In recent years, it no longer remains restricted to its known geographical belt, thereby altering its epidemiological scenario.

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Leishmaniasis refers to a diverse group of diseases that may affect viscera, skin or mucous membranes caused by infection due to parasites of genus Leishmania. Kalaazar (visceral leishmaniasis) is a chronic infection of reticuloendothelial system characterized by intermittent fever, hepatosplenomegaly, cachexia and anemia. In India, etiological agent is a protozoal parasite, Leishmania donovani, a hemoflagellate. Transmission occurs by the bite of infected sand fly. Parasitization of reticuloendothelial system, such as spleen, liver, lymph node and bone marrow, accounts for the salient features of the disease.

called gangrenous stomatitis, is characterized by gangrene of the cheek and adjacent structures and is believed to be caused by an organism, Treponema vincentii. This organism is capable of producing rapid tissue destruction in debilitated patient.

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Children on anti-leishmanial therapy should be monitored clinically (fever), hematologically (Hb, TLC, DLC), biochemi cally (CRP), by splenic size and parasitological index.

Prophylaxis The sheet anchor of prevention is control of sand fly and early detection and treatment of kala-azar cases. Spraying of houses and breeding places such as crevices in the walls with residual insecticides and use of mosquito nets during night are very effective. Kala-azar vaccine, based on combination of leishmanial antigen and BCG vaccine, is round the corner.













1. Bhattacharya SK, Sur D, Karbwang J. Childhood visceral leishmaniasis. Indian J Med Res. 2006;123:353-6. 2. Murray HW, Berman JD, Davies CR, et al. Advances in leishmaniasis. Lancet. 2005;366:1561-77. 3. Prasad R, Kumar R, Jaiswal BP, et al. Miltefosine: an oral drug for visceral leishmaniasis. Indian J Pediatr. 2004;71:143-4. 4. Singh UK, Prasad R, Mishra OP, et al. Miltefosine versus Amphotericin B in children with visceral leishmaniasis: a prospective, multicentric, observational study. Indian J Pediatr. 2006;73:1077-80. 5. Singh UK, Prasad R, Mishra OP. Visceral leishmaniasis. In: Gupte S (Ed). Recent Advances in Pediatrics, vol.15. New Delhi: Jaypee Medical Publishers; 2005. pp. 212-25. 6. Singh UK, Prasad R, Jaiswal BP, et al. Amphotericin B therapy in children with visceral leishmaniasis: Daily versus alternate day, a randomized trial. J Trop Pediatr. 2010;56:321-4.







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The specific treatment consists of administration of anti-leishmanial drug. In the last decade, a lot of new parenteral drugs have been tried and found to be effective but the availability of an oral anti-leishmanial drug has revolutionized therapy. Pentavalent antimonials, especially sodium stibogluco nate (SSG), were commonly used previously for treatment of kala-azar despite a gradual increase in resistance against them. WHO has recommended that SSG should be used in a dose of 20 mg/kg/day (maximum 850 mg) IM once daily for 30 days but duration may be extended up to 40 days in non-responders. Approximately 60–80% of injected drug undergoes renal excretion within 6 hours; hence toxicity is very low. Children tolerate this drug better than adults. Toxic effects of SSG include hypersensitivity, arthralgia, myalgia, hepatitis, renal dysfunction, myocarditis and rarely pancreatitis. Unfortunately majority of patients in endemic areas are resistant to SSG. Amphotericin-B, an antifungal antibiotic which acts by binding to and inhibiting synthesis of sterol in the membrane of parasites creating multiple holes is very effective. Government of India has recommended amphotericin as first-line drug in treatment of visceral leishmaniasis. The dose is 0.5–1 mg/kg IV with 5% dextrose over 6 hours daily or alternate day till a cumulative dose of 7.5–20 mg/kg. Toxic effects include anaphylaxis, thrombocytopenia, convulsions, chills, fever, thrombophlebitis, anemia, hypokalemia, renal, liver and cardiac damage. Thus all patients should be monitored clinically and for electrolyte disturbances particularly hypokalemia. Recently three new lipid associated formulations of amphotericin-B have been found to be very effective. They are liposomal amphotericin B, cholesterol dispersion amphotericin B and amphotericin B lipid complex of which the former is approved by FDA. The dose of liposomal amphotericin-B is 3 mg/kg IV on days 1–5, 14 and day 21.

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The main disadvantage is high cost of therapy but it achieves a higher concentration in reticuloendothelial system with more targeted response and no appreciable toxicities. Aminosidine is an effective (95%) and well tolerated anti-leishmanial drug. The dose is 15 mg/kg/day IM for 21 days. Some authors recommend this drug as first line antileishmanial drug in endemic areas of kala-azar. Miltefosine, a phosphocholine analog which was developed as antimalignant drug has shown to be highly active against L. donovani and cure rate is more than 95% in India. It is given orally in a dose of 2.5 mg/kg/day OD or BD for 28 days. Side effects are transient and reversible and include GI disturbances, hepatic and renal dysfunction. It is cheap, safe, very effective and easy to administer. Combination therapy using SSG, amphotericin B, miltefosine and aminosidine in various doses and schedules is under phase III trial and observed to be highly effective but final recommendation is yet to come. Splenectomy needs to be reserved for cases with poor response to conventional anti-leishmanial drug and massive splenomegaly. It should be followed by SSG, 20 mg/kg/day IM for 20–40 days and penicillin prophylaxis. Prior to splenectomy, children must be vaccinated against Meningococcus, Pneumococcus and H. influenzae.

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thers serological tests: Tests which detect antileishmanial antibodies may be positive for a long time even after cure or in healthy individuals living in endemic areas due to asymptomatic infection. DAT (Direct agglutination test) is very useful in diagnosis and epidemiological studies, whereas ELISA helps to follow the disease during and after therapy. DAT measures antileishmania antibody titers using freeze dried antigen. It is simple, cheap and effective. A titer of 1:1600 or above is taken as positive. Its sensitivity is 94.8% and specificity; 85.9%. The K39 dipstick test is highly specific for diagnosis of visceral leishmaniasis. It detects antibodies to a specific 39 amino acid sequence (K39) and easy to perform. Its sensitivity is 93.95 and specificity 90.6%. • N detection: The minicircle sequence of kDNA is unique and species specific. PCR offers the best approach to parasite detection and characterization by amplifying sequence found in minicircle of leishmania.

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to DEN-4. Viruses belong to the genus Flavivirus, family Flaviviridae which contains approximately 70 viruses.

ntroduction

Dengue fever was considered as a mild febrile illness in the mid-20th century; however the image of dengue underwent a drastic change in the mid-1950s. South East Asian countries experienced epidemics of a serious disease associated with dengue viruses. Patients afflicted with this new illness exhibited two potentially mortal symptoms; bleeding diathesis and shock. Dengue hemorrhagic fever (DHF)dengue shock syndrome (DSS) was the new name coined for this entity. By 1975, it had become a leading cause of hospitalization and death among children in many countries. In the 1980s, DHF began a second expansion to other Asian countries. India, Sri Lanka, Maldives, Bangladesh and Pakistan experienced major DHF epidemics. India is one of the worst hit countries. Hyperendemicity, i.e. circulation of multiple serotypes has become frequent. The recent epidemics in Sri Lanka and India were associated with multiple dengue virus serotypes, although DEN-3 is distinctly more prominent. By the end of the century the geographic distribution of dengue viruses has further expanded and DHF has emerged in the Pacific region and the Americas. Today, dengue has emerged as an important threat to public health worldwide (Fig. 5.14.1); it is estimated that over 50 million dengue virus (DENV) infections occur annually resulting in 500,000 hospitalizations and over 20,000 deaths.

Dengue viruses (DENV) are arthropod borne viruses. They use mosquitoes mostly the Aedes aegypti and rarely the Aedes albopictus, as vectors to perpetuate infection cycle. Vectors also serve to amplify viral replication. A. aegypti, the principal vector (Fig. 5.14.2), is a small, black-and-white, highly domesticated tropical mosquito that prefers to lay its eggs in artificial containers commonly found in and around homes. The adult mosquitoes like to feed on humans during daylight hours. There are two peaks of biting activity, early morning for 2–3 hours after daybreak and in the afternoon for several hours before dark. The female mosquitoes are very anxious feeders, disrupting the feeding process at the slightest movement, only to return to the same or a different person to continue feeding moments later. A. aegypti females will often feed on several persons during a single blood meal and, if infective, may transmit dengue virus to multiple persons in a short time. Therefore, it is not uncommon to see several members of the same household become ill with dengue fever within a 24–36 hours’ time frame. This particular behavior of A. aegypti makes it a very efficient epidemic vector. If A. aegypti mosquitoes bite a person with dengue illness during febrile viremic stage it may become infected and subsequently transmit the virus to other uninfected persons, following an extrinsic incubation period of 8–12 days.



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Transmission Dengue illnesses are caused by four closely related but antigenically distinct serotypes designated as DEN-1

Figure 5.14.1 Current global status of dengue illnesses  

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Dengue illnesses range from asymptomatic infection, to mild undifferentiated fever, to fatal shock. Till very recently WHO identified two types of dengue illnesses: dengue fever (DF) a mild self-limiting febrile illness and dengue hemorrhagic fever (DHF) a potentially fatal condition pathognomonized by leaky vasculopathy. As per disease severity DHF was further divided into four categories: • Grade : Thrombocytopenia, hemoconcentration, positive TT (tourniquet test) and absence of spontaneous bleeding. • Grade : Thrombocytopenia, hemoconcentration, posi tive TT and presence of spontaneous bleeding. • Grade : Thrombocytopenia, hemoconcentration, positive TT and circulatory insufficiency (feeble pulse, drop of 20 mm Hg or greater in arterial blood pressure, cold extremities and apprehension). • Grade V: Thrombocytopenia, positive TT, hemocon centration, imperceptible pulse and blood pressure. Grade III and IV are known as dengue shock syndrome (DSS). According to WHO guidelines, DHF cases must fulfill all four following criteria: • Fever or history of acute fever lasting 2–7 days. • Hemorrhagic tendencies evidenced by at least one of the following: a positive tourniquet test (TT), petechiae, purpura, ecchymoses; bleeding from mucosa, gastrointestinal tract, injection sites or other location hematemesis, and melena. • Thrombocytopenia (platelets less than 100,000/cumm). • Evidences for plasma leakage in DHF: More than 20% rise in hematocrit, fluid in serous cavities documented by X-ray or USG. ­

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The cardinal feature which discerns DHF from dengue fever (DF) is a transient increase in vascular permeability that results in the leakage of fluid from the plasma into the interstitium. Extravasated fluid primarily collects into serous cavities: peritoneum, pleura, and pericardium. The leakage results in hemoconcentration, and hypovolemia. After a few hours to days, the increased vascular perme ability spontaneously resolves, the extravasated fluid gets reabsorbed, and the patient recovers quickly. In minority of patients leak is severe and prolonged, progressively leading to hypovolemia, hypotension, shock and ulti mately death. Dengue hemorrhagic fever usually occurs in two clinical settings: secondary dengue infection at any age and primary dengue infection in an infant. In majority of human studies pre-existence of non-neutralizing antibodies either from previous infection or transplacental mother to child transmission is the most consistently documented risk factor for DHF. First infection with any of the dengue virus in a dengue virgin body results in self-limiting febrile illness. Recovery from this first infection is accompanied by generation of immunological responses. Epitopes present in E protein are

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Dengue is small spherical single stranded RNA virus with a lipid envelope. The viral genome encodes three structural proteins (capsid C_protein, membrane M_glycoprotein and envelope E_protein) and seven non-structural proteins (NS1, NS2a, NS2b, NS3, NS4a, NS4b, and NS5). NS1 is the only non-structural protein with a soluble form that can be detected in circulation. Infection with one dengue serotype provides lifelong immunity to that serotype, but there is no cross protective immunity to the other serotypes. Thus, persons living in an area of endemic dengue can be infected with three and probably four dengue serotypes during their lifetime.

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Figure 5.14.2 Aedes aegypti

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capable of inducing homologous as well as heterologous neutralizing and non-neutralizing antibodies. Levels of these antibodies have a central role in driving dengue infection to mild or serious disease. Infection with one DENV serotype results in lifelong immunity to infecting serotype. Neutralizing antibodies to DENV are responsible for specific protection. Infection also provides protection against other serotypes for initial few months. During a secondary infection with a different serotype, the presence of heterotypic neutralizing antibodies could prevent severe disease; however in the absence of neutralizing antibodies, heterotypic antibodies form complexes with dengue viruses, which facilitate enhanced cellular infection. This phenomenon is called antibody dependent enhancement (ADE). ADE theory elucidates observed occurrence of DHF in both clinical settings, primary infection in infants and during secondary infection at any age.

Several investigators have felt and reported various difficulties in using the old system. Commonly reported 229 difficulties are:

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With the realization that existing classification of the disease into DF, DHF (Grades 1 and 2), and DSS (DHF Grades 3 and 4) may not always be universally applicable for clinical

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The clinical course of the disease is divided into three phases: febrile, critical and recovery (Fig. 5.14.4).

ebrile Phase

Following a short incubation period of 2–7 days, there is an abrupt onset of high-grade fever. During fever, whole body is invariably covered with bloachable erythematous flush (Fig. 5.14.5). With suffused and swollen face, injected eyes, reddened ears, crimson malar area, swollen and purplish lips patients assume a measly look (Fig. 5.14.6). The flush deepens with advancing disease. In few of these patients, a classical m--aculopapular exanthem (Fig. 5.14.7) may erupt on the top of erythematous flush. Some patients may have sore throat, injected pharynx and conjunctival injection; however catarrh a typical characteristic of respiratory viruses is missing. Adolescents and older children often suffer

Figure 5.14.3 Suggested dengue case classification and level of severity  

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management, the WHO convened a meet of global dengue experts in 2008 in Geneva. Committee recommended a new case classification for dengue illnesses and put forward revised guidelines in 2009 for the management of dengue illnesses. As per new guidelines disease is now classified into three categories: • Dengue • Dengue with warning signs • Severe dengue (Fig. 5.14.3). C

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The classification rigorously tries to distinguish between DF, DHF, and DSS, although there is much overlap between the three. Examples include bleeding or occult bleeding tendency (+ TT) and mild thrombocytopenia could occur in DF. Documentation of all four requirements for the WHO definition of DHF (fever, hemorrhage, thrombocyt openia, and signs of plasma leakage) needs frequent assessment of packed cell volume and platelet counts which may not always be available or feasible. Moreover, a properly fluid managed patient from early stage of disease may fail to show 20% rise in hematocrit despite vascular leak. TT is an integral part of the existing scheme; however it poorly differentiates between DF and DHF. Moreover many children with non-dengue febrile illnesses may also have positive tests. The DF/DHF/DSS classification excludes severe dengue disease associated with organ involvement like hepatitis, encephalitis and myocarditis. The term DHF places undue emphasis on hemorrhage when the danger sign that should be watched for and managed is plasma leakage leading to shock.

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Figure 5.14.4 Course of a dengue illness

Figure 5.14.5 Bloachable erythematous flush

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In the early febrile phase of the disease it may not always be possible to distinguish dengue from non-dengue febrile diseases. A positive tourniquet test in this phase increases the probability of dengue diagnosis (Fig. 5.14.10). Leukopenia, atypical lymphocytosis, and mild throm bocytopenia are some of the commonly observed hematological changes during febrile phase of dengue 231 illness. ­

from headache, retro-orbital pain, photophobia, backache, myalgia and arthralgia. Anorexia, nausea and vomiting are not uncommon and usually lead to dehydration. Mild hemorrhagic manifestations like petechiae (Fig. 5.14.8) and mucosal membrane bleeding (e.g. nose and gums, conjunctiva) may be seen (Fig. 5.14.9), however massive gastrointestinal bleeding commonly reported in adults during febrile phase is less common in children.

 

 

Figure 5.14.6 Dengue facies (Measly look)

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Figure 5.14.9 Minor bleed (conjunctival hemorrhage)

Figure 5.14.10 Positive tourniquet test

After a variable febrile period of 2–7 days majority of dengue fever patients makes a smooth and complete recovery; however in a small number of patients disease deteriorates with defervescence and patient may pass into critical phase. Unfortunately initial clinical features are indistinguishable between severe and non-severe dengue cases; hence it is imperative that patient should be frequently monitored for warning signs for recognizing progression to the critical phase.

and conjunctival bleeding. Presence of these warning signs should alert clinician for regular monitoring and prompt fluid therapy to improve patient outcome.

Dengue with Warning Signs Cases destined to pass into critical phase may display the following warning signs: persistent vomiting, abdominal pain, hepatic enlargement, lethargy, restlessness, scanty urine, postural hypotension, clinical signs of fluid accumulation (ascites, effusion, edema), rising hematocrit with progressive thrombocytopenia, mucosal bleeding 232 (epistaxis, hematemesis, gum bleeding, metromenorrhagia

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Around the time of defervescence, in some of the patients an increase in capillary permeability sets in. Extravasations of plasma through these leaky capillaries result in progressive hemoconcentration. A parallel drop in platelets and progressive leukopenia usually precedes plasma leakage. Together these changes mark the beginning of the critical phase. Patients in this phase would display many of the above mentioned warning signs. In majority of the cases, the leak is transient lasting for a few hours; once it stops patient quickly stabilizes and completely recovers. According to new classification these patients should be classified as “dengue with warning signs”.



 

 

 

Figure 5.14.8 Dengue purpuric rash

 

Figure 5.14.7 Maculopapular rash

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Figure 5.14.12 Ascites with bilateral pleural effusion

 

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Figure 5.14.11 Clinical ascites

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Patients with profound leak usually need massive resu scitative fluid therapy during critical phase. With the resolution of vascular leak all the extravasated fluid returns to vascular compartment. This may cause congestive heart failure manifesting as tachycardia, tachypnea, muffling of heart sounds and basal rales. Problem is particularly augmented with colloid use. Massive pleural effusion and ascites (Figs 5.14.12 and 5.14.13) may further add to respiratory distress. This phase generally lasts for 12–24 hours and needs intense observation. Patient may need oxygen support and decongestive (diuretics) therapy to relieve respiratory distress.

Convalescence Termination of the illness is swift and is usually marked by a distinctive acral exanthem. A bright red confluent

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Respiratory Distress

Patients with prolonged and prolific leak would deteriorate. These deteriorating patients will manifest signs of impending shock (cold and clammy extremities, feeble or imperceptible peripheral pulse, delayed CRT, narrow pulse pressure and falling blood pressure). In patients with massive leak, plasma may continue leaking for two to three days. Extravasated fluid collects primarily into serous cavities like peritoneum, pleura, and pericardium (Fig. 5.14.11). Large ascites and pleural effusion are clinically detectable, however small effusions would need chest X-ray and abdominal ultrasound for demonstration. Amount of vascular leak evidenced as degree of hemoconcentration is the primary determinant of prognosis. Poorly managed patients may progressively pass into hypovolemia, hypotension and shock. Prolonged

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After 2–3 days, leak stops and plasma which had extra vasated during the leaky phase, returns back to circulation. Patient starts passing copious amount of dilute urine, develop bounding pulse, wide pulse pressure and rise in blood pressure. Appetite improves and patient feels better. Hemoconcentration resolves; due to dilutional effect hematocrit may go lower than normal. Platelets start rising and become normal by around 9th day of sickness. Typically effusions are slow to resolve and may take a few more days for complete clearance.

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Dengue illness may have serious manifestations other than shock. Hepatitis, myocarditis, encephalitis, and severe bleeding are few of the commonly encountered serious manifestations of a dengue illness. A new category “severe dengue” is created to include these serious symptoms. Category has three types of patients: • Patients with severe plasma leakage: – Shock [cold clammy peripheries, prolonged capillary refill time (CRT), narrow pulse pressure, fall in systolic pressure] – Fluid accumulation resulting in respiratory distress • Patients with profuse bleeding • Patients with significant organ involvement: – Hepatic involvement (Transaminases >1000 IU/L) – Patients with neurological involvement – Patients with cardiac involvement.

shock and organ hypoperfusion may result in progressive organ impairment, metabolic acidosis and disseminated intravascular coagulation (DIC). DIC may provoke severe uncontrollable bleeding. A sudden fall in otherwise elevated hematocrit during critical phase should alert clinician for occult internal bleeding.

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Figure 5.14.13 Puffy edematous face (fluid overload)

 

 

Figure 5.14.15 Annular petechial rash



these enzymes increase around the third day after the onset of the disease; they reach a peak on the seventh or eighth day and decrease to normal values within three to eight weeks. In contrast to viral hepatitis, the elevation in the level of aspartate transaminase (AST or SGOT) is normally greater than the elevation in the level of alanine transaminase (ALT or SGPT) in dengue patients. The disease is self-limiting, but some patients may have unduly severe hepatitis with markedly elevated transaminases, frank hemorrhages and hepatic failure which could culminate in death. Importantly these cases may not always have pathognomonic dengue vascular leak and could occur during febrile phase of the disease. Fortunately severe hepatitis is rare in pediatric age group.

Neurological Complications

 

Figure 5.14.14 Confluent petechial rash

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Cardiac Complications Heart can be affected with dengue infections. A global hypokinesia, low ejection fraction, ECG changes and rhythm disturbances are noted in some of the recent studies. Majority changes are transient and reversible.

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petechial rash (Fig. 5.14.14) erupts along the lateral margins of soles and palms. Ascending upwards and medially, the rash assumes a confluent character. In some cases there are small round areas of clear skin giving it a name of annular petechial rash (Fig. 5.14.15). Peripheral pruritus, asthenia and transient bradycardia are few other inconsequential clinical findings noted during convalescence.

Dengue infections can cause variety of neurological manifestations; prominent among them are convulsions, unconsciousness, myositis, spasticity and paresis. Current research suggests that dengue, especially DEN-2 and DEN-3 has strong neurotropism and can cause encephalitis due to direct viral invasion of the brain. Most neurological events are seen early in the febrile phase and are unrelated to the perfusion status.

Liver is commonly involved in dengue viral infection. Hepatomegaly and liver impairment in the form of elevated 234 transaminases is common occurrence in dengue illnesses. Changes usually parallel the disease severity. The levels of

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Proper dengue management has following principles: • Suspicion of disease. • Assessments and management of early febrile phase.

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Physical Examination Vascular leak resulting progressively in dehydration, hypovolemia, hypotension and shock is a major complication of dengue illnesses. Scanty urine, giddiness, inability to walk, unsupported and narrow pulse pressure are some of the significant clinical findings of ongoing vascular leak. Signs of pleural and peritoneal effusion (dull percussion note, abdominal pain and distension) are other important clinical evidences for vascular leakage. Enlarged and tender liver with or without icterus may suggest liver impairment. Abnormal mentation, impaired consciousness and convulsions may suggest early neurological dysfunction. Massive hemorrhages and mucosal bleed would be clinically apparent. However, diligent search is needed to find out petechiae, purpura and ecchymoses. A tourniquet test should always be performed; positive test suggests underlying bleeding tendency and augments probability of dengue diagnosis.

Investigations A CBC should be performed during first visit. Hematocrit test in the early febrile phase establishes the patient’s own baseline value which serves as reference figure for any change occurring during further course of disease. A progressive fall in platelet count with a progressive rise in hematocrit suggests progression to critical phase (DHF) of disease. These parameters exhibit a unique time-bound relationship with the disease. Changes start a little before

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Majority of dengue cases could be treated as outpatients; however they need close clinical observation during the febrile period and 2–3 days beyond the defervescence. Parents or caretakers should be given following instructions: • Ensure adequate child’s fluid intake: Fluids could be ORS, water, milk, buttermilk or fruit juices. Adequate fluid intake may reduce the number of hospitalizations. Instruct parents to collect child’s urine and compare the output against fluid intake, passing scanty urine with adequate oral fluid intake should alert clinician for vascular leak. • Use only paracetamol for pain and fever: Do not use aspirin, ibuprofen, mefenemic acid, nimesulide or other NSAIDs for fever or pain as these drugs interfere with platelet functioning. • Warn parents for warning signs: These include scant urine, giddiness, restlessness, anxiety, severe abdominal pain and cold extremities. • Carefully assess every patient exhibiting warning signs for impending shock, e.g. poor volume pulse, imperceptible pulses, narrowing of pulse pressure, and fall in blood pressure. Patient with these symptoms need immediate hospitalization for intensive IV fluid therapy. • In dengue illnesses crucial pathophysiology starts with defervescence; hence any child deteriorating or failing to improve with subsidence of fever should be carefully assessed for progression to critical phase. • Hospitalization: Instruct the caregivers that the patient should be brought to hospital immediately if any of the following occur: no clinical improvement or deterioration around the time of defervescence, severe abdominal pain, persistent vomiting, cold and clammy extremities, lethargy or irritability/restlessness, bleeding (e.g. black stools or coffee-ground vomiting), and not passing urine for more than 4–6 hours. Majority of patients without warning signs would tolerate oral fluids; however patients with anorexia, nausea and vomiting may need IV fluid therapy. Normal saline 235 D

Suspected patient should be assessed for hydration status: history of voiding (frequency, amount and color), quantity of oral intake, excessive diaphoresis, and history of diarrhea and vomiting. Vascular leak is a major dengue complication that occurs during peri-defervescence period; hence date and timing of fever onset should be noted. Frequent assessments for warning signs, dizziness, and altered mental status are necessary to recognize complications at early stage.

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Majority dengue patients present with undifferentiated febrile illness; it is difficult to recognize dengue unless clinician keeps a high suspicion index. A febrile patient with measly look and bloachable erythematous flush, presenting particularly during rainy season should immediately arouse suspicion for dengue illness. Respiratory viruses prevailing during rainy season could also present with similar erythematous flush; however a significant catarrh differentiates them from dengue illnesses.

the defervescence and peak around second or third afebrile day. Degree of rise in hematocrit bears a distinct correlation with the severity of the disease. Serology may not become positive during febrile phase but in NS-1, a soluble antigen of dengue virus appears in patient’s blood with onset of illness and may persist for 9 days. Demonstrable by ELISA; NS-1 carries a high sensitivity and specificity for dengue diagnosis. Serum transaminases, creatinine and electrolytes are some of the useful additional tests. Clinical signs of fluid leakage may not be apparent in mild cases. A decubitus X-ray chest used to be employed by past clinicians for demonstrating mild pleural effusion. However, sonography has made the things convenient; can demonstrate smallest amount of extravasated in any of the serous cavity. Gallbladder edema is one of the unexplained yet a consistent sonographic finding in dengue illnesses. M

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Identifying patients with warning signs. Recognizing early critical phase and initiating timely fluid therapy. Recognizing and managing severe dengue (shock, massive bleeding, and severe organ impairment).

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Severe Dengue Patients with severe dengue need urgent hospitalization and emergency treatment. In most of the cases astute resuscitation is the only intervention needed.

Dengue Shock Over the last few years IV fluid therapy has undergone a major conceptual shift. Currently fluid therapy is separated as fluid resuscitation and fluid replacement. Fluid resuscitation is a strategy in which larger volumes of fluids (e.g. 10–20 m /kg boluses) are administered for a limited period of time under close monitoring. Goals of the resuscitation are to improve central and peripheral circulation and end organ perfusion. Following resuscitation further plasma losses are continually replaced with IV fluid l

Two common types of IV fluids currently used in dengue shock are crystalloids and colloids. Theoretically, colloid solutions offer some advantages over crystalloid solutions, as they provide volume expansion over and above the actual fluid volume infused. The colloid molecules increase plasma oncotic pressure and reverse the net flux of fluid out of the intravascular compartment. Moreover pathophysiological studies indicate that there is preferential leakage of relatively small plasma proteins (e.g. albumin) as compared with larger molecules (e.g. IgG), which implies that resuscitation with colloid preparations of larger molecular weights may offer therapeutic advantages. However, these theoretical advantages have not been substantiated in clinical studies. A recent meta-analysis observed that colloids does decrease the hematocrit and pulse rates of children with DSS after the first two hours of fluid resuscitation; however these changes were transient and no significant advantage was found over crystalloids in reducing the recurrence of shock, the need for rescue colloids, the total amount of fluids, the need for diuretics, and in reducing mortality. General consensus is that crystalloids should be used for initial resuscitation while colloid boluses are reserved for patients presenting with hypotensive shock, recurrent shock and refractory hypotensive shock.

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Patients displaying warning signs are likely to pass into critical phase; they need hospitalization for close clinical observations and IV fluid therapy. Platelet count and hematocrit should always be obtained before fluid therapy. Initial values serve as reference for future changes. IV fluid therapy should be started with any of the isotonic solutions such as normal saline (0.9%) or Ringer’s lactate. Patients may need 5–7 m /kg/hour for 1–2 hours for initial hemodynamic stabilization. IV fluid is tapered off to 3–5 m /kg/hr for 2–4 hours, and then to 2–3 m /kg/hour or less according to the clinical response. Use minimum intra venous fluid volume required to maintain good perfusion. Patient need frequent reassessment for hemodynamic status (pulse rate, pulse pressure, blood pressure, CRT, urine output) and hematocrit. If the hematocrit remains the same or rises only minimally, continue with the same rate (2–3 m /kg/hour) for another 2–4 hours. Any worsening of hemodynamic status and rapidly rising hematocrit during critical phase is the indication for stepping up the IV fluid rate. Bolus of 5–10 m /kg/hour may be given for 1–2 hours then modify fluid infusion rates as per the hematocrit. After a variable period of few hours to few days (usually 24–48 hours) intravenous leak starts decreasing. Increasing urine output along with decreasing hematocrit in a stable patient is the best indication of ending of critical phase. Frequent monitoring of vital signs, peripheral perfusion, and detailed fluid balance is mandatory for all the patients till risk period is over. Frequency of monitoring is generally dictated by patient’s need. However at least 1–4 hourly watch on vital signs and 4–6 hourly monitoring of urine output are absolute must. The WHO insists on hematocrit assessments every 6–12 hourly and additionally before and after every bolus fluid replacement.

Patients exhibiting signs of severe dengue or warning signs need hospitalization. Patients presenting with profuse bleeding, with organ impairments need hospitalization and specific management. In majority of the dengue illnesses, intravenous fluid therapy of vascular leak is the most important aspect of management. In mild cases plasma leakage is small and transient, and patients recover spontaneously or shortly after administration of intravenous fluid. In severe cases there are large plasma losses, hypovolemic shock ensues, and it can progress rapidly to profound shock. Volume replacement is the mainstay for the treatment of this type of severe dengue. High continuous fluid (7–10 m /kg BW) replacement was the main theme of these recommendations. Over the last few years it was realized that many complications and deaths were due to inappropriate fluid management leading to fluid overload, and it was felt that dengue vascular leak could be managed with lesser fluid therapy. In 2009, the WHO came out with new set of guidelines with emphasis on resuscitation; accordingly shock is corrected with boluses of (10 m /kg BW) isotonic fluid while replacement is done with much smaller doses.

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or Ringer’s lactate given at maintenance rate in general suffices. Switch over to oral fluids as soon as patients tolerate. Patients should remain under close medical supervision at least for 2–3 days beyond defervescence.

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Dengue shock has a highly dynamic clinical course; it is crucial that patient should be regularly monitored. Frequency of assessment in generally is dictated by patient’s condition; it should be at least hourly till patient is hemodynamically stable. Regular monitoring (no less than 4 hourly) is mandatory even in a hemodynamically stable patient till fluid infusion is complete and patient is totally out of risk. Frequent assessment of vitals, pulse (peripheral pulses), blood pressure, pulse pressure, heart rate, abdominal girth, and urinary output are mandatory.

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boluses. This practice is followed till the patient is stabilized. Once patient improves, reduce the rate to 7–10 m /kg/hour for 1–2 hours, then change back to crystalloid solution and reduce the rate of infusion gradually over next 6–8 hours to maintenance doses. Multiple fluid boluses may need to be given during critical phase in a dengue shock patient. Extent and frequency of such boluses is dictated by patient’s hemodynamic response. Five percent albumin boluses have found to be an effective treatment in unresponsive dengue shock patients.

mmuni y, mmuniza ion and nfec ious iseases

over next 24–48 hours, however, recommendation for this fluid now is much smaller; fluid sufficient enough to maintain effective circulation and perfusion is advised. For resuscitation as well replacement only isotonic fluids must be used; hypotonic fluids have no place in dengue management. From management view point compensated shock should be separated from hypotensive shock. Compensated Shock (Normal systolic pressure, rising diastolic pressure, narrowing pulse pressure <30 mm Hg, postural hypotension) Start IV fluid resuscitation with isotonic crystalloid solutions at 5–10 m /kg/hr over one hour. Then reassess the patient’s condition (vital signs, capillary refill time, hematocrit, urine output). The next step depends on the situation. If the patient’s condition improves, IV fluids should be gradually tapered to 5–7 m /kg/hour for 1–2 hours, then to 3–5 m /kg/hr for 2–4 hours, then to 2–3 m /kg/hour. Patient with stable hemodynamic status may need only maintenance fluid therapy for next 24–48 hours. Following the first bolus if vital signs are still unstable (i.e. shock persists), check the hematocrit. In patients with high or rising hematocrit, repeat a second bolus of crystalloid solution or colloid at 10–20 m /kg/hour for 1 hour. After this second bolus, if there is improvement, reduce the rate to 7–10 m /kg/hour for 1–2 hours, and then continue to taper as above. Patients may need further boluses during next 24–48 hours. A hemodynamically unstable patient with decreasing hematocrit denotes internal bleeding; a timely blood transfusion is the most important intervention in this situation.

Hypotensive Shock

In order to maintain adequate tissue perfusion in the face of impending shock the pulse pressure narrows; therefore narrowing of the pulse pressure is the most significant parameter for defining dengue shock. Maintaining pulse pressure of more than 20 mm Hg is the most important aspect of guiding IV fluid therapy. A narrow pulse pressure less than 20 mm Hg is an indication for stepping up IV fluid rate.



l

Urine Output Maintenance of fluid input output chart is mandatory and should be continued till the patient is out of risk. A continuous bladder catheter enables correct monitoring of urine output. An acceptable urine output would be about 0.5 m /kg/hour. l



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A more aggressive approach is observed for hypotensive shock. An initial resuscitative bolus of 20 m /kg BW of colloid is pushed over 15 min so as to rescue patient from shock. If patient improves a further bolus of IV fluid (crystalloid/ colloid) 10 m /kg/hour is infused over next one hour. In a hemodynamically stable patient, fluid is gradually tapered over following 6–8 hours. Further fluid replacement for subsequent 24–48 hours is undertaken with maintenance doses of isotonic crystalloid infusion. In a hemodynamically unstable patient (i.e. shock persists), review the hematocrit before the first bolus. Low hematocrit indicates bleeding and needs blood transfusion. If the initial hematocrit was high compared to the baseline value, a second bolus of colloid solutions at 10–20 ml/kg is pushed over next 30 minutes to one hour. Review the hemodynamics after the second bolus if the condition stabilizes; reduce the rate to 7–10 m /kg/hour for 1–2 hours, then change over to crystalloid solution and reduce the rate of infusion as mentioned above. In a patient with unstable hemodynamics further management is dictated by assessment of hematocrit. Decreasing hematocrit is an indication for blood transfusion while increasing hematocrit is signal for further colloid

Pulse Pressure

Hematocrit Hematocrit should be monitored (before and after fluid boluses until stable, then 4–6 hourly). Changes in hematocrit are important therapeutic guides; however these changes should always be interpreted along with the hemodynamic status. A rising or persistently high hematocrit together with stable hemodynamic status and adequate urine output does not require extra IV fluid. In this situation, it is likely that the hematocrit will start to fall within the next 24 hours as the plasma leakage stops. On the other hand a rising 237

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Polyserositis due to fluid overload is the most common cause of this complication. Causes for fluid overload are: • Excessive and/or too rapid IV fluids. • Erroneous use of hypotonic rather than isotonic crystalloid solutions. • Inadvertent continuation of IV fluids even after leakage has stopped. • Overuse of colloids. • Inappropriate transfusion of blood products: fresh-frozen plasma, platelet concentrates, and cryoprecipitates. • Co-morbid conditions such as congenital heart disease, chronic lung and renal diseases. Polyserositis in severe dengue may not always be preventable; in severe dengue infused fluid, however appropriate it may be, is bound to leak into serous cavities causing polyserositis.

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Infuse 10 m /kg of fresh-packed red cells or 20 m /kg of fresh whole blood at an appropriate rate. Observe the clinical response: improvement in hematocrit, hemodynamic status and acid-base balance is an indicator of successful therapy. A repeat transfusion is indicated in case of falling hematocrit and inadequate clinical response. Stored blood loses 2,3 DPG, low levels of which impede the oxygen-releasing capacity of hemoglobin; resulting in functional tissue hypoxia, therefore it is important that only fresh whole blood or fresh red cells are given.

Platelet Transfusion There is no place for prophylactic platelet even with a count below 10,000 per cu mm if there is no evidence of bleeding. Prophylactic transfusion with platelets and fresh 238 frozen plasma do not produce sustained changes in the

Management Plan Widening of pulse pressure, rising blood pressure, bounding peripheral pulses and increased urinary output are suggestive signs that vascular leak is over and intravasation of fluid has started. Oxygen supplementation is mandatory for every patient with respiratory distress; remaining management of fluid overload is dictated by hemodynamics, hematocrit and phase of the disease. A falling hematocrit with wide pulse pressure and increased urinary output are indications to stop further intravenous fluid. Furosemide 0.1–0.5 mg/kg/dose IV once or twice daily would decrease the respiratory distress in a fluid overloaded patient. Monitoring of serum potassium and correcting the ensuing hypokalemia is important for patients treated with furosemide. Avoid diuretic therapy if there is any doubt that critical phase (vascular leak) is still on. Patients who are yet not out of shock, have low hematocrit levels and show signs of fluid overload may have occult hemorrhage. Such patients are benefited by fresh blood transfusion. If the patient remains in shock and has an elevated hematocrit, repeated small boluses of a colloid solution may help.

yselectrolytemia and lood Glucose isturbances D

There are reports of unusual bleeding manifestations with some of the dengue outbreaks but generally major bleeding in dengue illness is uncommon in pediatric age group. Adult patients are prone for major gastrointestinal tract and vaginal bleeding. Patients who have pre-existing acid peptic disease, who are on anticoagulant therapy or treated with non-steroidal anti-inflammatory agents are at risk for major bleeding complications. In pediatric patients major bleeding is almost always secondary to poorly managed shock culminating into multi-organ dysfunction and consequential DIC.

Tachypnea, dyspnea, wheezing, chest wall indrawing are some of the early signs of fluid overload. Tense ascites and pleural effusions may cause severe respiratory distress. Cough with frothy pink sputum heralds the inception of pulmonary edema and congestive heart failure.

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Clinical Features



Minor mucosal bleeding in form of epistaxis, gum bleed or conjunctival hemorrhages may occur in any patient with dengue illness; most of these patients remain stable and do not need any intervention beyond fluid resuscitation or replacement. Such bleeds rapidly improve during the recovery phase.



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coagulation status and platelet count in patients with DHF/ DSS. Platelets are given only if significant bleeding occurs.

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or persistently high hematocrit together with unstable vital signs (particularly narrowing of the pulse pressure) indicates active plasma leakage and the need for a further bolus of fluid replacement. Conversely, falling hematocrit together with unstable vital signs (particularly narrowing of the pulse pressure, tachycardia, metabolic acidosis, poor urine output) indicates major hemorrhage and the need for urgent blood transfusion. Decrease in hematocrit together with stable hemodynamic status and adequate urine output indicates hemodilution and/or intravasation of fluids suggestive of stopping of further intravenous fluids. Monitoring of arterial or venous blood gases, other organ functions such as renal profile, liver profile and coagulation profile should be performed as per individual case indication.

Possibilities of electrolyte disturbances like hyponatremia, hypokalemia, hyperkalemia, serum calcium imbalances and metabolic acidosis should be kept in mind while treating dengue shock. Dyselectrolytemia is uncommon and occurs

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Intense research is going on for dengue vaccine. The biggest challenge is to find out a tetravalent vaccine which could simultaneously induce long lasting protective immunity against all four viruses. Dengue vaccines in development are of four serotypes: live attenuated



engue Vaccine



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Recent clinical studies have noted that the viral load is much higher in blood of the patients who develop severe dengue (DHF and DSS) compared with patients suffering from the milder dengue fever (DF). This observation suggests that any drug which could lower the viral load would be effective in curbing the disease progression and would halt the adverse morbidity. Search for molecules which could interfere with viral replication is going on. Several potential viral targets have been found out; currently the most advanced targets are the NS3/NS2B protease and NS5 RNA-dependent RNA polymerase.



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Steroids, IV immunoglobulins and recombinant activated factor VII have been tried in some studies, but none of them was found useful in dengue management.

1. Bandyopadhyay S, Lum LC, Kroeger A. Classifying dengue: a review of the difficulties in using the WHO case classification for dengue haemorrhagic fever. Trop Med International Health. 2006;11(8):1238-55. 2. Capeding RZ, Brion JD, Caponpon MM, et al. The incidence, characteristics, and presentation of dengue virus infections during infancy. Am J Trop Med Hyg. 2010;82(2):330-6. 3. Clyde K, Kyle JL, Harris E. Recent advances in deciphering viral and host determinants of dengue virus replication and pathogenesis. J Virol. 2006;80(23):11418-31. 4. Halstead SB. Seminar: Dengue. Lancet. 2007;370:1644-52. 5. Halstead SB, Mahalingam S, Marovich MA, et al. Intrinsic antibody-dependent enhancement of microbial infection in macrophages: disease regulation by immune complexes. Lancet Infect Dis. 2010;10:712-22. 6. Jacqueline LD, Harris E, Bridget W, et al. The WHO dengue classification and case definitions: time for a reassessment. Lancet. 2006;368:170-3. 7. Jose G. Severe dengue: the need for new case definitions. Lancet Infect Dis. 2006;6:297-302. 8. Kapse AS. A study of an epidemic of dengue at Surat; Clinico-investigative analysis. In: environment and health in developing countries; 1998.pp.339-50. 9. Sharon LR, Michelle DV, Marissa MA. The use of colloids and crystalloids in pediatric dengue shock syndrome: a systematic review and meta-analysis. BMC Infect Dis. 2011;11:52. 10. Srikiatkhachorn A. Plasma leakage in dengue haemorrhagic fever. Thromb Haemost. 2009;102:1042-9. 11. WHO and TDR. Dengue: guidelines for diagnosis, treatment, prevention and control: 2009. 12. Wills BA, Oragui EE, Dung NM, et al. Size and charge characteristics of the protein leak in dengue shock syndrome. J Inf Dis. 2004;190:810-8.

Avoidable Ancillary Treatment

ibliography



In a severe fluid unresponsive hypotensive dengue shock, vasopressors and inotropes may be used as temporary measures. However it should always be used as a supportive measure to appropriate fluid therapy and never as a substitute.



Vasopressors and Inotropes



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djuvant Therapy

viruses, chimeric live attenuated viruses, inactivated or subunit vaccines, and nucleic acid-based vaccines. A DENDEN chimera is a dengue vaccine which is in advanced preclinical development stage. The tetravalent vaccine produced by combining the four chimeric dengue viruses is protective when administered to mice. Monkey challenge experiments have been conducted and preparations for clinical trials are underway.

mmuni y, mmuniza ion and nfec ious iseases

due either to incorrect uses of hypotonic solutions for resuscitation and replacement or diarrhea and vomiting resulting in gastrointestinal electrolyte losses. Regular blood sugar monitoring is necessary as both hypoglycemia and hyperglycemia could occur and destabilize a precariously positioned hemodynamics.

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hikungunya ever

the first 2 days of illness. iremia declines around day 3 or 4 and usually disappears by day 5. emagglutination inhibition and neutralizing antibodies can usually be detected after day 5. Clinical or silent infection is thought to confer lifelong immunity. A recent study has suggested C I tropism for muscular satellite cells, which can act as small reservoirs for virus or virus-encoded components or both for longer periods. V

ntroduction

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hikungunya Virus

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Chikungunya virus (Ch kv) a positive stranded, enveloped RNA virus, is a member of the Alphavirus genus and belongs to the Togaviridae family. Genetic analysis based on partial E1 envelope glycoprotein gene sequences showed presence of three distinct phylogroups. The first contained all isolates from West Africa; second comprised all Central, Southern and Eastern African strains (CSEA); and third contained isolates from Asia.

linical Manifestations

Chikungunya fever is characterized by triad of abrupt onset fever, rashes and arthralgia followed by other constitutional symptoms. The incubation period is usually 2–3 days (range 1–12 days). All age groups are affected, including newborns but full blown disease is common in adults. Fever rises abruptly, often reaching 39–40°C accompanied by intermittent shaking chills. This acute phase lasts for 2–3 days. The temperature may remit for 1–2 days, after a gap of 4–10 days, resulting in a ‘saddle back’ fever curve. Arthralgia is polyarticular, migratory and predominantly affects the small joints of hands, wrists, ankles and feet with lesser involvement of larger joints (Fig. 5.15.1). In acute stage, patients complain bitterly of pain, when asked to move and assume an attitude of flexion. Pain on movement

pidemiology

KV

Chikungunya fever is caused by an alphavirus and spread by bite of Aedes aegypti mosquito. The name derives from kungunyala, which means “to dry up or become contorted”, i.e. bent posture of patients. It has caused numerous outbreaks and epidemics in both Africa and South East Asia, involving thousands of children.

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Chikungunya virus is commonly transmitted to humans through the bite of infected mosquitoes of the Aedes genus, which usually bite during daylight hours. In Africa, C I appears to be maintained in sylvatic cycle involving wild primates like monkeys that may serve as reservoir of the virus. The secondary attack rate is 4–45%. A. aegypti, Aedes albopictus and Aedes polynesiensis are commonly involved in the transmission of virus, although Culex has also been reported for some transmission. A. aegypti, the principal vector of C I in India is anthropophilic, endophagic and bites during the day time. It mainly breeds in man-made discarded containers where rain water accumulates. A recent epidemic in India suggested that Asian tiger mosquito was responsible for spread. A mutation in the envelope protein gene (E1-A226 ) was reported in some strains of C I . This mutation is responsible for C I adaptation to the Asian tiger mosquito. With the global climate warming, C I could expand to new geographic locations.

Pathogenesis

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Chikungunya virus (Ch kv) replicates primarily in fibroblasts and macrophages but can replicate in various human cells, including epithelial and endothelial cells. iral entry occurs through a p -dependent, endocytic pathway. It is highly cytopathic and induces apoptosis of infected cells. In humans, C I produces symptoms after 48 hours of 240 mosquito bite. Patients have high viral load in blood during

 

Figure 5.15.1 Frequency of pain and arthritis by location during acute stage

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Management There is no specific treatment for Chikungunya fever. The illness is usually self-limiting and resolves with time. Supportive care with rest is recommended during the

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Prevention Prevention is entirely dependent upon taking steps to avoid mosquito bites, which includes wearing full sleeve clothes and elimination of mosquito breeding sites. Use of mosquito coils, repellents, electric vapor mats during the daytime and permethrin treated mosquito nets during sleep prevents transmission of disease. Drainage of water from coolers, tanks, barrels, drums and buckets and empty coolers when not in use, prevents mosquito bleeding. Active surveillance by health workers of cases should be undertaken. This will help in identifying the affected areas, so that control measures may be initiated. ector surveillance should also be done and will help in initiating early control measures and assess the impact of the measures taken. Education of people about the disease, mode of transmission, availability of treatment and adoption of control measures are important for prevention of disease. 241 V

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The current live vaccine (Lot 1-85, TSI-GSD-218) was developed in United States in USAMRIID and was produced at the Salk Institute, from GM strain 15561 by serial passage in MRC-5 cells. The results of phase I and phase II trials strongly suggest that live vaccine is safe and well-tolerated and produces no severe or frequent symptoms than found in placebo recipients. K

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Some patients show leukopenia with mildly decreased platelet count. Elevated levels of aspartate aminotransferase (AST) and C-reactive protein are also seen. owever, virus isolation is the most definitive tests in first week. Recently, RT-PCR technique for diagnosis has been developed using nested primer pairs amplifying specific components of three structural gene regions.  PCR results can be available within 1–2 days. Serologic diagnosis can be made by demonstration of four-fold increase in antibody in acute and convalescent sera or demonstrating immunoglobulin M (IgM) antibodies specific for C I . A commonly used test is the IgM antibody capture enzyme-linked immunosorbent assay (MAC-ELISA). Results of MAC-ELISA can be available within 2–3 days. Crossreaction with other flavivirus antibodies such as O’nyongnyong and Semliki may occur in MAC-ELISA; however, the latter viruses are relatively rare in South East Asia. A positive virus culture supplemented with neutralization is taken as definitive proof for the presence of C I .

uniza ion and nfec ious iseases

Laboratory iagnosis

acute joint symptoms. Movement and mild exercise tend to improve stiffness and morning arthralgia, but heavy exercise may exacerbate rheumatic symptoms. Non-aspirin and nonsteroidal anti-inflammatory drugs (NSAID) are recommended. In unresolved arthritis refractory to NSAID, chloroquine (10 mg/kg/day) has proved to be useful. Chloroquine inhibits viral replication by blocking p dependent endocytosis of C I into host cells. Although chloroquine blocks C I replication, therapeutic (antiviral) index of chloroquine in cell cultures is rather narrow. Thus, one should be cautious when planning the use of chloroquine as an antiviral treatment in infected individuals. Self-resolution occurs with cutaneous lesions. Patients with hyperpigmentation may be treated with sunscreens and topical steroids. All patients with only centrofacial involvement usually show complete clearance during follow-up by 3 weeks. Patients with more diffuse involvement show a slower resolution. Aphthous ulcers usually heal over 7–10 days with local cleaning and topical antimicrobials to prevent secondary infection. Iridocyclitis and retinitis have a typically benign clinical course. All the patients respond well to the treatment with preservation of good vision. Infected persons should be protected from further mosquito exposure (staying indoors and/or under mosquito net during the first few days of illness), so that they do not contribute to the transmission cycle.

uni y,

is worse in the morning, improved by mild exercise and exacerbated by strenuous exercise. Swelling may occur but fluid accumulation is uncommon. Patients with mild articular manifestation are usually symptom-free within a few weeks, but severe cases require months to resolve entirely. Cutaneous manifestations include flushing of the face and trunk. This is usually followed by maculopapular rash. Trunks and limbs are commonly involved, but face, palms and soles may also show lesions. Rashes may simply fade or desquamate. Petechiae may occur alone or in association with rash and observed during the acute stage of illness and convalescence. Pigmentary changes have been reported to be the most common cutaneous finding (42%), followed by maculopapular eruption (33%) and intertriginous aphthouslike ulcers (21.37%). Exacerbation of existing psoriasis, and unmasking of undiagnosed ansen’s disease may occur. Rash usually lasts for 1–7 days. Iridocyclitis and retinitis are the most common ocular manifestations associated with Chikungunya fever, with a typically benign clinical course. Less frequent ocular lesions include episcleritis. Other rare manifestations include meningoencephalitis, fulminant hepatitis and mild hemorrhagic manifestations. Most symptomatic patients (93.7%) complain of a chronic stage of the disease, which is characterized by pains in joints, bones or both. This persisting pain may be continuous or discontinuous with alternation of clinical remission and relapses (58.7%). Some infected individuals may also have fever at this stage.

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5. Mahendradas P, Ranganna S , Shetty R, et al. Ocular manifestations associated with chikungunya. Ophthalmology. 2008;115(2):287-91. 6. Mohan A. Chikungunya fever: clinical manifestations and management. Indian J Med Res. 2006;124:471-4. 7. Parola P, Lamballerie X, Jourdan J, et al. Novel chikungunya virus variant in travelers returning from Indian Ocean Islands. Emerg Infect Dis. 2006; 12:1493-9. 8. Pialoux G, Gauzere BA, Strobel M. Chikungunya virus infection: review through an epidemic. Med Mal Infect. 2006;36:253-63. 9. Queyriaux B, Simon F, Grandadam M, et al. Clinical burden of chikungunya virus infection. Lancet Infect Dis. 2008;1:2-3.

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1. Chhabra M, Mittal , Bhattacharya D, et al. Chikungunya fever: A re-emerging viral infection. Indian J Med Microbiol. 2008;26:5-12. 2. Chikungunya Fever Fact Sheet - CDC Division of ector Borne Infectious Diseases. Available from: http://www.cdc.gov/ ncidod/chikungunya/chickfact.htm.2006 3. Inamadar AC, Palit A, Sampagavi , et al. Cutaneous manifestations of chikungunya fever: observations made during a recent outbreak in south India. Intern J Dermatol. 2008;47:154-9. 4. Lahariya C, Pradhan S . Emergence of Chikungunya virus in Indian subcontinent after 32 years: a review. J ect Borne Dis. 2006;43:151-60.

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Poliomyelitis is caused by three antigenically distinct serotypes (type-1, 2 and 3) of polioviruses. The polioviruses are non-enveloped, positive-stranded RNA viruses and belong to the genus Enterovirus in the family picornaviridae. These viruses can retain activity for several days at room temperature and can be stored indefinitely frozen at –20°C. It is rapidly inactivated by heat, chlorine and ultraviolet light. The most frequent causes of epidemic polio are poliovirus type-1 followed by type-3.

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Infants born to mothers with antibodies are protected naturally against paralytic polio for a few weeks. Active immunity after natural infection (including inapparent and mild infection) is probably life-long but protects against the infecting serotype only.

In 90–95% of infected individuals, poliovirus infection is inapparent. In the remaining 5–10% of individuals infected by poliovirus, one of the three syndromes may occur. 1. Abortive poliomyelitis occurs in 4–8% of infections and is characterized by a minor illness with low grade fever, sore throat, vomiting, abdominal pain, loss of appetite, and malaise. Recovery is rapid and complete; there is no paralysis. 2. Non-paralytic poliomyelitis occurs in 1–2% of infections and is characterized by headache, neck, back and leg stiffness which occurs several days after the prodrome (fever, malaise, etc.). Presentation resembles other causes of aseptic meningitis and recovers within 2–10 days. 3. Paralytic poliomyelitis occurs in 0.5–1% of infections (i.e. one case of paralysis in every 100–200 infected children). Symptoms often occur in two phases, minor and major, and are often separated by several days without symptoms. The minor phase consists of symptoms similar to those of abortive poliomyelitis. The major phase of illness begins with muscle pain, spasms and the return of fever. This is followed by rapid onset of flaccid paralysis that is usually complete within 72 hours (Table 5.16.1). There are three types of paralytic poliomyelitis: 1. Spinal paralytic poliomyelitis is the most common form of paralytic poliomyelitis, seen in approximately 80% of paralytic cases. It results from a lower motor neuron lesion of the anterior horn of the spinal cord and affects the muscles of the legs, arms and/or trunk. The affected muscles are floppy and reflexes are diminished. The sense of pain and touch are normal. Paralysis is often asymmetrical, affecting legs more often than arms. 243

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Poliovirus is highly communicable disease for which human is the only reservoir. It multiplies in the intestine and is spread via fecal-oral route. The average incubation period is 7–10 days (range 4–35 days). The maximum excretion of virus occurs just before the onset of paralysis and during the first 2 weeks after the onset of paralysis. However, the virus is excreted intermittently for up to 2 months after infection. Poliovirus infection typically peaks in the summer months in temperate climates. There is no seasonal pattern in tropical climates. Reported number of confirmed polio cases worldwide reduced from an annual level of about 50,000 in 1980 to less than 1000 in 2001. Paralytic cases due to type-2 virus were last reported in 1999 in UP, India. However since 2000, 500– 2000 cases have been reported each year and incidence appears to have reached a plateau with wild poliovirus remaining endemic in three countries, viz. Afghanistan, Pakistan and Nigeria. Furthermore, there has been periodic reseeding of virus from these endemic countries to other countries in Africa, South-east and Central Asia and Europe. In 2010, 1349 polio cases were reported globally with 232 cases reported from endemic countries and 1117 cases from rest of non-endemic countries. Incidence has further reduced in 2011 with only 267 cases (89 from endemic countries and 178 from non-endemic countries) reported globally till 13 July 2011. Only one confirmed poliomyelitis (in comparison to 42 confirmed cases in 2010) case due to wild poliovirus which has been reported from West Bengal in 2011 (Chapter 5.5 for more details).



pidemiology



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Poliomyelitis is a highly infectious viral disease caused by any of the three types of poliovirus characterized by acute onset of flaccid paralysis, which mainly affects children under five years of age.

Polioviruses infect cells by adsorbing to specific genetically determined receptors. The primary site of replication is small intestine and regional lymph nodes. Poliovirus which probably accesses the CNS through peripheral nerves, primarily infects motor neuron cells in the spinal cord (the anterior horn cells) and the medulla oblongata.



Introduction

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Poliomyelitis

Immun ty, Immun zat on and Infect ous

5.16

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Vaccine ssociated Paralytic Poliomyelitis (V PP) and Vaccine erived Polio Viruses (V PVs) Vaccine associated paralytic poliomyelitis is defined as those cases of acute flaccid paralysis (AFP) in whom residual weakness persists after 60 days of onset of paralysis but from whose stool samples vaccine related poliovirus (and not wild poliovirus) is isolated. It occurs due to loss of attenuating mutations and reversion to neurovirulence during replication of vaccine virus in the gut. These neurovirulent viruses may cause paralysis in vaccine recipients (recipient VAPP) or their contacts (contact VAPP). The risk of VAPP is higher with type-2 poliovirus, in patients with humoral immunodeficiency and with the first dose that takes (and not with the first dose). The incidence of VAPP has been estimated to be 1 per 4.1 to 4.6 million doses distributed and 1 per 2.8 million with first dose in India. Corresponding figures for developed countries such as USA 244 is 1 per 2.4 million and 1 per 750,000 respectively.

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iagnostic ests tool for Virus Isolation

This test is recommended in every case of AFP. Virus usually can be found in the feces from onset up to 8 or more weeks after paralysis, with the highest probability of detection during the first 2 weeks after paralysis onset. Isolation of wild poliovirus from stool is the recommended method for laboratory confirmation of paralytic poliomyelitis. Two stool specimens are collected from each case for laboratory confirmation. “Adequate stool specimen is defined as two specimens collected at least 24 hours apart within 14 days of onset of paralysis, each of adequate volume (8–10 g or thumb size) and arriving at a WHO accredited laboratory in good condition (no desiccation, no leakage, adequate documentation and evidence that the cold chain was maintained).”

As the acute phase of illness (0–4 weeks) subsides, the recovery begins in paralyzed muscles. The extent of recovery is variable depending upon the extent of damage caused to the neurons by the virus. Maximum neurological recovery of the paralyzed muscle takes place in the first six months of the illness but slow recovery continues up to two years. After two years, no more recovery is expected and the child is said to have ‘post-polio residual paralysis’, which remains as such throughout life.

The differential diagnosis of abortive and non-paralytic polio includes other viral fevers. Paralytic poliomyelitis needs differentiation from other causes of acute flaccid paralysis. Paralytic poliomyelitis, Guillain-Barre syndrome, traumatic neuritis and transverse myelitis represent the most common causes of AFP, but the complete differential diagnosis includes numerous etiologies (hypokalemia, encephalitis, meningitis and other enterovirus infections). Distinguishing characteristic of paralytic polio are asymmetric, acute flaccid paralysis, mostly involving proximal muscles with fever and muscular pain at onset, rapid progression from onset to maximum paralysis (usually <4 days), intact sensory nerve function, and most often, residual paralysis or weakness after 60 days. Salient features of differentiation are summarized in Table 5.16.2.

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Paralytic manifestation in extremities begin proximally and progress to involve distal muscle groups (i.e. descending paralysis). Severe cases may develop quadriplegia and paralysis of the trunk, abdominal and thoracic muscles. Residual flaccid paralysis is usually present after 60 days. 2. Bulbar poliomyelitis accounts up to 2% of paralytic cases and results from a cranial nerve lesion, resulting in respiratory insufficiency and difficulty in swallowing, eating or speaking. 3. Bulbospinal poliomyelitis accounts for approximately up to 20% of paralytic cases and is a combination of spinal paralytic and bulbar polio.

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Vaccine derived polio viruses arise due to mutation and recombination in the human gut between vaccine virus and other neurovirulent enteric viruses and are 1–15% divergent from parent vaccine virus. These viruses are not only neurovirulent like those causing VAPP but are also transmissible and thus capable of causing outbreaks of disease. In 2010, a total of five cases of type 2 VDPVs were reported in India. A similar number (5 cases) and all due to type 2 VDPV have been reported in 2011 till 13 July. Recognition of VDPV is the primary reason why synchronous stopping of OPV use globally with continued vaccination with IPV is mandatory in post-polio eradication era.

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Table 5.16.1 Distinguishing features of paralytic poliomyelitis •  Fever at onset •  Rapid progression of paralysis within 2–3 days •  The legs are more commonly involved than the arms, and the large muscle groups are at greater risk than the small groups. The proximal muscles of the extremities tend to be more involved than the distal ones •  Asymmetrical distribution of paralysis with the most typical pattern being involvement of one leg only and less often one arm. It is less common for both legs and both arms to be affected. Quadriplegia is rare •  Preservation of sensory function with often severe myalgia •  Residual paralysis after 60 days

anagement

The aim of treatment is to promote recovery, to minimize residual muscle paralysis and disability. Treatment of the child with paralytic poliomyelitis varies with stage of illness and the severity of paralysis. Children with bulbo-spinal polio and respiratory paralysis would require hospitalization.

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CSF, WBCs, Protein Bladder dysfunction Nerve conduction velocity (NCV) – 3rd week EMG – 3rd week

Abnormal anterior horn cell disease Abnormal

Absent

Absent

Transient

Normal WBC; normal or slight increase in protein Present

Normal WBC; normal protein Never

Abnormal demyelination

No diagnostic value

Abnormal in sciatic nerve

Normal

Normal

Normal

<10 WBCs; High protein

•

trategies for Polio radication

In May 1988, the World Health Assembly committed the member nations of the World Health Organization (WHO) to achieving the goal of global eradication of poliomyelitis. This goal is defined as: • No cases of clinical poliomyelitis associated with wild poliovirus • No wild polioviruses found worldwide despite intensive efforts to do so. The following strategies to achieve polio eradication were adopted by the WHO for worldwide implementation in all polio-endemic countries.

•

E

S



•

•

Achieving and maintaining high routine coverage in infants younger than 1 year with at least three doses of oral polio vaccine (OPV3): Paralytic polio can be caused by any of the three serotypes of poliovirus. Trivalent OPV provides immunity against all three types. Three routine trivalent OPV doses should be received by infants at ages 6, 10 and 14 weeks. WHO and UNICEF also recommend that all newborns should receive a dose of trivalent OPV at birth (‘birth dose’ of OPV). Administering supplemental doses of OPV to all children aged less than 5 years during national immunization days to rapidly interrupt transmission: National immunization days (NIDs) are conducted at interval for a short period (a few days) in which a dose of OPV is administered to all children in the target age group, regardless of previous vaccination history. Surveillance of acute flaccid paralysis cases: This is done to identify all reservoirs of wild poliovirus transmission. This includes reporting of all acute flaccid paralysis cases, investigating them and investigating stool specimens for polioviruses in specialized laboratories. Maintaining a high level sensitivity of reporting will ensure that all cases of poliomyelitis are detected, reported and investigated. The surveillance is critical for achieving the goal of polio eradication, which is defined as the absence of any polio case for at least three consecutive years and the absence of isolation of wild poliovirus from communities. For surveillance purpose, a case of AFP is defined as any child less than 15 years of age, who has acute onset of flaccid paralysis for which no obvious cause is found or paralytic illness in a person of any age in which polio is suspected. Conducting ‘mop-up’ vaccination campaigns: When poliovirus transmission has been reduced to welldefined and focal geographic areas, intensive houseto-house, child-to-child immunization campaigns are

seases

In acute stage children with isolated limb/limbs paralysis should be advised complete rest, proper positioning of the affected limb and passive range of movement at the joints. Massage and intramuscular injection should be avoided during acute phase of illness. The child should be made to lie on firm bed and maintain limbs in neutral position. The child should lie with trunk and hip straight with slight flexion (5–10°) at knees and feet at right angle at ankle joint. This position can be maintained with pillows, rolled towels or sand bags. The support should also be given on lateral sides of limb or limbs to prevent external rotation. Warm moist fomentations and passive range of movements of all the joints of affected limb/limbs should be given. As the acute phase of illness subsides, recovery in muscle power is helped by giving physiotherapy in the form of active exercises aimed at strengthening weak muscle groups, improvement of functional skills of the child, helping ambulation and prevention of deformities. Physiotherapy plays an important role in management of children during recovery and post polio residual paralysis stage. Some children with fixed deformities and contractures may require orthopedic surgery.

i

Only in bulbar and bulbospinal High WBCs; normal or slight increase in protein Absent

Pain in gluteal region

i

Cranial nerves involvement

Cramps, tingling hypoanesthesia of palms and soles Often present VII, IV, X,XI, XII

i

Myalgia, no sensory loss

Traumatic neuritis Present Asymmetrical limb Decreased or absent

Di

Sensation

Transverse myelitis Rarely present Symmetrical lower limbs (LL) Absent in LL early hyperreflexia late Loss of sensation with sensory level

i

 

Immun ty, Immun zat on and Infect ous

Table 5.16.2 Differential diagnosis of paralytic poliomyelitis Signs and symptoms Poliomyelitis Guillain-Barre syndrome Fever at onset High, Present Not common Flaccidity Asymmetrical and proximal Symmetrical and distal DTR (Deep tendon reflex) Decreased or absent Absent

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B







1. Global Polio Eradication Initiative. Available at http:// polioeradication.org 2. Heymann D, Aylward B. Poliomyelitis. Orphanet Encyclopedia. August 2004. Available at http://www.orpha.net/data/patho/ GB/uk-Poliomyelitis.pdf 3. Nathanson N, Kew OM. From emergence to eradication. The Epidemiology of Poliomyelitis Deconstructed. Am J Epidemiol. 2010;172:1213-29. 4. National Polio Surveillance Project. http://www.npspindia. org 5. Poliomyelitis Eradication Field Guide, 3rd edition. available at http://www.paho.org/english/ad/fch/im fieldguide_polio. pdf 6. Simoes EAF. Polio viruses. In: Kliegman RM, Jenson HB, Behrman RE, Stanton BF (Eds). Nelson Textbook of Pediatrics, 18th edition. Philadelphia: Elsevier; 2008. 7. Sutter RW, Kew OM, Cochi SL. In: Plotkin SA, Orenstein WA, Offit PA (Eds). ‘Vaccine’, 5th edition. Philadelphia: Saunders; 2008.



Oral polio vaccine (OPV) is most often formulated as a trivalent vaccine, containing antigens for all three poliovirus serotypes (1, 2 and 3). Trivalent vaccine is used for routine immunization of infants as well as most of the PPI rounds. OPV has also been formulated as a monovalent oral polio vaccine (mOPV) and bivalent (P1 and P3), and has been used in specific areas where surveillance showed ongoing P1and P3 wild virus transmission. OPV should be administered orally, that is, directly into the mouth. Each single dose consists of two drops of live oral poliovirus vaccine. Oral polio vaccine is one of the most heat-sensitive vaccines in common use. The vaccine should be stored

ibliography



Dosage, Administration and Formulation



Oral polio vaccine (OPV) induces both circulating antibody and intestinal immunity, and by secondary spread, probably protects susceptible contacts. IPV protects against clinical disease and suppresses pharyngeal excretion of the virus, but has less of an effect on intestinal excretion. The seroconversion after three doses of OPV has been reported to be more than 95% in developed countries but recent review of data from developing countries has shown wide variation in the percentage of children seroconverting with rates of 73% for type-1, 90% for type-2 and 70% for type-3. This decrease may be due to recurrent diarrheal infections, malnutrition and other factors.

Inactivated polio vaccine (IPV) also known, as Salk vaccine is a mixture of the three polioviruses made by harvesting cell culture supernatants and submitting them to inactivation by formalin. When used as primary vaccination of infants, the vaccine produces seroconversion in 90–95% of children. IPV is relatively heat stable and is stable for 4 years at 4oC and for 1 month at 25oC. Major advantage of IPV is no risk of vaccine associated paralysis and it may be used in immunocompromised patients.



ral Polio Vaccine

Inactivated Polio Vaccine



O

There are currently two effective polio vaccines, the inactivated poliovirus vaccine (IPV), which was the first vaccine to become available in 1955, and the live attenuated oral polio vaccine (OPV), which was used in mass campaigns in 1959.



Polio Vaccines

below 8°C at all times. Unopened vials of OPV may be stored for up to 6 months at 20°C. With the development of the vaccine vial monitor (VVM) in 1996, health workers can evaluate whether cumulative heat exposure of a vial of vaccine has exceeded a pre-set limit, beyond which the vaccine should not be used.



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conducted over a period of days to break the final chains of virus transmission.

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5.17

hickenpox (Varicella)

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tiology

Varicella zoster virus is a double stranded DNA virus, a member of the herpes virus family. Humans are the only reservoir for VZV and cause primary, latent and recurrent infections. Primary infection causes chickenpox and results in a lifelong latent infection of sensory ganglion neuron. Reactivation of latent infection causes herpes zoster (shingles) which is not common in children.

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seases

Chickenpox is worldwide in distribution; epidemics do not have any definite periodicity. The epidemiology of varicella differs between temperate and tropical climates. In tropical climates, VZV seroprevalance reflects a higher mean age of infection and higher susceptibility among adults as compared to temperate climates. There is little data on the health burden of varicella in developing countries. Varicella morbidity and mortality may be higher than that in developed countries. Most of the children are affected at 15 years of age. Varicella epidemics occur mostly in the months of December to February. Within household contacts, transmission rate is 65–86%; more casual contacts such as occurring in a class room are associated with lower attack rates among susceptible children.

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pidemiology

The illness usually begins 14–16 days after exposure, although the incubation period can range from 10 to 21 days. The prodromal period starts as mild fever, headache, generalized body ache and tiredness. Fever is usually moderate ranging from 38°C to 39°C. After 2–3 days, the rash appears, initially as maculopapular which evolves into vesicles filled with clear fluid which becomes cloudy and umbilicated, described as ‘dew drops on rose petals’ (Fig. 5.17.1). The rash is intensely pruritic and distribution is typically central or centripetal. Lesions also occur in the oral mucosa, pharynx, conjunctiva and genitalia. New lesions appear for 1–7 days. While the initial lesions are crusting, new crops form on the trunk and then extremities. Simultaneous presence of lesions in various stages of evolution is characteristic of varicella. The lesions vary in number, from 10 to 1500 and leaves behind hypo- or hyperpigmentated marks that persist for days to weeks. Scarring is unusual unless the lesions are secondarily infected or scabs are removed prematurely. Herpes zoster occurs due to reactivation of latent VZV infection and is uncommon in childhood and is characte rized by clustered vesicular lesions on erythematous base, distributed over one or two dermatomes. Unlike in adults, severity is less (Fig. 5.17.2). ­

E

Chickenpox is a common childhood disease, caused by the Varicella zoster virus (VZV). Though generally considered as a benign infection, this can cause severe illness especially in newborns, immunocompromised children and elderly patients.

linical eatures



Introduction

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Lalitha Kailas

Breakthrough Varicella Breakthrough varicella occurs in a vaccinated child when exposed to varicella virus. It is defined as varicella

Pathogenesis

Figure 5.17.1 Varicella rashes as ‘dew drops on rose petals’  

The virus present in the respiratory secretions and in the fluid of skin lesions of an affected child is transmitted either by airborne spread or through direct contact. Viral replication occurs initially in the respiratory tract, followed by subclinical viremia. Host immune responses limit viral replication and facilitate recovery from infection. In immunocompromised children, however, viral replication continues with resultant injury to lungs, brain and other organs. Maximum period of infectivity is from 2 days prior to the onset of rash till all the lesions have crusted which is usually 5 days after the onset of rash.

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clinical findings of varicella including lesions that develop a unique hyperkeratotic appearance and continued new lesion formation for weeks or months have been described in children with HIV infection. Progressive varicella is a dreaded complication which follows primary varicella infection in children with congenital cellular immune deficiency, malignancy, HIV, after organ transplantation or those on chronic steroid therapy. It is characterized by severe visceral organ involve ment, coagulopathy and hemorrhage; and lesions will continue to develop for a longer time.

T

E

Varicella mbryopathy

 

Figure 5.17.2 Herpes zoster

C

developing more than 42 days after immunization and usually occurs 2–5 years following vaccination. Generally, it is mild with less than 50 skin lesions, predominantly maculopapular rather than vesicular rash, low or no fever, shorter (4–6 days) duration of illness and generally less contagious.

omplications

Bacterial Infections

iagnosis

Diagnosis is clinical and not usually difficult in a typical case. Often a history of exposure to the disease is helpful in reaching the diagnosis. Chickenpox should be differentiated form other exanthemata such as herpes simplex, enteroviral infections, insect bites and drug reactions. Laboratory abnormalities include leukopenia in the initial 72 hours, followed by relative lymphocytosis. Although multinucleated giant cells can be detected with nonspecific stains (Tzanck smear) they have poor sensitivity and do not differentiate VZV from herpes simplex viral infections. VZV can be identified quickly by direct fluorescence assay of cells from cutaneous lesions and by PCR amplification testing. VZV IgG antibodies can be detected by several methods and a fourfold increase in lgG antibodies is also confirmatory of acute infections. Testing for VZV IgM antibodies is not useful for clinical diagnosis.

Secondary bacterial infections of skin (cellulitis and abscess) occur most commonly due to Staphylococcus aureus and Streptococcus pyogenes which can lead to complications like septicemia and septic arthritis occasionally.

eonatal Varicella

Varicella is associated with high mortality in newborn. The risk in newborn is dependent upon the amount of maternal antibody that the fetus has acquired transplacentally before birth. If there is 1 week or more intervals between maternal chickenpox and delivery, it is likely that newborn received sufficient antibody to VZV to ameliorate neonatal infection. Alternatively, if interval was less than 1 week, the newborn is unlikely to have enough VZV antibodies and neonatal chickenpox may be exceptionally severe. D

Complications of varicella are not common; uneventful recovery is the rule except in immunocompromised persons.

N

Chickenpox in pregnancy is associated with increased risk of fetal malformations especially if infection occurs in the first or second trimester. The incidence of congenital varicella syndrome following gestational varicella in the first 20 weeks is approximately 2%. This is characterized by cicatricial skin scarring in a dermatomal fashion, limb defects, and ocular and brain abnormalities.

Neurologic Complications ­

­

Encephalitis and cerebellar ataxia are the common neuro logic complications encountered. They usually manifest 2–6 days after the onset of rash but may occur in the incubation period also. Clinical recovery is usually rapid and complete. Other complications include transverse myelitis, GuillainBarre syndrome and optic neuritis.

Respiratory Complications

M

Varicella pneumonia is a severe complication which is more common among immunocompromised and adults and it sets in during first 6 days after the onset of rash.

Other Complications ­

These include purpura fulminans, CNS vasculitis, auto 248 immune thrombocytopenia and Reye syndrome. Unusual

anagement

Management is symptomatic and includes antipyretics, antipruritic agents and good hygiene. Antiviral treatment modifies the course of both varicella and herpes zoster.

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Postexposure Prophylaxis Varicella zoster immunoglobulin (VZIG) is recommended for postexposure prophylaxis for susceptible individuals with significant contact with varicella or herpes zoster. Immunocompromised children and newborns of mothers with varicella within 5 days before delivery and 2 days after delivery should be protected with passive immunization. VZIG should be given as soon as possible but not later than 96 hours after exposure. The dose is 1.25 units/10 kg (maximum 625 units) body weight administered intramuscularly. The currently available VZIG is for IV use and administered at a dose of 0.2–1 m /kg. l



(as soon as possible preferably) is effective in preventing or modifying varicella especially in a household setting.

Immun ty, Immun zat on and Infect ous

There is controversy in treating uncomplicated varicella in a healthy child. Acyclovir is the drug of choice; 20 mg/kg/dose 4 times a day for 5 days is used to treat uncomplicated varicella. Treatment should be initiated within 24 hours of onset of the disease to get maximum effectiveness. Intravenous acyclovir is indicated in severe varicella and in immunocompromised individuals. For IV therapy, acyclovir is given in a dose of 10 mg/kg 8 hourly for 7 days. Treatment will reduce the duration of rash by one day and lesions by 25%. Intravenous acyclovir is also indicated for neonates who develop varicella from their mothers. Children with varicella should not receive salicylates due to increased risk of Reye syndrome.



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1. Maiya PP, Karunakaran, Bhat SR. Infectious Diseases. In: Bhat SR (Ed). Achar’s Textbook of Pediatrics, 4th edition. Hyderabad: Universities Press (India) Publishers; 2009. pp. 288-90. 2. Myers MG, Steward JF, LaRussa PS. Varicella zoster virus. In: Kliegman RM, Jenson HB, Behrman RE, Stanton BF (Eds). Nelson Textbook of Pediatrics, 18th edition, Vol. 1 New Delhi: Elsevier; 2008. pp. 1366-72. 3. Singhal T, Seth R, Bhatia V, et al. Infections and infestations. In: Ghai OP, Paul VK, Bagga A (Eds). Ghai Essential Pediatrics, 7th edition. New Delhi: CBS Publishers and Distributors; 2009. pp. 186-7. 4. Yewale V, Choudhury P, Thacker N. Varicella vaccine. IAP Guidebook on Immunization; IAP Committee on Immunization 2009-2011. Mumbai: Indian Academy of Pediatrics; 2011. pp. 111-15.

seases

Varicella is a vaccine preventable disease. Varicella vaccine is a live-attenuated vaccine derived from the original Oka strain, recommended after the age of 1 year. Up to the age of 12 years, one dose and after 12 years, two doses are given at an interval of 1 month. However as the incidence of breakthrough varicella is increasing, IAPCOI-2011 recommends two doses of vaccine at all ages. For primary immunization, the first dose should be given at the age of 15 months and second dose at the age of 5–6 years. For catch up vaccination, children below the age of 13 years should receive two doses at 3 months apart and above 13 years of age, two doses at 4–8 weeks interval. No booster is recommended. Vaccine given within 3–5 days of exposure





Bibliography



ctive Immunization



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Prevention

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Measles

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ntroduction

Measles is a contagious disease characterized by catarrhal symptoms, followed by appearance of a typical rash. The incidence of measles has come down world over with effective immunization but still it is a major cause of preventable blindness and still the leading vaccine preventable killer in children. India contributes 27% of global measles deaths. The WHO has started the Measles Surveillance Project in India from 2007. The South-East Asia Region (SEAR) has a goal of 90% reduction in measles mortality by 2010 in comparison to 2000 estimates, which was estimated to have been achieved by all countries in the region except India by 2008.

Pathogenesis Measles virus enters the human body through the respiratory epithelium of the nasopharynx. The virus replicates initially in these cells including the epithelial cells lining the buccal mucosa and conjunctiva. Later it spreads to the regional lymph nodes. Further replication of the virus leads to the primary viremia with seeding of the cells of the reticuloendothelial system. Infection of these cells leads to the secondary viremia, whereby the measles virus is disseminated through out the body, coincident with the clinical manifestations of the disease. Measles causes immunosuppression, which may persist for weeks to months and predisposes individuals to severe bacterial infection.

pidemiology C

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Measles is caused by a RNA virus, of genus morbillivirus, of the family paramyxoviridae. Only one serotype of measles is known. Measles is seen in early childhood in developing countries. The disease usually occurs in infants below 3 years of age. Infants are usually protected till the age of 4–6 months due to immunity acquired transplacentally from mother. Usually these antibodies are undetectable by the age of 9 months but antibodies may persist up to 12 months of age. The disease runs a mild course in healthy children, whereas the disease is severe in malnourished children. Transmission occurs either by direct contact or droplet spray. The period of infectivity is 4 days before and 4 days after appearance of rash. It is rarely subclinical. It is highly contagious and secondary attack rate is approximately 90% in susceptible household contacts.

250

tiology

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The clinical course of measles can be divided in four stages: incubation, prodromal stage, catarrhal stage and postmeasles stage of complications. The incubation period ranges from 10 to 12 days. In the later part of incubation period, the child shows prodromal symptoms which last for 2–4 days and consist of fever, malaise, coryza and tracheobronchitis. At the end of prodromal phase, the child gets fever which may be high grade. Koplik’s spots, which are pathognomonic sign of measles, are seen on day 2–3 of fever. These are grayish white or bluish white dots with reddish areola. Occasionally they are hemorrhagic mostly seen on buccal mucosa opposite lower molars but may be seen all over the buccal mucosa. Conjunctival congestion and photophobia is also classical of measles, which occurs before Koplik’s spots appear. Temperature rises abruptly as rash appears and often reaches 40°C or higher. Rash appears on 4th to 6th days of fever. It starts as faint erythematous maculopapular rash on upper lateral aspect of neck and typically behind the ears and increasingly involve face then spreading on to trunks and then to legs and arms over next 3–4 days. By the time rash appears on feet, it starts disappearing from face and fades down in the same pattern. Temperature also suddenly normalizes once rash starts fading and child suddenly looks well from sick look. The severity of disease is directly related to the extent and confluence of rash. In severe cases rash may become hemorrhagic. The rash fades in the next 3–4 days. As the rash disappears, it leaves behind the browny desquamation and brownish discoloration characteristic of post-measles state which disappears in 7–10 days.

E



Measles occurs both epidemically and endemically. The peak incidence is during winter and spring. One attack of measles confers lifelong immunity. Among the burden of vaccine preventable diseases world over, measles ranks first with 38% disease burden. The number of reported cases showed a decline from 1997 to 2005, and then there was a sharp rise in 2006. According to WHO, published in 2008, the reported cases of measles in India in 2006 were 60751 and in 2005 it was 52454. As per EPI fact sheet, documented measles immunization coverage in India was 67% in 2003 in children less than 1 year of age.

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Isolation of the patient from 7th day of exposure to 5 days after rash appearance is recommended.

Vaccine Measles can be effectively prevented by measles vaccine. The newborn baby is protected by transplacentally acquired

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1. Bhargava I. Measles. Control of Measles, Mumps and Rubella, 1st edition. New Delhi: BI Churchill Livingstone; 1995. 2. Epidemiology and Prevention of Vaccine-Preventable Diseases, 10th edition. Department of Health and Human Series CDC; 2007. 3. India EPI fact sheet, 2003, country Fact sheet WHO SEARO; 2004. 4. Mason WH. Measles. In: Kliegman RM, Jenson HB, Behrman RE, Stanton BF (Eds). Nelson Textbook of Pediatrics, 18th edition. Philadelphia: Elsevier; 2008. pp. 1331-7.



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Prevention

•

For a child, less than 6 months age (mother usually immune in India), there is no need for prophylaxis as child is already protected. For a child of 6–12 months age, if unimmunized, vaccinate with measles vaccine within 72 hours. For a child more than 12 months age, if unimmunized, vaccinate with measles or MMR vaccine within 72 hours of exposure. For immunocompromised child, give 0.5 m /kg immuno lobulin (maximum 15 m ) IM irrespective of immunity status.



Management is mainly supportive. The child may be given antipyretics, fluids and antihistaminics during acute phase. No antiviral therapy is available. The child may be isolated for the period of infectivity. There is inverse correlation between serum retinol concentration and measles severity. A single dose of vitamin A 100,000 units orally for children, 6–12 months of age and 200,000 units orally for more than 1 year of age children reduces mortality. Antibiotics may be indicated if there is evidence of otitis media or bacterial pneumonia.

•



E

SS

Management

Postexposure Prophylaxis



R

I

EN CNS S E S

In developing countries measles has a devastating course with a mortality of 1–3% which may go up during epidemics up to 5–15% and a high rate of complications.

uniza ion and nfec ious iseases

Prognosis

uni y,

Measles can affect various systems in the body resulting in following complications: • espiratory system: Post-measles bronchopneumonia empyema, mediastinal and subcutaneous emphysema and flaring of pulmonary tuberculosis. • G T: Diarrheal episodes are quite common after measles. • T: Otitis media. • : Measles encephalitis and encephalopathy. • ubacute sclerosing panencephalitis ( P ): It is a degenerative disease of the brain caused by a persistent infection with measles virus. It can manifest several years (usually 7 years) after measles infection. The patient develops progressive personality changes, developmental retardation, myoclonic seizures and motor disability. Measles virus has been isolated from the brain tissue of such patients. Their sera and CSF show a high titer of measles specific antibodies. • ye: Keratitis. • Cancrum oris (noma) and stomatitis. • ystemic: Acute malnutrition, secondary bacterial infections like septicemia with Streptococcus, etc.

maternal antibodies. The antibody gradually wanes and the infant becomes susceptible to measles starting from 6 months of age. By 9–12 months of age, most infants become susceptible. At this age, live attenuated measles vaccine offers good protection. Unconstituted vaccine remains viable for 2 years at 2–8°C, but once reconstituted it should be used within 4 hours as vaccine does not contain any preservative or antibiotic. Measles is a potent and effective vaccine with a seroconversion rate of 95–98%. As per National Immunization Program (NIP) in India and EPI policy, measles vaccine is given at 9 month of age as 0.5 m subcutaneous injection. MMR vaccine contains measles, mumps and rubella vaccine. The global recommendation now is two doses for MMR and varicella vaccine—the first dose at 15 months and the second at 4–6 years. It will be ideal to administer the second dose at 5th year along with DTP booster and OPV. Measles vaccine is contra indicated in pregnancy, children with primary immunodeficiency, untreated tuberculosis, cancer, organ transplantation or those receiving longterm immunosuppressive therapy or severely immuno compromised HIV-infected children.



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Mumps

tiology

pidemiology

Symptoms begin acutely with fever, malaise and headache to be followed parotitis, which is the most common manifestation and occurs in 30–40% of infected persons. It may involve one or both the glands. Earache, jaw tenderness with chewing, and dry mouth are among the presenting complaints that worsen over the next several days. Sucking a sour stimulus produces significant worsening of the pain. The swelling is at the angle of the jaw, and obliterates the angle, often extending to the lower portion of the ear which may 252 be lifted upward and outward. Defervescence and resolution

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The mumps virus is transmitted via saliva, through airborne droplets, by direct contact, fomites contaminated by saliva and possibly by urine. The secondary infection rates in susceptible populations have been as high as 80%. The period of maximum communicability extends from 1 day to 2 days before the onset of symptoms to 5 days thereafter. Incubation period is 2–4 weeks, average 16–18 days. The virus proliferates in the upper respiratory tract epithelium and then enters circulation. Viremia occurs after 12–25 days and lasts for 3–5 days. During viremia the virus spreads to multiple tissues. It then localizes in glandular and neural tissue. Infection with the virus or immunization is thought to confer lifelong immunity.

omplications

Pancreatitis is a manifestation of mumps and occurs in approximately 5% of the patients. Infection with mumps virus has been implicated as a possible cause of juvenile onset of diabetes but causal link has not been definitely proven. There is no evidence of impairment of fertility in postpubertal girls with oophoritis. Other complications include myocarditis, deafness unilateral or bilateral (transient or permanent), arthritis, optic neuritis, thyroiditis have been reported. Deafness caused by mumps virus may be unilateral in about 80%. It may be associated with vestibular reactions.

tiopathogenesis



E

The mumps virus is endemic worldwide, it also occurs in small epidemics. The only known host is the human. In unimmunized population epidemics tend to occur every 2–5 years, throughout the year but often with a peak in late winter or early spring.





E

Mumps virus is an RNA virus of the genus Paramyxovirus in the family Paramyxoviridae. Only one serotype of mumps virus is known.

­

Mumps is an acute viral infection which is characterized by swelling of one or more of the salivary glands, most commonly the parotid glands. It generally occurs in children and young adults. The salivary glands, the pancreas, the testes or ovary, the brain, the breast, the liver, the joints and the heart are the organs which are usually affected by the virus.

of parotid tenderness takes about a week. The orifice of the Stensen’s duct is commonly red and swollen. The submaxillary and sublingual glands are involved less often and may be without parotid swelling. Presternal pitting edema has been described due to lymphatic obstruction. Other than parotitis, orchitis is the second common feature in adolescent and post-pubertal males but unco mmon in prepubescent males. Epididymoorchitis, bilateral in 30%, usually occurs 1–2 weeks after parotitis, but it may occur without parotitis. Symptoms begin abruptly with testicular swelling and tenderness and associated nausea, vomiting, and headache. The testicle may enlarge three or four times and become very tender. Some degree of atrophy develops in nearly half of the affected organs but sterility is uncommon. Oophoritis in girls is much uncommon and may cause lower abdominal pain but does lead to sterility. CNS involvement, both in children and adults, is characterized by aseptic meningitis that occurs in 1–10% of patients. Meningeal symptoms may develop anytime between a week and before several weeks after the parotitis. Pleocytosis of cerebrospinal fluid with lymphocytic predominance of about 500 cells is usual, but total white cell counts may rise to over 2000 in the spinal fluid. CSF glucose is usually normal but may be low at times and the protein is normal or slightly elevated. These findings revert to normal after about a week and sequels are uncommon. Encephalitis is rare but it can be very serious with seizures and cortical blindness. Recovery is usually complete. Occasionally meningitis or encephalitis may occur without manifest parotitis. Aqueductal stenosis and hydrocephalus have been associated with mumps infection. Other CNS problems include transverse myelitis, cerebellar ataxia, facial palsy and Guillain-Barre syndrome. Mumps pancreatitis may be present with pain abdomen but diagnosis is difficult as serum amylase is elevated both in parotitis and pancreatitis but serum lipase is normal in former and elevated in later.

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Prognosis Mumps is a self-limited disease and prognosis is generally good in children.

The live attenuated mumps virus vaccine strains include Leningrad-Zagreb, Leningrad-3, Jeryl Lynn, RIT 4385 or

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Prevention

1. Epidemiology and prevention of vaccine-preventable diseases, 10th edition. Department of Health and Human Services CDC; 2007. 2. Gupta A. Mumps: epidemic parotitis. In: Parthasarathy A, Menon PSN, Nair MKC, Gupta P (Eds). IAP Textbook of Pediatrics, 4th edition. New Delhi: Jaypee Brothers; 2009. pp. 372-4. 3. Mumps. Red Book. 2009 Report of the Committee on Infectious Diseases, American Academy of Pediatrics, 28th edition. New Delhi: Jaypee Brothers; 2009. pp. 468-72. 4. Mumps virus infections. In: Brooks GF, Morse SA, Caroll KC, Mietzner TA, Butel JS (Eds). Jawetz, Melnick and Adelberg’s Medical Microbiology, 25th edition. New York: McGraw Hill Medical; 2010. pp. 563-5. 5. Singhal T, Amdekar YK, Agarwal RK. IAP Guidebook on Immunization. New Delhi: Jaypee Brothers; 2009.



There is no specific treatment. Symptomatic treatment includes simple analgesics. Mumps immunoglobulin treatment is of no value.

ibliography



Management



These are rarely done, but it is possible to identify infection acutely by detecting antibodies to the ‘S’ antigen by complement fixation antibody titers which rise in first week of illness, and V antigen by complement fixation antibody titers that follow with a rise several weeks later, and may persist at low levels for years. Neutralizing and hemagglutination inhibiting antibodies appear during convalescence.



erologic Tests



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Mumps virus can be isolated in cell culture inoculated with buccal swab, throat washing, saliva or CSF.



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Urabe AM9 strains and are grown in chick embryo or human diploid cell cultures. MMR vaccines are supplied in lyophilized form and should be frozen for long-term storage. In the clinic, these vaccines can be stored at 2–8°C. The vaccines should be protected from light. Reconstituted vaccine should be stored at 2–8°C, protected from light and used within 4–6 hours. Immunization is indicated at about 15 months of age in combination with measles and rubella vaccination and can be given at age of 12 months if child has not received measles vaccination at 9 months of age. The dose is 0.5 m subcutaneously. The vaccine can be given along with all other childhood vaccines except BCG vaccine. The virus does not spread from vaccinee to contacts. Two doses for MMR vaccines are recommended, the first dose at 15 months and the second at 4–6 years. The second dose can be given from 8 weeks onwards after the first dose of MMR. The second dose may be administered at 5th year along with DTP booster and OPV. Vaccine is not effective in preventing mumps after exposure.

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Onset is usually sudden and results in permanent hearing impairment. ECG changes typical of myocarditis are seen in 3–15% of patients with mumps. Usually there is complete recovery. Arthralgia, arthritis and nephritis are other less common complications.

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ubella

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The rubella virus is a cubical, medium-sized (70 nm) virus. It is an RNA virus of the genus Rubivirus in the family Togavirus. A capsid protein C surrounds the viral RNA. The virus has two transmembrane proteins, E1 and E2. Only one serotype has been identified.

linical Manifestations

Incubation period is 14–21 days. Initial prodromal symptoms include malaise, headache, mild catarrhal symptoms and lowgrade fever. Most characteristic features are retroauricular,

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iagnosis

Confirmation is by serology or viral culture. Virus can be isolated from throat and urine from 1 week before to 2 weeks after the onset of rash. Congenital rubella is associated with low platelet counts, abnormal liver function tests, hemolytic anemia, pleocytosis and very high IgM antibody titer. X-ray shows pneumonitis, bone metaphyseal longitudinal lucencies in congenital rubella syndrome. D

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tiology

ongenital ubella yndrome (

In pregnant women, rubella virus can cross the placenta and infect the developing embryo or the fetus resulting in various congenital malformations. The exact nature and extent of these malformations depend on the gestational age of the affected fetus. Risk for congenital defects is greatest with primary maternal infection. Congenital defects occur in about 90% infants if maternal infection occurs before 11 weeks of pregnancy and about 10–20% by the end of first trimester. CRS may result in spontaneous abortion or birth of a severely malformed baby. Maternal infection after 16th week is associated with low risk of congenital defects. Classically the CRS includes a triad of malformations, cataract, sensorineural hearing loss and congenital heart disease. It may also be a disease with multisystem involvement, a wide spectrum of clinical expression and long postnatal period of active infection with shedding of viruses. It can also lead to IUGR, microphthalmia, microcephaly, mental and motor retardation (Table 5.20.1). D





Humans are the only natural host of rubella virus. The virus is transmitted by aerosol droplets from person to person and transplacentally causing congenital rubella syndrome. Volunteer studies have shown that the virus remains in the nasopharynx from 7 days before to 14 days after the onset of rash. It replicates in the mucosal cells of upper respiratory tract and spreads to the regional lymph nodes, especially the posterior auricular and the suboccipital group. Small number of infants with congenital rubella can continue to shed the virus in nasopharyngeal secretions and urine and can transmit infection to susceptible contacts. Secondary attack rate is 50–60% in family contacts and almost 100% in closed populations like institutions or military barracks. Reliable statistics on CRS are rare in developing countries. The WHO estimates that worldwide more than 100,000 children are born with CRS each year, and most of them are in developing countries. Data regarding the prevalence of rubella in India is scarce. Sero-surveys have shown that 8–47% of women are susceptible to rubella infection.

CRS

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pidemiology

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The name “rubella” is derived from the Latin, meaning little red. The disease was first described by German physicians in the mid-eighteenth century, hence it is also known as German measles. This disease is often mild and attacks pass unnoticed as trivial infection. The disease may last 1–3 days with children recovering faster than adults. Its importance lies in its teratogenic effects. Infection during early pregnancy may cause fetal death or congenital rubella syndrome (CRS).

posterior cervical and suboccipital lymphadenopathy. Discrete rose colored spots on the soft palate (Forchheimer spots) may be seen in approximately 20% patients before the onset of skin rash. Skin rash is mostly discrete maculopapular but quite variable in size and confluence. It starts on face and spreads rapidly over trunk. Progression is so fast that by third day it usually clears up without significant desquamation. Occasionally conjunctivitis is seen. In women and young girls arthralgia and polyarthritis may occur. Any joint can be involved but small joints of hand are affected most frequently lasting for few days to few weeks and leaves no sequelae.

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It is often confused with mild variety of scarlet fever or rubeola. Other viral illnesses like roseola infantum, infectious

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Treatment No specific antiviral therapy is available for rubella. Antipyretics are used for symptomatic relief.

 

 

 

 

Transient neonatal manifestations Thrombocytopenia which may manifest as purpura Hepatosplenomegaly Meningoencephalitis Bony radiolucencies

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ibliography







­

The prognosis of childhood rubella is good; that of congenital rubella varies with the gestational age at the time of infection and organ involved.





Prognosis



mononucleosis, enteroviral infection and drug rash closely resemble rubella.

1. Cutts FT, Robertson SE, Diaz-Ortega JL, et al. Control of rubella and congenital rubella syndrome (CRS) in developing countries, Part 1: Burden of disease from CRS. Bull World Health Organ. 1997;75(1):55-68. 2. Levin MJ, Weinberg A. Infections: viral and rickettsial. In: Hay WW, Levin MJ, Sondheimer JM, Deterding DR (Eds). Current Diagnosis and Treatment: Pediatrics, 20th edition. New York: McGraw-Hill Medical; 2009. pp. 1107-47. 3. Mason WH. Rubella. In: Kliegman RM, Jenson HB, Behrman RE, Stanton BF (Eds). Nelson Textbook of Pediatrics, 18th edition, Vol 1. Philadelphia; Elsevier; 2007. pp. 1337-41. 4. Sharma H, Chowdhari S, Raina TR, et al. Sero-Surveillance to assess immunity to rubella and assessment of immuno genicity and safety of a single dose of rubella vaccine in school girls. Indian J Community Med. 2010;35(1):134-7.

 

 



 

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Late-emerging or developmental Late-onset interstitial pneumonitis, at age 3–12 months Chronic diarrhea Insulin-dependent diabetes mellitus Thyroid dysfunction

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Eyes Retinopathy Cataracts: pearly, dense, nuclear; 50% bilateral; always accompanied by retinopathy Microphthalmos

Reports from different parts of India highlight the existence of rubella leading to fetal malformations and wastage. However, the need for routine immunization to control rubella has not been duly recognized; hence not yet included in National Immunization Schedule. Rubella vaccine is a live attenuated vaccine which is available separately or as triple vaccine MMR that contain measles, mumps and rubella. Principal goal of rubella vaccination is to prevent CRS. The global recommendation along with IAPCOI (Indian Academy of Pediatrics, Committee of Immunization) is two doses of MMR vaccines—the first dose at 15 months and the second at 4–6 years; but the second dose can be given after 8 weeks interval. It will be ideal to administer the second dose at 5th year along with DTP booster and OPV. Special care should be taken in reproductive females to avoid pregnancy for 3 months after MMR vaccination. However, inadvertent vaccination during pregnancy is not an indication for termination of pregnancy.

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Cardiovascular system Patent ductus arteriosus Pulmonary arterial stenosis Ventricular septal defect

Prevention

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Ears and central nervous system Sensorineural deafness: unilateral or bilateral Central auditory deafness Mental retardation Speech defects



 

 

 

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General Fetal loss (spontaneous abortion and stillbirths) Low birth weight Micrognathia

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Table 5.20.1 Main clinical manifestations of congenital rubella syndrome

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abies

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According to the Association for Preventive Control of Rabies in India (APCRI), the last available annual incidence of human rabies deaths in India was 17137 and if an additional 20% is included for atypical form of rabies, the incidence rises to 20,566. In India 50–60% of the rabies death occurs in children, particularly under 15 years of age. Short stature of children leads to more bites in the upper part of the body which leads to shorter time for the virus to reach the brain. Playful nature and tendency to tease animals makes them more vulnerable. Softer skin results in more severe injury and finally they do not inform about the injuries because of the fear of painful injections. Bites by domestic and peri-domestic rabid mammals can cause the disease, but bites by house rats, squirrels and rabbits usually do not transmit rabies. Other than bites and scratch from infected animals, licks on broken skin or intact mucous membrane may transmit rabies. Rare causes of transmission include aerosol transmission in bats infested caves and human to human transmission by organ transplant (corneal transplant).

tiopathogenesis



Rabies virus is a single stranded RNA virus belonging to the genus Lyssavirus of the family Rhabdoviridae. It is a neurotropic virus having a phospholipid envelop. The virus is rapidly inactivated by oxidizing agents, quaternary ammonium compounds, soap and detergents. Once it enters the human body, it replicates in muscles in and around wounds. Then as it gains access to the nerve endings, it ascends passively in the axoplasm of the nerves. On reaching dorsal root ganglia, there is further replication and the virus traverses further to the anterior horn cells of 256 spinal cord. Once the central nervous system is involved,

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There are two distinct clinical forms: 1. Furious rabies or encephalitic type accounting for 80% of cases. 2. Dumb rabies or paralytic type accounting for 20% of cases. In both the types, initial presentation may be nonspecific with generalized malaise, headache and fever. Some may complain of numbness or tingling sensation at the bite site. In furious type, symptoms are related to spasm of the gullet with hydrophobia, aerophobia, dysphagia and other aggressiveness which ultimately leads to coma and death usually due to respiratory failure. In contrast, the paralytic type starts with ascending paralysis from lower limbs. The patient lives longer with gradual involvement of abdominal muscles, upper limbs and respiratory muscle leading to death due to respiratory failure.

Rabies is primarily a zoonotic disease which is transmitted to human usually by bite of an infected animal, mainly dogs. Other common household animals responsible include cats, cattle, and pigs and among wild animals are mongoose and jackals. Two interrelated cycles—sylvatic and urban, maintain the disease and dogs are the main reservoirs for urban cycle. With deforestation and increased urbanization, the urban cycle dependent on stray dog population has become the main force in maintaining and spreading rabies. Human rabies is highly endemic throughout the mainland of India with islands of Andaman and Nicobar in the east and Lakshadweep in the west being rabies free.

there is rapid and extensive replication of the virus. The incubation period of rabies in human is highly variable, as brief as 4 days to as long as 3 years (average 3 weeks to 3 months). Early initiation of the disease may be related to size of viral inoculum, bites in head and neck region due to close proximity to brain and in hands due to excessive innervation.



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iagnosis

Diagnosis of rabies is mainly clinical. Laboratory tests may be required in atypical cases. • Antemortem diagnosis is by detection of virus or viral antigen in saliva or CSF. Viral nucleic acids may be detected in infected tissue by reverse transcriptase (RT)PCR analysis. • Serological assays to detect antibodies to rabies virus are used for diagnostic, epidemiological and to assess immunological response following vaccination. • Postmortem diagnosis by demonstration of Negri bodies in brain tissue is pathognomonic of rabies.

Management Once symptoms of rabies have developed neither rabies vaccine nor rabies immunoglobulin (RIG) will improve prognosis and there is no specific treatment. In rabies endemic country like India every animal bite is suspicious and treatment should be started immediately. As the incubation period in rabies is long, it is possible to institute prophylactic postexposure treatment early enough before

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Two types of RIG, one equine rabies immunoglobulin (ERIG) and other human rabies immunoglobulin (HRIG) are available. Antisera of equine origin requires preadministration sensitivity testing as per manufacturer’s instructions as anaphylactic shock may occur. HRIG does not require prior sensitivity testing. ERIG and HRIG are available in concentration of 300 IU/mL and 150 IU/mL, respectively. The total dose of ERIG and HRIG are 40 IU/kg and 20 IU/kg with a maximum of 3000 IU and 1500 IU, respectively. The total calculated dose should be infiltrated into and around the wounds. Remaining amount, if any, must be administered by deep intramuscular injection at a site distant from the vaccine site. In case of multiple wounds, if total dose is not sufficient to infiltrate all wounds it may be diluted in normal saline as many folds to permit complete infiltration. If RIG is not administered along with vaccine, it can be started up to the seventh day following vaccination; thereafter the vaccine itself elicits an adequate antibody response. Rabies immunoglobulin (RVG) should never be administered at the same anatomical site or in the same syringe as vaccine. Transient tenderness at injection site or mild fever occurs following RIG therapy does not require any treatment. RIG should never be used intravenously.



Passive Immunization: Rabies Immunoglobulin (RIG)

uniza ion and nfec ious iseases

History of bite by a rabies vaccinated animal is not always a guarantee that the animal is not rabid. Animal vaccine failure does occur and considering the fatal nature of the disease, it is prudent to start prophylaxis. Provoked bites are also not a guarantee that the animal is not rabid. After starting the vaccination, the schedule may be modified in cases where the animal is suspected not being rabid (i.e. vaccinated animal)—if it remains healthy throughout an observation period of 10 days by converting postexposure prophylaxis to pre-exposure prophylaxis, by omitting the vaccine dose on day 14 and administrating on day 28 as per Essen schedule. However, this observation is valid for bites only by dogs and cats as natural history of rabies following bites by other mammals is not fully understood. Bites by all wild animals including mongooses should be treated at category III exposure. Bat rabies is not conclusively proved in India hence exposure to bats does not warrant treatment. Treatment should be started as early as possible following exposure but persons who present even months after exposure should be dealt with the same manner as recent exposure. Also infancy is not a contraindication for postexposure prophylaxis.



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General onsiderations in Postexposure Prophylaxis

with soap and water or water alone is essential. It should be followed by disinfection with ethanol or iodine (tincture or aqueous solutions). Suturing of the wound should be avoided, but if it is necessary loose sutures are applied following infiltration of rabies immunoglobulin. Administer tetanus toxoid or tetanus immunoglobulin or both as the condition demands.

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the virus reaches the nervous system. Before starting treatment, it is important to categorize the exposure according to WHO recommendations (Table 5.21.1).

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The postexposure prophylaxis (PEP) has three modalities which are of equal importance and should be followed meticulously. • Management of wound • Passive immunization: Rabies immunoglobulin (RIG) • ctive immunization: Anti-rabies vaccine (ARV).

Management of Wound As the virus remains localized in the site of bite for some time, wound toileting should be done even if the patient presents late. Immediate washing and flushing the wound

 

Table 5.21.1 Categories of exposure and use of rabies biologicals Category Type of exposure Recommended postexposure prophylaxis I Touching, feeding of animals No prophylaxis if history is or licks on intact skin reliable II Minor scratches or abrasions Wound treatment and antiwithout bleeding or licks on rabies vaccine broken skin and nibbling of uncovered skin Wound treatment plus rabies III Single or multiple immunoglobulin plus antitransdermal bites or rabies vaccine scratches or contamination of mucous membrane with saliva (i.e. licks)

Active Immunization: Antirabies Vaccine (ARV) Active immunization against rabies is by administration of either cell culture rabies vaccines (CCRV) or purified duck embryo vaccine (PDEV). The different vaccines available in our country are as follows: Cell culture vaccines: • Human diploid cell vaccine (HDCV) • Purified chick embryo cell vaccine (PCEC) • Purified vero cell rabies vaccine (PVRV).

Purified duck embryo vaccine (PDEV): All cell culture vaccines are in freeze-dried (lyophilized) form and should be stored and transported at temperature range of 2–8°C. Freezing does not damage lyophilized vaccine but PDEV is in liquid suspension form which should never be frozen but kept between 2°C and 8°C. Lyophilized vaccine should be administered after reconstitution with the diluents provided immediately prior to use. Under no circumstances, reconstituted vaccine should be kept for more than 6–8 hours. Side effects of cell culture vaccine are minimal with local pain and tenderness at injection site. Systemic effects include 257 fever, urticaria, malaise and rarely lymphadenopathy.

Postexposure Prophylaxis

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The dosage of all CCV is same irrespective of the age or body weight of the child. The vaccine should not be administered in gluteal region as fat impairs absorption of antigen with impaired immune response. In infants and smaller children, anterolateral aspect of thigh and older children deltoid region is the ideal site of vaccination. Two schedules of vaccination can be followed which are mentioned below but the former is currently in vogue in India. 1. Essen schedule: Five dose intramuscular regimen (1-1-11-1) given as a single injection on day 0, 3, 7, 14 and 28. 2. Zagreb schedule: Four dose intramuscular regimen (2-01-0-1) given as two doses on day 0 on either deltoids or anterolateral thigh followed by one dose on day 7 and one on day 21.



A child who has received full postexposure or pre-exposure prophylaxis may be given two booster doses either by IM regimen or ID regimen on days 0 and 3, irrespective of the time elapsed between initial vaccination and subsequent exposure. Proper wound management must be followed but they do not require treatment with RIG.

Postexposure Prophylaxis of mmunocompromised hildren They also merit rabies immunoglobulin and antirabies vaccine. Immunocompromised with category II exposure should receive rabies immunoglobulin in addition to full postexposure vaccination.





Postexposure Therapy for Previously Vaccinated

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Rabies vaccine may be used either by intramuscular (IM) regimen or intradermal (ID) regimen.

area) administered intradermally on days 0, 3, 7 and 28. Day 0 is the first day of vaccination and not the day of rabies exposure. 2. Thai red cross schedule (2-2-2-0-1-1): This schedule is same as the previous one excepting a single dose administered on days 28 and 90. Former schedule is preferred as the chances of dropouts are much higher in later.

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Inter-switching between different cell culture vaccines (CCV) is not recommended; however, under unavoidable conditions different brand may be use to complete PEP. All CCV and PDEV should have potency (antigen content) above 2.5 IU per dose.

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Vaccine Schedule

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M schedule: Three doses of vaccine on days 0, 3 and 28.



l

ibliography 1. American Academy of Pediatrics. Rabies. In: Pickering LK, Baker CJ, Kimberlin DW, Long SS (Eds). Red Book: 2009 Report of the Committee on Infectious Diseases, 28th edition. Elk Grove Village, IL: American Academy of Pediatrics; 2009. pp. 552-9 2. Kundu R, Ganguly N, Ghosh TK. IAP Protocol on Infectious Diseases in Children. Kolkata: IAP Infectious Diseases Chapter; 2008. pp. 57-71.

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schedule: Three dose of vaccine (0.1 m single dose) on days 0, 7 and 28.

l



This regimen requires considerably less vaccine. It reduces the volume of vaccine required and vaccine cost by 60–80%. Vaccines which are approved by DCGI (Drug Controller General of India) should be used. All the vaccines mentioned previously are approved except HDCV and PDEV for intradermal use. Vaccines should be stored at 2–8°C after reconstitution and should be used within 8 hours. If the vaccine intended for intradermal use is accidentally administered intramuscularly or subcutaneously, a fresh dose should be administered intradermally at a nearby site. Dose of 0.1 m of vaccine, irrespective of reconstituted volume, is administered intradermally per site. This regimen also requires trained staff and will be economically viable where multiple cases are available. Two regimens are currently used which are as follows: 1. Updated thai red cross schedule (2-2-2-0-2): Two doses of 0.1 m of vaccine at different sites (one on each deltoid

Children constitute special risk group for rabies exposure and the disease (rabies) is uniformly fatal. Hence, active consideration should be given to vaccinate children in endemic country like India where children very often come in contact with stray and pet dogs. Vaccine is usually administered from 3 years age when they start playing in streets and parks.



Intradermal (ID) Regimen

Pre-exposure Vaccination of hildren

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pidemiology S

As per the UNAIDS (United Nations Program on HIV/AIDS) report on global AIDS epidemic, there are 33.3 million adults and children living with HIV or AIDS in 2009 (prevalence in adults is about 0.8%). An estimated 2.6 million people became newly infected and 3,70,000 children contracted HIV during perinatal and breastfeeding period in 2009. The World Health Organization (WHO) estimates that 2.2 million children (<15 year of age) were living with HIV infection at the end of 2004. Annual AIDS related deaths have reduced from 2.1 million in 2004 to 1.8 million in 2009. Childhood AIDS related deaths have also reduced from 3,20,000 in 2004 to 2,60,000 in 2009. Of estimated 15 million people living with HIV in low and middle income countries, about 5.2 million people are receiving HIV treatment. S

Indian cenario India has third largest population of patients with HIV/AIDS. In 1986, the first known case of HIV was reported amongst female sex workers in Chennai. As of 2007, 2.31 million people in India are living with HIV. Of these, estimated 39% are females and 3.5% are children. The adult HIV prevalence in India has declined from estimated level of 0.41% in year 2000 to 0.31% in 2009. As per recent reports, India had 2.39 million people living with HIV at the end of 2009. HIV is more common in north-eastern and southern states of India. The prevalence is higher in urban areas (0.35%) than in rural areas (0.25%). As of 2007 in various Indian states, the antenatal clinic HIV prevalence was 0.25–1% (average 0.48%); sexually transmitted diseases (STD) clinic HIV prevalence was 0.42–17.2% (average 3.6%); intravenous drug use (IDU) HIV prevalence was 1.91–24.4% (average 7.2%); men having sex with men (MSM) HIV prevalence

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odes of HIV ransmission

HIV infection occurs through sexual contact, parenteral exposure to infected blood or blood products, sharing of needles by drug users or vertical transmission from the mother to child. The route of infection in pediatric population is mostly through vertical transmission. Most new adult and adolescent HIV infections occur through heterosexual transmission. As per 2009-2010 figures from India, heterosexual transmission accounts for 87.1% cases, parent to child transmission 5.4%, injecting drug use 1.6%, homosexual transmission 1.5%, blood or blood products use 1% and unknown route in 3.3% cases. Rate of transmission from mother to child varies from 12% to 30% with figures as high as 50% reported from Africa. Effective perinatal treatment of HIV-infected mothers with anti-retroviral (ARV) drugs has decreased these rates to below 2%. The vertical transmission can occur during intrauterine (5–10%), intrapartum (10–15%), or breastfeeding (5–20%) periods. The overall risk of transmission without breastfeeding is about 15–25%. With breastfeeding of 6 months duration, the risk is about 20–35% and with breastfeeding of 18–24 months, the risk increases to 30–45%. Mixed feeding also increases this risk of transmission. The mechanism of intrapartum transmission is exposure to infected blood and cervico-vaginal secretions during birth. Risk factors increasing the rate of vertical transmission include preterm delivery (<34 weeks), low maternal antenatal CD4 count, high maternal viral load, symptomatic disease in mothers, more than 4 hours duration of ruptured membranes, intrapartum hemorrhage and birth weight less than 2,500 g. Elective cesarean delivery can decrease HIV transmission. E

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Acquired immunodeficiency syndrome (AIDS) is caused by HIV, the human immunodeficiency virus-1 and 2. Children form 6% of global HIV disease burden, have rapid progression and a high mortality. The disease has now become a chronic disorder due to availability of antiretroviral therapy (ART) and drugs to treat opportunistic infections (OIs). HIV infection is not only a medical disorder but has social implications (especially in children, due to demise of parents) and economic consequences.

was 3.6–17.6% (average 7.4%); and female sex worker HIV prevalence was 0.4–17.91% (average 5.1%). As of 200809, these prevalence figures were 0.49% for antenatal attendees, 2.5% in STD clinics, 9.2% in IDU, 7.3% in MSM and 4.9% in female sex workers.

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Immun ty, Immun zat on and Infect ous

Pediatric Human Immunodeficiency Virus (HIV) Infection or cquired Immunodeficiency yndrome ( I )

tiopathogenesis tiology

HIV-1 and HIV-2 belong to the Retroviridae family (genus Lentivirus). The HIV-1 genome contains two copies of single-stranded RNA. At either ends of the genome, exist the “long terminal repeats”, which contain the regulation and expression genes of HIV. The HIV genome includes three major regions: GAG region (encodes the viral core 259 proteins including p24); POL region (encodes the viral

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Three clinical patterns of HIV disease have been described in children (prior to availability of the HAART). 1. apid progressors or rapid disease course (15–25%): In these, the onset of AIDS occurs within the first few months of life with a median survival time of 6–9 months (if left untreated). OIs and neurological manifestations are common. In resource-poor countries, most of HIVinfected newborns will have this rapidly progressing disease. 2. hort-term progressors or slower progression (60–80%): Majority of those infected perinatally (intra partum) have a median survival time of 6 years with slower progression. HIV related illnesses develop by 3–4 years progressing to AIDS by 6–7 years. They present clinically with recurrent bacterial infections, failure to thrive and lymphoid interstitial pneumonitis (LIP). 3. Long-term progressors or long-term survivors (<5%): Few of those perinatally infected have minimal or no progression of disease with relatively normal CD4 counts and very low viral loads for longer than 8 years. Possible mechanisms for this delay in disease manifestations include effective humoral immunity and/or cytotoxic T lymphocytic responses, host genetic factors, and infection with attenuated or defective virus.

linical eatures F

HIV virus is lymphotropic in nature. When the mucosa serves as the portal of entry, initial cells to be infected are the dendritic cells, which transport the virus to lymphoid tissues. In lymph nodes, the virus binds to cells expressing CD4+, primarily the helper T lymphocytes (CD4+ T cells) and cells of monocyte-macrophage lineage. The infected CD4+ lymphocytes get activated in lymph nodes and proliferate (causing generalized lymphadenopathy). When HIV replication reaches a threshold (usually within a month), a burst of viremia occurs leading to flu-like illness (fever, rash, lymphadenopathy, arthralgia, etc.). A complex immune (cellular and humoral) response is mounted by the immune system of host leading to control of the viremic episode in next 2–4 months and the patients enter a clinically silent latent phase. The long period of clinical latency (up to 8–12 years) does not indicate viral latency, but has very high virus turnover and depletion of CD4+ lymphocytes. Viral replication in infected monocytes may suggest their role as reservoirs of HIV and as effectors of tissue damage. CD8 T cells play an important role in containing the infection. During states of immunologic quiescence, a complex interaction of cytokines leads to a constant level of viral expression (especially in lymph nodes). With progression of the disease, there is increase in viral replication and progressive decline in CD4 cell counts ultimately compromising immunity and leading to opportunistic infections (OIs). Progression of the disease is related to gradual disruption of lymph nodes with loss of its ability to restrict the virus, the virus thus recirculates 260 producing high level of viremia and a rapid decline of CD4+

linical Patterns



Pathogenesis

T cells (during later stages). When compared with adults, the disease progression is more rapid in children, the immune system is more immature with higher CD4 counts, and high viremia in perinatally transmitted HIV leads to rapid progression in infants. Lymphopenia is usually only seen in older children or those with end-stage disease. Infections such as invasive bacterial infections and PCP (Pneumocystis jiroveci pneumonia) are more common in children while malignancies like Kaposi’s sarcoma are more common in adults.

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enzymes including reverse transcriptase and protease); and ENV region (encodes viral envelope proteins gp120 and gp41). The gp120 glycoprotein carries the binding site for CD4 molecule. The viral tropism for CD4+ T cells reduces the effectiveness of the host immune system. Other CD4-bearing cells include macrophages and microglial cells. After viral attachment, the gp120 and CD4 molecule undergo conformational changes, with the gp41 interacting with fusion receptor on cell surface. Viral fusion with the cell membrane occurs, allowing entry of viral RNA into cell cytoplasm. Viral DNA copies are transcribed from virion RNA (viral reverse transcriptase enzyme) with duplication of the DNA copies producing double-stranded circular DNA; which is transported into host cell nucleus and gets integrated into chromosomal DNA (referred to as ‘provirus’- which has the advantage of latency or dormancy for long period). The proviral DNA encodes production of viral RNA leading to synthesis of viral proteins required for viral assembly. The virus specific protease is important for HIV-1 viral assembly. The HIV-1 reverse transcriptase is error prone leading to multiple mutations, thus creating wide genetic variation in the isolates. HIV-1 transcription is followed by translation. The RNA genome is incorporated into newly formed viral capsid with generation of new virus particles, which then bud off from the host cell to infect other cells.

HIV infection is a disease with various clinical manifestations of varying severity. Important manifestations occurring in infancy and childhood include lymphadenopathy, hepatosplenomegaly, failure to thrive, chronic or recurrent diarrhea, recurrent pneumonia, oral thrush, recurrent otitis media, tuberculosis (TB), PCP, pyrexia of unknown origin, etc. Recurrent bacterial infections, chronic parotid swelling, lymphoid interstitial pneumonitis (LIP) and early onset progressive neurologic deterioration are manifestations seen more commonly in children as compared to adults.

WHO Clinical Staging of HIV/AIDS in Infants and Children This system is used in children proven to have HIV infection to decide the severity and also to determine the need for anti-retroviral therapy (ART). Only the common or important manifestations are mentioned below and readers are referred to the original WHO document for a complete list.

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The immune classification is based on absolute CD4 lymphocyte count or the percentage of CD4 cells. CD4 counts are relatively high in infancy and reduce steadily up to 6 years of age. WHO immunological classification for established HIV infection defines age related CD4 values. Below 11 months of age, the CD4% cut offs for mild, advanced and severe immunodeficiency are 30–35%, 25–29% and less than 25%, respectively. In children of 12–35 months of age, the cutoffs for mild, advanced and severe immunodeficiencies are 25–30%, 20–24% and less than 20%, respectively. For those between 36 months and 59 months, the cut-offs for mild, advanced and severe immunodeficiencies are 20–25%, 15– 19% and less than 15%, respectively. Above 5 years of age, absolute CD4 counts are used (cut-offs for mild, advanced and severe immunodeficiencies are 350–499 cells per cumm, 200–349 cells per cumm and less than 200 cells per cumm or less than 15%, respectively).

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sepsis, bacterial pneumonia, etc. which account for more than half of the infections in HIV-infected children. Also, meningitis, urinary tract infections, abscesses, and bone or joint infection may be seen. Milder recurrent infections (otitis media, sinusitis, skin or soft tissue infections, etc.) are also commonly seen and may become chronic. These infections are essentially similar to those in children uninfected with HIV; however duration of treatment may need to be prolonged. • uberculosis ( ): All forms of tuberculosis are seen in HIV-infected children including pulmonary, lymph node and extrapulmonary tuberculosis (including TB meningitis or disseminated TB) (Fig. 5.22.1). A Mantoux (tuberculin) test reaction of 5 mm or more is considered positive in HIV-infected children. Treatment is with standard anti-tubercular therapy with prolongation of the duration (if necessary). Emergence of multidrug resistant TB has necessitated use of second-line drugs. It is recommended that TB should be treated completely before starting anti-retroviral therapy (ART). If ART has to be started at the earliest, at least the intensive phase of antitubercular therapy (2 months) should be completed before starting ART. Rifampicin reduces level of protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). INH can be used for preventive therapy in those exposed to TB. • Pneumocystis carinii (jiroveci) pneumonia (P P): This is the most common OI in infants (mortality rate of 35%). The highest occurrence is at age of 3–6 months (highest mortality rate in children below 1 year). The infant presents with acute onset fever, dyspnea, tachypnea, cough, cyanosis and marked hypoxia. Insidious onset of cough and dyspnea may be seen in older children. The radiographic findings include interstitial infiltrates or diffuse alveolar disease (which progresses rapidly). Nodular lesions, streaky or lobar infiltrates, or pleural T

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linical stage 1: Asymptomatic or persistent generalized lymphadenopathy. • linical stage 2 ( ild): Unexplained persistent hepa tosplenomegaly, persistent parotid enlargement, herpes zoster, recurrent or chronic upper respiratory tract infections, etc. • linical stage 3 ( dvanced): Unexplained moderate malnutrition or wasting, persistent diarrhea, persistent fever, persistent oral candidiasis, lymph node or pulmonary tuberculosis, recurrent bacterial pneumonia, bronchiectasis, unexplained anemia or neutropenia or thrombocytopenia, etc. • linical stage 4 ( evere): Unexplained severe malnutrition or wasting, PCP, recurrent severe bacterial infections, esophageal or tracheobronchial or lung candidiasis, extrapulmonary tuberculosis, cytomegalovirus (CMV) organ infection, central nervous system (CNS) toxoplasmosis, HIV encephalopathy or cardiomyopathy or nephropathy, etc.

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Opportunistic Infections (OIs)

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With gradual deterioration of the immune system, children are at a high risk for infections from bacteria, viruses, fungi and protozoa. These OIs need to be diagnosed and treated early to prevent morbidity and mortality. Young children generally have primary infection and owing to lack of prior immunity, the infections often have a more fulminant course. Some important opportunistic infections are discussed below. Other OIs are summarized in Table 5.22.1. Table 5.22.2 enlists the drugs used for primary and secondary prophylaxis for OIs (readers should refer to more detailed guidelines before using these drugs). • ecurrent bacterial infections: About 20% of AIDSdefining illnesses in children are due to recurrent bacterial infections caused by Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus, Pneumococcus, E. coli, Salmonella, Enterococcus, Pseudomonas aeruginosa, etc. Common serious infections include bacteremia,

 

Figure 5.22.1 Computed tomographic scan of abdomen: Multiple enlarged conglomerated peripherally enhancing and necrotic lymph nodes (para-aortic, peripancreatic, periportal, and mesenteric) in an HIV-infected child with abdominal tuberculosis

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Retinitis

GI involvement, colitis

Esophagitis

Cytomegalovirus, CMV (usually with severe CD4 depletion below 50 cells/ cumm)

Persistent fever, anemia, hepatomegaly, generalized lymphadenopathy, translucent umbilicated papules. Seen in North-Eastern parts of India

CNS toxoplasmosis (meningitis with/without chorioretinitis)

Bacteremia, pneumonia, meningitis, osteomyelitis, sinusitis and skin, ear and upper respiratory infections

Penicilliosis

Toxoplasma

Recurrent bacterial infections

Disseminated disease/pulmonary involvement

Endoscopy: small confluent ulcers

Severe infection, visceral dissemination (including pneumonitis), recurrent, persistent and chronic infections

VZV (Varicella/ Herpes zoster virus)

Histoplasmosis

Mucosal biopsy and demonstration of CMV inclusion bodies

Orolabial ulcers, genital ulcers and HSV encephalitis

HSV (Herpes simplex virus)

Subacute or chronic meningoencephalitis

Fundoscopy: Yellowish white area of retinal necrosis with perivascular exudates and hemorrhage at the periphery

Pulmonary (rare) or disseminated disease (fever, malaise, weight loss, night sweats, diarrhea, abdominal pain, etc.)

Mycobacterium avium intracellulare - MAC (especially with CD4 count below 100 cells/cumm)

Cryptococcus neoformans

Clinical picture is classical. VZV specific IgM and PCR can help confirm infection

Organ-specific manifestations

M. tuberculosis

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Relevant investigations to be carried out depending upon the site of infection. All efforts should be made to isolate the causative organism

CT scan brain (ring enhancing lesions, intracranial granulomas and calcification). IgG antibodies in CSF

Isolation from blood, bone marrow, or sterile sites. Wright staining of skin scrapping

Recovery in culture (sputum, BAL, blood, bone marrow, etc.). Wright stain of peripheral blood leukocytes shows fungal elements. Antigen detection, antibodies and PCR

CSF: Cryptococcal antigen detection and culture. India ink preparation of CSF

Isolation of virus in culture. Detection of HSV 1 or 2 antigens from skin or mucosal scrapings by IF technique. HSV-DNA in CSF depending upon the site of infection

Isolation of organism by blood culture, typical histopathological features on biopsy of lymph node, bone marrow or other tissues

Demonstration of organism, specific histopathological features and supportive evidence in the form of contact tracing, chest radiograph and Mantoux test (>5 mm positive)

Demonstration of trophozoite (Wright stain) on specimen obtained by BAL or in sputum or tracheal secretion/lung biopsy. Chest radiograph shows interstitial infiltrates or diffuse alveolar disease. High level of lactate dehydrogenase

Manifests with fever, cough, breathlessness, cyanosis, tachypnea, fine rales, etc.

Pneumocystis carinii (jiroveci)

Diagnostic test/s

Clinical features

Infectious agent

Table 5.22.1 Opportunistic infections in HIV infection: clinical manifestations, diagnosis and treatment

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Appropriate antimicrobial therapy

Pyrimethamine-Sulfadiazine (with folinicContd... acid). Alternative drugs - clindamycin, azithromycin and TMPSMX

Induction therapy: Amphotericin B for 2 weeks Consolidation therapy: Itraconazole for 8 weeks Maintenance therapy: Itraconazole.

Amphotericin B

induction therapy: Amphotericin B with flucytosine or amphotericin B for 2 weeks Consolidation therapy: Fluconazole for 8–10 weeks or Itraconazole for 2 weeks

Ganciclovir for 14–21 days or foscarnet. Followed by lifelong maintenance therapy with ganciclovir

Acyclovir. Use foscarnet in cases resistant to acyclovir

Acyclovir

Clarithromycin or Azithromycin and Ethambutol. Treat for at least 12 months. 3rd drug added to prevent resistance (rifampicin, rifabutin, ciprofloxacin, levofloxacin, or amikacin)

Anti-tubercular therapy (with extended duration if required)

TMP-SMX (Trimethoprim-Sulfamethoxazole) or Pentamidine

Treatment

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CNS toxoplasmosis (meningitis with/without chorioretinitis)

Bacteremia, pneumonia, meningitis, osteomyelitis, sinusitis and skin, ear and upper respiratory infections

Rarer causes of chronic diarrhea

Chronic watery diarrhea with abdominal cramps, nausea and vomiting

Chronic diarrhea with weight loss

Toxoplasma

Recurrent bacterial infections

sospora belli and cyclospora

Cryptosporidia

Microsporidia

Stool examination demonstrating the acid fast oocyst and IF and ELISA

Stool examination demonstrating the acid fast oocyst and IF and ELISA

Stool examination demonstrating the acid fast oocyst and IF and ELISA

Relevant investigations to be carried out depending upon the site of infection. All efforts should be made to isolate the causative organism

CT scan brain (ring enhancing lesions, intracranial granulomas and calcification). IgG antibodies in CSF

Diagnostic test/s

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Albendazole or nitazoxanide

Nitazoxanide or azithromycin

TMP-SMX

Appropriate antimicrobial therapy

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Treatment

Abbreviations: LA, Latex agglutination; IF, Immunofluorescence; CNS, Central nervous system; CSF, Cerebrospinal fluid; BAL, Bronchoalveolar lavage; PCR, Polymerase chain reaction.

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Contd...

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of age. The primary cotrimoxazole prophylaxis may be discontinued after sustained immune reconstitution (for at least 6 months, i.e. in a child more than 5 years of age with CD4 counts more than 350 cells per cumm on two occasions, not less than 3 months apart). • andidiasis: Candidiasis is the most common fungal infection in HIV-infected children. Oral nystatin suspension or clotrimazole can be used for treatment. Oral thrush may progress to esophageal candidiasis which needs treatment with oral fluconazole (3–6 mg per kg per day) for 14 days.

Organ Specific Manifestations • Pulmonary or respiratory tract: Recurrent upper and lower respiratory tract infections (pneumonia) are common, and complications like invasive sinusitis and mastoiditis may also occur. Bronchiectasis with recurrent secondary infections may be seen (Fig. 5.22.2). Besides PCP, pathogens like viruses (CMV) and fungi (Aspergillus, Histoplasma, or Cryptococcus), can be the causes of lung disease. As stated earlier, pulmonary and extra-pulmonary tuberculosis is an important association. Lymphoid

Figure 5.22.2 High resolution computed tomographic scan of chest: Note the bilateral bronchiectatic changes in a HIV-infected child  

effusions may be seen. Diagnosis is confirmed by demonstration of P. carinii (jiroveci) with appropriate staining. Treatment is with intravenous cotrimoxazole (trimethoprim TMP-sulfamethoxazole SMX) (15–20 mg per kg per day of TMP and 75–100 mg per kg per day of SMX every 6 hourly) with adjunctive corticosteroids (prednisolone or dexamethasone) if the partial pressure of arterial oxygen (PaO2) is less than 70 mm Hg (in room air). The therapy can be completed for 21 days with oral TMP-SMX replacing the intravenous drug after clinical improvement. Cotrimoxazole (TMP-SMX) prophylaxis reduces the incidence of PCP infection (6 mg per kg per day of TMP). TMP-SMX also protects against development of infections by other bacteria, malaria, isospora, cyclospora as well as toxoplasmosis besides reducing the mortality in children. The 2009 WHO Guidelines for cotrimoxazole use state that the drug should be started in all HIV exposed infants and children at 4–6 weeks of age after birth and continued for at least 6 weeks after cessation of risk of HIV transmission (breastfeeding) and definitive exclusion of HIV infection in infants. In HIV-infected infants (<1 year of age), cotrimoxazole prophylaxis should be used in all, regardless of CD4 percentage or clinical status. For HIV-infected children between 1 year and 4 years of age, the prophylaxis is required if the child has WHO clinical stages 2, 3 or 4, regardless of CD4 percentage or if the child has CD4 percentage below 25% at any WHO stage (also an option of universal prophylaxis irrespective of clinical or immunological stage in this age group can be exercised by individual countries). For HIV-infected children at and above 5 years age, cotrimoxazole should be given for WHO clinical stage 2, 3 and 4 (if CD4 counts are not available) or WHO clinical stage 3 and 4 (irrespective of CD4 counts) or if CD4 count is less than 350 cells per cumm irrespective of WHO staging. Children with previous infection with PCP should be administered secondary prophylaxis similar to the primary prophylaxis. Secondary prophylaxis should not be discontinued in children below 5 years

-infected infants and children Agents used for secondary prophylaxis TMP-SMX or Dapsone Not recommended Clarithromycin plus ethambutol OR Azithromycin plus ethambutol Sulfadiazine plus pyrimethamine plus leucovorin OR Clindamycin plus pyrimethamine plus leucovorin Ganciclovir Fluconazole or Itraconazole Fluconazole Itraconazole Itraconazole

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Table 5.22.2 Primary and secondary prophylaxis for opportunistic infections in Pathogen Agents used for primary prophylaxis Pneumocystis carinii (jiroveci) TMP-SMX or Dapsone Mycobacterium tuberculosis Isoniazid Mycobacterium avium complex Clarithromycin or Azithromycin (Indications: CD4 below 50 in >6 years age, below 75 in 1–6 years of age, and below 500 if <1 year of age) Toxoplasma gondii TMP-SMX used for PCP prophylaxis also protects against toxoplasmosis. CMV Ganciclovir (CD4 below 50 cells/cumm) Candidiasis Not recommended Cryptococcus neoformans Not recommended Histoplasma capsulatum Itraconazole Penicillium marneffei Not recommended

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tions with TB (Fig. 5.22.4), Toxoplasma, CMV, JC virus (progressive multifocal leukoencephalopathy, PML), herpes simplex virus (HSV), and Cryptococcus, etc. can occur. • Gastrointestinal and hepatic manifestations: Can didiasis, periodontal disease, salivary gland disease, oral hairy leukoplakia and oral ulcerations can occur. Chronic or recurrent diarrhea with malabsorption, abdominal pain, dysphagia, and failure to thrive are common symptoms of gastrointestinal disease. Gastrointestinal disease can be caused by bacteria (Salmonella, Campylobacter, Mycobacterium Avium Intracellulare— MAC), protozoa (Giardia, Cryptosporidium, Isospora, microsporidia), viruses (CMV, HSV, rotavirus), or fungi (Candida). Infections may be localized or disseminated. HIV or AIDS enteropathy is the syndrome of malabsorption with partial villous atrophy which is not associated with a specific pathogen and has been postulated to be a result of direct HIV infection of the gut. Disaccharide intolerance is common in those with chronic diarrhea. Maintaining proper nutrition is important in children with failure to thrive. Hepatomegaly is common (viral replication in reticuloendothelial system). Fluctuating serum levels of transaminases with or without cholestasis is common. Anti-retroviral drugs (PIs or NRTIs) or other drugs used for the treatment of OIs (like antitubercular therapy) can also cause elevation of liver transaminases. Chronic hepatitis can be caused by CMV, hepatitis B or C, or MAC and may lead to portal hypertension or hepatic failure. Pancreatitis may occur due to drug therapy (pentamidine, didanosine or lamivudine) or OIs (MAC or CMV). • ardiovascular system: The reasons for cardiac 265 involvement can be HIV itself, intercurrent infections,

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interstitial pneumonitis (LIP) can occur in up to 25% of HIV-infected children. LIP is a chronic process with progressive alveolar capillary block. Clinically, LIP manifests with insidious onset of cough, tachypnea, clubbing and hypoxia with minimal rales or normal auscultatory findings. Hepatosplenomegaly, lymphadenopathy and parotid enlargement may occur. Chest radiograph shows chronic diffuse reticulonodular pattern with hilar lymphadenopathy. Presumptive diagnosis is based on clinical and radiological manifestations and lung biopsy is diagnostic. The hypoxia resolves with oral corticosteroids. • entral nervous system ( ): HIV is a neurotropic virus leading to primary CNS involvement. The incidence in perinatally infected children is 50–90% in developing countries (median age of onset at 19 months). Neurological manifestations can be caused by the HIV itself, OIs, tumors or drugs. The manifestations vary and range from developmental delay to progressive encephalopathy with loss or arrest of developmental milestones, impaired brain growth (acquired microcephaly), symmetric motor dysfunction, marked apathy, spasticity, hyper-reflexia, abnormal plantar reflex, gait disturbance, loss of language or motor skills, neuropsychiatric manifestations, etc. Older patients can have scholastic backwardness, cognitive deterioration, behavioral problems and learning disabilities. Neuroimaging reveals cerebral atrophy, increased ventricular size, basal ganglia calcifications, leukomalacia, etc. (Fig. 5.22.3). HIV encephalopathy needs early initiation of treatment with highly active anti-retroviral therapy (HAART) with drugs penetrating well in the CNS (zidovudine, stavudine, and efavirenz). Focal neurologic signs and seizures are may imply a co-morbid pathologic process (CNS tumor, OI or stroke). CNS infec-

 

Figure 5.22.4 Computed tomographic scan of brain: Note the ring enhancing lesion in the right frontal cortex with perilesional edema (tuberculoma) in an HIV-infected child

 

Figure 5.22.3 Computed tomographic scan of brain: Note the bilateral basal ganglia calcification, generalized cerebral atrophy, and dilatation of ventricles in a child with HIV-encephalopathy

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predisposed for thrombosis due to hyperviscosity (due to hypergammaglobulinemia) as well as protein C and protein S deficiency, however clinical disease (due to venous or arterial thrombosis) is rare. • alignancies: As compared to adults, malignant diseases are uncommon in children. Non-Hodgkin lymphoma and primary CNS lymphoma are known to occur. Epstein-Barr virus is associated with most lymphomas. Kaposi sarcoma (caused by human herpesvirus 8) is very rare in HIV-infected children. • ther organ involvement: Other organ involvement like HIV-arthropathy, myopathy, rheumatologic, endocrine and metabolic disorders may also be seen. D

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immune-mediated reactions and adverse effects of drug therapy (zidovudine). Usually the cardiac involve ment is clinically silent. Dilated cardiomyopathy, left ventricular hypertrophy, pulmonary hypertension and congestive cardiac failure can occur. Resting sinus tachycardia or sinus arrhythmia, pericardial effusion, cardiac tamponade, conduction disturbances, nonbacterial thrombotic endocarditis, and sudden death may be seen. Electrocardiography and echocardio graphy are helpful in assessing cardiac function. Supportive treatment is required (diuretics, vasodilators and inotropes). • enal disease: Nephropathy is an unusual presenting symptom of HIV infection. Renal disease can occur due to HIV infection of epithelial cells, immune-complex mediated, OIs, hyperviscosity (hyperglobulinemia) or use of nephrotoxic drugs. Focal glomerulosclerosis (80%) progressing to renal failure in 6–9 months, mesangial hyperplasia (10–15%), segmental necrotizing glomerulonephritis and minimal change disease may be seen. Polyuria, oliguria, hematuria and acute renal failure have also been seen. Nephrotic syndrome is the most common manifestation of pediatric renal HIV disease. Cases resistant to steroid therapy can be candidates for cyclosporine therapy. • ermatological disorders: Cutaneous manifestations seen in HIV-infected children are inflammatory or infec tious disorders which are not necessarily unique to HIV infection. The disorders tend to be more disseminated and respond less consistently to conventional therapy. Seborrheic dermatitis, severe eczema, recurrent or chronic episodes of HSV, herpes zoster, molluscum contagiosum, anogenital warts, candidial infections, tinea, onychomycosis, impetigo and scabies are common. • Hematologic disorders: Anemia is frequent (20– 70%) and can be due to chronic infection, inadequate nutrition (folic acid, vitamin B12 or micronutrient deficiency), autoimmune factors, virus-associated condi tions (hemophagocytic syndrome or parvovirus B19 red cell aplasia), and bone marrow suppression or due to adverse effect of drugs (zidovudine). In those with low erythropoietin levels, subcutaneous recombinant erythropoietin may be useful. Leukopenia occurs in almost one-third of untreated cases (and neutropenia often occurs). If anti-neutrophil antibodies are the cause, treatment with intravenous immunoglobulin (IVIG) is useful. Many drugs used for treatment or OI prophylaxis or anti-retroviral drugs (zidovudine) may also cause leucopenia or neutropenia. Treatment with subcutaneous granulocyte colony-stimulating factor can be used. Thrombocytopenia may occur in up to 20% of patients. It may be immunologic (i.e. circulating immune complexes or antiplatelet antibodies), or due to drug toxicity or idiopathic. Treatment with IVIG or anti-D offers some improvement. If ineffective, a 2–3 days course of high-dose steroids is an alternative. ART 266 can also reverse the thrombocytopenia. Patients are

Infection

HIV Antibody Detection Since all infants born to HIV-infected mothers are antibodypositive (IgG) at birth (passive transfer of maternal HIV antibody across the placenta), they cannot be used for definitive diagnosis till 18 months of age (till maternally transmitted antibody is lost). Most uninfected infants lose the maternal antibody between 6 months and 12 months of age (seroreverters). Presence of IgA or IgM anti-HIV in the infant’s circulation can indicate HIV infection (these immunoglobulins do not cross the placenta), but their assays are insensitive and non-specific (not used clinically). In a child above 18 months of age, demonstration of IgG antibody to HIV by a repeatedly reactive enzyme immunoassay (EIA) or enzyme-linked immunosorbent assay (ELISA) with a confirmatory test (immunoblot or immunofluorescence assay) establishes the diagnosis of HIV infection. Rapid HIV tests (single step with result within an hour) are also available.

Polymerase Chain Reaction (PCR), Culture and HIV P24 Antigen Assay HIV-DNA PCR (qualitative test—test of choice) or HIVRNA PCR (quantitative test—used to estimate viral load), HIV culture, or HIV p24 antigen immune-dissociated p24 (ICD-p24), are more useful in young infants for definitive diagnosis (by 1–6 months of age). At 4–6 months of age, the HIV culture or PCR can identify all infected infants. HIV-DNA PCR is the preferred; about 40% of infected newborns have positive test results in the first 2 days of life, with more than 90% testing positive by 2 weeks of age.

Testing Protocols Viral diagnostic testing should be performed within the first 48 hours of life. About 40% of HIV-infected infants can be identified at this time and many of these have a rapid progression of disease deserving aggressive therapy. In exposed children with negative virologic testing at 2 days of life, additional testing should be done at 1–2 months of age and at 4–6 months of age. A positive virologic assay (detection of HIV by PCR or culture, or p24 antigen) suggests HIV infection and must be confirmed by a repeat

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Recent WHO Guidelines on Diagnosis of HIV The WHO has advocated use of virological testing in infants and children below 18 months. These include HIV-DNA on whole blood specimen or dried blood spots (DBS), HIV-RNA on plasma or DBS and ultrasensitive p24 antigen (Up24 Ag) on plasma and DBS. The virological testing should be done at 4–6 weeks of age or at earliest opportunity thereafter and should be confirmed with a second specimen after initiating the ART without delay. HIV-exposed infants who have reactive serological assay at 9 months of age should have a virological test to identify infected infants who need ART. Symptomatic infants should undergo serological testing and if positive, virological confirmation. Children above 18 months should be tested with serological methods used in adults.

Infection

Though there is no cure for HIV infection, goals of treatment are to achieve normal growth and development, prevent OIs and organ involvement, and maintain good health and an acceptable quality of life.

Drugs used in ART and Combination Therapy Three main types of ART drugs include NRTIs (nucleoside reverse transcriptase inhibitors), NNRTIs (non-nucleoside reverse transcriptase inhibitors) and PIs (protease inhibitors). ARV agents are categorized by their mechanism of action (ability to inhibit the HIV reverse transcriptase or protease enzymes). Maximum viral suppression is possible by targeting different points in the viral life cycle and stages of cell activation, and delivering drug to all tissue sites. Thus, combination of three drugs, a thymidine analog NRTI (AZT/ZDV-zidovudine), a nonthymidine analog NRTI (3TC-lamivudine) to suppress replication in both active and resting cells, and a PI (lopinavir/ritonavir-LPVr or nelfinavir-NFV) or an NNRTI (efavirenz-EFV or nevirapine-NVP) is effective. Doses and adverse effects of various commonly used agents are listed in Table 5.22.3. Highly active anti-retroviral therapy (HAART) refers to a three-drug combination (two NRTIs plus one NNRTI or PI). Most NNRTI and PI drugs are inducers or inhibitors of the cytochrome P450 system. ZDV and d4T (stavudine) cannot be given together, so also a combination of ddI (didanosine) and d4T. There are syrup formulations of ZDV, 3TC, NVP (nevirapine) and EFV. Fixed drug combinations (which help in reducing the pill burden and improve compliance) are available through the national program.

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It is necessary that the OIs are stabilized before initiating the ART. Suppression of HIV replication to an undetectable level restricts the selection of anti-retroviral-resistant mutants. Sustainable suppression of HIV replication is best achieved by simultaneous initiation of combinations of anti-retroviral (ARV) agents and adherence to complex drug regimens.

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Presumptive diagnosis is made in patients (below 18 months) who have symptoms and signs suggestive of HIV infection where virological testing is not available. Presumptive diagnosis is made when an infant is confirmed HIV antibody positive and diagnosis of any of the AIDS-indicator condition can be made (or if the infant is symptomatic with two or more of the following: oral thrush, severe pneumonia or severe sepsis). Other factors supporting the diagnosis of severe HIV disease in an HIV antibody positive infant include recent HIV-related maternal death or advanced HIV disease in the mother and child’s CD4 count below 20%. These infants can be started on ART.

Anti-retroviral therapy (ART) does not eradicate the virus but only suppresses the virus, thus changing course of the disease to a chronic illness. ART should be given in consultation with an expert in pediatric HIV disease.

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test on second specimen as soon as possible. A diagnosis of HIV infection can be made with two positive virologic test results obtained from different blood samples. HIV infection can be reasonably excluded if an infant has had at least two negative virologic test results with at least one test performed at or after 4–6 months of age. In older infants, two or more negative HIV antibody tests performed at least 1 month apart after 6 months of age (in the absence of hypogammaglobulinemia or clinical evidence of HIV disease) can reasonably exclude HIV infection. For infants who are breastfeeding, a negative antibody test should be repeated 6–8 weeks after complete cessation of breastfeeding to confirm that the infant remains uninfected. In children above 18 months, ELISA antibody is reliable test (sensitivity and specificity above 99%). Positive ELISA should again be confirmed by Western blot test or repeat ELISA by using different kit. In developing countries, 2–3 ELISA tests (using different kits, one of which is a rapid ELISA test) can be used to confirm a positive report (same sample to be used).

Adherence Issues Adherence to treatment is a vital factor in deciding whether and when to initiate ART and whether the ART regimen will be successful. Compliance below 80–90% results in suboptimal suppression of viral load. Poor adherence to ART regimens results in sub-therapeutic drug concentrations and enhances development of drug resistance (particularly with PIs and NNRTIs). It is mandatory for participation of the family or caretaker in the decision to initiate ART as ART regimens are often unpalatable and require extreme dedication on the part of the caretaker and the child. Education on drug administration, follow-up visits, relationship of drug adherence to viral suppression and commitment of the family and the child are important in achieving success in ART treatment. 267

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Table 5.22.3 Commonly used anti-retroviral drugs No Anti-retroviral drug Class of drug Daily dosage 1 Zidovudine (AZT/ZDV) NRTI 8 mg/kg or 480 mg/m2 (two divided doses)

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NRTI

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Stavudine (d4T)

NRTI

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Abacavir (ABC)

NRTI

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Didanosine (ddI)

NRTI

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Nevirapine (NVP)

NNRTI

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Efavirenz (EFV)

NNRTI

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Nelfinavir (NFV)

PI

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Lopinavir/ Ritonavir (LPV/r) Ritonavir (RTV)

PI

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PI

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Adverse effects Anemia, leukopenia, gastrointestinal intolerance, headache, liver toxicity, myopathy, lactic acidosis, lipodystrophy 8 mg/kg (two divided doses) Gastrointestinal symptoms, rash, pancreatitis, peripheral neuropathy, lactic acidosis 2 mg/kg (two divided doses) Lipodystrophy, lactic acidosis, peripheral neuropathy, pancreatitis, headache, nausea, anemia, rash 16 mg/kg (two divided doses) Hypersensitivity, gastrointestinal symptoms, rash, pancreatitis, elevated triglycerides, lipodystrophy, lactic acidosis Gastrointestinal symptoms, pancreatitis, peripheral 240 mg/m2 (two divided doses) neuropathy, lactic acidosis 120 mg/m2 once daily for first 2 weeks. 240–400 Hepatitis, rash, hypersensitivity, headache, fever, mg/m2 (two divided doses). nausea Rash, neurological and psychiatric symptoms, 15 mg/kg (200–400 mg) once a day increased liver enzymes, potential teratogenicity Gastrointestinal symptoms, lipid abnormalities, 110–130 mg/kg (two divided doses) hepatitis 450 mg LPV with 115 mg ritonavir/m2 (two divided Gastrointestinal symptoms, lipid abnormalities, doses) pancreatitis, hepatitis Start with 400 mg/m2 and titrate up to 800 mg/m2 Gastrointestinal symptoms, lipid abnormalities, (two divided doses) pancreatitis, hepatitis >6 years age: 4 mg/kg (two divided doses) Local site reactions, hypersensitivity, immunemediated reactions

Enfuvirtide Fusion (subcutaneous) inhibitor injection Abbreviations: NRTI, Nucleoside reverse transcriptase inhibitors; NNRTI, Non-nucleoside reverse transcriptase inhibitors; PI, Protease inhibitor.

Initiation of ART and Regimens Various guidelines are available to initiate appropriate ART regimen. Ideally, HIV-infected children with symptoms or with evidence of immune dysfunction should be treated with ART, regardless of age or viral load. Recent WHO guidelines have recommended ART immediately upon diagnosis in infants and children below 2 years of age, while ART initiation has been advocated in patients with CD4 count below or equal to 750 cells/cumm (below/ equal to 25%) in children 2–5 years of age and CD4 count below or equal to 350 cells/cumm in children 5 years of age and above. Also, ART is recommended in children with WHO clinical stages 3 and 4 (irrespective of CD4 counts). For infants, not exposed to ARVs (or when this information is unknown), two NRTIs plus NVP should be started. For infants, exposed to maternal or infant NVP or other NNRTIs, the ART should contain two NRTIs plus LPV/r (ritonavir boosted lopinavir). In children between 12 months and 24 months of age, exposed to maternal or infant NVP or other NNRTIs, ART should be a combination of two NRTIs plus LPVr. For children of 12–24 months of age, not exposed to NNRTIs, the regimen should be two NRTIs plus NVP. In children more than 2 years up to 3 years, ART choice is two NRTIs plus NVP. For children of 3 years age and older, EFV can be used in place of NVP. 268 The NRTI backbone in infants and children can be 3TC plus AZT (ZDV, zidovudine) or 3TC plus ABC or 3TC plus d4T. If TB is diagnosed, anti-tuberculosis drugs should be

initiated and ART should be started after 2–8 weeks after the anti-tuberculous drugs are tolerated (to decrease incidence of immune reconstitution inflammatory syndrome, IRIS). For children on rifampicin, EFV is the preferred NNRTI (as rifampicin lowers NVP drug level by 20–58%). After 2 weeks of completing rifampicin based anti-tubercular therapy, it is better to switch back to NVP based ART regimen. For children below 3 years on antitubercular drugs, the preferred regimen is two NRTIs plus NVP or triple nuceloside regimen. It is advised to avoid AZT in children with severe anemia (<7.5 g/dL) or severe neutropenia (<500 cells/cumm).

Immune Reconstitution Inflammatory Syndrome (IRIS) Immune reconstitution inflammatory syndrome (IRIS) is a collection of signs and symptoms resulting from ability to mount an immune response to antigens or organisms associated with immune recovery on ART. IRIS represents the paradoxical emergence of transient to severe inflammationmediated symptoms as immune function is being restored with ART. It can occur in up to 10% of all patients initiated on ART. The incidence is up to 25% in those with CD4 count below 50 cells/cumm. IRIS leads to unexpected deterioration in clinical status of the patient on ART. Most of these are associated with mycobacterial infections (M. tuberculosis), P. carinii, Toxoplasma, Cryptococcus, hepatitis B and C viruses, CMV, etc. It is characterized by fever and worsening of the clinical manifestations of OIs or new

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Clinical monitoring, virologic assessment (HIV-RNA copies) and immunologic surveillance (CD4 lymphocyte count or percentage) should be performed regularly in children on ART. Initial virologic response should be achieved within 4 weeks of initiating ART. The maximum response to therapy usually occurs within 12–16 weeks. HIV-RNA levels should be measured at 4 weeks and 3–4 months after ART initiation. Once an optimal response has been reached, the viral load should be measured every 3–6 months. If the response is unsatisfactory, another viral load should be performed immediately to verify the results before changing ART. It may not, however, be feasible to estimate viral loads for monitoring and hence CD4 counts are often used in developing countries. CD4 cells respond more slowly to successful treatment and can be monitored less frequently (every 3–6 months). Potential toxicity to ART should also be monitored closely.

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High mutation rate of HIV impairs the success of ART. Failure to reduce the viral load to less than 50 copies/mL increases the risk for resistance. For some drugs (NVP or 3TC), a single mutation is associated with resistance, while for other drugs (ZDV or lopinavir) several mutations are needed for developing resistance. Testing for drug resistance is becoming the standard of care. The phenotypic assay measures the virus susceptibility in various concentrations of the drug and the genotypic assay predicts the virus susceptibility from mutations identified in the HIV genome isolated from the patient. Treatment success is noted to be higher in patients whose ART is guided by genotype or phenotype testing.

Drug Interactions Rifampicin reduces levels of NNRTIs and PIs. Antifungals increase levels of NVP, LPV and SQV (sequinavir). Drug interactions of ART can also occur with oral contraceptives, lipid lowering agents and anticonvulsants. M

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Monitoring the ART

Resistance to ART

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Anti-retroviral therapy should be changed when the existing regimen is failing (in an adherent child) as seen by increase in viral load (virological failure—persistent viral load above 5000 RNA copies/m after at least 24 weeks of ART), deterioration of the CD4 cell count (immunological failure in patients on ART for at least 24 weeks—CD4 counts <200 cells/cumm or CD4% <10% for child 2–5 years of age and CD4 counts <100 cells/cumm for child above 5 years), or clinical failure (appearance/reappearance of WHO clinical staging 3 or 4 events after at least 24 weeks on ART). Also, development of toxicity or intolerance to drugs is a reason to consider a change in therapy. Potential cross-resistance and adherence issues should be looked into. When a decision is made to change the anti-retroviral therapy, all drugs should ideally be changed. However, in many situations (previous ART experience, intolerance, or toxicity), this may not be possible and hence, at least two drugs should be changed based on the resistance mutation genotype (if available) or previous ART regimen used. After failure on a first-line NNRTI-based regimen, a boosted PI (LPVr preferred) plus two NRTIs are recommended second-line therapy. After failure of regimen containing AZT or d4T plus 3TC, the preferred regimen is ABC (abacavir) plus 3TC (alternative is ABC plus ddI). In case of failure of regimen containing ABC plus 3TC, the preferred regimen is AZT plus 3TC (alternative is AZT plus ddI).

Common adverse reactions to NRTIs include malaise, gastrointestinal symptoms, hepatitis, lactic acidosis, fatty liver, pancreatitis, myopathy, neuropathy, cardio myopathy, bone marrow suppression, rash, etc. Adverse effects to NNRTIs include rash, gastrointestinal symptoms, hepatotoxicity, granulocytopenia, etc. Adverse drug reactions to PIs include gastrointestinal intolerance, hyper lipidemia, lipodystrophy, hyperglycemia, rash, bleeding tendency, etc. These drug reactions may require reduction in the dose or at times replacement with other drug. Most of the toxicities are not severe and can be managed supportively (Table 5.22.3).

onitoring

Monitoring is required in patients on ART and even those not on ART. Besides clinical monitoring, investigations are required for monitoring the disease activity and response to treatment. Complete hemogram, liver functions, urine and stool examination, fundoscopy, echocardiography and height should be done at least annually. CD4 counts should be estimated every 3–6 monthly. Additional investigations may be required depending on the symptomatology, OIs suspected and organ involved. Checking the immunization status and looking for symptoms of OIs is required at each visit. It should be ensured that the child is on cotrimoxazole prophylaxis and concomitant medications should be noted. Assess criteria for ART initiation at every visit and also assess the family situation. Patients on ART should be followed up monthly. Children not on ART also require regular followup. C

Changing the ART

Toxicities of ART

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manifestations, typically within the first few weeks (2–12 weeks) after initiation of ART, but may also occur up to several months after initiation of ART. Deciding whether the symptoms represent worsening of a current infection or a new OI or an IRIS, or drug toxicity is often difficult. ART should be continued in those who can tolerate it. Also, the unmasked OI needs to be treated. Adding nonsteroidal anti-inflammatory agents or corticosteroids to alleviate the inflammatory reaction in IRIS is often useful, but the inflammation may take several weeks or months to subside.

ounseling

Counseling the parents or caretakers about the disease, course of illness and therapy is of utmost importance 269

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Prevention of Perinatal ransmission

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Prevention of perinatal transmission from mother-to-child has been achieved by administering ZDV chemoprophylaxis to the pregnant woman (started as early as 4 weeks of gestation) and continued during delivery and in the newborn for 6 weeks of life. This therapy decreases the rate of perinatal HIV-1 transmission to below 8%. Rates of perinatal transmission have been as low as 2% among women who have received HAART and all three components of the ZDV regimen. Women whose viral load at the time of delivery is more than 1,000 copies/m should be counseled about the potential benefit of cesarean section in reducing the risk for vertical transmission. Even if a mother has received no ART during gestation or delivery, the 6-week component of the ZDV prophylactic regimen (2 mg/kg every 6 hours) instituted for the newborn as soon as possible after delivery results in a significant reduction of transmission rate. Oral nevirapine, given once to women in labor and once to the infant during the first 48–72 hours of life, has been shown to reduce perinatal transmission by 50% (simple and highly cost-effective regimen for resource-poor countries). R

he WH ecommendations for Prevention of Perinatal ransmission O

Immunization is an important mode of preventing infections. All routine vaccinations can be given if the child is asymptomatic or has mild symptoms. Live vaccines are contraindicated in symptomatic patients with severe immunosuppression. Inactivated or killed vaccines should be preferred to live vaccines (e.g. inactivated polio vaccine instead of oral polio vaccine). Vaccines like Hib, annual influenza vaccine, pneumococcal, varicella and hepatitis A vaccine are also recommended. However, immunizations may not always offer adequate protection in HIV-infected children. Varicella and MMR vaccine should not be given to child with AIDS or severe immunesuppression. Counseling and psychosocial support is the cornerstone for management of HIV-infected children, whether or not they receive ART. The caretakers should be counseled about the importance of good hand washing, avoiding raw or undercooked food (prevent Salmonella infection), avoiding drinking or swimming in lake or river water or being in contact with young farm animals (to prevent Cryptosporidium infection), and the risk of playing with pets (to prevent Toxoplasma from cats). Simple interventions like good general hygiene, dental care, adequate nutrition (including nasogastric and parenteral nutrition if required), balanced diet, timely immunizations, vitamin A supplementation, plotting weight and height on growth charts, provision of safe and stimulating environment, developmental evaluation and interventions like occupation therapy or speech therapy, etc. can help a 270 child with HIV to be free of infections and grow well. It is

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Immunization and upportive reatment

Better understanding of the pathogenesis and availability of effective ART has considerably changed the outcomes. In developed countries, progression of HIV to AIDS and the mortality rate have decreased with improved quality of life. Even with partial decrease in the viral load, children have significant clinical and immunologic advantages. High viral load (>100,000 copies/mL) or CD4 lymphocyte percentage of below 15% is associated with higher mortality. In developing countries where limitations exist as regards availability of ART and diagnostic tests, clinical staging system can be used to predict progression of disease. Lymphadenopathy, splenomegaly, hepatomegaly, LIP and parotitis are indicators of a comparatively better prognosis. Children with OIs (PCP or MAC), encephalopathy, or wasting syndrome have poor prognosis (75% die before 3 years of age). Persistent fever with or without oral thrush, serious bacterial infections (meningitis, pneumonia and sepsis), hepatitis, persistent anemia (<8.0 g/dL) with or without thrombocytopenia (<100,000/cumm) also suggest a poor prognosis.

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PCP prophylaxis has already been discussed. Prophylaxis against MAC is required in children with severe immunosuppression (i.e. CD4 lymphocyte count <500 cells/cumm in children <1 year, <75 cells/cumm in 1–6 years age, and <50 cells/cumm in children >6 years age) and the drugs of choice are clarithromycin (7.5 mg/kg twice a day orally) or azithromycin (20 mg/kg once a week orally or 5 mg/kg daily orally). Primary prophylaxis against OIs can be discontinued if patients have sustained (>6 months) immune reconstitution with HAART. Intravenous immunoglobulin (IVIG) (dose 400 mg/kg every 4 weeks) has been recommended to prevent recurrent serious bacterial infections for symptomatic patients who have suffered from at least two documented serious bacterial infections within 1 year; have laboratory-documented inability to make antigen-specific antibodies; or in those who have hypogammaglobulinemia. S

recommended that in asymptomatic patients, the energy intake should be increased by 10% while in symptomatic patients; it needs to be increased by 25–30%. In severely malnourished patients 50–100% additional energy is required.

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in treatment of patients. Decision for treatment should be taken after confirming issues of adherence in light of understanding of the caretaker, the availability of medications, access to healthcare and socioeconomic condition. Starting ART is not an emergency and adherence should be ensured.

HIV-infected mothers who require ART should be started on daily ART as soon as possible irrespective of gestational

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Since HIV is known to be transmitted through breast feeding, it is necessary to balance HIV prevention (by omission of breastfeeding) with protection from other causes of childhood mortality. Complete avoidance of breastfeeding may be ideal to prevent this transmission but needs to be weighed against the possibility of the child having infections (due to unhygienic practices and nonavailability of support systems for replacement feeding) and under-nutrition (by use of suboptimal replacement feeding), thus causing morbidity and mortality. The WHO has recommended setting of national or sub-national recommendations for infant feeding in HIV exposed children. Counseling and support should be given to the mothers known to be HIV- infected to either breastfeed and receive antiretroviral (ARV) interventions OR avoid breastfeeding completely to prevent transmission of HIV to the child. It is necessary to consider the socioeconomic and cultural context of the population, availability and quality of health services, local epidemiology, and main causes of infant and child mortality. Mothers who are HIV-infected

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In HIV exposed infants, at birth, the baby’s mouth and nostrils should be wiped as soon as the head is delivered, infants should be handled with gloves till all blood and maternal secretions are washed off, and the cord should be clamped soon after birth (avoid milking). In sexually active adolescents, prevention of transmission involves use of condoms and health education to avoid unprotected sex with older or multiple partners and avoiding use of illicit drugs.

seases

HIV and reastfeeding ( he WH ecommendations)

should be provided lifelong ART or ARV prophylaxis to reduce transmission to the infant. When ARV drugs are not available, breastfeeding may still provide infants a greater chance of survival and mothers should be counseled to exclusively breastfeed for first 6 months of life and continue breastfeeding thereafter unless environmental and social circumstances are safe and supportive of replacement feeding. Mothers who decide to stop breastfeeding should do so gradually over a period of 1 month and the mothers or infants receiving ARV prophylaxis should continue the ARV drugs for 1 week after fully stopping the breastfeeds. In such cases, the infants should be provided with appropriate and safe replacement feeds. For those on replacement feeding, it is necessary to ensure safe water and good sanitation, sufficient supply for normal growth and development, adequate hygiene (to prevent diarrhea and malnutrition), family support and access to comprehensive child healthcare.

Immun ty, Immun zat on and Infect ous

age [AZT+3TC+NVP/EFV or TDF (tenofovir) + 3TC/FTC (emtricitabine) +NVP/EFV) and the infant should receive daily NVP or twice daily AZT from birth until 4–6 weeks of age (irrespective of the mode of infant feeding). EFV should not be used in first trimester (use NVP instead). HIV-infected women who do not require ART for their own health do require effective antiretroviral (ARV) prophylaxis to prevent transmission during pregnancy, labor and delivery, postpartum and during breastfeeding. Herein, two options are available (option A and option B). Option A is maternal AZT (twice daily AZT starting from as early as 14 weeks gestation and continued though the pregnancy and at onset of labor single drug NVP and initiation of twice daily AZT + 3TC for 7 days postpartum) with infant ARV prophylaxis. If maternal AZT was provided for more than 4 weeks antenatally, omission of the single drug NVP and AZT + 3TC tail can be considered, in such cases, continue the maternal AZT during labor and stop at delivery. Infant ARV prophylaxis includes daily NVP from birth for a minimum of 4–6 weeks and until 1 week after all exposure to breast milk has ended in those who are breastfed; while those infants who are on replacement feeds, daily NVP or single drug NVP plus twice daily AZT should be continued from birth until 4–6 weeks of age. Option B includes maternal triple ARV prophylaxis with infant ARV prophylaxis. Maternal triple ARV prophylaxis includes triple ARV (AZT + 3TC + LPVr/ ABC/EFV or TDF + 3TC/FTC + EFV) starting from 14 weeks of gestation and continued until delivery or if breastfeeding, continue until 1 week after all infant exposure to breast milk has stopped. The infant prophylaxis in option B includes daily NVP or twice daily AZT from birth until 4–6 weeks of age irrespective of mode of infant feeding.

Indian Initiatives The Government of India set up the National AIDS Control Program (NACP I) in 1992 and the National AIDS Control Organization (NACO). The State AIDS Control Societies (SACS) was set up in 25 societies and 7 union territories. In 1999, the second phase of the National AIDS Control Program (NACP II) was introduced and in 2007, the third phase of the National AIDS Control Program (NACP III) was initiated. NACP III (2007-2012) includes four pronged strategies of preventing infection through saturation of coverage of high risk groups with targeted interventions, greater care for larger number of people living with HIV/ AIDS, strengthen infrastructure systems and human resources and strengthen nationwide strategic information management system. The objective of NACP III is to reduce incidence in high prevalence states by 60% and reduce incidence in vulnerable states by 40%. Currently, India spends about 5% of its health budget on HIV/AIDS. The target for NACP III is to provide free ART to 3,00,000 adults and 40,000 children through 250 ART centers, achieve and maintain high level of drug adherence and to provide comprehensive care, support and treatment by establishing 350 community care centers. As per NACO, there are 293 ART centers in India with 367,901 adult and 23,252 pediatric patients alive and on ART treatment (as of January 2011). It is encouraging that in 2009-2010, rupees 980.15 crores were allotted for NACP with about 90% actual expenditure.

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1. Antiretroviral drugs for treating pregnant women and preventing HIV infection in infants: Recommendations for a public health approach. 2010 version. World health Organization. Available from: http://whqlibdoc.who.int/ publications/2010/9789241599818_eng.pdf. [Accessed July 7, 2011]. 2. Co-trimoxazole prophylaxis for HIV-exposed and HIVinfected infants and children: Practical approaches to implementation and scale up. World Health Organization and UNICEF 2009. Available from: http://www.who.int/hiv/ pub/paediatric/cotrimoxazole.pdf. [Accessed May 19, 2011]. 3. Global report: UNAIDS report on the global AIDS epidemic 2010. Joint United Nations Programme on HIV/ AIDS (UNAIDS). Available from: http://www.unaids.org/globalreport/ documents/20101123_GlobalReport_full_en.pdf. [Accessed May 19, 2011]. 4. Guidelines for HIV care and treatment in infants and children (November 2006). Indian Academy of Pediatrics, National AIDS Control Organization with support from Clinton Foundation, UNICEF and WHO. 5. Guidelines on HIV and infant feeding 2010: Principles and recommendations for infant feeding in the context of HIV and a summary of evidence. World health Organization, UNAIDS, UNFPA and UNICEF. Available from: http://whqlibdoc.who. int/publications/2010/9789241599535_eng.pdf. [Accessed May 19, 2011]. 6. HIV/AIDS Programme. Strengthening health services to fight HIV/AIDS: Antiretroviral therapy for HIV infection in infants and children: Towards universal access. Recommendations for a public health approach. 2010 revision. World health

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ibliography

Organization. Available from: http://whqlibdoc.who.int/ publications/2010/9789241599801_eng.pdf. [Accessed May 19, 2011]. HIV/AIDS Programme. Strengthening health services to fight HIV/AIDS: WHO case definitions of HIV for surveillance and revised clinical staging and immunological classification of HIV- related disease in adults and children. World health Organization 2007. Available from: http://www.who.int/hiv/ pub/guidelines/HIVstaging150307.pdf. [Accessed May 19, 2011]. HIV/AIDS Programme. Strengthening health services to fight HIV/AIDS: WHO recommendations on the diagnosis of HIV infection in infants and children. World health Organization 2010. Available from: http://whqlibdoc.who. int/publications/2010/9789241599085_eng.pdf. [Accessed May 19, 2011]. Shah I. Neonatal and pediatric HIV. In: Gupte S, Gupte SB (Eds). Recent Advances in Pediatrics-19 (Hot Topics). New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2010.pp.363-84. Shah SR, Tullu MS, Kamat JR. Clinical profile of pediatric HIV infection from India. Arch Med Res. 2005;36:24-31. Tullu MS, Kher A. Laboratory diagnosis of HIV Infection. In: Shah I, Shah NK, Manglani M (Eds). IAP Speciality Series on Pediatric HIV. Mumbai: Indian Academy of Pediatrics; 2006. pp. 30-35. Udgirkar VS, Tullu MS, Bavdekar SB, et al. Neurological manifestations of HIV infection. Indian Pediatr. 2003;40: 230-4. Yogev R, Chadwick EG. Acquired immunodeficiency syndrome (human immunodeficiency virus). In: Kliegman RM, Behrman RE, Jenson HB, Stanton BF (Eds). Nelson Textbook of Pediatrics, 18th edition. Philadelphia: Saunders (Elsevier); 2007. pp. 1427-43.

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pidemiology

Pathophysiology

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Leptospira gains access to the human body through cuts and abrasions in the skin and intact mucous membranes. The primary lesion caused by Leptospira is damage to the endothelial lining of small blood vessels, vasculitis with leakage with resultant ischemic damage to the liver, kidneys, meninges and muscles.









The clinical spectrum of leptospirosis varies widely. According to the WHO the disease can present in one of the four ways: 1. As a mild influenza like illness. 2. As Weil’s syndrome with jaundice, renal failure, hemorrhage and myocarditis. 3. As meningitis or meningoencephalitis. 4. As pulmonary hemorrhage with respiratory failure.

According to The Indian Leptospirosis Society, this illness should be suspected when a child presents with history of abrupt onset fever and body ache, headache with any one or more of the following features:



nicteric Leptospirosis

This occurs as a biphasic illness with septicemic phase followed by an immune phase. Septicemic phase is associated with the multiplication of Leptospira in the bloodstream, cerebrospinal fluid and other tissues. Immune phase is characterized by the development of antibodies to Leptospira and disappearance of the organisms. Distinction between first and second phase may not be clinically apparent.

Septicemic Phase

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The rat is the principle source of infection. Other important reservoirs include wild mammals, domestic and firm animals. The infected animals excrete spirochetes in urine for an extended period of time. Human infection occurs due to exposure to water or soil contaminated with rat urine. Leptospirosis occurs in an epidemic form in India during the monsoon and immediate post-monsoon period. It can also be endemic in areas resulting from exposure to leptospiral contamination of stagnant water with sewerage. Recreational water activities like swimming, canoeing and water skiing in contaminated water are other reasons to acquire leptospirosis.

Jaundice Oliguria Cough and breathlessness Hemorrhagic tendency Signs of meningeal irritation or altered sensorium or convulsions. Leptospirosis can occur as anicteric disease which is more common with less severe manifestation or as rare icteric form which is more severe.

The child may present with fever of abrupt onset, associated with muscle pain, headache, nausea, vomiting, abdominal pain, etc. Less common findings include conjunctival suffusion, a transient skin, photophobia and mild signs of meningism. The septicemic phase lasts 4–7 days.

Immune Phase There is brief asymptomatic interlude between the septicemic and immune phase. The important clinical features are in the immu ne phase are: • • • •

Fever which is less pronounced than in early phase. Aseptic meningitis with abnormal CSF pleocytosis is seen occasionally among children. Hepatitis is characterized by enlargement of the liver, elevation of bilirubin with a modest increase in liver enzymes. Renal involvement is characterized by abnormal findings in the urine analysis (hematuria, proteinuria and casts), azotemia with oliguria or anuria. Renal failure is the principal cause of death of fatal case.

Icteric Leptospirosis (Weil’s yndrome) S

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Leptospirosis is an acute febrile generalized disease whose manifestations can range from the mild self-limiting to fatal multiorgan involvement. Leptospirosis, an infectious disease that affects humans and animals, is considered the most common zoonosis in the world. It is caused by pathogenic spiral bacteria that belong to the genus Leptospira. The genus Leptospira was originally thought to have two species: L. interrogans which is pathogenic and L. biflexa which is non-pathogenic. Seventeen genomospecies of pathogenic Leptospira has been identified, which has been divided into more than 250 serovars according to their antigenic composition.

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Weil’s syndrome is characterized by liver, kidney, and vascular dysfunction in addition to the other symptoms of anicteric leptospirosis. Individuals with Weil’s syndrome will usually develop jaundice without hepatocyte destruction and azotemia by the third to seventh day of illness. The liver 273 may be enlarged and there may be right upper quadrant

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Laboratory iagnosis Leptospira can be cultured from blood or CSF during the first 10 days of illness and from the urine for several weeks beginning at second week. The following tests are currently available for routine diagnosis. T l

Dark field microscopy (DFM) is used to detect eptospira in blood within the first 10 days of illness and from the urine from the second week onwards. False-positive results are common due to extrusion of fibrillar material from RBCs mimicking leptospirosis. Urine samples must be examined within half an hour of collection.

Detection of Antibodies to Leptospirosis

MSAT

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Initiation of treatment early in the disease before seventh day shortens the clinical course. Penicillin is the drug of choice and the dose is 250,000 units/kg/24 hour in four divided doses for a period of 7 days. For penicillin allergic children, erythromycin, amoxicillin, and ciprofloxacin (especially in patients with uveitis) are alternate choices for children under the age of 8 years. Tetracycline, 10–20 mg/kg/day, in four divided doses for 7 days or doxycycline 100 mg twice daily for 7 days may be used for children above 8 years.

Prevention Rodent control and avoidance of contact with contaminated water and soil will prevent infection. Parents should instruct child not to wade through flood waters, or play in stagnant water.



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Antibodies to leptospirosis start appearing 5 days after the onset of fever. Therefore timing of tests is important. Serologic tests form the mainstay in the diagnosis of leptospirosis. 1. acroscopic slide agglutination test ( ): It is a genus specific test and uses killed Leptospira as antigen. 2. Ig LI and Ig specific dot LI tests: These tests detect genus specific IgM antibodies which tend to become positive early in the disease around fourth day of illness. The above mentioned tests are sensitive about 80– 90%, but not specific. They do not differentiate between pathogenic and saprophytic Leptospira and the infecting serovar cannot be identified.

reatment

ibliography 1. Tullu ML, Karande S. Leptospirosis in children: A review for family physicians. Indian Journal of Medical Sciences. 2009;63:368-78.

Dark Field Microscopy

icroscopic agglutination test ( ): It is a serovar specific test and is the gold standard of serological tests to detect leptospirosis due to its high specificity. The MAT is usually positive 10–12 days after onset and reaches a peak by the third week. It involves the use of a battery of live leptospiral cultures to be used as antigen. It is done in specialized laboratories. The available antisera may not identify all Leptospira serotypes; specific serotypes commonly seen in the community are usually identified including the virulent and serious types. Initial high titer of 1:100 or rising titers (fourfold increase) obtained 2 weeks apart are diagnostic. M



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tenderness. With increasing severity of jaundice, the individual is at greater risk of developing renal failure, hemorrhage, and cardiovascular collapse. Uremia, oliguria, and anuria may occur with the onset of kidney failure unless dialysis is provided. Fatalities due to icteric leptospirosis are typically due to renal failure, cardiopulmonary failure and fatal hemorrhages.

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5.24.1 Pulmonary uberculos s Vimlesh Seth Pulmonary tuberculosis is the most common form in children which mostly heals but may lead to various complications as well.



Tuberculosis (TB) is one of the most widespread infections and affects almost one-third of the world’s population. It is the first infectious disease to be declared a global health emergency. Women and children are the worst affected. Studies conducted on the social impact of TB have projected that over three lakh children are orphaned in India by the disease every year and over a lakh women are rejected by their families once they suffer from the disease, inspite of the disease being treated free of cost by Government funds. Childhood tuberculosis is neglected in endemic areas with resource constraints in high-burden countries as in India because: • The children are considered to develop the mild form of disease. • Mostly the lesions are sputum-negative and thought to contribute little in the transmission of disease.

compared to adults. These fundamental differences are due to the immature immune system of young children. Out of extrapulmonary TB, lymph node tuberculosis is the most common.



Introduction

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Ghon’s lesion results at the site of initial deposition of organisms. For the first 4–6 weeks, unrestrained multiplication of the bacilli occurs within the Ghon focus and bacilli drain via local lymphatics to the regional lymph nodes and beyond. The upper lobe lymph nodes drain to ipsilateral paratracheal nodes, whereas rest of the lung drains to perihilar and subcarinal nodes with dominant lymph nodes flow from left to right. The Ghon focus is associated with or without some pleural reaction and the affected regional nodes. Occult dissemination frequently occurs during this early proliferative phase before cell mediated immunity is fully activated. This is the stage when active contact tracing and aggressive screening can be useful. Uncomplicated hilar adenopathy remains the most common disease manifestation in children and is considered the hallmark of primary tuberculosis. Asymptomatic hilar adenopathy is more indicative of recent primary infection than active disease in terms of pathophysiology, microbiology and natural history (Figs 5.24.1.1 to 5.24.1.4). Within the Ghon’s focus, containment is usually successful. Unrestrained proliferation of the organisms and poor containment may cause progressive parenchymal damage with ultimate breakdown of Ghon’s focus. Infants and children with HIV who have poor cell mediated immunity are most vulnerable to this type of cavitation. In contrast immune-competent adolescents seem to mount an ‘excessive’ (damaging) immune response in an attempt to contain the organisms. Children with adult-type of disease are frequently sputum-smear positive and contribute to disease transmission particularly in congregate settings such as schools. Exuberant lymph node enlargement, associated with edema and small airway size in children less than 5 years cause most of the complications of extraluminal 275 compression. Polyps or granulomatous tissues secondary

seases

However, this is not true. Children when develop disease at adolescence, it is the adult type bacillary disease which contributes to transmission. Further another point which is often dismissed is that children developing tuberculosis at adolescence are treated like adults with Directly Observed Short-Course (DOTS) intermittent chemotherapy for 6 months only. However, in adolescent girls, organs of reproduction like ovary and fallopian tubes are often involved, which require longer course of therapy and evaluation should be done at least once by the ultrasound of abdomen. Female children often develop sterility at a later age, if not treated for a longer duration. In endemic areas, children contribute a significant proportion of the disease burden and suffer severe tuberculosis related morbidity and mortality particularly when associated with HIV infection and are above the age of 10 years. According to WHO report 2009, globally there were an estimated 9.27 million incident cases of TB in 2007, but there is no mention even of sputum-positive cases in children. Hence, it puts greater responsibility on practicing pediatricians to not only treat children with tuberculosis properly but make sincere efforts to diagnose TB cases in the whole spectrum in childhood. Tuberculosis is caused by Mycobacterium tuberculosis. It mainly affects the lungs, though it can affect other organs as well. Mycobacterium bovis and Mycobacterium africanum are the other group of organisms which can cause disease. Children are more likely to develop disease after infection and are significantly more likely to develop extrapulmonary and severe disseminated disease as

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Figure 5.24.1.2 PPD showing consolidation

Figure 5.24.1.3 Collapse consolidation of right upper lobe

Figure 5.24.1.4 Cavity



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to inflammatory changes in the bronchial wall cause intraluminal obstruction. Rupture of a lymph node can also cause this type of obstruction due to deposition of caseous material. In children (less than three years and or immune compromised) infection rapidly progresses to disease. Lungs are the portal of entry of M. tuberculosis to the body. The risk of infection proceeding to disease is more in infants due to decreased monocyte recruitment at the site of infection, reduced microbial killing, less effective major antigen presenting cells (APC) and poor response of naïve T cells.

 

 

 

 

Figure 5.24.1.1 X-ray film of PPC showing left hilar adenopathy with ill-defined parenchymal lesion

Phase I There is a positive tuberculin skin test response, chest X-ray shows primary complex, and this phase occurs 3–8 weeks after primary infection.

Phase II This phase represents the period of highest risk for development of tuberculosis meningitis and miliary

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This phase is the period of development of osteoarticular tuberculosis in children under 5 years and lasts 1–3 years after primary infection and continues until the primary complex is calcified.

Pleural ffusion Pleural effusion may be minimal associated with primary complex in young infants. Massive effusion occurs at a later age.

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Progressive primary disease (PPD) is the result of progression of primary disease. Child may present with moderate to high-grade fever and cough. Expectoration of sputum and hemoptysis are usually associated with advanced disease and development of cavity or ulceration of bronchus. This type is usually present at adolescence but if present in infancy, HIV is to be ruled out.

Child is pretreated with 200 μg of salbutamol given via metered dose inhaler with attached spacer or nebulizer to prevent the occurrence of bronchoconstriction. A jet nebulizer attached to oxygen at a flow rate of 5 liter/min or compressor can be used to deliver 5 m of 3% sterile saline for 15 minutes. Sputum is obtained either by expectoration in children (who are able to cooperate) or by suctioning through the nasopharynx or oropharynx using a sterile, mucus extractor of catheter size 6. Specimen should be transported directly to the laboratory for processing. l

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Pulmonary primary complex (PPC) is the most commonly encountered presentation in the outpatient setting. Cough with some constitutional symptoms may or may not be present. Such symptoms with the persistence of a doubtful shadow on chest X-ray even after an appropriate course of antibiotics, in the presence of a contact in the household who is sputum-positive, must not be ignored.

pecimens for emonstration of M. tuberculosis

In pulmonary tuberculosis, specimens to be collected are sputum, gastric lavage, bronchoscopic lavage fluid or pleural fluid. Recent reports suggest good results of isolation of M. tuberculosis from induced sputum. The latter can be safely and effectively performed in infants and young children. Induced sputum provides a satisfactory and more convenient specimen for bacteriological confirmation of pulmonary tuberculosis in both HIV infected and uninfected children. M

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Pulmonary Primary omplex

ronchoscopy and ronchoalveolar avage L

Miliary tuberculosis is an illness characterized by heavy hematogenous spread and progressive development of innumerable small foci throughout the body. The disease is most common in infants and young children. The onset of illness is often sudden. In the clinical

Early morning gastric aspirate (GA) obtained by using a nasogastric tube before the child wakes up and peristalsis empties the stomach of the respiratory secretions swallowed overnight is the best specimen for demonstration of M. tuberculosis. For higher yield, specimen should be neutralized with sodium bicarbonate if a delay in processing specimen is expected. B

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iliary uberculosis

Gastric avage L

Fever, troublesome cough with or without expectoration, dyspnea, wheezing or cyanosis may be present. Partial compression of the airway can lead to emphysema. Features of collapse may be present if a large airway is completely compressed.

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Diagnosis is by clinical features, presence of contact in the family history, positive tuberculin test, and suggestive findings on chest X-ray. Demonstration of M. tuberculosis in a specimen from lungs is the gold standard but it is not always present.

seases

Primary infection usually passes off unrecognized with no striking clinical or radiological manifestations (described as asymptomatic Mantoux positivity).

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iagnosis

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Phase V This phase represents the period in which late mani festations of TB including pulmonary reactivation disease occurs and occurs more than 3 years after primary infection.

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Phase IV

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This phase is the period of pleural effusion in children over 5 years and bronchial disease in those below 5 years and occurs 3–7 months after primary infection.

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Phase III

symptoms child may have high-grade fever, dyspnea and cyanosis. The pulmonary findings are minimal in the form of fine crepitations. In addition, there may be hepatosplenomegaly. In another group, the onset may be insidious with the child appearing unwell, febrile and losing weight. Due to involvement of meninges and brain, neurotuberculosis (TBM) may occur. Such children require a lumbar tap for examination of CSF to rule out TBM.

Immun ty, Immun zat on and Infect ous

tuberculosis in infants and occurs 1–3 months after primary infection.

This has got no advantage over properly done gastric aspirate. Bronchoscopy may be considered when there is 277

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AFB

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iehl- eelsen ( ) staining: Yield is 20% and depends on the extent of pulmonary disease and number of specimens tested. • pecial staining for : Fluorochrome stained smears can be viewed more efficiently. • Auramine O staining.

Culture A variety of media are in use for cultivation of M. tuberculosis. These include Lowenstein Jensen (LJ) and Middlebrook 7H11 media. The culture on these media takes a long time and hence the development of following techniques: BACTEC Radiometric Assay, Septi-Check AFB system and Mycobacterial growth indicator tube system (MGIT). In the BACTEC system sputum is used, the experience with gastric lavage is limited. It is expensive but time taken is only 9–14 days.

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Smear

Pleural effusion may occur with or without lung lesion (Fig. 5.24.1.5). In miliary tuberculosis, there are multiple lesions of size of 2–5 mm (Fig. 5.24.1.6). Occasionally chest radiograph may be normal and lymphadenopathy may be detected only on computed tomography (CT). However, it does not mean CT scan is to be done routinely as a modality of diagnosis for pulmonary tuberculosis in children. L

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ethods for Identification of M. Tuberculosis

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doubt in diagnosis or a possibility of resistant tuberculosis is considered.

For the detection of latent tuberculosis new in vitro diagnostic aids that measure a component of cell-mediated immune response to M. tuberculosis are available. It is based on the quantification of interferon-gamma (IFN-

Polymerase Chain Reaction (PCR)

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emonstration of Host esponse on xposure to M. Tuberculosis R

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Specificity varies from 80% to 100%. It also requires the presence of AFB in sputum. It is not cost effective for pediatricians in practice.

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kin est as a easure of ell Immune esponse

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Serology, i.e. ELISA test has no role in the diagnosis of pulmonary tuberculosis in children. It should not be done.

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Figure 5.24.1.5 Massive pleural effusion on left side  

The test should be performed with 1TU PPD with RT 23 and tween 80. An induration of more than 10–15 mm is considered positive when there are associated radiological findings.

adiology





The typical chest X-ray appearance of a pulmonary primary complex is given in Figure 5.24.1.1. Enlarged lymph nodes are usually seen in hilar or right paratracheal region. Adenopathy alone may be the sole manifestation of primary tuberculosis. Consolidation in progressive primary disease (PPD) is usually heterogeneous, poorly marginated with predilection of involvement of apical or posterior segments of upper lobe or superior segment of lower lobe (Fig. 5.24.1.2). Collapse may occur if large airway is obstructed (Fig. 5.24.1.3). Bronchiectasis may occur in PPD because of destruction and fibrosis of lung parenchyma resulting in retraction and irreversible bronchial dilation, cicatricial bronchostenosis secondary to localized endobronchial infection resulting in obstructive pneumonitis and distal bronchiectasis. In 278 children cavitary disease is uncommon (Fig. 5.24.1.4).

 

Figure 5.24.1.6 Miliary shadows with right paratracheal adenopathy

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Though DOT short-course chemotherapy regimen has been found to be very effective in adults, it is not possible to have the same kind of infrastructure for children across board. The criteria of AFB positivity are difficult to meet. The ground reality is that even the children of adults who are

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Flow chart 5.24.1.1 Proposed diagnostic algorithm for pediatric pulmonary TB, (Abbreviations: CXR, Chest X-ray; Mx, Mantoux test; Dx, Diagnosis)

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gamma) released (IGRA) from sensitized lymphocytes in whole blood incubated with different antigens from M. tuberculosis. ESAT-6 and culture filtrate protein 10 (CFP-10) are the commonly used antigens. Commercially available tests based on the estimation of interferon-gamma (IFNgamma) are Quanti FERON-TB(R), Gold in-tube (QFT-IT) and T-SPOT.TB. At present, the major limiting factor to replace tuberculin skin test with these tests is their cost. Sensitivity of IGRA based tests may be less in younger age as compared to tuberculin skin test. The significant advantage of the tests is that prior BCG vaccination does not interfere with the results and multiple visits are not required. The suggested algorithm for diagnosis of pulmonary TB in children is given in Flow chart 5.24.1.1.

reatment

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One of the important biologic determinants of success of therapy is the paucibacillary nature of the disease in children. The bacillary count according to the extent of disease is as follows: • Cavity = 109 • Primary complex = 104–105 • Mantoux positive = 103–104 Short-course chemotherapy, with duration of treatment as short as 6 months has become the standard practice. A meta-analysis of a number of studies has revealed that daily regimen is superior to twice a week intermittent regimen. Table 5.24.1.1 gives the category based treatment of tuberculosis in children as per WHO classification as is used at pediatric TB clinic, All India Institute of Medical Sciences. However, the regimens used are daily.

 

Table 5.24.1.1 Standardized (clinical categories, clinical conditions and suggested drug regimens in children) Categories drug

As suggested by WHO for adults

Suggested conditions in children

Suggested regimens

Category I

New sputum positive Pulmonary TB

PPD, TBL Pleural effusion Abdominal TB or Osteoarticular TB Genitourinary TB* CNS TB

2 HRZE 4 HR

Category II

Relapse Treatment failure Return after adult default (Interrupted treatment)

Relapse Treatment failure Interrupted treatment

2 SHRZE 1 HRZE 7 HRE

Category III

Sputum-negative pulmonary with limited parenchymal involvement Extrapulmonary (less severe forms)

Single lymph node Small effusion Skin TB PPC

2 HRZ 4 HR

Abbreviations: PPC, Pulmonary primary complex; PPD, Progressive primary disease; TBL, Tubercular lymphadenitis; CNS TB, Central nervous system tuberculosis. *In genitourinary tuberculosis, dose to be adjusted as per creatinine clearance

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linical eatures

Tuberculous lymphadenitis most frequently involves the cervical lymph nodes followed in frequency by mediastinal, axillary, mesenteric, porta hepatis, perihepatic and inguinal lymph nodes. Mycobacterial infection should be considered in the differential diagnosis of a cervical swelling especially in an endemic area. Lymphadenitis may affect a single node and is usually unilateral (Figs 5.24.2.1 and 5.24.2.2).









1. Global epidemiology of pediatric tuberculosis. 2. Consensus statement on childhood tuberculosis – 2010 IAP Working Group on Tuberculosis and 3. Tuberculosis Control Program in children – Lacunae and Experiences. In: Seth V, Kabra SK (Eds). Essentials of Tuberculosis in Children, 4th edition. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2011. 2. Marais BJ, Gie RP, Schaff HS, et al. The natural history of childhood intrathoracic tuberculosis. A critical review of literature before chemotherapy era. Int J Tuberc Lung Dis. 2004;8:392-402. 3. Menon PR, Lodha R, Sivanandan S, et al. Intermittent or Daily short-course chemotherapy for tuberculosis in children. A systematic review and meta-analysis of randomized controlled trials. Indian Pediatr. 2010;47:67-73. 4. Seth V, Kabra SK. Pulmonary tuberculosis. In: Seth V, Kabra SK (Eds). Essentials of Tuberculosis in Children, 4th edition. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2011. pp. 101-21. 5. Seth V. Tuberculosis in children. In: Parthasarathy A, Menon PSN, Aggarwal RK, et al. (Eds). IAP Text Book of Pediatrics, 4th edition. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2009. pp. 315-28.

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paratracheal nodes are first site of spread of infection from lung parenchyma. Cervical tuberculous lymphadenitis may represent a spread from the primary focus of infection in the tonsils or adenoids. In the initial stage of superficial lymph node involvement, progressive multiplication of the M. tuberculosis occurs.

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sputum-smear positive for AFB are not screened as desired by pediatricians in the program.

Vimlesh Seth

Introduction

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Figure 5.24.2.1 Single cervical lymph node (Closed view)  

Tuberculous lymphadenitis is the most common form of extrapulmonary TB recorded in children in the ambulatory form in TB endemic areas. It is present in 8–10% of those diagnosed with TB in India.

pidemiology



In TB endemic areas where bovine tuberculosis is well controlled, M. tuberculosis is the most common cause. Lymphadenitis may affect a single node or a localized group of nodes (regional adenopathy) and is usually unilateral. Prevalence of TB lymphadenitis varies from 30% to 40% in cases of tuberculosis. In rural India it has been reported as 4.4 per 1000 children.

Pathogenesis

Figure 5.24.2.2 Single cervical lymph node  

Tuberculous lymphadenitis is a local manifestation of the systemic disease. It may occur during primary tuberculous infection or as a result of reactivation of a dormant focus. The primary infection may spread to regional lymph nodes. From the latter, organism may continue to spread via the lymphatic system to other nodes or may pass through the 280 nodes to reach blood stream from where it can spread to virtually all organs of the body. Hilar, mediastinal or

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Tuberculin test is quite often positive in tuberculous lymphadenitis due to comparative better immune status of children. The test may be positive in about 70–80% of cases.

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iagnosis

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A high index of suspicion is needed for the diagnosis of mycobacterial cervical lymphadenitis. For early diagnosis, a thorough history, physical examination, tuberculin test, radiological examination, fine-needle aspiration cytology and smear and culture of the aspirate for AFB should be taken. Differential diagnosis includes: • Infections (viral, bacterial, fungal) • Neoplasms (lymphoma) • Collagen vascular disease and diseases of reticuloen dothelial system.

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Chest radiograph, ultrasound, CT and MRI of the neck can be performed in mycobacterial lymphadenitis. Asso ciated chest lesion as seen in chest radiograph are very common in children. Singular or multiple hypoechoic and multiloculated cystic lesions surrounded with thick capsule can be demonstrated on ultrasound of the neck.

CT Conglomerated nodal masses with central lucencies, a thick irregular rim of contrast enhancement and inner nodularity are some of the findings on CT. There is varying degree of homogeneous enhancement in smaller nodes.

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MRI

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Discrete, matted and confluent masses can be seen on MRI. Necrotic foci when present are more frequently seen in the periphery along with soft tissue edema in mycobacterial adenitis rather than lymphoma. In T1- and T2-weighed images there is low and high signal intensity respectively if there is necrosis in the cervical mass.

reatment

Antituberculosis treatment is the mainstay in the management of TB lymphadenitis according to National Tuberculosis Program. Directly observed treatment, shortcourse (DOTS) intermittent chemotherapy is recommended. TB lymphadenitis is categorized under treatment category III. Those with smear positive TB lymphadenitis with pulmonary involvement and when patient is severely ill, he or she is categorized as category I. Duration of treatment may be sufficient for 6 months for many patients. However, each patient has to be individualized and longer duration of treatment may have to be given in some patients. It is difficult to define a clear cut ‘end point’ for assessing the efficacy of such extrapulmonary tuberculosis with delayed response to treatment. Delayed response to treatment and non-tuberculous mycobacterial infection usually requires a surgical intervention. Paradoxical reaction, i.e. enlargement of lymph nodes with worsening of symptoms can occur during anti tubercular treatment. In few cases dead bacilli may persist on smear examination in FNAC but antitubercular therapy is to be given only in culture-positive cases.

From draining sinus or aspirate after FNAC.

Culture

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The presence of 10–100 bacilli per cubic millimeter of the specimen is enough for a positive culture result. Several media can be used as described under pulmonary tuberculosis. Culture results are variable (10–69%). Histo pathology of the FNAC material can be quite diagnostic.

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Smear

Radiology

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Tuberculin Test

Immun ty, Immun zat on and Infect ous

In this male child, the mother was being treated for pulmonary tuberculosis. Child had Mantoux test positive (16 × 16 mm) and FNAC showed granulomas consistent with tuberculosis. The duration of symptoms may range from few weeks to several months before diagnosis. Multiplicity, matting and caseation are three important findings of tuberculous lymphadenitis. The following classification of various stages has been defined by Jones and Campbell: • Stage 1: Enlarged, firm, mobile, discrete nodes showing non-specific reactive hyperplasia. • Stage 2: Large rubbery nodes fixed to surrounding tissue owing to periadenitis. • Stage 3: Central softening due to abscess formation. • Stage 4: Collar stud abscess formation. • Stage 5: Sinus tract formation. Clinical features depend upon the stage of the disease. The lymph nodes are usually nontender unless there is: • Secondary bacterial infection • Rapidly enlarging nodes • Co-infection with HIV is evident. The lymph node abscess may burst infrequently leading to a chronic non-healing sinus and ulcer formation. Classically tuberculous sinuses have thin, bluish, undermined edges with scanty water discharge. Tuberculous mediastinal lymphadenitis is more common in children. Rarely cardiac tamponade may occur due to mediastinal lymph nodes. Mediastinal lymph nodes and upper abdominal lymph nodes may cause thoracic duct obstruction, chylothorax and chylous ascites. Contact history is positive in about 22% of cases.

urgery

It provides a rapid tissue diagnosis and confirms the bacterial type. Surgery increases the cure rate with excellent cosmetic results. Surgical techniques include aspiration,

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HIV Infection and nti-retroviral herapy

Tuberculosis meningitis (TBM) is the most common type of CNS tuberculosis encountered in children in India. The frequency of TBM is closely related to the incidence of primary infection with tubercle bacilli. Incidence of TBM varies from 1% to 4% of total inpatient admissions in different parts of India.

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Neurotuberculosis is classified as follows: • eningovascular: – Tuberculosis meningitis and meningoencephalitis – Spinal arachnoiditis – Radiculomyelitis/myelitis • Parenchymal: – Tuberculoma (tuberculous granuloma) – Tuberculous abscess –

In developing countries, tuberculous involvement of the brain and spinal cord are common neurological disorders. It is one of the important manifestations of extrapulmonary tuberculosis, largely found in children below 5 years of age. In a recent retrospective review of existing cards of children under Revised National Tuberculosis Control Program (RNTCP), nearly two-thirds of the patients (63.3%) were of extrapulmonary tuberculosis, but not a single case of neurotuberculosis. This brings out a very important point that there is complete missing of neurotuberculosis under program conditions in RNTCP. Even the latest guidelines for diagnosis of neurotuberculosis laid down by Indian 282 Academy of Pediatrics (2010) fail to pick up any case of neurotuberculosis. The other highlight is that the age group

The characteristic pathologic features of TBM are meningeal inflammation, dense basal exudates, vasculitis and hydro cephalus. The parenchymatous lesions in the brain are commonly located at superficial part of the brain (rich focus), base of the brain and along the superolateral surface. The brain tissue underlying the tuberculous exudates shows varied degree of edema, perivascular cuffing and microglial reaction, collectively termed as “border-zone encephalitis”. Other parenchymal lesions include infarction, diffuse edema and tuberculoma. Diffuse tubercular encephalopathy is characterized by diffuse edema of the brain, perivascular myelin loss and hemorrhagic leukoencephalopathy. Hydro cephalus results from obstruction to the flow of the CSF in the subarachnoid space by dense basal exudates and interference in the CSF absorption by the arachnoid granulation.

–

Introduction

Pathology

–

Vimlesh Seth

Infection usually occurs after inhalation of the bacilli in infected respiratory secretions. In lungs, Mycobacterium tuberculosis multiplies in alveolar macrophages. Within 2–4 weeks, through blood circulation, bacilli spread to extrapulmonary sites and produce small granulomas in the meninges and adjacent brain parenchyma. These small granulomas are known as ‘rich focus’. When mycobacteria contained within these lesions are released into the subarachnoid space, they cause meningitis. Decreased immunity is believed to play a role in the rupture of Rich foci. In miliary tuberculosis there is direct involvement of the brain. The bacilli enter the central nervous system by traversing the blood brain barrier (BBB).

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1. Dhingra V, Mishra V, Mishra R, et al. Fine needle aspiration cytology as a diagnostic tool in pediatric lymphadenitis. J Clin Diagnostic Res. 2011;4:1-4. 2. Jones PG, Campbell PE. Tuberculous lymphadenitis in childhood. The significance of anonymous mycobacteria. Br J Surg. 1932;50:302-14. 3. Marais BJ, Donald PK. Tuberculous lymphadenitis. In: Seth V, Kabra SK, (Eds). Essentials of Tuberculosis in Children, 4th edition. New Delhi: Jaypee Brothers Medical Publishers; 2011. pp. 122-27.

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The treatment of mycobacterial lymphadenitis in HIV infected patients is same as in those without HIV. Rifampicin decreases the serum concentration of anti-retroviral drugs to subtherapeutic levels. In these cases rifapentine should be given instead of rifampicin along with INH in continuation phase. The CD4+ and CD8+ T lymphocyte counts must be estimated and highly active anti-retroviral treatment (HAART) must be administered when indicated. Paradoxical reaction can occur during antituberculous therapy. Affected nodes may enlarge or new nodes may appear representing an immune response to kill mycobacteria. This can occur in 6–30% of patients within the first 2 months of tubercular lymphadenitis. TB lymphadenitis is best treated with antitubercular drugs and surgical intervention is required in a few cases only.

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(<5 years) in whom neurotuberculosis occurs is significantly lacking under program conditions. Hence practicing pediatricians have a greater responsibility in early diagnosis of these cases.

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incision and drainage, and curettage, complete excision of the affected lymph nodes. When lymph nodes are fluctuant and ready to drain, antigravity aspiration should be done. Only simple incision and drainage are associated with prolonged postoperative wound discharge and hypertrophic scarring.

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The determination of adenosine deaminase activity can be of benefit as a rule-in or rule-out test when values of lesser than 4 μ/L and greater than 8 μ/L are used. It cannot discriminate between tuberculosis meningitis and partially treated bacterial meningitis. False-positive results can also be found in patients infected with HIV who have other HIV-associated neuro logical disease, such as cryptococcal meningitis, lympho matous meningitis and cytomegalovirus disease. ­



CSF Adenosine Deaminase Activity

seases

The diagnosis is based on clinical case definition and children must have comprehensive physical and neurological examination at the time of admission. The data available about neurotuberculosis is mostly from tertiary care hospitals. A standardized data entry form should be used to document demographic data, clinical symptoms and signs, laboratory findings, Mantoux test results, chest radiograph, CSF and cranial CT scan findings. Lately beside magnetic resonance imaging (MRI), magnetic resonance spectroscopy is available at very few tertiary care superspecialized centers to distinguish between tuberculoma and neurocysticercosis. Severity of the disease can be classified at admission as per the Medical Research Council (MRC) guidelines as follows: • tage I (early): Conscious, nonspecific symptoms, with no neurological signs. • tage II (intermediate): Signs of meningeal irritation with slight or no clouding of sensorium with or without minor neurological deficits (cranial nerve palsy or limb paresis). • tage III (advanced): Severe clouding of sensorium, convulsions, focal neurological deficits with or without involuntary movements. The responsibility on practicing pediatricians is to send cases in stage I and II to a referral center.

Routine analysis of CSF in most patients with tuberculosis meningitis shows the following: • Clear appearance. • Pleocytosis range 5–1000 cells/μL (median, 50–450 cells/μL) with a lymphocyte predominance. • A raised protein concentration (0.5–3 g/L). • A low glucose concentration (absolute value <2.2 mmol/L and a CSF to plasma ratio <50% (median, 27%). Findings in patients with HIV are almost similar as reported in most studies. CSF findings that favor the diagnosis of tuberculosis over bacterial meningitis include clear appearance, white cell count less than or equal to 900–1000/μL, neutrophil content less than 30–75% and protein concentration greater than 1 g/L. These findings can be present in associated cryptococcal meningitis.

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uberculosis eningitis and eningoencephalitis

based on clinical features, cerebrospinal fluid changes and imaging characteristics. Bacteriological confirmation is not possible in all cases. Serological tests do not have sufficient sensitivity and specificity.



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econdary involvement of nervous system: Spinal cord disease (compression) Miliary tuberculosis of brain secondary to hemato genous dissemination. Focal lesions, intracranial tuberculomas and tuberculous abscess are usually located in cerebral or cerebellar hemispheres, uncommonly in brainstem and very rarely in spinal cord. – –

Immun ty, Immun zat on and Infect ous

•

The specificity of tuberculosis meningitis diagnosis can be increased by molecular diagnostic tests. A systematic review and meta-analysis of commercial nucleic acid amplification tests for the diagnosis of tuberculosis meningitis has shown a combined average sensitivity of 56% and specificity of 98%. Because of its high specificity, a positive commercial nuclear acid amplification test is regarded as a definite test in patients with suspected tuberculosis meningitis and offers particular value in patients who have previously received tuberculous treatment. Detection of M. tuberculosis antigens and antibodies in CSF is of no value.

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Tuberculosis meningitis is an important manifestation and is associated with high morbidity and mortality. Diagnosis is

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One or more of the following criteria must be looked for: • linical entry criteria: Symptoms and signs of meningitis including one or more of the following: headache, irritability, vomiting, fever, neck stiffness, convulsions, focal neurological deficits, altered consci ousness or lethargy. • aboratory criteria: AFB seen in the CSF; Mycobacterium tuberculosis cultured from CSF; or CSF M. tuberculosis positive by commercial nucleic acid amplification test in a patient who presents with symptoms or signs suggestive of meningitis. • efinite tuberculosis meningitis: Clinical entry criteria plus one or more of the laboratory criteria.

Molecular Diagnostic Tests

erebral Imaging

The role of cerebral imaging is well established in the diagnosis of tuberculosis meningitis. Severe disease is often associated with abnormalities on CT. Hydrocephalus and basal meningeal enhancements are the most common radiological features of tuberculosis meningitis (Figs 5.24.3.1 and 5.24.3.2). Eighty percent of children have hydrocephalus and 75% basal meningeal enhancement. Hydrocephalus is less common (45%) in adolescents and so 283 is basal meningitis (8–34%).

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Figures 5.24.3.1A and B Advanced TBM with hydrocephalus, multiple cranial nerve palsies, hemiplegia on right side and hemiballismus on the left but the child had complete recovery on treatment

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Figures 5.24.3.2A to C (A) Conscious child with TBM; (B) CT head showing dense basal exudates; (C) CT head showing basal exudates with improvement in hydrocephalus

CT Findings in Tuberculosis Meningitis

Samples from Sites other than CNS

The combination of basal meningeal enhancement, infarcts and hydrocephalus has 100% specificity. Basal meningeal enhancement is most sensitive (89%).

Lung, lymph node, liver, bone marrow, urine, ascitic fluid and gastric aspirate further increase the chance of a positive diagnosis. The gastric aspirate and induced sputum are especially useful in children.

Chest Radiograph Suggestive chest radiograph abnormalities are seen in 33–60% of patients. A higher evidence of disease elsewhere is found in patients with associated HIV for which it is advisable to have CT chest and ultrasound 284 abdomen.

Mantoux Test and Family History

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Mantoux test is usually positive in about only 30% of cases. Tuberculin used is 1 TU with tween 80. Almost a similar proportion, i.e. about one-third had positive family history.

reatment

Appropriate chemotherapeutic regimens should be administered as early as possible.s However, there is no unanimity concerning chemotherapeutic regimens or optimal duration of treatment. The patient’s clinical stage at presentation is the most important prognostic factor. Corticosteroids should be administered to all patients in stage III. Surgical procedures are directed at the management of hydrocephalus. Focal lesions, intracranial tuberculomas and tuberculous abscess do not require surgical intervention and respond well to antituberculous treatment along with steroids. Most factors found to correlate with poor outcome can be directly traced to the stage of the disease at the time of

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Magnetic resonance imaging (MRI) is commonly used for the detection of abnormalities such as meningeal enhancement, infarcts and tuberculomas especially of lesions involving the brainstem. When HIV is associated with tuberculosis meningitis, hydrocephalus and basal meningeal enhancement is present less often. They have higher frequency of infarcts, gyral enhancement and mass lesions compared with patients who do not have HIV. Cerebral atrophy is also more common when there is associated HIV. These radiological findings can be present in other causes of meningitis, such as Cryptococcus, cytomegalovirus encephalitis and toxoplasmosis.



Magnetic Resonance Imaging

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Effect of corticosteroids on intracranial pressure, computed tomographic findings and clinical outcome in young children with tuberculosis meningitis shows that they significantly improve the survival rate and intellectual outcome of children with TBM. Serial CT scanning shows enhanced resolution of basal exudates and tuberculomas by steroids. Corticosteroids do not affect the incidence of basal ganglia infarction significantly.

Hepatotoxicity

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Drug regimens used in TBM are described in Table 5.24.3.2.

 

Table 5.24.3.1 The recommended doses of anti-tubercular drugs by IAP Drugs*

Daily regimen (mg/kg)

Intermittent (mg/kg)

Isoniazid**

5–10

15

Rifampicin

10

15

Pyrazinamide

30–35

35

Ethambutol

20

30

Streptomycin

15–20

20

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Medical Management of Cerebral Edema

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Mannitol (20%) is most frequently used in the emergency treatment of cerebral edema. The practicing pediatrician can safely give it in the dose of 5 m /kg stat followed by 2 ml/kg 6 hourly for eight doses. It should be used only for the first 48–72 hours to avoid the risk of secondary increase in intracranial pressure due to fluid and electrolyte imbalance.

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rug egimens

Hepatotoxicity may be seen in malnourished and those with disseminated disease. In case of overt toxicity there is pain abdomen, vomiting and hepatic enlargement. The following Flow chart 5.24.3.1 shows the management of hepatotoxicity.

seases

A secured microbiological diagnosis is seldom, if ever, achieved in neurotuberculosis and the decision to start treatment must never be delayed for microscopic confirmation of acid-fast bacilli. Antituberculosis chemo therapy must be started empirically and immediately in any patient with clinical suspicion of tuberculosis meningitis when supported by CSF analysis and brain imaging. This is because there is significant morbidity and mortality associated with late institution of therapy in advanced disease. In TBM, the drug should be able to penetrate the blood brain barrier (BBB) and achieve effective concentration in CNS. The consensus statement of Indian Academy of Pediatrics (IAP) recommends the doses of antitubercular drugs as in Table 5.24.3.1.

Antiepileptic Drugs Hyponatremia and raised intracranial pressure can cause seizures in acute phase. These get settled by treating the underlying cause. The seizures occurring later than the first week are associated with infarct and tuberculoma. These require initiation of antiepileptic drugs. Flow chart 5.24.3.1 Management of hepatotoxicity  

Antituberculosis Treatment

D

Corticosteroids

Immun ty, Immun zat on and Infect ous

diagnosis, e.g. coma at presentation is a bad prognostic feature and interventions such as shunt do not improve the outcome except mortality is converted into severe morbidity. The only way to reduce morbidity and mortality is by early diagnosis, timely recognition of complications and institution of the appropriate treatment strategies. In case of doubt as to whether the patient has partially treated pyogenic meningitis or TBM, it is prudent to start dual therapy with antibiotics and antitubercular therapy and reassess the patient in 7–10 days.

* All the drugs should be administered on a single daily dose in an empty stomach ** Vitamin B6 is not necessary in children taking INH.



 

Table 5.24.3.2 Drug regimen used in TBM protocols Drug regimens Intensive Continuation Total duration used in TBM phase** phase** (months) protocols IAP Consensus 2HRZE 10 HRE 12 7H3R3 Cat I of DOTS -9 DOTS RNTCP* 2H3R3Z3E3 * Intermittent therapy **H (INH), R (Rifampicin), Z (Pyrazinamide), E (Ethambutol).

285

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Contrast enhanced computed tomography is utilized as the initial imaging modality.

Magnetic Resonance Imaging



­

Magnetic resonance imaging (MRI) differentiates the follo wing three types of tuberculoma: 1. Non-caseating granuloma 2. Caseating granuloma with solid center 3. Caseating granuloma with liquid center. In spite of the following well-defined differences between neurocysticercosis and tuberculoma, rarely mag netic resonance spectroscopy has to be undertaken to differentiate the two (Table 5.24.3.3).

Modern imaging techniques such as CT and MRI have clearly shown that hydrocephalus is very common and plays an important role in increasing the intracranial tension (ICT) with subsequent brain damage. Surgical intervention by shunt procedure depends upon the extent of hydrocephalus and needs the attention of a pediatric surgeon.

Imaging Techniques





Surgical Management of Hydrocephalus

neurocysticercosis (NCC), brain abscess, fungal infection and malignancy.

Pathogenesis

linical eatures

The size and site of tuberculoma as well as the presence of concurrent meningitis determines the clinical features. The common symptoms are seizures without associated meningeal signs or evidence of tuberculosis elsewhere in the body. Infratentorial tuberculoma may present with raised ICT. D

T

­ ­

Immature faintly enhancing tuberculomas have a more likely chance of resolution with antituberculous chemo therapy and corticosteroids. In contrast, as well formed and probably large-sized (>3 cm) granuloma may have a risk of paradoxical enlargement.

pinal ord isease ( ompression) econdary to Vertebral steomyelitis O

Spinal TB can involve the bones of vertebral column (Pott’s disease) and the cord (myelitis, abscess, and granuloma). Though Pott’s disease is the most common form of skeletal Table 5.24.3.3 Differences between neurocysticercosis and tuberculoma Tuberculoma

Neurocysticercosis

May present at any age

Rare before the age of 3 years

Progressive neurological deficit

Generally no neurological deficit, post-ictal focal deficits of varying severity resolve with in a matter of days to weeks

F

C

The center of the tuberculoma when becomes necrotic forms caseous debris, while the periphery tends to encapsulate with fibrous tissue. Tuberculous abscess is due to the liquefaction of the caseous material. It is due to the presence of polymorphonuclear leukocytes. It ranges from a few millimeters to 3–4 cm in size.

Prognosis

iagnosis

Diagnosis rests on clinical assessment, imaging findings and 286 response to therapy. The seizures are usually lateralized. The differential diagnosis that needs to be considered includes

C

Tuberculoma is a manifestation of tuberculosis which occurs in solid organs. It usually occurs in an area of tuberculous cerebritis as a cluster of microgranuloma which when coalesces forms a mature noncaseating granuloma. Approximately 1.4–15.9% cases of space occupying lesions are due to tuberculoma.

The treatment protocol for intracranial tuberculoma includes antitubercular treatment like TBM. In addition, symptomatic management of raised ICT and seizures is required. Steroids are required to decrease ICT. Usually respond to anti tuberculosis treatment and resolves over 3–6 months.

D

uberculoma or uberculous Granuloma T

T

N

Parenchymal eurotuberculosis

reatment

C

Spinal tuberculous arachnoiditis is a rare complication of CNS tuberculosis. It is an inflammatory condition that involves the arachnoid lining along the spinal tract. Involvement of the spinal arachnoid lining secondary to intracranial tuberculosis meningitis is the most common pathogenesis affecting the thoracic region.

S

A

pinal uberculous rachnoiditis T

S

The most important prognostic factors predicting a fatal outcome in HIV-negative children with neurotuberculosis are coma at diagnosis.

­



Prognosis

S

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Phenobarbitone should not be used for treatment as it has cerebral depressant effect and induces hepatic microsomal enzymes which cause increased hepatotoxicity due to production of acylating agents of INH.

Ring size is usually >20 mm, irregular Usually smaller, regular rounded outline with marked cerebral edema outline with less cerebral edema May be supra or infratentorial

Usually supratentorial

Likely to cause midline shift

Usually no midline shift

*MRS has lipid peak

No lipid peak

T2 relaxation time shorter

T2 relaxation time longer

* MRS: Magnetic resonance spectroscopy

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Prognosis Site and stage of disease are important variables that affect the outcome. Severe malnutrition, delays in starting ATT, degree of compression and neurological deficit also determine the prognosis. Cord involvement indicates poor prognosis.

Paradoxical Response to Chemotherapy in Neurotuberculosis

i i i i Di

Introduction Abdominal tuberculosis (ATB) is less common as main organs affected with tuberculosis (TB) are lungs, central nervous system and lymph nodes in children. It is mostly reported from pediatric surgical centers. Abdominal TB is defined as TB infection of abdomen, including gastrointestinal tract, peritoneum, mesentery, abdominal lymph nodes, liver, spleen and pancreas. It can be a complication of untreated pulmonary disease. Mycobacterium tuberculosis is the principle causative agent and rarely Mycobacterium bovis and non-tuberculous Mycobacterium are responsible. E

­

Paradoxical responses to chemotherapy in neurotuber culosis can occur at any time even up to 1 year during chemotherapy despite a regular standard antituberculosis treatment. New granulomas or abscesses may appear in children receiving chemotherapy for TBM during followup. Hydrocephalus may also appear despite a regular chemotherapy in treated TBM cases. Immature faintly

i

Vimlesh Seth

T

In addition to institution of antituberculosis treatment (with steroids), surgery may be required if features of spinal cord compression are present.

T

bdom nal uberculos s i

A















5.24.4

reatment of pinal uberculosis S

T

The neurological problems can arise due to physical compression of neural tissues like spinal cord and nerves, inflammation of these structures and their coverings by the disease, edema and vascular thrombosis. The neurological deficit can be as insignificant as tingling, numbness and mild weakness or as catastrophic as complete loss of sensations, power, and bladder and bowel control.



T

omplications of pinal uberculosis





TC

S

C

Plain radiograph CT scanning and MRI Bone scan with 99m .

seases

• • •

1. Aneja S, Maheshwari A, Seth V. Clinical manifestations, diagnosis and management of neurotuberculosis. In: Seth V, Kabra SK (Eds). Essentials of Tuberculosis in Children, 4th edition. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2011. pp. 161-80. 2. Dayal R, Senthil Kumar P, Katoch VM, et al. Diagnostic value of real time PCR for neurotuberculosis. Indian Pediatr. 2010;47:631-32. 3. Marais S, Thwaites G, Shoemon JF, et al. Tuberculosis meningitis a uniform case definition for use in clinical research. The Lancet Infectious Diseases. 2010;11:803-12. 4. Schoeman J, Malan G, Toorn RV, et al. Home-based treatment of childhood neurotuberculosis. J Trop Pediatr. 2009;55:14954. 5. Seth R, Kalra V, Sharma U, et al. Magnetic resonance spectroscopy in ring enhancing lesions. Indian Pediatr. 2010;47:803-4. 6. Seth V. Neurotuberculosis. In: Parthasarathy A, Menon PSN, Aggarwal PK, et al. IAP Textbook of Pediatrics, 4th edition. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2009. pp. 336-42. 7. Udani PM, Gulati S, Seth R, et al. Pathology, pathogenesis, case studies of neurotuberculosis. In: Seth Vimlesh, Kabra SK (Eds). Essentials of Tuberculosis in Children, 4th edition. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2011. pp. 150-160, 180-99.

Imaging

ibliography



Stage, site of the disease (bone or spinal cord) and presence of complications determines the clinical features. Constitutional symptoms precede the occurrence of specific symptoms related to the involvement of vertebral bone. Back pain (spinal or radicular) is the earliest and the most common symptom. Spinal movements are restricted and spine is tender due to prevertebral spasm. Cold abscess is often present in the dorsolumbar spine. Traversing of tuberculous caseous material can lead to the presence of cold abscess in the thigh, in the back along the posterior spinal nerves, in the buttock along the superior gluteal nerve. Involvement of upper cervical spine though less common, can cause dangerous and rapidly progressive symptoms.

B

F

C

linical eatures

enhancing tuberculomas have a more likely chance of resolution with antituberculosis chemotherapy and corticosteroids while a well formed and probably large sized (>3 cm) granuloma may have a risk of paradoxical enlargement.

Immun ty, Immun zat on and Infect ous

involvement by tuberculosis, the spinal involvement occurs in less than 1% of patients with TB. The other forms like intramedullary tuberculoma, epidural abscess and spinal arachnoiditis are rare in pediatric age group.

pidemiology

Exact epidemiology of abdominal tuberculosis is not known. It forms 0.8–3.6% of total admissions and intestinal TB contributes to 15% of all intestinal obstructions and 5–7% of all gastrointestinal perforations.

287

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Primary involvement of the intestines and other abdominal viscera is very rare now. Intestinal involvement may be due to swallowing of infected sputum. Boiling of milk before consumption has made infection with M. bovis rare, but it is mostly silent bacteremia occurring intermittently which leads to dissemination of TB causing intra-abdominal infection. The pathogenesis leading to development of intestinal TB is shown in Flow chart 5.24.4.1. The chance of infection depends on the virulence of the Bacillus and its number. Acid fast Bacillus (AFB) has an affinity for lymphoid tissue which is abundant in the gastrointestinal tract and relative stasis in ileocecal area with alkaline pH in large and small intestine favors their survival.

Intestine Ulcerative Hypertrophic Ulcero-hypertrophic

Lymph nodes Mesenteric Retroperitoneal

Peritoneum

Visceral organs

 

 

Exudative or ascitic Plastic or adhesive

 

 

 

 

 

 

 

 

 

Table 5.24.4.1 Sites and types of abdominal tuberculosis

Liver Spleen Pancreas

linical eatures F

C

Most of the symptoms are nonspecific and variable. The peritoneal and nodal form is more common in children than intestinal form. The presentation can be acute, chronic or acute on chronic. The symptoms depend upon the site of disease and the type of pathological involvement.

T

This region is most commonly involved in older children. It can present as ulcerative, stricturous or hypertrophic type. The former presents with chronic diarrhea and features of malabsorption. Subacute intestinal obstruction is the manifestation in stricturous or hypertrophic type along with vague lump in the abdomen. Involvement of other sites such as colorectal and anal areas is rare. As a part of disseminated disease, spleen, pancreas and hepatobiliary region can be involved.

sophagus

Esophagus may be rarely involved due to extension of disease from adjacent lymph nodes in mediastinum. Endoscopy or fine-needle aspiration cytology (FNAC) is necessary for diagnosis.

 

Flow chart 5.24.4.1 Pathogenesis of abdominal tuberculosis

mall Intestinal and Ileocecal uberculosis T

Different sites and types of abdominal TB are shown in Table 5.24.4.1. The common site of involvement is small intestine (ileum). Next in frequency is peritoneal involvement. Contiguous extension from adjacent organs is commonly reported in adolescent girls with tuberculous salpingitis and tuberculosis of the spine.

There is female preponderance in peritoneal tuberculosis. This type presents as abdominal distension and ascites. Fever and night sweats may be present. Diffuse abdominal tenderness with doughy feeling can be the presenting signs. Enlarged mesenteric lymph nodes may be the other manifestation. S

ite of Involvement

Peritoneal uberculosis

E

S



i

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extbook of Ped atr cs T

Pathogenesis

T

Gastric uberculosis The involvement of the stomach is rare due to presence of acid in stomach and paucity of lymph nodes. Symptoms are nonspecific. T

A

Investigations for bdominal uberculosis

D

echniques of efinitive iagnosis D

T

It is often not possible to get microbiological diagnosis as it is a paucibacillary disease. Diagnosis of abdominal TB is based on any of the following criteria in the presence of strong clinical suspicion: • Demonstration of AFB in the lesion or ascitic fluid. • Growth of M. tuberculosis on culture of tissue or ascitic fluid. • Operative and histologic evidence of abdominal TB.

Demonstration of Acid Fast Bacillus

A

288

Smear and culture for AFB on the following specimens: • scitic fluid: The yield of AFB by smear and culture from ascitic fluid is very low. It can be demonstrated by smear

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Ascitic Fluid Analysis The ascitic fluid is either straw colored or clear and is exudative in nature. Proteins more than 3 g/dL, cells more than 1000/cumm (mostly lymphocytes) and ascitic/blood glucose ratio less than 1.1 g/dL are suggestive of TB. Ascitic fluid adenosine deaminase (ADA) has been considered to be a useful screening test in children. A level of more than 33 units has a sensitivity and specificity of 93% and 96%, respectively with positive predictive value of 93%.

Malabsorption Studies Malabsorption is documented due to decreased small intestinal mucosal surface, lymphatic obstruction, fistula formation between small and large intestines, and deconjugation of bile salts secondary to bacterial overgrowth. However, the tests are not diagnostic.

i

­

i

Serodiagnosis

i

The usual ELISA test for antibodies and antigens is not helpful, polymerase chain reaction (PCR) and some newer seromarkers such as chemokine IP-10 (CXCL-10) are being investigated for diagnosis of TB.

Differentiation between Abdominal TB and Inflammatory Bowel Disease (Crohn’s Disease)

i

omplications

Di

C

These two diseases are great mimickers as both being chronic inflammatory diseases of the bowel. Table 5.24.4.2 describes some of the differences between the two.

Intestinal obstruction is the most common complication which requires surgical intervention. Adhesions and enlarged lymph nodes are usually responsible for obstruction. Fistula formation and confined perforation with abscess are also common. Intestinal hemorrhage due to enteric tuberculosis is less common and is usually mild. Intraperitoneal hemorrhage can be massive due to erosion of a large vessel. Malabsorption is a common complication.

reatment

Antituberculosis chemotherapy is the mainstay in the management of abdominal TB. Surgical procedures are required for the treatment of complications and tissue

Table 5.24.4.2 Differences between intestinal TB and Crohn’s disease Intestinal TB Crohn’s disease Fever ++ Fever + Hypertrophic lesions Cobblestone appearance and apthous ulcers Caseating conglomerate Non-caseating granuloma AFB –ve granuloma, AFB +ve Anorectal fistula and anal lesion Common less common Excellent response to therapy No response to anti-TB, therapy; requires anti-TB immunosuppressive therapy  

­

Characteristic features on ultrasound of early abdominal tuberculosis are mesenteric thickness of 15 mm or more, increased mesenteric echogenicity and mesenteric lympha denopathy. Portal hypertension can be the other condition in which there can be mesenteric thickness. Intra-abdominal fluid can be seen which may be free or loculated and clear or complex with debris and septae. Ultrasound is superior to CT in picking up ascites. Tuberculosis has a predilection of involvement of periportal, peripancreatic and mesenteric lymph nodes rather than retroperitoneal lymph nodes.

In the presence of abdominal symptoms, positive histo pathology of peripheral lymph nodes is helpful in diagnosis.



D

S

T

Abdominal Ultrasound

Histopathology of Peripheral Lymph Nodes

seases

These include Mantoux test, chest X-ray, family screening, plain X-ray abdomen, abdominal ultrasound, percutaneous fistulogram, barium meal and follow through and barium enema.

Acid fast Bacillus can be demonstrated in gastric aspirate, stool, sputum and urine. However, their demonstration does not confirm the diagnosis of abdominal TB.

T

F AFB

O A

ther Investigations to upport the iagnosis of bdominal uberculosis

Demonstration of AFB

Immun ty, Immun zat on and Infect ous

in <3% of cases, cultured in <20%. The yield of culture can be increased up to 80% if one liter of ascitic fluid is concentrated. • ine needle aspiration cytology: FNAC from intraabdominal mass is well-established mode of quick diagnosis. A mass could be due to lymph nodes, intestines and rolled up omentum. Aspiration can be US/CT guided if the mass is deep seated. Specimen thus obtained can be examined by smear, culture for AFB and histopathologically. • in the biopsy tissue: Various ways to obtain biopsy material include upper GI endoscopy, lower GI endoscopy, peritoneal biopsy, laparoscopy or peritoneoscopy, laparotomy, liver biopsy and splenic aspirate. For all these procedures, practicing pediatrician has to have high index of clinical suspicion and should refer the child to pediatric gastroenterologist.

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ibliography

C

N

R

T

TB

­



Phase III: he evised ational (1992 nwards)

ontrol Program

i

­

With the appearance of HIV-AIDS epidemic and the spread of multidrug resistant TB, Central Health Council imple mented the Revised National Tuberculosis Control Program (RNTCP). It adopted the internationally recommended Directly Observed Treatment Short-course (DOTS) strategy. The major organizational change was the creation of sub-district level (called TB unit). It consists of a full time treatment supervisor (STS) and a laboratory supervisor (STLS). In addition, a medical officer from the general health system served as a medical officer. They have to supervise 5 lakh population and five designated microscopy centers. In addition, a wide network of DOT (directly observed treatment) centers with DOT providers were made available. T

O

C





T

N

C

D

Phase II: evelopment of the ational uberculosis ontrol Program (1960-1990) The National TB Control Program (NTCP) conducted operational research and the program was integrated into general health services orienting services towards chest 290 symptomatics. The attention was diverted from sanatoria to domiciliary treatment.

p

R

U

In the initial phase of NTP, the major emphasis was on adults with hardly any guidelines for children. Routine availability of sputum sample was less and so was the availability of chest X-ray. Combination of history, suggestive symptoms and signs, history of contact with sputum smear-positive case and a positive tuberculin test used to be the basis of diagnosis. The problem of supply of pediatric formulation is still not fully solved. Hence for RNTCP, there was the issue of underregistration of pediatric TB cases in the program. In spite of consensus workshops by Indian Academy of Pediatrics and tuberculosis specialists, these problems are still not solved.

This was before the discovery of anti-tuberculous drugs. The ‘sanatorium movement’ which originated in England recommended a balanced diet, fresh air and regulated exercise. Around this time, effective anti-TB drugs began to be available—streptomycin (1944), para-aminosalicylic acid or PAS (1946), thiacetazone (1950), isoniazid (1952) and rifampicin (1966).

D

D

E

T

Phase I: he arly ays (1910-1960)

M

Prevention, iagnosis and anagement of Pediatric uberculosis nder ntc T

First anti-tuberculosis measures taken in India were of an unplanned and adhoc nature confined mainly to hospitals and sanatoria. The chronology of tuberculosis (TB) control in India can be divided into three phases.

D

C

volution of uberculosis ontrol Program T

E



Mycobacterium tuberculosis remains the single most serious, infectious pathogen in the world. It is a major global public health problem in much of the developing world. Almost 50% (4 million) cases are sputum smear-positive out of the total 9 million occurring every year.

Directly observed treatment short-course (DOTS) is a systematic program which has five components: 1. Political and administrative commitment. 2. Good quality diagnosis by sputum-smear microscopy. 3. Uninterrupted supply of good quality drugs. 4. Standardized short course chemotherapy including directly observed treatment (DOT). 5. Recording, systematic monitoring and accountability. Full nationwide coverage was achieved in March 2006 covering over a billion population in 632 districts or reporting units.

Introduction

irectly bserved reatment hort- ourse



Vimlesh Seth

S

D

g

T

at onal uberculos s ontrol Pro ram i

C

5.24.5

N



1. Thapa BR, Rawal P, Angara R. Abdominal tuberculosis. In: Seth V, Kabra SK (Eds). Essentials of Tuberculosis in Children, 4th edition. New Delhi: Jaypee Brothers Medical Publishers; 2011. pp. 128-49.

Chemotherapy of TB underwent revolutionary changes in the seventies owing to the availability of well-tolerated and highly effective drugs—rifampicin and pyrazinamide. The ground reality did not improve even with the introduction of this expensive short-course chemotherapy. Compliance was a big problem. This lead to phase III of the program.

O



B



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diagnosis. Role of short course chemotherapy has not been well evaluated in children. Pediatricians usually prefer longer continuous therapy for 9–12 months (2HRZE 7HR). It is more so in nodal tuberculosis. Hepatic transaminases should be monitored periodically and if hepatic toxicity develops, it is managed accordingly. Antituberculosis therapy reduces fibrosis along with healing, hence reduces predisposition to adhesions and stricture formation. Compliance has to be maintained as in tuberculosis of other organs. Role of surgery is limited to tissue diagnosis in case of peritoneal, lymph node TB and for the management of complications which usually include obstruction, perforation and fistula formation.

iagnosis

Clinician should suspect pulmonary TB in children presenting with:

vip.persianss.ir

ew: A patient who has never been treated for TB or previously treated for less than one month with antituberculosis drugs. • elapse: Sputum smear-positive after having been treated completely or has been declared cured. • reatment after default: A patient who returns to treatment, positive bacteriologically, following interruption of treatment for 2 months or more. • ailure: Any TB patient who is still sputum smearpositive after 5 months of treatment. Also a patient in category II but becomes smear-positive.

i

R

N

•

i

C

T

ypes of ases

T

i i

­

M

Diagnosis based on positive culture but negative AFB smear; or TB in a patient with symptoms suggestive of TB with three sputum-smear negative for AFB but with suggestive radiology.

onitoring

seases

Pulmonary TB, Smear-Negative

Directly observed treatment short-course is the reco mmended strategy under RNTCP for all pediatric TB patients as given in the Table 5.24.5.1. The medication is available in the form of combipacks in patient-wise boxes linked to child’s weight as given in Table 5.24.5.2.

Tuberculosis in a patient with at least two initial sputumsmear examination positive for AFB; or TB in a patient with one sputum-smear examination positive plus suggestive radiological abnormalities; or TB in a patient with one sputum-smear examination positive for AFB plus sputum culture positive for AFB.

reatment of Pediatric

Di

Pulmonary TB, Smear-Positive

TB

C

D

isease lassification

It includes TB of any other organ except the lung.

T

Bacteriological testing Tuberculin test Radiology Children showing neurological symptoms like irritability, refusal to feed headache, vomiting or altered sensorium may be suspected to have TBM.

• • •

Extrapulmonary TB

F



Fever and/or cough for more than 3 weeks, with or without • Loss of weight or no weight gain • History of contact with a suspected or diagnosed case of active TB disease within the last 2 years Scoring systems have got no value for the diagnosis of TB in children. In addition one should also look for:

Immun ty, Immun zat on and Infect ous

•

Pediatric-focused monitoring is an integral part of the program. Algorithm for clinical monitoring of childhood TB patient on treatment is given in Flow chart 5.24.5.1.

 

Table 5.24.5.1 Treatment groups, types of patients and regimens prescribed Treatment groups Types of patient

Regimen1 Intensive phase(IP)

Continuation phase (CP)

New

Sputum smear +ve Sputum smear –ve Extrapulmonary

2H3 R3Z3E3

4H3R3

Treated previously

Smear +ve relapse Smear +ve failure Smear +ve treatment after default

2H3R3Z3E3S3, 1H3R3Z3E3

5H3R3E3

1

Prefix indicates month and subscript indicates thrice weekly

 

Table 5.24.5.2 Suggested pediatric dosages for intermittent therapy Drugs

Dosage (mg/kg)

Different weight bands for purpose of treatment (kg) 6–10

11–17

18–25

26–30

Isoniazid

10

75

150

225

300

Rifampicin

10

75

150

225

300

Pyrazinamide

30–35

250

500

750

1250

Ethambutol

30

200

400

600

1000

Streptomycin

15

_

_

_

_

291

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T

tandard reatment utcomes under

RNTC

*IP: Intensive phase

S

 

T

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Flow chart 5.24.5.1 Algorithm for clinical monitoring of childhood TB patients on treatment

P

The definitions of these standard treatment outcomes are as follows:

Cured Initially sputum-smear positive has become sputumsmear negative at the end of treatment and on at least one previous occasion.

Treatment Completed • •

Patient who has completed treatment but who does not meet the criteria to the classified as a cure or a failure. Sputum-smear positive patient who has completed treatment with negative smear at the end of intensive phase but not at the end of treatment.

• •

Sputum-smear negative patient who has completed treatment and has not become sputum-smear positive at any phase of treatment. Extrapulmonary TB patient who has received full course of treatment but has not become smear-positive during any phase of treatment.

Death Patient who dies at any time during the course of treatment.

Failure TB patient who is smear-positive at 5 months or later during treatment and also a patient initially sputum smearnegative becomes sputum-positive at the end of second months.

292

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Drugs

16-25 kg

26-45 kg

>45 kg

1.

Kanamycin

500 mg

500 mg

750 mg

2.

Ofloxacin

400 mg

600 mg

850 mg

(Levofloxacin)

(200 mg)

(500 mg)

(750 mg)

3.

Ethionamide

375 mg

500 mg

750 mg

Relapse

4.

Ethambutol

400 mg

800 mg

1000 mg

Patient previously treated for TB who has been declared cured or treatment completed and is diagnosed with bacteriologically positive tuberculosis now.

5.

Pyrazinamide

500 mg

1250 mg

1500 mg

6.

Cycloserine

250 mg

500 mg

750 mg

7.

PAS (80% Bioavailability) 5 g

10 g

12 g

8.

Pyridoxine

100 mg

100 mg

Transferred Out

Eighteen months of ofloxacin, ethionamide, cycloserine and ethambutol. Pyridoxine (100 mg) is administered to all patients on RNTCP MDR-TB treatment regimen. The dosage and weight band recommendation is given in Table 5.24.5.3. C

uberculosis in H -Infected hildren iv

T

C

There is rapid progression of tuberculosis from infection to disease in children who acquire HIV infection by vertical transmission. HIV makes diagnosis of TB in children even more difficult. Anti-TB treatment is the same as for HIV negative under RNTCP.

G in Preventing

BC

T

Di

Continuation Phase

rug-resistant uberculosis in hildren

World Health Organization recommends BCG for all children except those with symptoms of HIV disease/AIDS.





B



Drug-resistant tuberculosis occurs mainly due to poor treatment adherence by the patient or poor management by the physician. In children, drug-resistance usually comes from adults. Drug-resistance in children should be suspected if the child is in contact with a known case of drug resistant TB, or the adult contact dies. Child shows deterioration after initial improvement both clinically and radiologically. As children have pauci-bacillary disease, secondary resistance is less likely to develop. Initial drug resistance for isoniazid is reported to be 10–15% and 2–3% for rifampicin. DOTS plus strategy is used under RNTCP. It was started in 2007 and full coverage is expected by 2012. A MDR-TB suspect who is sputum-culture positive and has M. tuberculosis strain resistant to isoniazid and rifampicin based on drug sensitivity testing (DST) from a RNTCP accredited laboratory the following drug regimen is to be used:

i

Six months of injectable kanamycin, ofloxacin, ethionamide, cycloserine, pyrazinamide and ethambutol. The intensive phase is extended by 3 more months if the 4th month follow-up sputum culture is positive.

TB

b

Intensive Phase

seases

Contact survey of all children of a sputum smear-positive adult, particularly mother, should be done and if positive, a full course of anti-TB treatment given. In addition children below 6 years in contact with a smear-positive adult in the family but found not suffering from TB should be given isoniazid prophylaxis (5 mg/kg/day) for 6 months to prevent transmission in pediatric population. Prophylactic INH therapy should be administered irrespective of acillus Calmette Guerin (BCG) vaccination status.

D

i

hemoprophylaxis

50 mg

ibliography 1. Chauhan LS. Prospective of prevention, diagnosis and management of tuberculosis in the National Program. In: Seth V, Kabra SK (Eds). Essentials of Tuberculosis in Children, 4th edition. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2011. pp. 616-33.

C

A patient who has been transferred to another TB unit or district; her/his treatment outcome is not known.

i

S. No.

i

Table 5.24.5.3 The dosage and weight band recommendations

A patient who has not taken treatment for 2 months or more after starting treatment.

Immun ty, Immun zat on and Infect ous

Defaulted

293

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iphtheria

Pathogenesis 294 Corynebacterium diphtheriae is a member of a group of aerobic, nonmotile, uncapsulated, nonsporulating, and

linical Manifestations D

nterior Nasal iphtheria ­

Anterior nares colonization leads to chronic serosan guineous or seropurulent discharge, erosive rhinitis without fever or significant toxicity. A whitish membrane may be observed on the septum. D

Pharyngeal and Tonsillar iphtheria The faucial (pharyngeal) form is most common. It is manifested with sore throat, malaise, and mild-to-moderate fever. Initially there is mild pharyngeal erythema, usually followed by progressive formation of a whitish tonsillar exudate, which over a period of 24–48 hours changes into a grayish membrane that is tightly adherent and bleeds on an attempted removal. Cervical adenopathy and soft tissue edema result in the typical bull neck appearance and stridor. D

Laryngeal iphtheria Laryngeal involvement is manifested as hoarseness, stridor and dyspnea.

utaneous iphtheria D







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Humans are the only natural reservoir of C. diphtheriae, although occasionally it has been isolated from a variety of domestic animals. Spread occurs in close-contact settings through respiratory droplets or direct contact with respiratory secretions or skin lesions. The majority of nasopharyngeal C. diphtheriae infections result in asympto matic carriage, with clinical disease developing in only about one in seven individuals. Diphtheria immunization protects against disease but does not prevent carriage. Vaccination with diphtheria toxoid (formalin-treated toxin) was introduced in the 1920s. Immunization of children in an era when the majority of older individuals had natural immunity resulted in a dramatic drop in the incidence of diphtheria and an even more rapid decline in the proportion of toxigenic strains isolated, presumably because the selective advantage of the tox gene promotion of greater replication and spread of the organism is lost in an immune host. In most Western countries, toxigenic C. diphtheriae has virtually been eliminated. Vaccine-induced immunity to diphtheria wanes with time, and there is a growing cohort of individuals with no natural diphtheria immunity. Serosurveys indicate that 20–60% of adults in industrialized countries have diphtheria antitoxin levels below minimal protective levels. As long as a high proportion of the population remains susceptible, the danger of reintroduction or reemergence of toxigenic strains exists. Since 1990 there has been a major resurgence of diphtheria in several countries of the former Soviet Union. In 2005, India contributed 5,826 (71%) of the 8,229 diphtheria cases reported globally. New numbers released by the Central Bureau of Health Intelligence (CBHI), under the Union Ministry of Health and Family Welfare in 2010, a total of 3,129 cases of diphtheria were reported out of which 731 were found to be from Delhi and a huge 90% of reported diphtheria deaths (163 out of 177) recorded in 2010 was also in Delhi.



pidemiology

C

Diphtheria is a potentially acute disease caused by exotoxinproducing Corynebacterium diphtheriae, a Gram-positive bacillus. Morbidity and mortality result from the bacterial toxin that may cause obstructive pseudomembranes in the upper respiratory tract (croup) or damage myocardium and other tissues.

pleomorphic organism. Both nontoxigenic and toxigenic C. diphtheriae strains exist. Toxigenicity is conferred when a nontoxigenic organism is infected with a betaphage carrying the gene for the toxin (tox). C. diphtheriae has three biotypes—gravis, mitis, and intermedius—that are distinguished by colonial morphology and varying biochemical and hemolytic reactions. Strains may be distinguished for epidemiologic purposes by molecular techniques. Corynebacterium ulcerans can also produce classic diphtheria, including local respiratory tract and distal toxic complications. Corynebacterium diphtheriae colonizes the mucosal surface of the nasopharynx and multiplies locally without blood stream invasion. Released toxin causes local tissue necrosis with the formation of a tough, adherent pseudomembrane composed of a mixture of fibrin, dead cells, and bacteria. The membrane usually begins on the tonsils or posterior of the pharynx. In more severe cases, it spreads over the pharyngeal wall, fauces, and soft palate and into the larynx, resulting in respiratory obstruction. Toxin entering the blood stream causes tissue damage at distant sites, particularly the heart (myocarditis), nerves (demyelination), and kidney (tubular necrosis). Nontoxigenic strains may cause mild local respiratory disease, sometimes including a membrane.

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ntroduction

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Classic cutaneous diphtheria is an indolent, nonprogressive infection characterized by a superficial, ecthymic,

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The specimen should be collected immediately after clinical diagnosis with the swab from the inflamed tissue and one sent for staining and the other for the culture. It is obtained from the nose and throat and any other mucocutaneous lesion. A portion of membrane should be removed for culture. Evaluation of a direct smear using Gram stain is used to accurately identify the organism and subsequently with the special stain like Albert’s stain, Ponders stain, the metachromatic granular structure is identified. Alert the laboratory to the suspicion of diphtheria because isolation of C. diphtheriae requires special culture media. C. diphtheriae may be grown on various selective media, including tellurite agar or specially enriched Loeffler, Hoyle, Mueller, or Tinsdale medium. Culture isolates of coryneform organisms should be identified to the species level, and toxigenicity and antimicrobial susceptibility tests should be performed for C. diphtheriae isolates. Elek test is used for toxigenicity, to determine whether the organism is able to produce the diphtheria toxin or not.

The differential diagnosis includes streptococcal and viral tonsillopharyngitis, infectious mononucleosis, Vincent’s angina, candidiasis and acute epiglottitis.

Imm n t Imm n t n n In t D



­

­

C D

iagnosis

fec ious iseases

Most complications of diphtheria, including death, are attributable to effects of the toxin. Myocarditis typically occurs in the first or second week after the onset of respiratory symptoms and develops either suddenly or insidiously with signs of low cardiac output and congestive failure. Conduction disturbances like ST-T wave abnormalities, arrhythmias, and heart block may occur without myocarditis. Neurologic impairment is manifested as cranial nerve palsies and polyneuritis. Palatal or pharyngeal paralysis (or both) occurs during the acute phase; peripheral neuritis, symmetrical and predominantly motor, occurs 2–12 weeks after onset of the disease. Motor deficit may range from minor proximal weakness to complete paralysis. Complete recovery is the rule. Other complications include otitis media and respiratory insufficiency due to airway obstruction, especially in infants.

The goals of treatment are to neutralize the toxin rapidly, eliminate the infecting organism, provide supportive care and prevent further transmission. The mainstay of therapy is equine diphtheria antitoxin and should be administered based on clinical grounds. A single dose ranging in quantity from 20,000 units for localized tonsillar diphtheria up to 100,000 units is given for extensive disease with severe toxicity. Antitoxin may be administered intramuscularly or intravenously; particularly for more severe cases, the intravenous route is preferred. Tests for sensitivity to antitoxin should be performed before administering it and desensitization carried out if necessary. Antibiotic therapy should be started simultaneously. Parenteral penicillin (4–6 million units/day) or macrolides like erythromycin, clarithromycin and azithromycin are the drugs of choice. The antibiotic is given for 10–14 days. General supportive care includes ensuring a secure airway, electrocardiographic monitoring for evidence of myocarditis, treating heart failure and arrhythmias, and preventing secondary complications of neurologic impairment such as aspiration pneumonia. The patient should be in strict isolation until follow-up cultures are negative. Convalescing patients should receive diphtheria toxoid. The local health department must be notified. Close contacts should have cultures performed and be administered prophylactic antibiotics. All contacts without full primary immunization and a booster within the preceding 5 years should receive diphtheria toxoid. Antibiotic therapy is not a substitute for antitoxin therapy. Some patients with cutaneous diphtheria have been treated for 7–10 days. Elimination of the organism should be documented by negative results of at least two successive cultures of specimens from the nose and throat (or skin) obtained 24 hours apart after completion of therapy. Treatment with erythromycin is repeated if either culture yields C. diphtheriae.

u iza io a d

omplications

Management

u i y,

nonhealing ulcer with a gray-brown membrane. Diphthe ritic skin infections cannot always be differentiated from streptococcal or staphylococcal impetigo, and these conditions frequently coexist. In most cases, a primary process such as dermatosis, laceration, burns, bite, or impetigo becomes secondarily infected with C. diphtheriae. Extremities are more often affected than the trunk or head. Pain, tenderness, erythema, and exudate are typical. Local hyperesthesia or hypoesthesia is unusual.

Prevention Immunization with diphtheria toxoid is the only effective means of primary prevention. The primary series is four doses of diphtheria toxoid (given with tetanus toxoid and pertussis vaccine) at 6, 10, 14 weeks and 15–18 months; a preschool booster dose is given at 4–6 years of age. Thereafter, boosters (Td) should be given as part of the adolescent immunization visit (i.e. at 10 and 16 years of age), followed by doses administered every 10 years. Since 2005, the CDC recommends the routine use of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap), in adolescents 11–18 years of age in place of tetanus and diphtheria toxoid (Td) vaccines. In addition, the CDC recommends routine use of a single dose of Tdap for adults 19–64 years of age to replace the next booster 295 dose of Td.

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Although most infections with C. diphtheriae are asympto matic or run a relatively mild clinical course, high casefatality rates (>10%) have been reported even in recent outbreaks. In pre-vaccination era, diphtheria had a very high case fatality rate in the preschool children. With the widespread vaccination in both developed and developing countries, the incidence of diphtheria has decreased but there is also decrease in the circulating toxigenic C. diphtheriae organisms resulting in less natural boosting of antibody levels. Hence, if adequate booster dose is not given, the chances of outbreaks will be there, leading to increase case fatality rates. Hence the ideal public health policy should put efforts to reach at least 90% coverage with three doses of diphtheria toxoid in children below 1 year of age. In countries where

1. Bacteriological and epidemiological characteristics of diphtheria cases in and around Delhi -a retrospective study. Indian Journal of Medical Research. 2007;126(6):545-52. 2. Bitragunta S, Murhekar MV, Yvan J, et al. Persistence of diphtheria, Hyderabad, India, 2003–2006. Emer Infec Dis. 2008;14(7):1144-7. 3. Buescher  ES. Corynebacterium diphtheria. In: Kliegman RM, Stanton BF, Behrman RE (Eds). Nelson Textbook of Pediatrics, 18th edition. Philadelphia: WB Saunders; 2009. pp. 1153-7. 4. Centers for Disease Control and Prevention:  Respiratory diphtheria-like illness caused by toxigenic Corynebacterium ulcerans—Idaho, 2010. MMWR. 2011;60(3):77. 5. Clarridge JE, Popovic T, Inzana TJ. Diphtheria and other corynebacterial and coryneform infections. In: Hausler WJ, Sussman M (Eds). Topley and Wilson’s Microbiology and Microbial Infections, Vol. 3. New York: Oxford University Press; 1998. p. 347. 6. Galazka AM, Robertson SE. Diphtheria: changing patterns in the developing world and the industrialized world. Eur J Epidemiol. 1995;11(1):107-17. 7. Philip AM. Corynebacterium Diphtheria. In: Mandell GL, Bennette JE, Dolin R (Eds). Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, 7th edition. Philadelphia: Churchill Livingstone; 2009. pp. 2678-93. 8. World Health Organization. Diphtheria vaccine—WHO position paper. Wkly Epidemiol Rec. 2006;81:24-31.

Prognosis

ibliography





diphtheria has been successfully controlled, immunity levels should be maintained by booster doses.



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In countries that are rendered non-endemic through high immunization coverage, the primary vaccination series of three doses should be extended by at least one booster dose. Revaccination of adults against diphtheria (and tetanus) every 10 years may be necessary to sustain immunity in some epidemiological settings. Particular attention should be given to revaccination of healthcare workers. To further promote immunity against diphtheria, combined diphtheria toxoid and tetanus toxoid rather than tetanus toxoid alone should be used when tetanus prophylaxis is needed following injuries.

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It is observed that the frequency of pertussis cases in India is higher during the months of November to June.

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seases

Bordetella pertussis and Bordetella parapertussis cause whooping cough. Bacteria spread via aerosolized droplets from coughing of infected individuals. Transmission can occur through direct face-to-face contact, sharing a confined space, or through contact with oral, nasal, or respiratory secretions from an infected source. The organism damages ciliated respiratory epithelium. Bronchopneumonia deve lops with desquamation of the epithelium of small bronchi, causing bronchiolar obstruction and atelectasis. Bronchiectasis may develop and persist. The global incidence is estimated at 48.5 million cases and 295,000 deaths annually. The case-fatality rate among infants in low-income countries may be as high as 4%. Neither natural infection, nor vaccination provides lifelong immunity. Protection against pertussis wanes 3–5 years after vaccination and is not detected after 12 years. Since the 1980s, incidence has cyclically increased, and peaks occur every 2–5 years. From 1980-2005, the reported incidence of pertussis in the US dramatically increased across all age groups. Although the largest increase has been among adolescents and adults, the annual reported incidence remained highest among infants less than one-year-old, at 55.2 cases per 100,000 population. There is also a shift in the epidemiology of pertussis, with more cases being reported in older age groups, which is due to waning immunity to Bordetella pertussis, a number of years after immunization. Adolescents and adults have been identified as the source of pertussis transmission to infants. Infectious disease experts are investigating means of preventing disease transmission to infants. Options include vaccination of adolescents and adults in close contact with infants, maternal vaccination to provide passive antibody protection to the infant, and vaccinating infants with pertussis vaccine at birth.



pidemiology



E

Pertussis, or whooping cough, is an infection of the respiratory tract characterized by a paroxysmal cough. Before the availability of a vaccine, pertussis was the major cause of morbidity and mortality among infants and children. In 1940s, vaccination reduced reported cases of pertussis by more than 99%. However, pertussis still remains a disease of public health concern.

Typically, the incubation period of pertussis ranges from 3 days to 12 days. It is an illness lasting 6 weeks and goes through catarrhal, paroxysmal, and convalescent stages, each lasting from 1 week to 2 weeks. The catarrhal phase is similar to common upper respiratory infections with nasal congestion, rhinorrhea, sneezing, conjunctival injection and discharge. While most infectious in the catarrhal phase, pertussis may remain communicable for 3 or more weeks after the onset of cough. Paroxysmal phase presents with paroxysms of intense coughing lasting up to several minutes. In older infants and toddlers, the paroxysms of coughing may be followed by a loud whoop as inspired air goes through a still partially closed airway. Infants younger than 6 months have apneic episodes and are at risk for exhaustion. Facial congestion with coughing and posttussive vomiting are common symptoms. Patients in the convalescent stage have a chronic cough, which may last for weeks. Uninterrupted coughing, feelings of suffocation or strangulation, and headaches may be seen in older children, and adolescents, instead of the distinct stages. Physical examination contributes little to the diagnosis in patients with uncomplicated pertussis. Fever is typically absent. Most patients do not have signs of lower respiratory tract disease. Conjunctival hemorrhages and facial petechiae result from intense coughing. Premature infants and patients with underlying cardiac, pulmonary, neuromuscular, or neurologic disease are at high risk for complications of pertussis (e.g. pneumonia, seizures, encephalopathy, and death). Older children, adolescents, and adults often have mild or atypical illness. Approximately one-half of adolescents with pertussis cough for 10 weeks or longer. Complications among adolescents and adults include syncope, sleep disturbance, incontinence, rib fractures, and pneumonia. Infants less than 6 months old are more likely to have severe disease, to develop complications, and to require hospitalization. Pneumonia occurs in approximately 13% of infants with pertussis either from B. pertussis infection or from secondary infection with other pathogens. Rarer, CNS complications such as seizures and encephalopathy are thought to result from severe paroxysm-induced cerebral hypoxia and apnea, hypoglycemia and small intracranial hemorrhages. Reported deaths in young infants have increased considerably over last 20 years. From 1990-1999, the case fatality rate was approximately 1% in infants younger than 2 months and less than 0.5% in infants aged 2–11 months. Males and females are equally affected. The conditions that should be differentiated from pertussis include afebrile pneumonia syndrome, bronchiolitis, chlamydial infections, mycoplasma infections and respiratory syncytial virus infection. 297

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Pertussis

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observed paroxysms are not severe; premature infants; and infants or children with underlying pulmonary, cardiac, or neuromuscular disease. Vitals and oxygen saturation of hospitalized patients should be monitored continuously, especially in relation to coughing paroxysms. Attention should be paid the young infant’s hydration and nutritional status. Patients who are severely ill may require treatment in an ICU. The use of corticosteroids and β2-adrenergic agents for the treatment of pertussis is not supported by current evidence.

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Laboratory confirmation of pertussis is difficult and delayed. Therefore, typical symptoms along with history of incom plete or absent pertussis vaccination, and lymphocytosis help in making a presumptive diagnosis of pertussis. Leukocytosis (15,000–50,000/µL) with absolute lympho cytosis occurs during the late catarrhal and paroxysmal phases and correlates with severity of the disease. A confirmed case is defined as one with any cough illness in which B. pertussis is isolated and cultured, or a case with typical symptoms confirmed by PCR or epidemiologic linkage to a laboratory-confirmed case. Specimen for culture is obtained by deep nasopharyngeal aspiration and inoculation in Bordet-Gengou agar, Regan-Lowe or modified Stainer-Scholte media causes growth in 3–4 days. Recovery of organisms is highest during catarrhal and early paroxysmal stages. Previously immunized or antibiotic treated patients may produce a negative culture; however, this does not exclude the diagnosis of pertussis. PCR assay and antigen detection are very sensitive, provide results rapidly, and can be used later in the disease course or after antimicrobial therapy, because the tests do not rely on the isolation of viable organisms. Serologic tests are currently available for investigational use only. Imaging studies typically add little to the diagnosis of pertussis. Chest roentgenogram may reveal perihilar infiltrates or edema with variable degrees of atelectasis. Consolidation is indicative of secondary bacterial infection or, rarely, pertussis pneumonia. Occasionally, pneumothorax, pneumomediastinum or air in the soft tissues may be seen.

Prevention Administration of the vaccine containing cellular and acellular components stimulates the production of antibodies with specific protective properties. All children less than 7 years of age should receive the pertussis vaccine either DTP or DTaP. Adolescent 11 through 18 years of age should receive a single dose of Tdap. The preferred age of Tdap is 11 through 12 years of age.

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Management aims at limiting the number of paroxysms, providing assistance when necessary, and maximizing nutrition, rest, and recovery. The mainstay therapy in patients with active pertussis infections is supportive. Antibiotics initiated during the second stage do not affect the duration and severity of illness, but can hasten the eradication of B. pertussis and help preventing spreadness. For patients aged 1 month or older, macrolides such as erythromycin (40–50 mg/kg/day in four divided doses for 14 days), clarithromycin (15–20 mg/kg/day in two divided doses for 5–7 days), and azithromycin (10–12 mg/kg/day once a day for 5 days) are the preferred agents. Azithromycin is the recommended agent in the youngest patients. Patients older than 2 months with hypersensitivity to macrolides may be treated with trimethoprim-sulfamethoxazole (8 mg/kg/day and 40 mg/kg/day in two divided doses for 5–7 days). Most patients older than 1 year can be treated on an outpatient basis. Frequent reviews are necessary based on patient’s age, disease severity and presence of co-morbid conditions. Hospitalization should be advised for patients at risk of severe disease and complications, including infants younger than 3 months; infants aged 3–6 months, unless

1. American Academy of Pediatric Committee on Infectious Diseases. Prevention of pertussis among adolescents: recommendations for use of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine. Pediatrics. 2006;117(3):965-78. 2. American Academy of Pediatrics. Pertussis. In: Pickering LK (Ed). Red Book: 2006 Report of the Committee of Infectious Disease; 2006. pp. 498-520. 3. Centers for Disease Control and Prevention. Preventing tetanus, diphtheria, and pertussis among adults: use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine. Morb Mortal Wkly Rep. 2006;55:1-33. 4. Centers for Disease Control and Prevention. Pertussis--United States, 1997-2000. Morb Mortal Wkly Rep. 2002;51(4):73-6. 5. Cherry JD, Heininger U. Pertussis and other Bordetella infections. In: Feigin RD, Demmler GJ, Cherry JD, Kaplan SL (Eds). Textbook of Pediatric Infectious Diseases, Vol. 1, 5th edition. Philadelphia, PA: WB Saunders; 2004. pp. 1588-608. 6. Edwards K, Decker MD. Pertussis vaccine. In: Plotkin SA, Orenstein WA (Eds). Vaccines, 4th edition. Philadelphia, PA: Saunders; 2004. pp. 471-528. 7. Mikelova LK, Halperin SA, Scheifele D, et al. Predictors of death in infants hospitalized with pertussis: a case-control study of 16 pertussis deaths in Canada. J Pediatr. 2003;143(5):576-81. 8. Tiwari T, Murphy TV, Moran J. Recommended antimicrobial agents for the treatment and postexposure prophylaxis of pertussis: 2005 CDC Guidelines. MMWR Recomm Rep. 2005;54:1-16. 9. Vitek CR, Pascual FB, Baughman AL, et al. Increase in deaths from pertussis among young infants in the United States in the 1990s. Pediatr Infect Dis. 2003;22(7):628-34. 10. Zhang L, Prietsch SO, Axelsson I, et al. Acellular vaccines for preventing whooping cough in children. Cochrane Database Syst Rev. 2011;CD001478.

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anifestations

The incubation period of tetanus is around 10 days (range 3–30 days). On the basis of clinical findings, three different

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eonatal etanus

This typically occurs when the umbilical cord is cut with an unsterilized instrument and manifests within 3–12 days of birth. It is generalized tetanus, a serious condition and often fatal. Progressive difficulty in feeding (sucking and swallowing) with associated hunger and crying are generally seen. Paralysis and diminished movement, stiffness to touch, spasms with or without opisthotonus are the clinical features. Opisthotonus may be extreme or sometimes absent.

Localized etanus T

The causative organism Clostridium tetani is a Gram-positive, anaerobic, spore forming organism. It forms terminal spores resembling drumsticks. The spores are resistant to boiling, usual antiseptics and chemical agents like phenol. They can survive autoclaving at 121°C for 10–15 minutes. Clostridium tetani usually enters the body through wound. The bacilli itself is noninvasive. The spores germinate in anaerobic conditions. They produce two types of toxins: tetanospasmin and tetanolysin. Of these, tetanospasmin is a neurotoxin and is responsible for the clinical signs and symptoms of the disease. Toxins act at several sites within the nervous system.

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tiology

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V d

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It is usually present with a descending pattern. The first sign most of the time is trismus or lockjaw due to spasm of masseter muscle. Headache, restlessness and irritability may be early symptoms followed by stiffness of the neck, difficulty in swallowing and rigidity of abdominal muscles. The spasms can be precipitated by bright light, noise and even touch. The rigidity of facial muscles leads to the sardonic smile of tetanus or risus sardonicus, a typical grinning appearance. Rigidity and spasm of back and abdominal muscles causes arching (opisthotonus). Laryngeal and respiratory muscle spasm can lead to airway obstruction and asphyxia. Constipation and retention of urine may also occur. Hyperpyrexia, hypertension, excessive sweating, tachycardia and cardiac arrhythmia can occur due to sympathetic nerve involvement. Paralysis is evident in the first week, stabilizes in second week and ameliorates in the next 1–4 weeks.

seases

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pidemiology

Tetanus occurs worldwide and is an important cause of neonatal death in developing world. The causative organism C. tetani is part of the normal flora in human and animal intestines and is disseminated through the excreta and found in soil and dust. In spore form they are hard and long lasting in soil and dust. As the spores of C. tetani are ubiquitous, wound contamination is unavoidable. The contamination of wound, unhygienic and improper handling of the umbilical cord in newborns, lack of hygienic habits and aseptic care during and after delivery in women are the main risk factors for infection. Tetanus can occur in a child having chronic ear discharge. It is the only vaccine preventable disease that is infectious but not contagious from person to person. Among the burden of vaccine preventable diseases world over, tetanus ranks fourth with 13% disease burden. The incidence is high in tropical countries with humid climate. According to WHO in 2009 global reported cases were 9,836 and estimated deaths in children <5 years were 61,000. The reported cases of tetanus in India in 2006 were 2587, of which 600 cases were neonatal tetanus. More cases are reported from rural than urban areas.

C

Generalized etanus

This is painful spasms to the site of infection precede generalized tetanus. Cephalic tetanus with bulbar muscle involvement is seen with wounds of the head, face, nostrils or with chronic otitis media. Retracted eyelids, deviated gaze, trismus, risus sardonicus, spastic paralysis of the tongue and pharyngeal muscles are the presenting features. D

E

Tetanus historically called ‘Lockjaw’ is an acute often fatal, severe exotoxin-mediated infection caused by Clostridium tetani. Rosenbach in 1886 demonstrated for the first time these slender bacilli. The disease first described by Carlie and Rattone is characterized by severe muscular spasms or acute spastic paralysis, is caused by the action of a potent neurotoxin produced during the growth of the bacteria in dead tissues.

i

forms of tetanus have been described: • The most common type (80%) is “generalized tetanus”. • “Localized tetanus” produces pain and spasm of the muscles in proximity to the site of injury. Occasionally this form of disease may precede generalized form. • “Cephalic tetanus” is a rare form of the disease seen in children with otitis media.

Introduction

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etanus

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iagnosis

Diagnosis is mainly clinical. The typical setting is an injured unimmunized patient or baby born to an unimmunized 299 mother presenting within 2 weeks with trismus, rigid muscles and clear sensorium. The organism can be isolated from wound or ear discharge. vip.persianss.ir



related injuries, rhabdomyolysis, myoglobinuria, bone fractures and renal failure.



Aspiration of secretions leading to pneumonia is one of the major complications. Autonomic system irregularities in the form of cardiac arrhythmias, asystole, and labile blood pressure may be noted. Few children may get seizure





1. Arnon SS. Tetanus. In: Kliegman RM, Jenson HB, Behrman RE, Stanton BF (Eds). Nelson Textbook of Pediatrics, 18th edition. Philadelphia: Elsevier; 2007. pp. 1228-30. 2. Centers for Disease Control and Prevention. Diphtheria, tetanus and pertussis: recommendations for vaccine use and other preventive measures. MMWR. 1991;40:1-28. 3. Epidemiology and Prevention of Vaccine-Preventable Diseases, 10th edition. Department of Health and Human Services CDC; 2007. 4. World Health Organization. The “high risk” approach: the WHO – recommended strategy to accelerate elimination of neonatal tetanus. Wkly epidemiol Rec. 1996;71:33-6.



ibliography



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Tetanus is an entirely preventable disease. Active immunization is the best method to prevent tetanus. All children should be immunized with three doses of DPT at 6, 10 and 14 weeks followed by booster doses at 18 months and 5 years of age. Boosters should be given at 10 years and then every 10 years. Td or Tdap is the vaccine of choice above 7 years of age. Neonatal tetanus could be prevented by immunizing the pregnant women with two doses of tetanus toxoid (preferably Td) between 16 weeks and 36 weeks of pregnancy, and with only one dose of Td in the subsequent pregnancies.



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The average mortality of tetanus is 45–55%. For neonatal tetanus the mortality is 60–70%. The most important factor influencing outcome is supportive care. Recovery from tetanus does not confer immunity; therefore active immunization of the patients following recovery is imperative.

V d

ti e

Wound anagement All wounds should be cleaned, necrotic tissue and foreign material should be removed. As shown in Table 5.27.1, wounds which are not minor require human TIG except those in fully immunized patients. In patients with history of unknown or incomplete immunization, crush, puncture or bone projecting wounds, wounds contaminated with soil, saliva or feces, avulsion injuries, compound fractures, 250 units of TIG should be given IM. In cases where the wound could not be properly debrided or wound more than 24 hours old, 500 units of TIG should be given. Tetanus toxoid may be administered immediately depending on the immunization status of the child.

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Prognosis



M

It comprises of wound debridement, immunoglobulin administration, antibiotics and supportive care. The aim of therapy is to neutralize all toxins, eradication of C. tetani and wound environment conducive to anaerobic multiplication and supportive care. Human tetanus immunoglobulin (TIG) 3,000–6,000 units IM is recommended to be given immediately. TIG has no effect on toxin which is already fixed to the neural tissue and does not penetrate the blood-CSF barrier. It can neutralize circulating tetanospasmin. If TIG is not available, human IVIG can be used. Antitetanus serum is recommended only when TIG is not available. It can be given in a single dose of 50,000–100,000 units, half the dose IM and the rest intravenously after skin test. Penicillin is the antibiotic of choice for C. tetani. Penicillin G 200,000 units/kg body weight can be given intravenously in four divided doses for 10–14 days. Local wound, discharging ears, umbilical cord should be cleaned and debrided if needed. All patients with generalized tetanus require muscle relaxant. Diazepam is preferred as it causes both muscle relaxation and seizure control. Initial dose is 0.1–0.2 mg/kg every 3–6 hours given intravenously. Midazolam, baclofen can also be used. The best survival rates with generalized tetanus are achieved with neuromuscular blocking agents like vecuronium and pancuronium. These drugs produce general flaccid paralysis which can be managed by mechanical ventilation. Meticulous nursing care is imperative. The patient should be kept in a quiet, dark environment with minimum auditory or visual stimuli. Maintenance of nutrition, fluid and electrolyte balance, suctioning of secretions and cardiorespiratory monitoring should be done. Provision for tracheostomy should be kept ready.

Table 5.27.1 Wound management Clean minor wounds All other wounds# History of tetanus TT/Td/ TIG TT/Td/ TIG* toxoid doses Tdap Tdap Unknown, Yes No Yes Yes Less than three doses, Immunocompromised More than three doses No** No No*** No # Including, but not limited to, wounds contaminated with dirt, feces, soil, saliva; puncture wounds; avulsions; and wounds resulting from missiles, crushing, burns, and frostbite. *TIG: Tetanus immunoglobulin (250–500 units IM). **Yes, if more than 10 years since last dose. ***Yes, if more than 5 years since last dose.



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Rickettsial iseases in India





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Fever of undetermined origin is the most frequent presen tation of rickettsial disease. Fever is usually abrupt onset, high grade, sometimes with chills, occasionally with morning remissions and associated with headache and myalgia. In fact diagnosis of rickettsial disease should always be considered in patients with acute febrile illness accompanied with headache and myalgia, particularly in endemic areas with history of tick exposure or contact with dogs.

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Early signs and symptoms of these infections are notoriously nonspecific and hence high index of suspicion is of paramount importance for their early diagnosis. Various clinical features of rickettsial infections are as follows:

Rickettsial diseases have a global distribution (except Antarctica) and recent reports suggest their continuing presence in India as well. The presence of rickettsial disease in India has been documented in Jammu and Kashmir, Himachal Pradesh, Uttaranchal, Rajasthan, Assam, West Bengal, Maharashtra, Kerala and Tamil Nadu. Recent studies from western Maharashtra and central India have documented that Rickettsial diseases are an important reemerging infections in India.

Family Rickettsiae comprises three genera namely Rickettsia, Orientia and Ehrlichia. Former members of this family, Coxiella burnetii which causes Q fever and Rochalimaea quintana causing trench fever have been excluded because the former is not primarily arthropod-borne and the latter not an obligate intracellular parasite. Various members of this family can be grouped into four biogroups as shown in Table 5.28.1 based on the lipopolysaccharide group antigen. Man is an accidental host except for louse borne epidemic typhus caused by Rickettsia prowazekii. Transmission to humans occurs by infected arthropod vector or exposure to infected animal reservoir host. Vector to human transmission occurs as vector defecate while feeding (flea feeding

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Family Rickettsiae comprises a group of microorganisms that phylogenetically occupy a position between bacteria and viruses. Rickettsia are small, nonflagellate, Gram-negative pleomorphic cocco-bacilli adapted to obligate intracellular parasitism and transmitted by arthropod vectors like fleas, ticks, mites and lice.

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reflex) so that feces contaminates pruritic bite wounds (seen with typhus fever group) or primarily by bite, where regurgitation of infected saliva occurs during feeding (seen with spotted fever group and scrub typhus). Vasculitis is the basic pathogenetic mechanism and is responsible for skin rash, microvascular leakage, edema, tissue hypoperfusion and end-organ ischemic injury.

Introduction

tiopathogenesis

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Narendra Rathi

Headache and Myalgia Severe frontal headache and generalized myalgia especially in muscles of the lumber region, thigh and calf is seen in variable proportion of cases.

Rash Though rash is considered as hallmark of rickettsial disease, it is neither seen at presentation nor in all the patients. Thus it should be remembered that spotted fevers could be spotless too! Rash usually becomes apparent after 3–5 days

 

Table 5.28.1 Biogroups of Rickettsia S.No. Biogroup Disease 1 Spotted fever Rocky mountain spotted fever (RMSF)

2

3 4

Typhus

Scrub typhus Miscellaneous

Vector Tick

Organism Rickettsia rickettsii

Rickettsial pox Indian tick typhus/Boutonneuse fever/Mediterranean spotted fever (MSF) Epidemic louse borne typhus

Mite Tick Louse

Rickettsia akari Rickettsia conorii Rickettsia prowazekii

Brill-Zinsser disease (recrudescent typhus) Endemic/Murine flea borne typhus Scrub typhus Ehrlichioses and anaplasmosis TIBOLA (tick borne lymphadenopathy) DEBONEL (Dermacentor borne necrosis-eschar-lymphadenopathy)

Louse Flea Chigger Tick Tick Tick

Rickettsia prowazekii Rickettsia typhi Orientia tsutsugamushi Ehrlichia, Anaplasma Rickettsia slovaca Rickettsia slovaca

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necrotic area, resembles the skin burn of cigarette butt (Fig. 5.28.3). A necrotic eschar usually has an erythematous rim and is associated with regional lymphadenopathy.

Generalized Lymphadenopathy and Hepatosplenomegaly It is found in majority of scrub typhus patients.

Systemic Features

Eschar

­

Clinical features referable to various systems are sometimes seen in rickettsial infections. Gastrointestinal symptoms like nausea, vomiting, abdominal pain and diarrhea are seen with varying frequency. Constipation is seen particularly in epidemic typhus. Respiratory symptoms like cough and distress are sometimes seen. Neurological manifestations like dizziness, drowsiness, disorientation, tinnitus, photophobia, delirium, meningismus, and visual disturbances are seen more commonly with typhus group infections.

Periorbital edema, conjunctival hyperemia, epistaxis, acute reversible hearing loss and arthralgia are sometimes reported. M

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Clinical laboratory findings include normal to low total leukocyte count, during early course of the disease with marked shift to left, low platelet counts and high erythrocyte sedimentation rate. There may be hyponatremia, hypoalbu minemia and raised hepatic transaminases. Serological diagnosis is difficult during the acute stage of the disease as definite diagnosis usually requires examination of paired serum samples after convalescence. Most common serological test for confirmed diagnosis is indirect immunofluorescence assay, but not until the second week of the disease diagnostic titer is detectable.

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A necrotic eschar at the inoculating site is seen in variable proportion of Indian tick typhus, scrub typhus and rickettsialpox cases. The site of initial tick bite is inapparent in other rickettsial infections. Eschar, a black

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of onset of symptoms. Initially rash is in the form of pink, blanching, discrete macules which subsequently becomes maculopapular, petechial or hemorrhagic. Sometimes palpable purpura (typical of vasculitis) is seen (Fig. 5.28.1). Occasionally petechiae enlarge to ecchymosis and gangrenous patches may develop. Rarely gangrene of digits (Fig. 5.28.2), earlobes, scrotum, nose or limbs may develop secondary to vasculitis and thrombosis. Distribution of rash is initially on the extremities near ankles, lower legs and wrists. Thereafter rash spreads centripetally to involve whole body. Presence of rash on palms and soles, considered so typical of rickettsial disease, can be seen in other diseases like infective endocarditis, syphilis, meningococcemia, enteroviral diseases and adverse drug reactions. The rash of typhus group infections is quite atypical, initially appearing on trunk, spreading centrifugally and usually sparing palms and soles.

Figure 5.28.2 Pedal edema with gangrenous changes in toes  

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Figure 5.28.3 Eschar near medial canthus of right eye  

 

Figure 5.28.1 Palpable purpuric rash

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Prevention

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1. Edwards MS, Feigin RD. Rickettsial and Ehrlichial diseases. In: Feigin RD, Cherry JD, Demmler-Harrison, Kaplan SL (Eds). Textbook of Pediatric Infectious Diseases, 6th edition. Philadelphia: Saunders Elsevier; 2009. pp. 2669-83. 2. Rathi N, Rathi A. Rickettsial infections: Indian perspective. Indian Pediatr. 2010;47:157-64. 3. Rathi NB, Rathi AN, Goodman MH, et al. Rickettsial Diseases in Central India: Proposed Clinical Scoring System for Early Detection of spotted fever. Indian Pediatr. 2011;48(11):86772.







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Avoiding tick bites, limiting exposure to tick habitats, inspecting the body carefully for ticks after being in a tick habitat and removing attached ticks immediately by grasping with tweezers close to skin and pulling gently with steady pressure are various means of prevention. Antibiotic prophylaxis after tick bite is usually not beneficial.

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Definitive treatment should be instituted on the basis of clinical and epidemiological clues as early as possible to avoid severe disease and fatal outcome. Various antibiotics useful for treating different rickettsial diseases are tetracyclines preferably doxycycline, chloramphenicol, macrolides (especially azithromycin, clarithromycin, and roxythromycin) and fluoroquinolones (especially ciprofloxacin, ofloxacin, pefloxacin, and levofloxacin). Doxycycline is the drug of choice. Dose is 5 mg/kg/day in two divided doses for children below 45 kg and 200 mg/day in two divided doses for children above 45 kg. Duration of therapy should be minimum 5–7 days or at least 3 days after defervescence. It can be used for treatment of rickettsial diseases in children below 8 years of age as tooth discoloration is dose dependent. Chloramphenicol should be used in case of doxycycline allergy (50–100 mg/ kg/day every 6 hours IV, maximum 3 g/day).

Respiratory (interstitial pneumonitis and ARDS), neurologic (meningoencephalitis), renal (acute renal failure), dissemi-

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Untreated cases can have fatality rates as high as 30–35%, but when diagnosed early, they are often easily treated and carry extremely good prognosis.

reatment

omplications

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Prognosis



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nated intravascular coagulation, hepatic failure, gangrene and myocarditis are various complications seen in rickettsial infections.

Immun ty, Immun zat on and Infect ous

Blood or tissue samples can be tested for rickettsial nucleic acid by PCR, but it is relatively insensitive as the level of rickettsemia is very low. As no clinical or laboratory clues are specific for early diagnosis, diagnosis should be made with compatible clinical presentation, history of tick exposure, epidemiological data, suggestive laboratory parameters and rapid defervescence with appropriate antibiotics.

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Leprosy

as the most common mode of entry of leprosy bacilli into the contact person. After inhalation, these inhaled leprosy bacilli enter the respiratory system from where they are disseminated by blood to skin and peripheral nerves where depending on the host immune response, the disease may manifest either as tuberculoid leprosy (where there is good cell mediated immune response to Mycobacterium leprae) or may manifest at lepromatous leprosy (where there is anergy to M. leprae). Other portals of entry include scratched, abraded or insect bitten skin which facilitates passage of organism via the droplets laden with leprosy bacilli through the epidermis into the dermis, and ingestion of infected breast milk.

ntroduction

Leprosy, also known as Hansen’s disease, is a chronic granulomatous disease caused by Mycobacterium leprae. It particularly affects the skin and nerves besides affecting all the organs.

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The only source of infection is the infected human being. The capacity of multibacillary leprosy patients to infect is 4–11 times that of patients with paucibacillary leprosy.

irect Transmission

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ncubation Period

This varies from a few months to as long as 20 years with an average between 2 years and 5 years. Onset of this disease is usually gradual but may be sudden in highly susceptible people. D

arly igns of the isease

The early signs include: A hypopigmented patch in the skin, present for a long duration, non irritating with loss of sensation to touch, pain and temperature. • Thickening of the skin, more red and shiny in appear­ ance than the surrounding parts; this is more promi­ nent on face and hands. • Loss of sensation, numbness, feeling of “pins and needles” or “crawling of ants”, tingling sensation in any part of the body, especially in hands and feet. There may be paresis in hands and feet or difficulty in fine movements of fingers. • Appearance of spontaneous blisters and ulcers, espe­ cially in the fingers. -

•

lassification



For direct transmission, a prolonged and close contact is required. An ‘intrafamilial’ contact with a patient is more risky than an ‘extrafamilial’ one. Untreated lepromatous patients discharge as many as 304 100 million bacilli from their nasal secretions everyday. These bacilli remain viable outside the human body for several days. Inhalation of these bacilli, via droplets, is now regarded

linical Manifestations

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S

ource of nfection and Mode of Transmission

Mycobacterium leprae remains viable for several days outside the human body. Occasionally, leprosy may spread by fomites being used by a patient suffering from multibacillary leprosy. Localized infections via infected syringes and tattooing needles have been reported.

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According to the “WHO Global Leprosy Situation 2010”, out of a total of 211,903 registered cases of leprosy in the world, 87,190 reside in India. All the countries of SEAR have now achieved the elimination target of less than 1/10,000 population. India achieved the leprosy elimination target at the end of 2005. Though the total number of registered cases of leprosy came down to 87,190 in 2010 in India, the new case detection rate did not reduce concomitantly. Pediatric leprosy constitutes about 10% of the total disease burden. The age group most commonly affected in the pediatric leprosy population is 5–14 years, though in very high endemic countries, prevalence in age groups 0–4 years is also significant. Leprosy affects males more then females. It is not a hereditary disease and it was found that infants born to leprous parents, if separated soon after birth and protected from the exposure, escaped from the disease. HIV infection has not been documented to alter the risk of leprosy in areas of high prevalence. Achieving eradication of the disease from the elimi­ nation stage is a giant task. It requires the cases to be identified at an early stage and treated promptly so that deformity and spread of infection can be prevented. For the diagnosis of early and suspicious cases of leprosy newer diagnostic concepts of molecular biological approaches like PCR, in situ PCR and in situ hybridization have evolved and are the need of the time.



pidemiology

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5.29

According to the classification laid down by Indian Association of Leprologists, the cases have been divided into five broad groups, viz. indeterminate, borderline,

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) Leprosy

orderline Lepromatous ( L) Leprosy

In borderline lepromatous leprosy there are a large number of asymmetrically distributed lesions which are heterogeneous in appearance. Macules, papules, plaques

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B

In this subtype, the lesions are more numerous and heterogeneous. The lesions may become confluent or even plaques may be present. The borders are poorly defined and the erythematous rim fades into the surrounding skin. Hyperesthesia is more common than anesthesia.

euritic Leprosy

This may be of primary or secondary variety. In the former, the nerves are directly infected without any skin lesion while in the latter infection spreads up the nerves from leprous skin lesions. The affected nerves become thickened and tender, producing sensory motor and trophic changes in their areas of distribution. This dysfunction leads to deformities, neuropathic ulcers and lagophthalmos which may result in serious eye complications. Neuritic leprosy most commonly involves the ulnar, median, lateral popliteal, tibial, great auricular and rarely radial nerves. It also affects the V and VII cranial nerves. R

B

Mid orderline (

BB

Here the lesions are greater in number but smaller in size than in tuberculoid leprosy. There may be small satellite lesions around older lesions and the margins of the borderline tuberculoid lesions are less distinct and the center is less atrophic and anesthetic. This form usually involves thickening of two or more superficial nerves.



B

orderline Tuberculoid ( T) Leprosy

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Borderline leprosy is further classified into three subtypes, on clinical and histological criteria.

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orderline Leprosy

The nasal symptoms chiefly constitute, stuffiness, crust formation and blood stained discharge. Edema of legs and ankles is always bilateral, usually prominent late in the evening and disappears after overnight rest. Skin lesions may take the form of macules, papules, nodules and a combination of them. Numerous symme­ trically distributed erythematous or coppery, shiny, macules with ill defined margins are usually the first ones to appear. Patients may have a leonine facies due to loss of eyebrows and eyelashes. There is no sensory impairment in these lesions but as the disease progresses many peripheral nerves get symmetrically affected. Due to enormous bacillary infiltration, nerves are initially softer and larger than normal and are tender. In advanced cases, nerves become thin and hard due to fibrosis and result in extreme anesthesia. The skin smear is almost always positive and the lepromin test is negative. This form of lepromatous leprosy (LL) is the most infectious, prone to lepra reactions and if left untreated, the prognosis is poor. The features of lepromatous these varieties of leprosy are summarized in Table 5.29.1. As age advances, the disease moves from tuberculoid end of the spectrum towards the lepromatous end.

uniza ion and nfec ious iseases

Most cases of lepromatous leprosy develop from borderline leprosy (BB or BL). This form of leprosy is relatively uncommon in the pediatric age group. There are two symptoms, which may precede the classical skin lesions by months or years, and serve to alert the physician to a possible early diagnosis. They are: • Nasal symptoms • Edema of legs

Tuberculoid Leprosy It is characterized by the presence of single or few asymmetrical, well defined, hypopigmented, erythematous or copper colored patches with sensory impairment. The entire patch or only its margins is raised above the level of the surrounding skin. At times, these patches may not be raised above the level of the surrounding skin. Initially, a single nerve trunk related to the lesions is affected. The nerve trunk becomes enlarged, hard, and tender and later may form a nerve abscess. In this form of leprosy, the lepromin test is positive and there is absence of bacilli in the skin smear. On biopsy, foci of lymphocytes, epithelioid cells and Langhan’s giant cells are seen. This form of leprosy is the most common, especially in children, and is relatively benign and stable with a good prognosis.

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Lepromatous Leprosy (LL)

This type of leprosy is seen in only 10–20% of infected individuals and is the earliest detectable form of leprosy. This is characterized by presence of a single hypo­ pigmented macule measuring 2–4 cm in diameter, with a poorly defined border without any erythema or induration. Anesthesia may be minimal or even absent. Biopsy may show a granuloma but bacilli are rarely seen in the section. In 50–75% of patients, this lesion heals spontaneously, and in the remaining cases it gradually progresses to one of the classic forms.

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ndeterminate Leprosy

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and nodules may all co exist. Usually, the individual lesions are small unless confluent. Anesthesia is mild and superficial nerve trunks are spared.

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tuberculoid, lepromatous and polyneuritic. The borderline group is further subdivided into BB, BL and BT types.

eactions

Reactions are acute exacerbations due to changes in the host parasite immune relationship. They are common during 305 initial years of treatment. The following types are noted:

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Type 1

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Serological Assays

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F

Specific serological tests can detect subclinical infection. The major serological assays include: 1. luorescent leprosy antibody absorption test ( L ): This technique is highly sensitive in detecting the antibodies against M. Leprae antigen by immune fluorescent technique and is useful in identifying healthy contacts of patients who are at risk of developing disease. 2. adioimmunoassay ( ): It detects antibodies to the cell wall antigen of M. Leprae. RIA

R

In some cases of indeterminate lesions it becomes necessary to carry out a histological examination for the purpose of diagnosis and classification of the lesion.



Histopathology

-

ABS

-

Sites of bacteriological examination are usually from the most affected parts of the lesion. If no definite patches or areas of thickened skin are visible, smear should be taken from ear lobules and buttock. Smears should be made by “slit and scrape” method and stained by Ziehl Neelsen staining. Smears are positive in LL, BL and some BB and BT cases. It is of limited help in TT and indeterminate lesions and patients with early atypical clinical presentation.



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mear xamination

Lepromin test: Lepromin test is not a diagnostic test for leprosy but is has been found to be useful for classifying the disease. This test is positive in cases of TT and BT, negative in LL, BL and weakly positive and variable in BB leprosy. The lepromin negative contacts have been found to be a much higher risk of developing disease, than the lepromin positive contacts. This test signifies cell mediated immunity of a person, against or its antigen. Two kinds of lepromin are commonly used: 1. Crude antigen of Mitsuda. 2. The refined antigen of Dharmendra.

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Test for Cell Mediated Immunity

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ti e

Diagnosis of leprosy is based on the presence of any one of the following cardinal signs: • Characteristic skin lesion with partial or total loss of sensation in the affected skin lesion or in the area of the skin supplied by the peripheral nerve involved, with or without the presence of thickened nerves. • Presence of acid fast bacilli in the skin smear.

mmunological Methods



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iagnosis

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Type 2 rythema nodosum leprosum ( L) reactions: This occurs in lepromatous and borderline lepromatous cases as a systemic inflammatory response. There is high fever, migrating polyarthralgia, orchitis, iridocyclitis and lymphadenitis. Tender red papules or nodules resembling erythema nodosum are seen characteristically.

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It is a semi quantitative estimation of the density of bacilli present in the skin smears and biopsies and is measured on two scales, namely the Dharmendra scale and Ridley scale. It measures the total acid fast bacilli in microscopic field, which includes both live and dead bacilli. Patients are labeled as having paucibacillary infection when there are <5 skin lesions and no bacilli on skin smears. They are labeled as having multibacillary infection when there are >6 skin lesions and bacilli are present on skin smears. The bacterial index can range from 0 (No bacilli in 100 oil immersion field) to 6 (>1000 bacilli per field). -

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eversal reaction: This is seen in borderline cases and consists of acute tenderness and swelling at the site of lesion. Irreversible nerve injury can occur if this reaction is not treated immediately.

acillary ndex I

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Table 5.29.1 Clinical aspects of tuberculoid, borderline and lepromatous leprosy Types of leprosy Features TT BT BB BL LL Number of lesions Single usually Single or few Several Many Very many Size of lesions Variable Variable Variable Variable Small Surface of lesions Very dry, sometimes Dry Slightly shiny Shiny Shiny scaly Sensation in lesions Absent Markedly diminished Moderately diminished Slightly diminished Not affected Hair growth Absent Markedly diminished Moderately diminished Slightly diminished Not affected AFB in lesions Nil Nil or scanty Moderate numbers Many Very many (plus globi) AFB in nasal scrapings/ Nil Nil Nil Usually nil Very many (plus globi) in nose blows Lepromin test Strongly positive (+++) Weakly positive (+ or ++) Negative Negative Negative Abbreviations: AFB, Acid fast bacilli; TT, Tuberculoid; BT, Borderline tuberculoid; BB, Mid borderline; BL, Borderline lepromatous; LL, Lepromatous leprosy.

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Treatment of eactions

Drugs commonly used in these conditions are antimalarials like chloroquine (given orally), antimonials, e.g. potassium antimony tartrate IV and fantosin IM, clofazimine, corticosteroids and thalidomide (all the three given orally). Symptoms like iritis and neuritis occurring during reactions (or occurring independently) should be properly treated in order to avoid irreversible sequelae, i.e. deformities and neuropathic ulcers.

uration of Therapy

The WHO study groups has recommended treatment of paucibacillary cases for only 6 months and of multibacillary cases for 12 months. Table 5.29.2 Dosage of antileprosy drugs for children with paucibacillary leprosy (Indeterminate, TT, BT) Age group (Years) Dapsone: Daily dose Rifampicin: monthly unsupervised (mg) dose supervised (mg) 3–5 25 150–300 6–14 50–100 300–450 15 100 600  

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Another molecular biological approach is the utility of in situ PCR on the slit skin smears. It was found that with an average positivity of 72%, in situ PCR on slit skin smears was better than that on skin biopsies (60%). In addition it

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In Situ PCR on Slit Skin Smears

It is now a well known fact that, simultaneous administration of several different antibacterial agents may prevent the emergence of drug resistant mutants. The dosage schedule for children as recommended by the WHO is shown in Tables 5.29.2 and 5.29.3. In the MDT, it is assumed that clofazimine is acceptable for children and, therefore, no child will require ethionamide or prothionamide which are potent hepatotoxic drugs. Parents should be advised to give rifampicin on empty stomach and clofazimine with meals or with a glass of milk. Red staining of skin and lesions is very common with clofazimine.

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Multidrug Therapy (M T)

In Situ PCR

In situ hybridization uses a labeled complementary DNA/ RNA strand to localize specific DNA/RNA in a portion or section of tissue. In situ hybridization significantly enhances the diagnosis in early cases. It showed a positivity of about 42.8% in early (I/BT) and 46.7% in BB/BL group, thus enhancing the diagnosis by 18.1%.

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Leprosy patients should be treated with patience, perseverance and understanding. Besides the medical treatment, the patients and their parents need moral support and reassurance. Parents should be explained hygienic measures, proper diet and importance of taking treatment completely and regularly.

Identification of organisms can be done in a more rapid and specific way, both from culture and directly from clinical specimen, by recombinant DNA technology. Based on the gene sequences of M. Leprae, several probes have been designed in recent years. During the recent years, several gene amplification techniques (PCR) for amplifying M. Leprae specific sequences from variety of specimens have been published. These have been reported to be highly sensitive and specific.

In Situ Hybridization

uni y,

Management

Molecular iological pproaches

In situ PCR, also called slide PCR, is a method to run PCR directly on small tissue samples, tissue microarrays (TMA), or other small cell samples, rather than extracting DNA or RNA first, and then performing PCR, rtPCR, or qPCR from the extracted material. In situ PCR showed a positivity of 57.1% in early/localized form of leprosy (indeterminate/BT) and 61.5% in BB/BL group. When compared to histopathological examination, a significant enhancement of 15% in diagnosis was seen. Hence, it can be concluded that in situ PCR, with added advantages of providing structural correlates and concomitant study of tissue pathology, improves diagnostic yield in early doubtful cases of leprosy and when histopathology in non specific.

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has the added advantages of being minimally invasive and less cumbersome and can be performed even at sites from where skin biopsy is difficult.

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ISA

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nzyme-linked immunosorbent assay ( L ): PGL ELISA was found highly positive in multibacillary cases, but positivity in paucibacillary and subclinical cases was quite low. Further simplified dot ELISA and dipstick ELISA using a monoclonal antibody targeting PGL 1 have also been studied. Serological testing is not useful for diagnosis as it does not detect most paucibacillary cases and it remains positive even after treatment of multibacillary patients. 3.

Table 5.29.3 Dosage of antileprosy drugs for children with multibacillary leprosy (bb, bl, polyneuritic) Age groups Dapsone: daily dose Rifampicin: monthly Clofazimine (years) unsupervised (mg) dose supervised (mg) Unsupervised dose (mg) Monthly dose (mg) 3–5 25 150–300 100 once weekly 100 6–14 50–100 300–450 150 once weekly 150–200 15 100 600 50 daily 300

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The result of 5–9 years follow up study conducted on 120,000 randomized individuals in South Africa, indicate that BCG booster vaccination (two dose BCG regimen given at 0 and 3 months) provides 50–75% protection against leprosy. The combined BCG M. leprae vaccine offered no additional benefit. In order to accelerate the elimination of leprosy as a public health problem in India the following activities should receive high priority: 100% MDT coverage and accessibility, high treatment completion and cure rates and

1. Dayal R, Agarwal M, Natarajan M, et al. PCR and in situ hybridization for diagnosis of leprosy. Indian J Pediatr. 2007;74:645 8. 2. Dayal R, Singh SP, Mathur PP, et al. Diagnostic value of in situ polymerase chain reaction in leprosy. Indian J Pediatr. 2005;72:1043 6. 3. Leprosy. In: Park K (Ed). Textbook of Preventive and Social Medicine, 19th edition. Bhanot Publishers; 2007. pp. 264 76. 4. Powell DA. Hansen disease (Mycobacterium leprae). In: Kliegman, Behrman, Jenson, Stanton (Eds). Nelson Textbook of Pediatrics, 18th edition. Philadelphia: Elsevier Saunders; 2008. pp. 1255 8. 5. WHO Health Organization: Leprosy. Global situation. Wkly Epidemiol Rec. 2007;82:225 32. -

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There is no established vaccine against leprosy as yet.



Leprosy Vaccine



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inclusion of leprosy in the training curricula of the general health staff of all categories.

Prophylaxis

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anifestations

Pandemic H1N1 2009 infection, though milder than previous influenza pandemics and with less mortality, affected healthy young people more often than the elderly people. In India, 33% of cases were reported in 5–19 years of age group and 40% in 20–39 years of age group; seroepidemiology study done from Pune, India during the peak transmission showed that the peak seroprevalence in general population was 7.7% in adults, 13.2% in children, 28.3% in 15–19 years old and only 3.5% in >60 years old. Seroprevalence was higher in people exposed to children and sick patients and was 20% in hospital staff, 35.6% in general medical practitioners, 26% in school staff. Another study in USA showed that 25–50% of cases who were hospitalized or died were young and healthy and had no co-morbidities. Pregnancy, asthma, other lung diseases, diabetes, morbid obesity, autoimmune disorders and associated immunosuppressive therapies, neurological disorders and cardiovascular disease are some of the risk factors for increased morbidity and mortality associated with pandemic influenza. Spectrum of illness can vary from non-febrile upper respiratory tract infection to severe and often fatal pneumonia. Most develop typical ILI with cough, cold, fever, malaise, sore throat, and headache; and recover spontaneously. Up to 40% can develop gastrointestinal symptoms like diarrhea and vomiting. During peak transmission, 10–30% of patients presenting with ILI tested positive for novel H1N1 virus, 2–10% of these patients needed hospitalization, and 30% of hospitalized patients needed ventilation. Mortality due to pandemic H1N1 2009 has been estimated to be less than 0.5% (0.0004–1.47%), but it is difficult to estimate as many cases are mild or subclinical giving an incorrect denominator. The most commonly reported symptoms include cough, fever, sore throat, malaise and headache. Fever is absent in 309 some outpatients and in up to 1 in 6 surviving hospitalized Di



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Antigenic shift leading to point mutations in the H and or N antigens of the circulating influenza viruses occurs regularly which results in outbreaks or epidemics in the community from time to time. When both the H and N antigens change such way that they are antigenically totally different from the past circulating strains it is called as antigenic shift and it results in pandemic as the population has no immunity to the new virus. The novel H1N1 2009 strain responsible for current pandemic is a re-assortant virus with gene segments from viruses of swine (European, North American and Asian; five segments), birds (two segments) and humans (one segment). However this novel virus is not infective in swine and is actually a misnomer. Novel H1N1 2009 virus is antigenically different from the earlier human H1N1 viruses. It was believed that this virus has no cross protection from previous exposure to seasonal H1N1 virus. However we now know that the novel H1N1 2009 virus infection is milder in elderly population and hence there seems to some cross protection between this virus and the 1918-1919 H1N1 virus.

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Novel H1N1 virus is transmitted via nasopharyngeal route like any other influenza virus. Hence virus spreads mainly via coughing, sneezing, hands, social contact, and from medical interventions like suctioning, nebulization and open ventilation which generate respiratory mist. It can spread by infected fomites like shared napkins and handkerchiefs. Person is infective from 1 day before to 7 days after novel H1N1 infection. If illness persists beyond 7 days, person remains infective till resolution of symptoms.

seases

On 18th March 2009, Mexico reported cases of influenzalike illness (ILI) in children from whom a novel influenza type A virus was isolated. The disease then spread further in Mexico, USA and other parts of world. On 11th June 2009, the WHO declared phase 6 of the first influenza pandemic of the current century caused by novel H1N1 2009 type A strain. As of 1st August 2010, more than 214 countries and overseas territories or communities have reported laboratory confirmed cases of pandemic influenza H1N1 2009, including over 18449 deaths. In India, as on 3rd October 2010, 190,990 cases of hospitalized severe influenza like illness (ILI) were tested using PCR on nasopharyngeal swabs, of which 44,687 tested positive for pandemic H1N1 2009 and 2475 died of the disease. This is of course the tip of the iceberg as is evident from a seroepidemiology study done from Pune, India during the peak transmission showed that the peak seroprevalence was 7.7% in adult general population, 13.2% in children general population. On 10 August, 2010, the WHO announced that the world was in postpandemic phase as the peak of transmission was over, though fresh cases continued to be reported from various countries including India. Now novel H1N1 infection has become part of seasonal circulating virus though for some more time it will continue to infect and affect more severely the younger people more frequently than others.

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Pandemic Influenza

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Definitive diagnosis of pandemic H1N1 infection is made by RT-PCR test done on clinical specimens like nasopharyngeal swab, nasal swab, throat swab, wash or aspirate or tracheal aspirate (in case of intubated child). The specimen should be collected by experienced clinician or microbiologist. The swab should be placed in transport medium containing tube and stored and transported at 4°C within 24 hours of collection; or else it should be stored at –70°C. Its sensitivity and specificity in a symptomatic patient is nearly 100%. Results normally take 24–48 hours. Serological testing is not recommended as it can only tell whether the strain is type A or type B and cannot differentiate between pandemic H1N1 and other type A seasonal influenza strains. Government of India guidelines recommend to reserve PCR based test only for severe hospitalized patients and not for outdoor patients who should be any way started on oseltamivir on clinical grounds. PCR based test is also useful to monitor drug sensitivity to oseltamivir and genetic drift 310 in the pandemic H1N1 virus.

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Once influenza like illness (ILI) is suspected one should follow the national guidelines in managing patients. Patients with some fever but no other features of ILI like cough, cold, sore throat, vomiting, loose stools, etc. are classified as group I and are treated at home with paracetamol, adequate fluid intake and asked to follow-up if other symptoms of ILI develop. For patients who have ILI but without dangers signs like respiratory distress, breathlessness, excessive vomiting, persistent high fever, somnolence, inability to take or retain adequate fluids, convulsion or cyanosis, etc. are classified as group II and are treated at home with oseltamivir as shown in Table 5.30.1 along with paracetamol, adequate fluids, and asked to return for follow-up if any of the danger signs develop. Testing with nasopharyngeal swab for PCR is not recommended for group II patients. They are also counseled to take rest and measures of infection control at home as discussed later to prevent spread of infection to their contacts and in community. Once any of the danger signs develop as mentioned before, these patients are classified as group III and are hospitalized in isolation wards created for treating pandemic H1N1 patients. Their nasopharyngeal swab is sent for PCR at government approved laboratory. Pending the report, they are given oseltamivir. In addition they are treated with IV or oral fluids, symptomatic treatment, oxygen therapy and other respiratory support including ventilation as required. All measures of infection control are strictly undertaken as discussed later. Salicylates should be avoided in a child with ILI due to risk of Reye’s encephalopathy.

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Most deaths occurred due to severe pneumonia, ARDS or multiorgan failure with renal failure. Mean time from onset of disease to death is 10 days (2–22 days). Thirty percent of patients with fatal pandemic influenza had secondary bacterial infection mainly with Pneumococcus as proven by PCR for Pneumococcus on postmortem lung specimens. Other complications known to occur, though rare, include rhabdomyolysis, renal failure, myocarditis, hemophagocytic syndrome. There are patients who are at risk of developing complications following influenza infection because of underlying medical conditions that includes those who have chronic pulmonary (including asthma), cardiovascular (except hypertension), renal, hepatic, neurologic, hemato logic, or metabolic (including diabetes mellitus) disorders; those who are immunosuppressed (including immuno suppression caused by medications or by human immuno deficiency virus); those who are or will be pregnant during the influenza season; those aged 6 months to 18 years and receiving long-term aspirin therapy and who therefore might be at risk for experiencing Reye syndrome after influenza virus infection; and residents of nursing homes and other chronic-care facilities.

Management includes supportive care in most and use of specific antimicrobial agent oseltamivir in select cases as per national guidelines.

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The novel pandemic H1N1 influenza A virus is susceptible to neuraminidase inhibitors (oseltamivir, zanamivir) but resistant to M2 ion channel inhibitors (amantadine and rimantadine). Antiviral therapy should be started as early as possible, preferably within 48 hours of onset of illness to be maximally effective. However it should be started even if it is delayed at any stage of active disease when ongoing viral replication is anticipated or documented. It is especially recommended in individuals at high risk of complications like children less than 5 years of age, patients with progressive respiratory disease including pneumonia and those with high risk medical conditions. Oseltamivir is preferred being oral agent and with minimum side effects and gives higher systemic level. Zanamivir is delivered by inhalation with low systemic absorption. Oseltamivir is the recommended treatment for lower respiratory tract complications. Rare neuropsychiatric symptoms such as confusion or abnormal behavior have

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patients. Gastrointestinal symptoms (nausea, vomiting and/or diarrhea) occurred in up to 38% of outpatients in the US. Approximately 2–5% of confirmed cases in the US and Canada, as well as 6% in Mexico needed hospitalization. Among patients presenting with acute respiratory illness for care in Mexico, 13% tested positive for new influenza A (H1N1) virus infection (about one-fifth have had seasonal influenza), of whom about 10% have been hospitalized and one-third of those hospitalized required mechanical ventilation.

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Novel H1N1 infection can be prevented by general measures as well as specific vaccination.

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At the Healthcare Facility Healthcare personnel are at great risk of spread of virus from a suspected case of H1N1 influenza, especially there is uncontrolled mist of respiratory tract secretions of the patient generated like with open nebulization, suctioning or open ventilation systems. Use of protective gears like N95 mask (Ideal) or surgical disposable mask, head cap, and gowns; and strict hand hygiene before and after touching the patient are strongly recommended for those handling patients of H1N1 influenza, which includes healthcare workers and care taker. Such patients also have to be isolated in a reserved area with separate entrance and exit where no or minimum human visitors are allowed.

seases

Adequate hydration, proper nutrition, use of moist oxygen, early detection of respiratory failure and timely management with moist oxygen and ventilatory support are some of the important general supportive measures. Antibiotics are not used routinely and are reserved for cases with suspected secondary bacterial infection. Pneumococcus and Staphylococcus are important organisms involved in secondary infection in pandemic influenza in children. Routine use of corticosteroids is best avoided. Infection control measures are of utmost importance in preventing spread of disease to close contacts.

Availability of hand sanitizers at public places will help spread of virus for people touching things of common interest. Avoidance of mass gathering also will prevent spread of virus. Closure of schools though practiced during peak transmission, is not found to be effective and is impractical. General awareness about how the virus spreads and messages regarding hand hygiene and cough etiquette help regulate personal behavior and spread of virus.

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Hand hygiene and cough etiquette are important measures for a patient who is managed at home. Surgical mask is not as effective and tends to clog within 2–4 hours making it ineffective and uncomfortable. Only N95 masks are highly effective in preventing spread of virus, but are expensive, not easily available and are best used in hospital set up. Hand sanitizers are useful in preventing spread of the virus to contacts. Isolation in home for 5–10 days also helps in preventing spread to contacts at work places.

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occurred after beginning treatment for seasonal influenza with oseltamivir, particularly in children and adolescents, but the contribution of oseltamivir to these events is unknown. Inhaled zanamivir has been temporally associated with bronchospasm and patients with pre-existing airway disease appear to be at increased risk for this severe adverse reaction. Recommended regimens of using antiviral therapy are shown in Table 5.30.1. There is no role of using preventive antiviral therapy due to risk of development of drug resistance. Two hundred seventy-eight cases of oseltamivir resistant novel H1N1 viruses have been reported to the WHO.

Influenza Vaccines

Table 5.30.1 Recommended antiviral treatment regimens Oseltamivir: For adolescents,13–17 years of age, and for adults the recommended oral dose is 75 mg oseltamivir twice daily for 5 days. For children recommended doses are as follows: By weight: 15 kg or less:

30 mg orally twice a day for 5 days

15–23 kg:

45 mg orally twice a day for 5 days

24–40 kg:

60 mg orally twice a day for 5 days

>40 kg:

75 mg orally twice a day for 5 days

For infants:

First vaccine against novel H1N1 strain was monovalent vaccine against novel H1N1 strain was approved for manufacturing by US FDA on 15th September 2009, and was available for mass use in US on 5th October 2009. Now, novel H1N1 vaccines are available as a live, attenuated trivalent vaccine (LATV) for intranasal administration and as trivalent inactivated, split-virus or subunit vaccines for injection (TIV) which again are with or without adjuvant. There are several manufacturers of these vaccines. Most of the manufacturers use chicken eggs for producing these vaccines.

Vaccine Compositions

<3 months:

12 mg orally twice a day for 5 days

3–5 months:

20 mg orally twice a day for 5 days

6–11 months:

25 mg orally twice a day for 5 days

(Available as 75 mg per tablet and syrup containing 12 mg per ml) (Duration of treatment can be extended up to 10 days in a severe case) Zanamivir: Zanamivir is indicated for treatment of influenza in adults and children (>5 years). The recommended dose for treatment of adults and children from the age of 5 years is two inhalations (2 x 5 mg) twice daily for 5 days.

Before the current novel H1N1 pandemic, seasonal H1N1, H3N2 and type B influenza viruses were co-circulating since 1977. Accordingly influenza vaccine was a trivalent vaccine containing circulating seasonal H1N1, H3N2 and type B strains. Manufacturing flu vaccines is literally a race against the time. Every year the circulating virus drifts and hence the vaccine strains change accordingly. The WHO reference laboratory collects samples isolated from patients with influenza like illness from various sentinel sites in different 311 countries throughout the year and decides on the strains to

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children compared to elderly people. Rarely, such influenza vaccines can cause allergic reactions such as hives, rapid swelling of deeper skin layers and tissues, asthma or a severe multisystem allergic reaction due to hypersensitivity to certain vaccine components. Live vaccines are given via a nasal spray, and can commonly cause runny nose, nasal congestion, cough, and can less frequently cause sore throat, low grade fever, irritability and headache and muscle aches. Wheezing and vomiting episodes have been described in children receiving live influenza vaccines.

Schedule

Efficacy/Effectiveness

Influenza vaccine is to be given annually as the vaccine changes every year as discussed before. Two doses are recommended at 4 weeks interval in the first year for children less than 9 years of age. Subsequently one dose is given annually.

Randomized placebo controlled vaccine efficacy trials using novel H1N1 vaccines are neither feasible nor ethical. Hence case controlled studies have looked at the effectiveness of the monovalent novel H1N1 vaccines in UK, Germany and Canada. The effectiveness has been found to be 96.8% (95.2–97.9) in 14–59 years old and 83.3% (71.0–90.5) in more than 60 years old in Germany. In Canada, the effectiveness was found to be 100% (79.5 to 100) in 6 months to 10 years old children. In UK, the effectiveness was 77% (11 to 94) in children less than 10 years of age, 100% (80 to 100) in 10–24 year olds, 22% (−153 to 76) in 25–49 year olds and 41% (−71 to 80) in 50+ year olds.

Inactivated Flu Vaccine

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Inactivated flu vaccine can be used only for children more than 6 months of age; both for healthy subjects and population at risk of medical complications of influenza infection. Children from 6 months to 3 years of age receive 0.25 m per dose and those above 3 years receive 0.5 m per dose.

Live Attenuated Influenza Vaccine (LAIV) Cold adapted live nasal flu vaccines are recommended only for healthy non-pregnant 2–60 years of age subjects. Children aged 2–9 years require two doses given 1 month apart. Children above 9 years of age require one dose. LAIV should be used if one has received another live vaccine within the last 4 weeks. Dose is split equally between two nostrils administered using a nasal sprayer.

Side Effects These vaccines commonly cause local reactions in 30% of vaccine recipients such as soreness, swelling and redness at the injection site, and less often fever, muscle- or jointpains or headache. These symptoms are generally mild; 312 do not need medical attention, and last for 1–2 days. Fever, aches and headaches can occur more frequently in

Immunogenicity With experience of using seasonal flu vaccines in past, it has been shown that hemagglutinin (HA) titers of more than 1:40 are considered as seroprotective and known to provide at least 50% protection against seasonal H1N1 disease. Monovalent novel H1N1 vaccines have shown that more than 90% of children achieve seroprotection rates with one or two doses. Two doses are better in children less than 3–9 years of age. In general, the GMT achieved after one or two doses are more than 1000 units per m . Adjuvanted vaccines are better immunogenic and hence need lesser antigen doses than non-adjuvanted vaccines. The WHO recommends that children more than 6 months and less than 9 years need two doses. l



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be used in the Northern vaccine (by February) and Southern vaccine (by August) and provides the seed vaccine virus to the manufactures. The manufacturers then prepare vaccine for commercial and public health use and come out with vaccine in next 6 months so as to be used before next flu season (by September for Northern vaccine and by March for Sothern vaccine). Vaccines without adjuvant contain 7.5 µg of hemagglutinin (HA) of each of the three types (total 22.5 µg) per dose for children less than 3 years and 15 µg per dose of each of three types (total 45 µg) for more than 3 years of age. Vaccines with adjuvant usually contain half the dose of HA per virus type. Adjuvants used include ASO4, AFO3, etc. In the year 2009 novel H1N1 strain replaced the circulating seasonal H1N1, H3N2 and B strains. Hence monovalent vaccines (live as well as inactivated) containing novel H1N1 virus strain were manufactured and used. As the pandemic got over, gradually novel H1N1 strain became endemic and other strains circulating before the pandemic started co-circulating with the pandemic strain and hence in 2010, like in past, trivalent flu vaccines (live as well as inactivated) were manufactured containing novel H1N1 strain (A/California/7/2009 (H1N1)-like], seasonal H3N2 strain [H3N2 (A/Perth/16/2009 (H3N2)-like], and type B strain [B/Brisbane/60/2008-like]. The vaccine strains have remained the same even in 2011.

Contraindications Flu vaccine is not indicated in less than 6 months old children. TIV is contraindicated in patients with past history of anaphylactic reaction to egg or previous flu vaccine. GBS within 6 weeks of previous dose of flu vaccine is a precaution for subsequent use of TIV. Like with any vaccine, any severe acute illness is a temporary contraindication to use flu vaccine till the person recovers from the illness. LAIV is contraindicated in less than 2 years and more than 50 years old subjects. It is also contraindicated if the child having moderate-to-severe febrile illness, receiving salicylates, has anaphylactic reaction to egg protein, have reactive airway disease; and patients at risk of medical complications following influenza infections, pregnant women, and contacts of immune compromised conditions requiring protected environment like stem cell transplant recipients.

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1. Centers for Disease Control and Prevention. Prevention and control of influenza with vaccines recommendations of the Advisory Committee on immunization Practices (ACIP), 2010. MMWR. 2010;59:1-68. 2. John TJ, Moorthy M. 2009 pandemic influenza in India. Indian Pediatr. 2010;47:25-37. 3. MOHFW GOI. Guidelines on categorization of influenza a H1N1 cases during screening for home isolation, testing, treatment and hospitalization. Available at http://mohfwh1n1.nic.in. [Accessed on October 4, 2009]. 4. Shah N. H1N1 2009 pandemic – lessons learnt. Indian Pediatr. 2011;48:363-4.

5. Shah N. H1N1 guidelines. Reply. Indian Pediatr. 2010;47:102-3. 6. Shah N. Pertinent queries on Swine flu (H1N1). Indian Pediatr. 2009;46:813-4. 7. WHO Guidelines for Pharmacological Management of Pandemic (H1N1) 2009 Influenza and other Influenza Viruses. Available at http://www.who.int/entity/csr/resources/ publications/swineflu/h1n1_guidelines_pharmaceutical_ mngt.pdfWHO. [Accessed on October 4, 2009]. 8. WHO. Use of antiviral drugs against influenza A(H1N1). Available at http://www.who.int/csr/disease/swineflu/ frequently_asked_questions/swineflu_faq_antivirals/en/ index.html. [Accessed on October 4, 2009].

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Section

Diseases of Central Nervous System































Neuroanatomic Localization in Children: Vrajesh Udani Prenatal Development and C Malformations: PA Mohammed Kunju Neurodegenerative Disorders: Naveen Sankhyan Neurocutaneous Disorders: Devendra Mishra Seizures, Epilepsy and Nonepileptic Events: Rekha Mittal Headaches and Migraines in Children: Munni Ray Movement Disorders: Anoop Verma Encephalitis and Encephalopathies: Rashmi Kumar Infections of the Central Nervous System: Pratibha Singhi Coma in Children: Arun Bansal Childhood Brain Tumors: Kamer Singh Rana Raised Intracranial Pressure: Sunit Singhi Childhood Stroke: Satinder Aneja Floppy Infant–Clinical Approach: Bibek Talukdar Neuromuscular Disorders in Children: Sheffali Gulati Cerebral Palsy, Mental Retardation and Autism: MS Mahadeviah Learning Disabilities and Attention Deficit Hyperactivity Disorder: Sunil Karande Global Developmental Delay and Early Intervention: Sunanda K Reddy ns





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Section Editor : Pratibha Singhi

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commonly asymmetric (intervertebral disc prolapse, tumors) with weakness/sensory loss/reflex change in a segmental distribution. Peripheral neuropathies (hereditary sensorimotor neuropathies) generally cause more distal weakness and sensory loss with early areflexia. Guillain Barré syndrome affects radicals and peripheral nerves. Neuromuscular junction disorders (myasthenia, botulism, snake bite) often involve ocular and pharyngeal muscles early and have retained reflexes; often the weakness fluctuates. Muscle disease usually involves proximal more than distal muscles and reflex loss is seen primarily in weak muscles.

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Pediatric neurological disorders are more diffuse than focal and hence accurate localization to discrete neurologic regions is difficult and probably not critical. As an example, children who have cerebral palsy do not really need the rigorous exercise of neuroanatomical localization in most instances. This chapter cannot cover the whole of neurologic localization and has highlighted this exercise in conditions like motor paralysis (hemiplegia, paraplegia, etc.), ophthalmoplegia and visual loss.

The final common pathway of motor pathway is the lower motor neuron (LMN), i.e. alpha motor neuron in the ventral horn of the spinal cord and the motor nuclei of the cranial nerves in the brainstem. Axons then exit as motor roots; traverse in the peripheral nerve, which innervates the muscle extrafusal fibers via the neuromuscular junction and affects contraction (Fig. 6.1.1). A “motor unit” comprises of the motor neuron, the axons from it and the muscle fibers it innervates. These could be few, for example in extraocular muscles or several hundred in larger truncal muscles.

Anatomy The corticospinal (CST) and corticobulbar tracts (CBT) exert direct supraspinal influences on the alpha motor neuron and cranial nerve motor nuclei (Fig. 6.1.2). The CST arises

Localization

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The LMN disorders cause varying degrees of weakness, hypotonia and areflexia. Motor neuron disorders (polio­ myelitis/spinal muscular atrophies) cause muscle was­ ting, proximal more than distal weakness, and early areflexia. Radiculopathies are usually painful and can be symmetric [Guillain Barré syndrome (GBS)] or less

Figure 6.1.2 The corticospinal and corticobulbar tracts

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Figure 6.1.1 Organization of a spinal segment

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Localization The upper motor neuron (UMN) syndrome typically has weakness, spasticity, hypereflexia and extensor plantar though in acute lesions hypotonia and hyporeflexia, may predominate initially. Distribution of weakness could be hemiplegia, quadriplegia (UL = LL), diplegia (LL > UL), double hemiplegia (UL > LL), paraplegia and monoplegia. The lesions causing these various syndromes could be in the cortical motor/premotor cortices, subcortical white matter in the corona radiata, brainstem and spinal cord. Generally cortical/subcortical lesions cause incomplete deficits with less spasticity while spinal cord and sometimes brainstem lesions cause more complete deficits and more spasticity. If there is a UMN facial paresis on the same side as the paresis, the lesion is necessarily above the pons. Table 6.1.1 outlines the clinical localization of lesions in the motor pathway.

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not only from the primary motor cortex, lateral premotor cortex and the medial supplementary motor cortex, but also receives input from the postcentral sensory cortex and other areas. The motor cortex has somatotopic organization with maximum representation for the lips, jaw, thumb and fingers. Anterior to the motor areas is the frontal eye field, which controls contralateral horizontal gaze. The CST descends into the corona radiate, posterior limb of the internal capsule where it is adjacent to ascending sensory fibers, the optic radiations and the thalamus/caudate and putamen; from there it winds down into the cerebral peduncle in the anterior midbrain where it lies close to the oculomotor nerve and red nucleus. It then traverses the anterior pons where the VIth and VIIth nerve nuclei are situated and finally forms the medullary pyramid anterior to the lower cranial nerve nuclei; 90% of the CST fibers decussates to then descend in the spinal cord as the lateral CST. Brainstem cerebellar peduncles—superior, middle and inferior are close by and serve ipsilateral cerebellar functions. The CBT has a similar origin and descends in the genu of the internal capsule, medial cerebral peduncle and the pons; it provides bilateral input to the motor cranial nerve nuclei, i.e. the Vth, VIIth innervating the upper facial muscles, IXth, Xth and XIIth; the VIIth nerve nuclei innervating the lower facial muscles receive contralateral corticobulbar input. The CST lies in the lateral funiculus of the spinal cord, ventrolateral to the uncrossed ascending posterior columns and posterior to the crossed lateral spinothalamic tract.

Paralysis of the external ocular muscles can be caused by lesions in the brainstem ocular motor nuclei, the nerves, the neuromuscular junction or the muscles. The ocular motor system is responsible for volitional and reflex vertical and horizontal conjugate eye movements whose primary goal is to keep a binocular image on the fovea at all times.

 

Table 6.1.1 The clinical localization of lesions in the motor pathway Common etiologies

Cortical/ sucortical

– – – – –

– Distal weakness > proximal – Lateral lesions UL/face > leg – Medial lesions Leg > UL/face – Deficits rarely complete

– – – –

Seizures Cortical sensory loss Aphasia/apraxia Contralateral gaze palsy (transient) – Bilateral lesions pseudobulbar palsy (drooling, dysphagia)

Mono/hemiplegia – Stroke – Granulomas – Demyelination (ADEM) – Encephalitis (HSV) Quad/Diplegia – Brain injury (HIE, PVL, TBI) – Leukodystrophies

Internal capsule

– Hemiplegia

– Complete deficits (UL = LL = Face)

– Hemisensory deficits – Hemianopia – Dystonia

– Stroke – TBM (granulomas/infarcts) – Encephalitis

Brainstem

– Hemiplegia – Quadriplegia

– Complete deficits

– Ipsilateral CN deficits – Ipsilateral ataxia

– Glioma – Encephalitis – Leigh’s disease

Spinal cord

– Paraplegia – Quadriplegia – Hemiplegia (Hemicord syndrome)

– – – –

– Bladder/Bowel involved (earlier in intramedullary) – Sensory level (Hemicord syndromes)—ipsilateral position/vibration loss, contralateral pain/ temperature

– – – – –

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Complete deficits Severe spasticity Flexor spasms LMN signs at level of lesion; UMN signs below

 

 

 

 

 

 

 

           

 

 

 

 

 

 

 

 

   

 

 

       

Hemiplegia Diplegia Quadriplegia Monoplegia Double hemiplegia

 

Associated symptoms/signs  

Characteristics  

Motor syndrome  

Site

Myelitis Trauma Meningomyelocele Neoplasm Hereditary spastic paraparesis

Abbreviations: UL, Upper limb; LL, Lower limb; ADEM, Acute disseminated encephalomyelitis; HSV, Herpes simplex virus; HIE, Hypoxic-ischemic encephalopathy; PVL, Periventricular leukomalacia; TBI, Traumatic brain injury; TBM, Tuberculous meningitis; LMN, Lower motor neuron; UMN, Upper motor neuron

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Six muscles—the recti and the obliques control eye movements. The lateral rectus is innervated by the abducens (VI) nerve and the superior oblique (SO) is innervated by the trochlear nerve (IV) nerve while the other four muscles—the medial rectus, superior rectus, inferior rectus and inferior oblique are innervated by the oculomotor (III) nerve. Figure 6.1.3 outlines the action of the different muscles. The levators of the eyelid are innervated primarily by the IIIrd nerve and also receive some sympathetic supply. Dilators of the pupils is mediated by the sympathetic supply while the constrictors receive parasympathetic innervations.

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Oculomotor (IIIrd) Nerve (Fig. 6.1.4)





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The IIIrd nerve nucleus lies in the upper midbrain, fibers for the superior rectus cross to the opposite side while the levators get bilateral innervations; all other muscles get ipsilateral innervations including the parasympathetic pupilloconstrictor fibers. After exit the IIIrd nerve traverses the subarachnoid space (SAS) and is close to major arteries—the posterior communicating and the carotid. After the SAS, the nerve lies in the lateral wall of the cavernous sinus with the IVth, VIth and the ophthalmic branch of the Vth nerve (V1) close to the intracavernous carotid artery. It then enters the orbital apex via the superior orbital fissure along with the aforementioned nerves and here is also close to the optic nerve.

Trochlear (IVth) Nerve (Fig. 6.1.4)

 

Figure 6.1.4 The ocular motor nerves



The nucleus lies in the lower midbrain after which it exits dorsally and decussates immediately and then has the longest intracranial course in the SAS making it vulnerable to traumatic injury. The nerve then has a similar course in the cavernous sinus and the orbital apex before it innervates the SO.

Abducens (VIth) Nerve (Fig. 6.1.4)



Localization Oculomotor Nerve Third nerve palsy would have ptosis, exotropia in primary gaze (due to unopposed action of the lateral rectus), absent adduction, elevation and weakened depression in the abducted eye. The pupil would be dilated and unreactive though partial palsies can spare the pupil. Nuclear lesions cause ipsilateral weakness in adduction and depression with bilateral ptosis and bilateral deficit in elevation. Fascicular lesions in the brainstem often involve adjacent CST or substantia nigra/red nucleus to give crossed hemiplegia or tremor. Brainstem encephalitis, Leigh’s disease and late stages of herniation syndromes with bilateral midbrain lesions are some causes in childhood. In the SAS, isolated IIIrd nerve palsies are the rule and the causes include uncal herniation, meningitis, 317 tumors, parainfectious neuritis and possibly recurrent





The nucleus is in the pontomedullary junction near the facial nerve colliculus. The nerve then exits anteriorly after connecting to the contralateral IIIrd nerve via the medial longitudinal fasciculus (MLF). In the SAS the nerve ascends the brainstem and is close to the petrous apex and then courses over the tentorial edge.

The further course through the cavernous sinus and orbital apex before innervates the lateral rectus, which is similar to the other ocular motor nerves.

 

Figure 6.1.3 Actions of the extraocular muscles

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Fourth nerve palsy causes paresis of depression in the adducted position with mild elevation of the eyeball in primary gaze. There is often a compensatory head tilt. Isolated IVth nerve palsy is seen after trauma and is most often congenital.

Destructive lesions (e.g. infarcts) of the frontal eye field will paralyze (usually transiently) contralateral horizontal conjugate gaze so that the unopposed ipsilateral gaze will turn the eyes toward the lesion. Irritative lesions (focal seizures) will result in gaze to the opposite side. Destructive lesions of the PPRF (e.g. glioma) will cause ipsilateral conjugate gaze paresis and hence the eye will look away from the lesion. Congenital ocular motor apraxia is a disorder with defective/absent horizontal saccades; the children use head thrusts to fixate on an object. It is seen with Joubert’s syndrome and ataxia telangiectasia.

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Lesions posterior to the pretectum—enlarged IIIrd ventricle of hydrocephalus, pineal tumors, etc. cause the Parinaud’s syndrome with upgaze palsy, lid retraction (“sun set sign” in hydrocephalus) and convergence retraction nystagmus. Lipidoses, like Gaucher and Niemann Pick, are other important causes. -

Localization in the isual System Localization of visual loss to different parts of the visual pathway is difficult in children and even more in infants because of the difficulties in testing visual acuity and visual fields accurately. Much of the following discussion is therefore more relevant in the older child and teenager.

Anatomy The visual field and the retina have an inverted and reversed relationship; the upper visual field fall on the inferior retina and vice versa, and the nasal field fall on the temporal retina and vice versa (Fig. 6.1.5). The optic nerves receive their axons from the retinal ganglion cells (first order neurons) and proceed through the optic canal in the posterior orbit where they lie close to the IIIrd, IVth, Vth and VIth nerves entering the orbit. A little more than half of the optic nerve fibers from the nasal retina (serving the temporal field) cross to the opposite side in the optic chiasm while the uncrossed temporal retinal fibers (serving the nasal field) continue

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Saccades (fast conjugate movements to fixed target) are initiated in the frontal/parietal eye fields; fibers then



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Lesions at the cavernous sinus (like thrombosis) and orbital apex (like orbital cellulitis) cause multiple ocular motor palsies with sensory loss in the V1 area and pain; at the orbital apex, visual loss and proptosis are additionally seen. Also a Horner’s syndrome may be associated. Other locations include the brainstem (glioma) where associated long tract signs are usual, SAS (meningitis) and part of peripheral conditions like GBS or the Miller Fisher syndrome. Ocular muscle involvement in myasthenia can mimic any pupil sparing ocular motor neuropathy. It is often diffuse/bilateral but can be remarkably asymmetric. Ptosis is almost invariable. Chronic progressive external ophthalmoplegia can be isolated or part of many myopathies—most commonly mitochondrial. Ptosis with bilateral diffuse ophthalmoplegia with pupillary sparing is characteristic and is typically confused with ocular myasthenia.

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This is controlled by a cluster of nuclei in the upper dorsal midbrain so called pretectal area. These centers then connect to the relevant oculomotor and trochlear nerve nuclei through the MLF to control upgaze and downgaze.

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Sixth nerve palsy would have paresis of ipsilateral abduction with esotropia in primary gaze. Nuclear lesions often cause a combined VIth and VIIth nerve palsy. Ipsilateral horizontal conjugate gaze is also affected. Contralateral hemiplegia may also occur. Common lesions include pontine glioma and congenital agenesis like in Moebius syndrome. In the SAS, the nerve is susceptible to raised ICP or even low intracranial pressure and hence one may get a “false localizing” sign. Meningitis, apical petrositis and parainfectious neuritis are other causes.





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descend and cross to innervate the prepontine reticular formation (PPRF) which projects to the adjacent abducens nerve nucleus. This then connects with the contralateral oculomotor nerve nucleus through the MLF. Pursuit movements are generated in the parietal temporal occipital junction with ipsilateral projections to the abducens nucleus.



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ophthalmoplegic migraine. As the pupillomotor fibers are at the nerve periphery extrinsic compressive lesions involve the pupil while intrinsic lesions like in Miller Fisher syndrome/GBS usually spare it. Pearls: When pupils are spared always consider ocular myasthenia (often unilateral, asymmetric); Miller Fisher syndrome, usually bilateral.

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Optic neuritis isolated or associated with acute disseminated encephalomyelitis, neuromyelitis optica or multiple sclerosis are the common acquired lesions. Hereditary ON like Leber’s are rarer causes of painless acute monocular visual loss. When acute visual loss is associated with pain, diplopia, ptosis, ophthalmoplegia and/or proptosis, an orbital process like cellulitis should be considered. Though tumors like optic glioma are slow growing and produce progressive visual loss, they are often noticed suddenly and may be mistaken as an acute optic neuritis. Disc edema can be caused by an anterior optic nerve process like optic neuritis or by raised intracranial pressure, i.e. papilledema. Early visual loss is typical of optic neuritis while papilledema causes enlargement of the blind spot and visual loss due to secondary optic atrophy occurs later. Chiasmatic lesions like craniopharyngioma/glioma characteristically produce mono or binocular visual loss and as they involve crossing nasal fibers, they produce a bitemporal hemianopia. They may extend laterally and cause ocular motor neuropathies if the cavernous sinus area is invaded or superiorly causing hydrocephalus. Retrochiasmal lesions produce a homonymous hemianopia (HH)—ipsilateral nasal/contralateral temporal fields, which may be congruent or incongruent, but respects the vertical meridian. Lesions in the parietal optic radiations cause inferior quadrantic HH and temporal optic radiations cause a superior quadrantic HH. Lesions in the occipital lobe produce a complete HH but the occipital tip, which represents macular (central) vision, is often spared and hence visual acuity may be unaffected. In bilateral occipital lesions, bilateral often asymmetric HH and decreased visual acuity are usual. Pupils characteristically remain unaffected. Transient binocular visual loss causes include migrainous visual aura and occipital lobe seizures. More prolonged loss can be seen with posterior reversible edema syndrome, hypoxic–ischemic encephalopathy, traumatic brain injury, posterior circulation strokes, etc. Perinatal brain injuries like hypoglycemic brain injury and periventricular leukomalacia both with predilection for the posterior areas.

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Monocular visual loss is due to lesions in the eye/optic nerve. Binocular visual loss is due to both eyes/optic nerves or of the optic chiasm or retrochiasmal lesions. Optic neuropathies (ON) cause central visual loss, impaired color vision, abnormal visual fields, initially swollen (papillitis) or normal (retrobulbar) disc, which becomes pale over 4–6 weeks and the relative afferent pupillary defect (RAPD) in unilateral/asymmetric ON. With unilateral/ asymmetric visual loss there is reduced/no signal reaching the brainstem parasympathetic nuclei leading to less/no pupillary constriction bilaterally when light is flashed in the affected eye. This difference in pupillary constriction between the affected and the normal eye is the basis of the RAPD.

1. Biousse V, Newman N. Neuro Ophthalmology Illustrated. New York: Thieme Medical Publishers; 2009. 2. Brazis P, Masdeu J, Biller J. Localization in Clinical Neurology, 6th edition. Philadelphia: Wolters Kluwer/Lippincott Williams and Wilkins; 2011. 3. Campbell W. Dejong’s The Neurologic Examination, 6th edition. Philadelphia: Lippincott Williams and Wilkins; 2005. 4. Fenichel G. Clinical Pediatric Neurology: A Signs and Symptoms Approach, 5th edition. Philadelphia: Saunders; 2005. 5. Swaiman K. Neurologic examination after the Newborn Period until 2 years of age. In: Swaiman K, Ashwal S, Farriero D (Eds). Pediatric Neurology Principles and Practice, 4th edition. Philadelphia: Mosby Elsevier; 2006. pp. 37 46. 6. Swaiman K. Neurologic Examination of the Older Child. In: Swaiman K, Ashwal S, Farriero D (Eds). Pediatric Neurology Principles and Practice, 4th edition. Philadelphia: Mosby Elseiver; 2006.pp.17 35.

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on the same side. Below the optic chiasm lies the pituitary gland while above it is the hypothalamus. The optic tract with contralateral nasal fibers and ipsilateral temporal fibers then synapse with the lateral geniculate body neurons, which then proceed to the primary visual cortex in the occipital calcarine cortex via the optic radiations. Fibers in the optic tract leave to reach the midbrain IIIrd nerve nucleus, which forms the efferent arc of the pupillary light reflex and causes ipsilateral and consensual pupillary constriction. The inferior optic radiation courses through the temporal lobe and contains fibers for the upper visual field while the superior parietal optic radiation has fibers for the inferior nasal field. Anteriorly the optic radiations are close to the internal capsule, which contains the motor and sensory long tracts. The optic radiations then converge to the visual cortex. The tip of the occipital lobe receives input from the macular region.





 

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Figure 6.1.5 The visual pathway—effects of lesions

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PA Mohammed Kunju The rostral end of the neural tube closes first and the caudal neuropore closes last between T11 and S2 vertebral level. Brain and upper spine is formed by this primary neurulation [for the timing of events (Fig. 6.2.1)]. It can be understood that all these developments occur before the time women realize they are pregnant. S

With widespread availability of imaging tools like MRI and US scan, diagnosis of congenital nervous system malformations has become common, and therefore practicing pediatricians will often be asked to give opinion on outcome, possible management and chance of recurrence. So an up-to-date knowledge of embryology and imaging features is necessary. Current concept of neuroembryology has changed a lot from the classic descriptive morphogenesis to the integration of molecular genetic programming that direct cellular and regional differentiation. This approach has provided precise spatial and temporal sequences of the anatomic malformations; both macroscopic and functional. Molecular genetic programming range from early processes that establish the axes of the neural tube and gradients of genetic expression, to late processes that establish identity of specific types of neurons, the type of neurotransmitter they synthesize and the synaptic connections they make. Variations in these stages may explain the unpredictable clinical manifestation of malformations. For example, two cases of corpus callosum agenesis with nearly identical imaging findings may differ in that one may have epilepsy refractory to pharmacological control, whereas the other may have no clinical seizures at all.

econdary Neurulation

At 4–5 weeks of gestation, distal spine and the most caudal part of the spinal cord (i.e. conus medullaris and filum terminale) develops from the neuroepithelium caudal to the site of posterior neuropore closure by a process of secondary neurulation. This part of the spinal cord forms not as a tube, but rather as a solid cord of neural cells in which ependymal cells differentiate in its core and canalize the cord. Because of differential growth between the vertebral column and the spinal cord, the conus becomes more rostral during later development. The cavity of the developing brain shows three dilatations. Craniocaudally, these are prosencephalon, mesencephalon and rhombencephalon. Prosencephalon becomes telencephalon (cerebral cortex, caudate and putamen) and diencephalon (thalamus, hypothalamus and globus pallidus). Mesencephalon is the midbrain. Rhombencephalon also becomes subdivided to metencephalon (pons and





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Normal mbryonic evelopment and verview of Pathogenesis The events of neural maturation after initial induction and formation of the neural tube are: • Neurulation or formation of the neural tube • Proliferation of neuroblasts • Programmed death (apoptosis) of excess neuroblasts • Neuroblast migration • Axonal growth • Electrical polarity of the cell membrane • Synaptogenesis • Biosynthesis of neurotransmitters • Myelination of axons.

Primary Neurulation

Figure 6.2.1 Steps of neural tube formation  

Neural plate is formed as a thickening of the primitive ectoderm that overlies the notochord 2. Invagination of it forms the neural groove and neural tube is formed by separation from the overlying surface ectoderm. Initial closure of the neural tube is accomplished in the area corresponding to the junction of the cervical spinal cord 320 and medulla, and moves rapidly both caudally and rostrally.

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Neuronal Migration Neurons after mitotic proliferation at the subependymal germinal matrix (subventricular zone) migrate to their final site to establish the synaptic connections. This begins at 6 weeks of gestation (42 days). Migration proceeds along radial glial fibers that span the entire cerebral mantle to pial membrane at the surface of the brain. In the cortex this occurs in an “inside out” manner—layer 6–2 migrate in the reverse order. However, layer 1 migrates first.

Disorders of Neuronal Migration Disorders of neuronal migration include heterotopia, focal cortical dysplasia, lissencephaly and pachygyria. Three types of aberrations can occur:

1. Neuroblasts never having begun migration from the periventricular region produce periventricular nodular heterotopia.

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The majority of malformations that occur early in gestation have a genetic basis, whereas those that begin late in gestation are more likely to be secondary to destructive lesions. Factors like radiation, drugs, malnutrition, chemicals and infections may induce malformations by a teratogenic influence that acts at a particular time of ontogenesis. S

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The classification of central nervous system (CNS) malfor mations is provided in Table 6.2.1. Table 6.2.1 Classification of central nervous system malfor­ mations •  Neurulation (neural tube defect) (3–4 weeks of gestation)   –  Anencephaly   –  Iniencephaly   –  Encephalocele   –  Myelomeningocele   –  Chiari malformation •  Prosencephalic formation (2–3 months of gestation)   –  Holoprosencephaly   –  Agenesis of corpus callosum   –  Septo-optic dysplasia •  Neuronal proliferation (3–4 months of gestation)   –  Microcephaly vera   –  Macrocephaly (Soto syndrome)   –  Neurocutaneous syndromes (tuberous sclerosis) •  Neuronal migration disorders (3–5 months of gestation)   –  Heterotopias   –  Lissencephaly: pachygyria   –  Schizencephaly   –  Focal cortical dysplasia   –  Polymicrogyria •  Disorders of cerebellar development (32 days to 1 year gestation)   –  Hypoplasia of the vermis, e.g. Joubert syndrome   –  Dandy-Walker malformation •  Destructive brain lesions   –  Hydranencephaly   –  Porencephaly  

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The embryonic neural tube consists of three zones: ventricular, mantle and marginal. Proliferation of neuro epithelial cells in the ventricular zone generates neurons and glial cells. Active mitoses cease well before the time of birth in most parts of the human nervous system, except few sites. A population of “stem cells” with mitotic potential in the subventricular zone and hippocampal dentate gyrus has generated considerable interest because of a potential for regeneration of the damaged brain. Disorders of neuronal proliferation include hypoplasia of the brain (e.g. cerebellar hypoplasia), microcephaly and megalencephaly.

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During the rapid growth of cells within the neural plate and invagination of the neural groove to form neural tube, differentiation of a conglomerate of cells occur at the two fusing lips of the closing neural tube. These are the neural crest cells, which migrate distally along predetermined pathways to form the peripheral/cranial sensory root ganglia, sympathetic and parasympathetic ganglia, chromaffin tissue, adrenal medulla, melanocytes, leptomeninges and Schwann cells. Failure of correct migration or differentiation can lead to a number of abnormalities like Hirschsprung disease, neuroblastoma, DiGeorge syndrome, neurofibromatosis type 1, intestinal aganglionosis, melanoma and albinism.

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2. Neuroblasts after beginning migration, arrested in the subcortical white matter, produce subcortical laminar heterotopia. 3. Neuroblasts reach the cortical plate but lack correct layering, lead to abnormalities of gyration, such as lissencephaly or pachygyria. After the above steps, development further proceeds with axonal growth and dendritic arborization, establishment of electrical polarity of the cell membrane, synaptogenesis, biosynthesis of neurotransmitters (inhibitory and excitatory) and myelination of axons. Defect in these steps are seen in various chromosomal, metabolic and hypoxic encephalopathies and can lead to mental retardation and epilepsy.

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cerebellum) and myelencephalon (medulla). The cavities of the brain vesicles are later designated as lateral ventricle (cavity of telencephalon), third ventricle (cavity of diencephalon), aqueduct (cavity of mesencephalon) and fourth ventricle (cavity of rhombencephalon). Failure of primary neurulation leads to open neural tube defects (NTDs) and a defect in secondary neurulation leads to closed NTDs.

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nencephaly

Anencephaly (Greek an, “without”; enkephalon, “brain”; with open cranium) is failure of the closing of anterior neuropore at 24 days of gestation. As a result, forebrain is exposed or extrudes from skull, a condition known as exencephaly. Two types are recognized. In holoanencephaly, there is complete absence of brain. In meroanencephaly, rudiments of the basal ganglia, brainstem and cranial vault are replaced by an amorphous vascular-neural mass (area cerebrovasculosa). Death in utero occurs in approximately 7% of anencephalic pregnancies; 34% of such babies are born prematurely and 53% at term. The prenatal diagnosis is done by amniotic fluid examination for elevated α-fetoprotein and ultrasonographic finding of absence of calvaria and brain above orbit as early as 12 weeks of gestation.

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Figures 6.2.2A and B Occipital encephalocele

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Encephalocele is classified according to the anatomic site of cranial defect: • Occipital encephalocele (Figs 6.2.2A and B) lies between lambda and foramen magnum. • Parietal encephalocele lies between bregma and lambda. • Sincipital (frontoethmoidal) encephalocele lies between bregma and anterior margin of ethmoid bone. • Basal encephalocele herniates through ethmoid or sphenoid bone in to nasal pharynx.

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Most lesions are lumbosacral in location, but myelomeningocele may also occur in the thoracic or even the cervical region, usually as an extension rostrally of lumbosacral lesions. In its full expression, the following features are present:

The treatment of choice of small encephaloceles is surgical excision and closure of overlying cutaneous defects. Seizures and hydrocephalus are common but treatable complications. Nasopharyngeal encephaloceles may be a cause of recurrent meningitis from cerebrospinal fluid (CSF) rhinorrhea.

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Failure of bony fusion in the posterior midline of the skull (cranium bifidum) or the vertebral column (spina bifida) results in a bony cleft through which the meninges and varying quantities of brain or spinal cord may protrude. The term dysraphism is used to indicate the persistent continuity between posterior neuroectoderm and cutaneous ectoderm. In spina bifida, the herniation is called meningocele or meningomyelocele, depending on whether the meninges herniate alone or together with spinal cord parenchyma and nerve roots. Spina bifida can be “aperta” with open NTD and “occulta” with closed NTD. Open NTD frequently involves the entire CNS with associated hydrocephalus and Chiari II malformation. Closed NTD is localized and confined to the spine and brain rarely affected. In cranium bifidum, the term encephalocele refers to herniation of brain tissue and meninges and meningocele when herniation only of meninges.

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In spina bifida occulta, no herniation of the meninges is present and the skin of the back is completely epithelialized. Suspect in children with recurrent meningitis of occult origin: • Examine for a small sinus tract in the posterior midline region, including the back of the head. Patches of hair, a lipoma, discoloration of the skin or a dermal sinus (Figs 6.2.3A to C) in the midline of the low back signifies an underlying malformation of the spinal cord, L5 and S1 spinal cord, including syringomyelia, diastematomyelia and a tethered cord • Surgical referral mandatory • Clear indications for surgery include the finding of progressive neurologic defects, the presence of an associated tumor or a dermal sinus that carries the risk of meningitis or deep abscess, or a history of meningitis • Myelomeningocele.

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Figures 6.2.3A to C (A and C) Spina bifida occulta; (B) MRI with tethering and dermal sinus

The treatment of myelomeningocele is the surgical closure of small defects in the neonatal period itself. Large defects associated with complete paraplegia and flaccid neurogenic bladder, often accompanied by hydronephrosis, severe hydrocephalus and other cerebral malformations, are dealt with appropriately. A decision not to treat such infants or

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not to prolong survival poses a moral question addressed by the physicians in consultation with parents, hospital ethics committees, and other individuals whom the parents may identify. Aggressive treatment is the current strategy. These include repair of myelomeningocele, a shunting procedure for hydrocephalus, early surgical decompression of the medulla and cervical cord if hindbrain dysfunction appears. Clubfeet and dislocated hips may require casting and operative procedures. • Neurogenic bladder: About 80% of patients have this, which most commonly manifests as a small, poorly compliant bladder and an open and fixed sphincter. Options of management include the following: – Clean intermittent catheterization by parents, and ultimately the patient, prevents urinary tract infections and reflux leading to pyelonephritis and hydronephrosis – Periodic urine cultures and assessment of renal function – Artificial urinary sphincter to increase outlet resistance – Surgical urinary diversion (e.g. suprapubic vesicos tomy) – Augmentation cystoplasty to increase bladder capacity in combination with the use of oxybutynin. • ong-term ambulation potential: It is determined by the level of lesion. – Sacral: As the patient is able to plantar flex the ankles and move the toes, nearly all children and adolescents will ambulate, with minimal assistive devices – Low lumbar: The patient is able to flex the knee and dorsiflex the ankle. Nearly half of younger children and nearly all adolescents will ambulate, with varying degrees of braces or crutches – Midlumbar: The patient is able to flex the hips and extend the knee. The percentage of those able to ambulate is midway between those with high and 323 low lumbar lesions –

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Most lesions are lumbosacral in location, but myelo meningocele also may occur in the thoracic or even the cervical region, usually as an extension rostrally of lumbosacral lesions. In its full expression, the following features are present: • The presence of unfused or excessively separated vertebral arches of the bony spine (spina bifida) • Cystic dilation of the meninges that surround the spinal cord (meningocele) • Cystic dilation of the spinal cord itself (myelocele) • Type II Chiari malformation is commonly present and aqueductal stenosis coexists in 50% of cases. Hydrocephalus is a common complication, which will require early treatment (Figs 6.2.4A to C). The level of involvement determines much of the clinical deficit. Infants with myelomeningocele typically have an increasing neurologic deficit as the myelomeningocele extends higher into the thoracic region. • A lesion in the low sacral region causes bowel and bladder incontinence associated with anesthesia in the perineal area but with no impairment of motor function • A myelomeningocele in the midlumbar region tends to produce LMN signs due to abnormalities and disruption of the conus medullaris • Infant with upper lumbar lesion shows a flaccid paralysis of the lower limb, an absence of deep tendon reflexes, poor response to touch and pain, and a high incidence of clubfeet and subluxation of the hips.

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Figures 6.2.4A to C Cervical meningomyelocele with Arnold-Chiari malformation II

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Neural tube defects can be detected prenatally by ultrasonography, the α-fetoprotein level in amniotic fluid or maternal serum and amniotic fluid acetyl cholinesterase. Sonological diagnosis of a myelomeningocele is usually prompted by recognition of the associated Chiari II malformation in the second trimester. Diagnostic signs are “lemon” and “banana” signs. Lemon sign is due to the abnormal cranial vault that is narrowed rostrally and the banana sign represents the cerebellum surrounding the brainstem in a small posterior fossa. The risk of recurrence of NTDs after one affected child increases to 3–4% and to 10% with two previous abnormal pregnancies. There is strong evidence that maternal periconceptional folic acid supplementation reduces the incidence of NTDs in pregnancies at risk by at least 50%. The US Public Health Service has recommended that all women 324 of childbearing age and who are capable of becoming pregnant take 0.4 mg of folic acid daily and that women

who have previously had a pregnancy resulting in an NTD be treated with 4 mg of folic acid daily, beginning 1 month (preferably 3 months) before the time pregnancy is planned.

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High lumbar: The patient is able to flex the hips, but there is no knee extension. About one-third of children and adolescents will ambulate, but only with extensive assistive devices – Thoracic: As no hip flexion, no young child will ambulate and one-third of adolescents can be ambulated with the aid of extensive braces and crutches. –

Chiari I Malformation Chiari I malformation consists of displacement of cerebellar tonsils at least 3–5 mm through the foramen magnum into the upper cervical canal. Type I is clinically the least severe and generally asymptomatic during childhood. The presentation may be insidious, and it is associated with mental retardation and epilepsy in a small minority. There may be paroxysmal vertigo, drop attacks, vague dizziness and headache, which may be increased by the Valsalva maneuver. Occipital headache precipitated by exertion may progress to torticollis, downgaze nystagmus, periodic nystagmus and oscillopsia. MRI findings in patients with Chiari I malformations include malformations of the base of the skull and of the upper cervical spine, including hydromyelia, syringomyelia and syrinx.

Chiari II Malformation (Arnold-Chiari Malformation) The vermis, pons, medulla and an elongated fourth ventricle are displaced into the cervical canal. Type II is the most common of those diagnosed during childhood. A variety of cerebellar, brainstem and cortical defects can occur.

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Holoprosencephaly Holoprosencephaly (HPE) is a malformation in which the two cerebral hemispheres appear fused in the midline due to a failure of cleavage in the midsagittal plane of the embryonic cerebral vesicle at 33 days of gestation. Four variant forms are described: alobar, semilobar, lobar and the middle interhemispheric variant. The most common associations of HPE are chromosomal defects (trisomy 13 and deletions) and maternal diabetes mellitus. Facial abnormalities including cyclopia, cebocephaly and premaxillary agenesis are common. Endocrine dysfunction may be present, associated with hypothalamic or pituitary involvement. The most severe form, alobar HPE, is characterized by a single ventricle, an absent falx and fused basal ganglia. Mortality and morbidity are variable and care must be taken before prognostication.

Treatment The treatment of HPE depends on the complications, such as seizures, hydrocephalus and hormonal disturbances. Educational potential and need for supports depend

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Clinical Symptoms Clinical symptoms of ACC may be minimal in children of normal intelligence. Detailed neurological examination discloses deficits in the interhemispheric transfer of perceptual information for verbal expression. Mental retardation or learning disabilities occurs in some cases. Epilepsy is common and may relate more to minor focal cortical dysplasia than to the callosal agenesis itself. Similarly interhemispheric lipoma replacing part of the corpus callosum is associated with a high incidence of epilepsy. Hypertelorism is present in many and often is associated with divergent squint.

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Syringomyelia is the development of a fluid-filled cavity or syrinx within the spinal cord. Hydromyelia is a dilatation of the central canal by CSF. This can occur as a developmental anomaly, associated with Chiari malformations or can be an acquired lesion of the spinal cord secondary to trauma, infarction or intramedullary tumors. Syringomyelia usually involves the cervical area. Symptomatic presentation depends primarily on the location of the lesion within the neuraxis. Common manifestations are dissociated sensory loss, muscle atrophy that begins in the hands, and spasticity of lower limbs. Identification and treatment of associated dysraphism have the greatest impact on arresting progression of syringomyelia. Surgery includes suboccipital and cervical decompression with laminectomy and syringotomy (dorso lateral myelotomy).

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Diagnosis Diagnosis of callosal agenesis depends on neuroimaging. In the newborn, before the closure of anterior fontanels occurs, ultrasonography will show the absence of the corpus callosum; it may also show parallel lateral ventricles, interhemispheric cysts, hydrocephalus and other related anomalies. The electroencephalogram (EEG) characte ristically shows interhemispheric asynchrony (checkerboard pattern), with or without multifocal spikes. ­

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Type IV is cerebellar hypoplasia without a connection with the other malformations.

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Antenatal Diagnosis of Agenesis of the Corpus Callosum Antenatal diagnosis is possible from 20 weeks of gestation. CT scan findings include widely separated, parallel lateral ventricles with straight medial border, colpocephaly (enlarged posterior horns) and extension of the third ventricle into the interhemispheric fissure (devil’s horn appearance). MRI is the imaging procedure of choice. D

Type III involves an occipitocervical bony defect with herniation of cerebellum into the encephalocele. Type III comprises of the features of types I and II, but the entire cerebellum is herniated throughout the foramen magnum, with a cervical spina bifida cystica. Hydrocephalus is a common feature.

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Agenesis of the corpus callosum (ACC) is an anomaly (2.3% prevalence) that may occur in isolation or in association with other CNS malformations. Agenesis of the corpus callosum may be complete, partial or atypical. Secondary destruction of corpus callosum occurs with hypoxic-ischemic ence phalopathy (HIE), surgery or infarcts. Other cerebral malformations may coexist with callosal dysgenesis, e.g. interhemispheric cysts, intracranial lipomas and neuronal migration disorders (NMD). Various genetic syndromes are associated with ACC, e.g. trisomy 8, 11 and 13; Aicardi syndrome consisting of ACC, chorioretinal lacunae, vertebral anomalies, mental retardation and infantile spasm in girls.

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It is associated with encephalocele, noncommunicating hydrocephalus and myelomeningocele in almost 100% of cases.

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Microcephaly Microcephaly is defined by a head circumference, as measured around the forehead and the occipital protuberance that is more than three standard deviations below the mean for age, gender and race. Head circumference should also be compared with previous 325 measurements of the same child, ideally from birth, to

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Table 6.2.2 Causes of macrocephaly Conditions with a thickened skull causing large head –  Hemolytic anemia –  Rickets –  Cleidocranial dysostosis Subdural fluid –  Hematoma –  Hygroma –  Empyema Brain parenchyma –  Anatomical megalencephaly: genetic megalencephaly, Sotos syndrome   –  Metabolic megalencephaly: Alexander disease, Tay-Sach disease •  Brain and ventricle   –  Hydranencephaly   –  Porencephaly •  Ventricle   –  Hydrocephalus   –  Holoprosencephaly

Primary Microcephaly Primary microcephaly results from a variety of insults that cause anomalies of induction and migration. Micrencephaly denotes a small brain or cerebral hypoplasia determined by imaging or neuropathologic examination. It can be transmitted as an autosomal recessive or as an autosomal dominant disorder. Numerous migrational anomalies are seen, including schizencephaly, lissencephaly, pachygyria, polymicrogyria and ACC. • utosomal recessive: Characteristic facies with slanted forehead, prominent nose and ears • utosomal dominant: Milder phenotype • yndromes with microcephaly: Down, Edward, Cri-duchat, Cornelia-de-Lange, Rubinstein-Taybi and SmithLemli-Opitz.

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issencephaly ( gyria, Pachygyria, Macrogyria)

Lissencephaly means smooth brain. It is characterized by the absence of cerebral convolutions and a horizontally placed Sylvain fissure giving a figure of “8” appearance on axial MRI. In pachygyria (macrogyria), the pathology is less severe than that in lissencephaly, and areas of normal laminar organization are seen. Clinically, these infants present with severe infantile spasms, failure to thrive, microcephaly and gross







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Secondary microcephaly can be due to radiation, con genital TORCH infections, drugs like phenytoin (fetal hydantoin syndrome), maternal alcoholism (fetal alcohol syndrome), maternal diabetes mellitus and maternal hyperphenylalaninemia, intracranial infection hyperthermia, malnutrition and HIE. Postnatally acquired progressive microcephaly can be due to Rett syndrome and HIV encephalopathy. Investigations and management depend on the possible etiology and associated manifestations. The recurrence of microcephaly is relatively high; the exact frequency depends on the incidence among the kindred. Prenatal diagnosis by ultrasound has been attempted by serial biparietal diameter measurements. However, it discriminates poorly between affected and unaffected fetuses until late pregnancy.

When gray matter lies in the white matter area it is called as heterotopia. They include subcortical laminar (band heterotopia) and bilateral periventricular nodular heterotopia. In the first one a band of gray matter heterotopia lies within the subcortical white matter parallel to the overlying cerebral cortex but separates from it by white matter (Figs 6.2.5A and B). In bilateral periventricular nodular heterotopia, islands of neurons and glial cells occur in the subependymal regions around the lateral ventricles. Intractable seizure is the common manifestation. A

Secondary Microcephaly

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determine whether microcephaly is congenital or acquired. An abnormally small brain results either from anomalous development during the first 7 months of gestation (primary microcephaly—genetic) or from an insult incurred during the last 2 months of gestation or during the perinatal period (secondary microcephaly—nongenetic).

Macrocephaly Large head can be due to various causes other than hydrocephalus. The common causes starting from skull inwards are provided in Table 6.2.2. D

Neuronal Migration isorders

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Recently with MRI, it is clear that the incidence of NMD is much greater than had been estimated. The conditions associated with NMD include the phakomatoses, a variety of metabolic, genetic and chromosomal syndromes, and maternal and environmental causes. Migratory disorders develop when neuroblasts of the subependymal germinal 326 matrix fail to reach their intended destination in the cerebral cortex.

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The clinical picture of schizencephaly includes seizures, hypotonia, hemiparesis or spastic quadriparesis. Imaging studies usually show bilateral, symmetric or asymmetric clefts.

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Figure 6.2.7 Schizencephaly

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Schizencephaly is characterized by clefts placed symmet rically within the cerebral hemispheres and extending from the cortical surface to the underlying ventricular cavity (Fig. 6.2.7). It should be distinguished from porencephaly caused by a vascular insult to the brain. Porencephalic cysts communicate with the ventricular system or may extend to the cerebral cortical surface but do not destroy the thin pial membrane. Banks of schizencephaly will be lined by heterotopic gray matter.



Polymicrogyria

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Polymicrogyria results from an insult to the brain sustained before the fifth month of gestation. Brain will resemble a chestnut kernel and is characterized by gyri that are too small and too numerous. The clinically polymicrogyric children present as hypotonic cerebral palsy (mental retardation and hypotonia with active deep tendon reflexes). Another specific syndrome of opercular polymicrogyria or congenital bilateral perisylvian syndrome has been delineated. They have seizures, mental retardation and pseudobulbar manifestation (dysarthria, abnormal tongue movements and dysphagia).

andy-Walker Malformation

The Dandy-Walker malformation consists of posterior fossa cyst due to ballooning of the posterior half of the fourth ventricle. Failure of the foramen of Magendie to open is the primary pathology. Aplasia of the posterior cerebellar vermis, heterotopia of the inferior olivary nuclei, pachygyria of the cerebral cortex, and other cerebral and visceral anomalies are usually present. Infants present with a rapid increase in head size and a prominent occiput. Most children have evidence of long tract signs, cerebellar ataxia and delayed motor and cognitive milestones, probably due to the associated structural anomalies. Management is like that of hydrocephalus.

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mental delay. Eye abnormalities like hypoplasia of the optic nerve and microphthalmia are seen. Two types of lissencephaly are described: 1. Miller-Dieker syndrome, classical or type I lissencephaly with four-layered cortex. Children with Miller-Dieker syndrome have characteristic facies, including a prominent forehead, bitemporal hollowing 2. Anteverted nostrils, a prominent upper lip and micrognathia (Figs 6.2.6A and B) 3. Walker-Warburg syndrome and Fukuyama congenital muscular dystrophy, characterized by an almost complete absence of cortical layering.

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Figures 6.2.6A and B Lissencephaly: Miller-Dieker syndrome

The cerebral hemispheres are absent or represented by membranous sacs with remnants of frontal, temporal or 327 occipital cortex dispersed over the membrane. As it is

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Table 6.2.3 Clinical features of hydrocephalus Sign and symptoms in infants •  Poor feeding •  Head enlargement •  Irritability •  Sutural separation •  Reduced activity •  Dilated scalp veins •  Vomiting •  Tense anterior fontanel •  Open posterior fontanel •  Setting-sun sign •  Transillumination •  Due to the underlying etiology   –  Features of spinal dysraphism   –  Cranial bruit in cases of vein of Galen arteriovenous malformation   –  Chorioretinitis: intrauterine infection such as toxoplasmosis

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Symptoms in children •  Slowing of mental capacity •  Headaches (initially in the morning) •  Neck pain and head tilt suggesting tonsillar herniation •  Vomiting, more significant in the morning •  Blurred vision: due to optic atrophy •  Double vision: due to sixth nerve palsy •  Failure of up-gaze and of accommodation indicating pressure on the tectal plate •  Macewen sign: a “cracked pot” sound is noted on percussion of the head •  Stunted growth and sexual maturation from third ventricle dilatation: obesity, precocious puberty or delayed puberty •  Difficulty in walking secondary to spasticity: because the periventricular lower limb UMN fibers are stretched by the hydrocephalus  





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Medical treatment is used to delay surgical inter vention. It may be tried in premature infants with posthemorrhagic hydrocephalus (in the absence of acute hydrocephalus). Normal CSF absorption may resume spontaneously during this interim period. – Decreasing CSF secretion by the choroid plexus - Acetazolamide - Furosemide – Increasing CSF reabsorption - Isosorbide (effectiveness is questionable) Monthly head circumference measure and if it exceeds more than 2.5 cm/month surgical consideration. ­

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Clinical features of hydrocephalus are influenced by the patient’s age, etiology, location of obstruction, duration and are provided in Table 6.2.3.

Level of CSF blockage is best investigated by magnetic resonance imaging and also for associated Chiari malformation or cerebellar or periaqueductal tumors. Cerebrospinal fluid driven transependymally into the periventricular white matter (interstitial edema) is a relatively definite indication for surgery. • Ultrasound through the anterior fontanel in infants is useful for evaluating subependymal and intraventricular hemorrhage, and in following infants for possible development of progressive hydrocephalus. • Genetic testing and counseling recommended when X-linked hydrocephalus is suspected

Evaluate CSF in posthemorrhagic and postmeningitic hydrocephalus for protein concentration and to exclude residual infection.

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Repeat Lumbar Punctures Repeat lumbar punctures for hydrocephalus after intra ventricular hemorrhage, since this condition can resolve spontaneously. If reabsorption does not resume when the protein content of CSF is less than 100 mg/dL, spontaneous ­

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Hydrocephalus, an excessive volume of CSF in the skull results from an imbalance between the formation of CSF and its absorption. The increased pressure and the ventricular enlargement follow account for the clinical findings. Any block in the CSF pathway from the site of formation to that of absorption results in increased CSF pressure. By convention, hydrocephalus is divided into noncommu nicating (obstructive) and communicating (nonobstructive) forms. • In noncommunicating hydrocephalus, the obstructive site is within the ventricular system, including the outlet foramina of the fourth ventricle. • Communicating hydrocephalus occurs when full communication occurs between the ventricles and subarachnoid space. It is caused by overproduction of CSF: choroid plexus papilloma, defective absorption of CSF (subarachnoid hemorrhage, meningitis, leukemic infiltrates and intrauterine infections) or venous drainage insufficiency (achondroplasia, or venous thrombosis). The term congenital hydrocephalus applies to the ventriculomegaly that develops in the fetal and infancy periods, often associated with macrocephaly. The most common causes of congenital hydrocephalus are stenosis of the aqueduct of Sylvius, Arnold-Chiari malformation or Dandy-Walker malformation. These patients may stabilize in later years due to compensatory mechanisms but may decompensate, especially following minor head injuries. The incidence of congenital hydrocephalus is 3 per 1,000 live births.



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presumed to be due to bilateral occlusion of the internal carotid arteries, posterior circulation structures like midbrain and brainstem are relatively intact.

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Endoscopic Third Ventriculostomy for Obstructive Hydrocephalus

Shunts

Instead of the installation of a shunt hardware in the body, CSF pathway is diverted away from blockage by endoscopic third ventriculostomy. This allows the CSF to flow directly to the basal cisterns, thereby shortcutting any obstruction.

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Ventricular tap in infants Open ventricular drainage in children and adults Lumbar punctures in posthemorrhagic and postmeningitic hydrocephalus Ventriculoperitoneal or ventrículo-atrial shunt.

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1. Fenichel GM. Clinical Pediatric Neurology: A Signs and Symptoms Approach, 6th edition. Philadelphia: ElsevierSaunders; 2009. 2. Hans J, Donkelaar T, Lammens M, et al. Clinical Neuroembryology—Development and Developmental Disorders of the Human Central Nervous System. New York: Springer; 2006. 3. Johnston MV, Kinsman S. Congenital Anomalies of the Central Nervous System. In: Kliegman R, Stanton B, Behrman R, St. Geme J, Schor N (Eds.) Nelson Textbook of Pediatrics, 19th edition. Philadelphia: Elsevier-Saunders; 2011. pp. 198392.



ibliography



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It depends on the etiology. Hydrocephalic children are at increased risk for various developmental disabilities. Though gross mental retardation is absent, the mean IQ is reduced compared with the general population. Long-term follow-up for possible shunt complication like infection, block and associated neurological deficits must be done in a multidisciplinary setting.



Rapid-onset hydrocephalus with increased intracranial pressure is an emergency. The following can be done, depending on each specific case:

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Only about 25% of patients with hydrocephalus are treated successfully without shunt placement. • Establish a communication between the CSF (ventricular or lumbar) and a drainage cavity (peritoneum, right atrium or pleura) • Remember that shunts are not perfect and that all alternatives to shunting should be considered first • A ventriculoperitoneal shunt is used most commonly • A ventrículo-atrial shunt (vascular shunt): It shunts the cerebral ventricles through the jugular vein and superior vena cava into the right cardiac atrium. It is used when the patient has abdominal abnormalities (e.g. peritonitis, morbid obesity or after extensive abdominal surgery) • A lumboperitoneal shunt is used for communicating hydrocephalus, CSF fistula or pseudotumor cerebri.

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resorption is unlikely to occur. Surgical treatment is the preferred therapeutic option.

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Neurodegenerative isorders Naveen Sankhyan

pidemiology

Pathogenesis Both intrinsic and extrinsic factors are involved in pathogenesis. The underlying gene defect may affect the whole population of neurons or functionally related group of neurons. The nerve cells may be affected as a whole or certain components may be preferentially involved, e.g. axon, myelin, etc. Synaptic connections, neurotransmitter synthesis or action or neuromodulators may be affected by some disease processes. For most disorders, the precise process by which the abnormal enzyme activity or abnormal metabolite accumulation causes brain damage is yet be defined. In some disorders the culprit metabolite has been identified, e.g. psychosine in Krabbe leukodystrophy, polyglutamine in Huntington disease, and abnormal sterol in defects of cholesterol synthesis. Extrinsic factors like fasting, high protein load, fever, hypoglycemia, etc. may contribute to worsen the underlying condition. A

The true burden of NDD in India remains unknown. However, most of the common NDDs have been reported from India. Among the white matter degenerations “megalencephalic leukodystrophy with subcortical cysts” (Figs 6.3.1A and B)

is particularly common in India especially in the Agarwal community.

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Figures 6.3.1A and B Axial T2W MRI of brain showing abnormal diffusely hyperintense white matter in a 3-year-old child with “megalencephalic leukodystrophy with subcortical cysts” (A). Note the temporal cysts on the FLAIR image (B)

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Neurodegenerative disorders (NDD) are characterized by neuroregression. Neuroregression in children is associated with loss of memory, ability to think, understand and recognize along with personality changes or distressing behavior. Vision loss, hearing loss, tone abnormalities and epilepsy are other common symptoms. This neurological deterioration is not explainable by any other concurrent systemic illness. Although most of the childhood NDD are fatal, an accurate diagnosis is crucial for genetic counseling, prognostication, initiating prevention strategies and prenatal diagnosis. E

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The objective of a careful initial evaluation is to ascertain the age of onset, extent and evolution of the disease (white matter, gray matter, cerebellum, etc.) (Table 6.3.1). As a first step to clinical evaluation, pseudoregression should be excluded in all cases. Regression can occur without an underlying neurodegenerative process due to poorly controlled seizures, over-medication with anticonvulsants, intercurrent systemic illness and secondary neurological problems in a static encephalopathy, e.g. loss of mobility due to development of joint contracture, seizures, movement disorder, etc. or depression or other emotional problems especially in older children.

 

Table 6.3.1 Clinical features of gray and white matter diseases Feature Gray matter White matter Dementia Early Late Seizures Early and prominent Late Psychological symptoms May be present Uncommon Basal ganglia signs and symptoms Often present Absent Retinitis pigmentosa May be present Absent Primary optic atrophy Rare May be seen Primary neuropathy Rare May be seen Imaging (MRI) Cortical atrophy, abnormalities in basal ganglia, Clearly identifies abnormalities in white matter cerebellum Electroretinogram May be abnormal Normal Visual evoked response May be abnormal Normal Brainstem auditory evoked responses Usually normal Abnormal

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Flow chart 6.3.1 A simplified approach to a child less than 2 years with suspected degenerative brain disorder

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A detailed history is aimed at ascertaining the age of onset, and the spheres of development affected—motor, cognitive, vision and hearing. Family history of three generations is important to identify the possible modes of transmission. There are certain specific clues in general physical and systemic examinations, which give an indication to the nature of disorder (Table 6.3.2). After a careful history and examination, one is generally able to decide about the range of pathology within the nervous system and whether other organ systems are involved or not. Broadly, if one is able to assign the patient into one of the following groups, the further evaluation is easier. • Gray matter degenerations: poliodystrophies • White matter degeneration: leukodystrophies • rogressive ataxias • Basal ganglia disorders • Multisystem disorders with neuroregression.

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During infancy delayed milestones are common mani festation of neuroregressive disorders. Since the child has not gained many distinctive abilities, the loss of abilities

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Abbreviations: DBD, Degenerative brain disorder; MPS, Mucopolysacchari dosis; NPD, Niemann-Pick disease

 

Table 6.3.2 Some clinical pointers in hereditary neurodegenerative disorders Organ/feature Abnormality Disorders Head Microcephaly NCL, Krabbe disease, Rett syndrome Macrocephaly MPS, Alexander disease, Canavan disease, GM1 gangliosidosis, Tay-Sachs disease, MLSC Hair Alopecia Biotinidase deficiency Pigmentary changes PKU, Menkes disease Wooly, kinky hair Menkes disease (Fig. 6.3.7) Skin Rash Biotinidase, holocarboxylase deficiency Subcutaneous nodules Farber disease Angiokeratomas Fabry disease Fat pads, focal atrophy Congenital disorders of glycosylation Hyperpigmentation Adrenoleukodystrophy Eyes Cataract Galactosemia, Zellweger disease, Wilson disease Retinitis pigmentosa Peroxisomal disorders, NCL, mitochondrial encephalomyopathies, MPS, PKAN, ABLP Cherry red spot Tay-Sachs disease, Niemann-Pick disease, GM1 gangliosidosis Optic atrophy NCL, MLD, Krabbe disease, Canavan disease, GM2 gangliosidosis Ears Deafness MPS, ALD, mitochondrial disorders, peroxisomal disorders Hyperacusis Krabbe, Tay-Sachs disease Abdomen Hepatosplenomegaly MPS, GM1 gangliosidosis, Gaucher disease, Niemann-Pick disease Hernia GM1 gangliosidosis, MPS Nervous system Peripheral neuropathy MLD, Krabbe disease, mitochondrial disorders Hydrocephalous/raised MPS, infantile Alexander disease intracranial pressure Cardiac Cardiomyopathy FAOD, mitochondrial disorders, Friedreich ataxia, AVED, Pompe disease Valvular defects MPS, Zellweger syndrome, Fabry disease Abbreviations: NCL, Neuronal ceroid lipofuscinosis; MPS, Mucopolysaccharidosis; MLSC, Megalencephalic leukodystrophy with subcortical cysts; PKU, Phenylketonuria; PKAN, Pantothenate kinase associated neurodegeneration; ABLP, Abetalipoproteinemia; MLD, Metachromatic leukodystrophy; ALD, Adrenoleukodystrophy; FAOD, Fatty acid oxidation defects; AVED, Ataxia with vitamin E deficiency

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Flow chart 6.3.2 A simplified approach to a child less than 2 years with suspected degenerative brain disorder with no extraneural abnormalities

 

Figure 6.3.2 Gum hypertrophy and coarsening in a 18-month-old child with infantile GM1 gangliosidosis

mental deterioration, seizures and vision loss. Yet another group of children, presents with recurrent neurological deterioration interspersed with apparent recovery (organic aciduria, mitochondrial disorders, urea cycle disorders, etc.). •

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is difficult to quantify or localize. Commonly, the infant lacks visual interest or socialization has poor head control and inability to use hands. Other common symptoms are developmental retardation with severe hypotonia especially with feeding difficulties and/or vomiting and failure to thrive. Many disorders that present in the second year of life are frequently recognizable by the obvious loss of motor abilities. This may result from corticospinal, cerebellar, extrapyramidal or peripheral nerve involvement. The second year of life is also the age for disorders with gradually increasing dysmorphism, skeletal abnormalities and cognitive decline [mucopolysaccharidosis (M S) and mucolipidosis]. Some children may present with progressive

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In older children, the presentation of neuroregression begins after a considerable period of normal development. The onset and course of the disorder can also be more accurately determined. It is now much easier to view individual patients as having the predominant involvement of a particular area of the nervous system. The major clinical problem one faces is the varied ways in which the same disorder can present. This is particularly so for autosomal dominant disorders.

Abbreviations: NCL, Neuronal ceroid lipofuscinosis; MLD, Metachromatic leukodystrophy; MLSC, Megalencephalic leukodystrophy with subcortical cysts; PMD, Pelizaeus-Merzbacher disease

In girls with regression in cognitive spheres starting in infancy, microcephaly and associated with loss of purposeful hand movements “Rett syndrome” should be considered. Additionally, a possibility of HIV encephalopathy should always be kept in mind and a systematic evaluation for risk factors should be undertaken.

 

Flow chart 6.3.3 Approach to progressive neurological deterioration in 2–5 years age group

332 Abbreviations: MLD, Metachromatic leukodystrophy; ALD, Adrenoleukodystrophy; PKAN, Pantothenate kinase associated neurodegeneration; NCL, Neuronal ceroid lipofuscinosis; MERRF, Myoclonic epilepsy with ragged red fibers; MPS, Mucopolysaccharidosis

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Figure 6.3.4 Axial FLAIR MRI of brain showing posterior dominant abnormal hyperintense white matter in a child with adrenoleukodystrophy. The splenium of corpus callosum also prominently involved

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Figure 6.3.3 Axial FLAIR MRI of brain showing bilateral periventricular abnormal hyperintense white matter in a child with metachromatic leukodystrophy

 

Flow chart 6.3.4 Approach to progressive neurological deterioration in 5–15 years age group

Abbreviations: ALD, Adrenoleukodystrophy; MS, Multiple sclerosis; PKAN, Pantothenate kinase associated neurodegeration; SSPE, Subacute sclerosing panencephalitis; NCL, Neuronal ceroid lipofuscinosis; MERRF, Myoclonic epilepsy with ragged red fibers; AVED, Ataxia with vitamin E deficiency

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Subacute sclerosing pan-encephalitis (SS E), though not a hereditary NDD is a common cause of neuroregression in our country. It should be considered in all children with behavioral changes, cognitive deterioration with or without myoclonic jerks.

Investigations They are guided by history and examination. I

maging: A high resolution MR imaging with spectroscopy would be the best to pick up abnormalities. In certain patients it may provide a diagnostic clue, for e.g. pantothenate kinase associated neurodegeneration with “eye of tiger” sign in globus pallidi (Fig. 6.3.5). MR imaging with spectroscopy helps in diagnosis of certain disorders such as Canavan disease, mitochondrial encephalopathies and creatine deficiency disorders • adiographs: A skeletal survey would be important to look for abnormalities in certain storage disorders such as M S (Figs 6.3.6A and B) P

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Figure 6.3.5 Coronal T2W MRI in a child with pantothenate kinase associated neurodegeneration showing the bilaterally hypointense globus pallidi with an area of central hyperintensity  

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lipofuscinosis – Hair microscopy: Menkes Disease (Fig. 6.3.7) Specific investigations are done based on clues obtained from preceding investigations: – Serology: HIV, SS E – Urine copper, serum ceruloplasmin: Wilson disease (Fig. 6.3.8) – Urine MPS: mucopolysaccharidosis – Enzyme analysis: lysosomal storage disorders, biotinidase deficiency – Urine organic acids: organic acidemias – Very long-chain fatty acids (VLCFA) and plasmalogen levels: peroxisomal disorders – Mutation testing: this can be undertaken if the diagnosis is quite certain and the test is available. –

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rine and blood assay for plasma ammonia, blood lactate and pyruvate, plasma amino acids: These tests guide the course of further investigations in a suspected neurometabolic disorder to arrive at the diagnosis • lectrophysiological tests: Include visual evoked potentials, brainstem auditory evoked responses, nerve conduction studies, electroencephalography, electromyography and somatosensory evoked potentials. Helps delineate the extent of central and peripheral nervous system involvement in the patient • Histopathological and ultrastructural information from selected biopsies – Bone marrow: storage cells are seen in Niemann- ick disease, Gaucher disease – Conjunctival, skin, rectal biopsy: Neuronal ceroid –

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Figures 6.3.6A and B (A) X- ray of hands of a child with infantile GM1-gangliosidosis showing mild changes of dysostosis multiplex with early conical shape of proximal bases of 2–5 metacarpals with tapering of the proximal phalanges; (B) Lateral radiograph of the spine in child with infantile GM1gangliosidosis showing mild changes of dysostosis multiplex with breaking of the lumbar vertebra

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Figure 6.3.8 MRI in a child with Wilson disease showing the involvement of bilateral basal ganglia  

Figure 6.3.7 Note the sparse, hypopigmented curly, stubby hair in a child with Menkes disease

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ing disorder. In general an earlier onset of disease predicts a poorer outcome. However, several late onset diseases can also rapidly progress, e.g. adrenoleukodystrophy.

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• A thorough clinical evaluation that includes a detailed history, family history, general physical and systemic evaluation forms an important starting point for further evaluation. • If the history and examination are strongly indicative, more specific diagnostic testing can be undertaken, e.g. HIV testing, urine M S, V CFA, etc. • Always keep the treatable causes in mind and exclude them systematically, based on the clinical presentation. • Second line investigation is generally undertaken best at research and referral centers with expertise in handling these children. • While managing these children, always focus on issues, which make the child’s life comfortable, e.g. control seizures, spasticity, adequate nutrition and skin care, etc.

ibliography 1. Fenichel GM. Clinical ediatric Neurology; A Signs and Symptoms Approach, 5th edition. hiladelphia: Elsevier; 2005. 2. yon G, Kolodny EH, astores GM. Neurology of Hereditary Metabolic Diseases in Children, 3rd edition. New York: McGraw-Hill companies; 2006. 3. Michelson DJ, Shu SK. Cognitive and Motor regression. In: Swaiman KF, Ashwal S, Ferriero DM. ediatric Neurology, 4th edition. hiladelphia: Elsevier; 2006. pp. 821-44. 4. Neurologic syndrome. In: Clarke JTR. A Clinical Guide to Inherited Metabolic Diseases, 3rd edition. Cambridge: Cambridge University ress; 2006. pp. 28-89. P

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Figure 6.3.9 Note the coarsening of facial features, large tongue in an infant with hypothyroidism





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Prognosis

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One of the very important aspects of management of a child with NDD is to accurately establish the diagnosis. This becomes important not only for proper care and prognostication but also for accurate prenatal diagnosis to prevent further children being affected by the same disease. The diagnosis may also help identify pauci or presymptomatic siblings or other family members who may benefit from early therapy, e.g. zinc therapy in Wilson disease. It would be wise to refer the parents for prenatal diagnosis to an equipped center before they plan any future pregnancies.

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upportive easures It is never wise or correct to say that the disease is “untreatable”. Such statements only result in the parents feeling a profound sense of anguish, abandonment and loneliness. Something can almost always be done to help the child. Supportive treatment may add significantly to the quality of life of a child with neurodegenerative disorder. Measures to reduce spasticity, control seizures, control pain, improve nutrition, prevent constipation, prevent bed sores, and to enhance mobility, all contribute to the quality of life of the patient and indirectly to the quality of life of the parents and any unaffected siblings.

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Firstly, never miss out a treatable cause of neuroregression like hydrocephalus, HIV infection, hypothyroidism, (Fig. 6.3.9) lead toxicity, etc. It must be remembered that many NDD are amenable to treatment (Table 6.3.3).

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Table 6.3.3 Few examples of treatment in neurodegenerative disorders Disease Therapeutic agent Gaucher disease Enzyme replacement, Miglustat Fabry disease Enzyme replacement Attenuated variants of Enzyme replacement Mucopolysaccharidosis type I (MPS I) Pompe disease Enzyme replacement Ataxia (Co-Q deficiency) Coenzyme Q10 Ataxia with vitamin E deficiency Vitamin E Minimally symptomatic X-linked Bone marrow transplant adrenoleukodystrophy MPS 1H-Hurler disease Bone marrow transplant Glycogen storage disease Liver transplant Glutaric aciduria–II, Biotinidase Co-factor replacement deficiency

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Neurocutaneous isorders

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Devendra Mishra Neurocutaneous disorders are disorders, which frequently involve the skin in addition to the nervous system. Many of these may initially present with the cutaneous findings, and recognition of the characteristic features helps in identifying the disorder and anticipating the neurological problems. Table 6.4.1 lists and summarizes the clinical features of these disorders. The commoner ones would be discussed in detail. C

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Table 6.4.1 Characteristic features of various neurocutaneous disorders Tuberous sclerosis Hypopigmented macules (ash leaf macules), complex seizures (including infantile spasms), cortical tubers, angiofibroma (adenoma sebaceum), connective tissue nevus (shagreen patch) Neurofibromatosis NF 1: Multiple café-au-lait spots, neurofibromas, Lisch nodules (iris hamartomas), axillary or inguinal freckling, optic glioma, learning difficulties NF 2: Vestibular schwannomas Sturge-Weber Facial hemangioma (port-wine stain), leptome syndrome ningeal angioma, seizures, developmental delay Ataxia-telangiectasia Progressive ataxia, recurrent sinopulmonary infections, ocular telangiectasia and increased preponderance for lymphoreticular malignancies Incontinentia pigmenti Hyperpigmented skin lesions, CNS abnormalities, hypopigmented lesions in hypomelanosis of Ito Klippel-TrenaunayUnilateral limb hypertrophy, subcutaneous Weber syndrome hemangioma, macrocephaly, hydrocephalus von Hippel-Lindau Cerebellar hemangioblastoma and retinal disease angiomas presenting in young adults PHACE syndrome Posterior fossa malformations, hemangiomas, arterial abnormalities, coarctation of aorta and other cardiac abnormalities, and eye abnormalities

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Figure 6.4.1 `MRI brain T1 weighted image showing cortical tubers (white arrow) and subependymal tubers (black arrow) in tuberous sclerosis

develop into subependymal giant cell tumors in 5–10% patients). Epilepsy is the commonest presenting feature and almost all types of seizures are reported. Majority have seizure onset during infancy with infantile spasms developing in up to one-third of children with TSC. Skin manifestations include angiofibromas (erroneously called as adenoma sebaceum), which appear in the preschool age and are progressive. These are present as pinkish papules in patches around the nose, cheek and chin (Fig. 6.4.2). Hypopigmented macules over trunk and limbs (ash leaf macules) are apparent at birth and may increase in size with age. These are better seen with Wood’s light. Connective tissue hamartomas (shagreen patch) are usually found in the lumbosacral region. After the neurological involvement, renal involvement causes the most morbidity and consists of angiomyolipomas and renal cysts. The former are seen in up to 80% patients, may appear in childhood, and are occasionally symptomatic, causing pain, obstruction or hemorrhage. More important from the pediatric perspective is the cardiac rhabdomyoma, which is seen in up to 60% and is maximal at birth or early childhood, regressing spontaneously later. They may even be detected prenatally. Depending on the location, these can cause obstruction, conduction defects and valvular dysfunction. Nearly half the patients have retinal hamartomas and other ocular problems. Hamartomas of other organ systems are also reported, and females may exclusively have pulmonary involvement.



It is a multisystem disorder with an incidence of nearly 1 in 5,800 live births (prevalence 1:10,000). It is transmitted as an autosomal dominant trait with variable penetrance. Two genes tuberous sclerosis complex 1 [TSC1 (located on 9q34, gene product hamartin) and TSC2 (located on 16p13, gene product tuberin)] have been identified. The lesions are caused by hamartomas and hamartias, and there is a wide variation in clinical expression of the disease. Seizures occur in about 85%, mental retardation in around 50%, skin lesions in more than 95%, and autism in up to half of the patients. More importantly, diagnosis can be made even in the presence of only skin or neuroimaging findings. The neurological affection is the most important clinically. The major brain abnormalities include cortical tubers (Fig. 6.4.1), and subependymal nodules (which may



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Management includes medical management of epilepsy. Drug resistant patients may be helped by epilepsy surgery, if a single tuber is responsible for majority of the seizures. Infantile spasms in TSC respond well to vigabatrin. Some associations between autism spectrum disorders and tuber load have been reported. Interventions for developmental and behavioral problems should be provided.

Neurofibromatosis Two major types of neurofibromatosis have been delineated:

Neurofibromatosis 1 Neurofibromatosis 1 is transmitted in autosomal dominant manner (gene NF1 located on 17q11.2 chromosome, product is neurofibromin) with a prevalence of 1:4,000, and most commonly involves the nervous system and the skin. As opposed to TCS, the commonest presentation is the skin features, of which the most important are the café-au-lait spots (Fig. 6.4.3). These are present at birth and may increase in infancy. In prepubertal children, they need to be more than 5 mm in size and at least 6 in number to suspect neurofibromatosis. Inguinal freckling (starting in the preschool age) and later in the axillae and base of neck is also seen. Cutaneous neurofibromas are discrete, soft or

 



Neurofibromatosis 2 It is the central form of neurofibromatosis. The hallmark is bilateral vestibular schwannomas, which may appear at any age and usually present with tinnitus with or without hearing loss. Juvenile lens opacities (present in approximately 80%) and retinal hamartomas are also seen in children. MRI evaluation is the investigation of choice, though brainstem auditory evoked responses may be helpful, especially for follow-up. Management No specific management is required for NF1 other than regular evaluation for complications, e.g. focal neurological deficit, abnormal puberty, optic pathway tumor, scoliosis, hypertension. Fifty percent of the cases occur sporadically and thus unaffected parents have a low recurrence risk. Schwannomas in NF2 are managed surgically. Genetic testing for diagnosis and prenatal testing is available for both NF1 and NF2.

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Specific diagnostic criteria, which include major and minor features, have been provided. Neuroimaging, developmental assessment, and eye, cardiac and renal evaluation are recommended at diagnosis for all patients, and then as indicated by manifestations. Follow-up for neuroimaging is suggested every 1–3 years as there is a possibility of development of subependymal giant cell tumor.

firm papules, which can occur at any age and at any location. Plexiform neuroma is a tumor involving a longitudinal section of a nerve and its branches. Hamartomas of the iris (Lisch nodules) appear after 5 years of age and are seen in more than 90% adults with NF1. Optic gliomas and astrocytomas of the intracranial structures may occur. MRI in under-5 children may show unidentified bright objects. Congenital glaucoma may occur occasionally. Spontaneous limb fractures (with pseudoarthrosis), macrocephaly, short stature and scoliosis are also reported. Approximately, 50% patients have developmental disabilities including attention-deficit hyperactivity disorder.

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Figure 6.4.3 Café-au-lait macules in neurofibromatosis 1

 

Figure 6.4.2 Facial angiofibroma (adenoma sebaceum) in a child with tuberous sclerosis complex and autism

This disorder is one of the most easily identifiable among the neurocutaneous disorders due to the characteristic facial

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Figure 6.4.5 Corneal telangiectasia in a girl with ataxia-telangiectasia

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1. Barbagallo JS, Kolodzieh MS, Silverberg NB, et al. Neurocutaneous disorders. Dermatol Clin. 2002;20:547-60. 2. Kandt RS. Tuberous sclerosis complex and neurofibromatosis type 1: the two most common neurocutaneous diseases. Neurol Clin. 2003;21:983-1004. 3. Smirniotopoulos JG. Neuroimaging of phakomatoses: Sturge-Weber syndrome, tuberous sclerosis, von HippelLindau syndrome. Neuroimag Clin N Am. 2004;14:171-83. 4. Thiele EA, Korf BR. Phakomatosis and allied conditions. In: Swaiman KF, Ashwal S, Ferriero DM (Eds). Pediatric Neurology: Principles and Practice, 4th edition. Mosby, US; 2006.pp. 771-96.

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Management of seizures is similar to that due to any other cause. Epilepsy surgery is a viable option for drug-resistant seizures. Dermatological manifestations should be treated at the earliest (even in infancy), usually by pulsed dye laser therapy. Glaucoma should be managed medically or surgically depending on the underlying abnormality and response.

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• The skin should be specifically examined in every patient with epilepsy/neurological problems. • Recognition of suggestive dermatological findings helps in identifying the neurocutaneous disorder. • Early diagnosis of neurocutaneous disorder is helpful in prognostication, and anticipating complications and optimizing management.

valuation Evaluation includes cranial MRI (preferably gadolinium enhanced) and/or CT, which are diagnostic (Fig. 6.4.4). By the age of 20 years, almost 90% have typical linear, parallel intracranial calcification evident on skull radiograph (tram-track sign) in parietal or parieto-occipital region. Ophthalmological assessment for ocular manifestations is essential. anagement

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features. The disease occurs sporadically with a prevalence of 1:50,000, and is due to the presence of residual embryonic blood vessels. The essential features are the angiomas of the face (port-wine stain) and ipsilateral leptomeningeal angiomas. The usual facial involvement is in the upper face and eyelids, although lips, intraoral structures and pharynx may also be involved. Trunk and extremities of either side are occasionally affected. Ipsilateral parietal and occipital regions are most commonly affected by the leptomeningeal angiomas, which occasionally may be bilateral. Majority (75– 90%) of the patients present with seizures that are frequently refractory to medical management. Approximately onethird of the patients develop contralateral hemiparesis, and nearly half may have mental retardation and developmental problems. Around 60% patients have recurrent headaches. Ocular problems include glaucoma (in 25% patients due to choroidal involvement), heterochromia iris and strabismus.

gene on chromosome 11q22-q23), and is characterized by progressive ataxia, recurrent sinopulmonary infections, ocular telangiectasia and increased preponderance for lymphoreticular malignancies. Ataxia starts at around 2 years of age and gradually increases leading to loss of ambulation by 12 years. Telangiectasia, characteristically present on the bulbar conjunctiva (Fig. 6.4.5), appears by the age of 3–6 years, and may also be seen on the face or extremities. There may be presence of nystagmus, strabismus and ocular motility abnormalities. Immunologic functions are deranged (commonly decreased secretory IgA) and there may be a loss of skin elasticity. Elevated a-fetoprotein levels help in diagnosis in early childhood. Patients have a greatly increased risk of developing tumors (lymphoma, leukemia, Hodgkin disease, brain tumors, etc.). Death usually occurs by adolescence or young adulthood, and is due to infection or malignancy.



 

Figure 6.4.4 Linear intracranial calcification on noncontrast CT of the head in an 8-year-old child with Sturge-Weber syndrome

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The plan of investigations depends on suspected cause (see “management of acute seizures and status epilepticus”).







 

Table 6.5.1 Clinical manifestations during seizures •  Abnormal motor activity, which may be a tonic contraction or single or repetitive jerks •  Impairment or loss of consciousness or awareness •  Abnormal behavior •  Abnormal sensory phenomena, e.g. abnormal sensation in one part of the body, visual phenomena, smell, taste •  Abnormal experience: Fear anger illusions or hallucination. Children often run to the parent when this occurs •  Autonomic symptoms

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The exact pathophysiology of epileptogenesis is still not well understood. However, it is known that seizures are produced when there is an abnormality in the: • Neurotransmitters levels • Ion channels or • Receptors. In many of the genetic epilepsies, there are abnormalities of the ion channels or receptors due to mutations, resulting in epilepsies. These abnormalities can result in hyperexcitability of neurons, which thus have a tendency to seizures. The other epilepsies result from neuronal damage because of various insults like infections, trauma and vascular events. I

Cryptogenic epilepsies are epilepsies, which are expected to have a cause, but despite investigations, no cause is found.

Pathophysiology

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Idiopathic epilepsies (now known as genetic epilepsies) are epilepsies, which have no underlying cause except a genetic predisposition to epilepsy.

Etiology is multifactorial, and almost any insult to the brain can result in seizures. Epilepsy can result from brain injury due to infections, infestations, hypoxic damage, birth injury, malformations of the brain, genetic or metabolic causes (Table 6.5.2).



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In India, prevalence rates for epilepsy are 5.59 per 1,000 populations. Males and females are equally affected and these rates are the same in different geographical areas.

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Epilepsy is recurrent seizure for which there is no immediate precipitating cause.

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The area of the brain producing the discharge The type of discharge The age of the patient

Epileptogenesis is the sequence of events that converts normal neuronal networks into hyperexcitable epileptogenic networks.

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A seizure is the clinical manifestation of an abnormal excessive paroxysmal electrical discharge from the brain. This electrical discharge is conducted to the body and produces a seizure. It could manifest in many different ways (Table 6.5.1). The type of seizure depends on the following:

Provoked or acute symptomatic seizures are seizures occurring during the course of an acute illness, e.g. meningitis or head injury.

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An EEG is the most important test for investigating epilepsy. It is a graphic recording of the electric activity of the brain. An EEG is normal not due to normal patterns, but because it 339 has no abnormal patterns.

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Other investigations depend on suspected etiology in case of symptomatic epilepsies. These include metabolic and genetic tests.

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In any given population with epilepsy, 30% may undergo remission without treatment. This emerges from studies of epilepsy in poor countries where no treatment has been given for epilepsy because of financial constraints. Of those who are treated, 60–70% undergoes remission, while the remaining has intractable seizures.

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Classification of eizures and pileptic yndromes It is very important to identify the syndrome wherever possible, for starting correct treatment and prognostication, and to identify etiology and genetics. In the past, there existed confusion between epilepsies and seizure types. Many of the epilepsies were classified and described by the names of the persons who first described them. There was no uniformity in the classification and descriptions used in different parts of the world. The International League Against Epilepsy (ILAE) described a classification of seizures in 1981, and epilepsies and epileptic syndromes in 1989, which has been modified in 2006. Table 6.5.4 shows classification of seizures. S

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Neuroimaging gives important information about the etiology in cases of symptomatic epilepsies (Figs 6.5.7 and 6.5.8). MRI is preferred since small lesions like cortical dysplasia cannot be picked up on CT scan. Generally neuroimaging should be done in all cases except where clinical features and EEG are suggestive of idiopathic epilepsy. Positron emission tomography and single photon emission computed tomography are functional scans that may be done to study the perfusion. They are used in preepilepsy surgery workup in refractory epilepsy and help in identifying epileptic foci.

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It is important to remember that EEG can be normal in cases of epilepsy, while abnormal EEG does not necessarily mean an epileptic disorder. Fifteen percent of cases of epilepsy have a normal EEG, while 10% of the normal population has an abnormal EEG. Thus the EEG must be interpreted in the clinical context (Table 6.5.3 and Figs 6.5.1 to 6.5.5). Ictal recordings are preferable over interictal ones. Special provocation procedures like sleep deprivation, hyperventilation and photic stimulation can be used to increase the yield of EEG. Video EEG is an EEG recording where the EEG and video recordings are done at the same time. It may help to differentiate non-epileptic events (NEE) from seizures, and also help in identification of the type of seizure (Fig. 6.5.6).

Limitations   Normal EEG does not exclude epilepsy   Must always be interpreted in the clinical context   With the exception of 3Hz spike wave discharges and hypsarrhythmia EEG is a poor guide to seizure control Abbreviations: SSPE, Subacute sclerosing panencephalitis; EEG, Electroen­ cephalogram

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Table 6.5.3 Electroencephalogram: information and limitations Information   Epileptic versus nonepileptic attacks   Seizure type and epilepsy syndrome (Figs 6.5.1 to 6.5.3)   Photosensitivity   Partial seizures: To identify the focus (Fig. 6.5.4)   Identify etiology, e.g. SSPE (Fig. 6.5.5)   Monitor progress: Only in some epilepsies, e.g. typical absence seizures, West syndrome. In most cases clinical response should be the criterion for judging response to treatment. Routine EEGs during treatment are not required   Withdrawal of drugs: EEG is not required. Only clinical seizure control should decide whether drug is to be stopped

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Table 6.5.2 Etiology of seizures and epilepsy Causes of seizures Causes of epilepsy Sequelae of any of the acute causes Infections of seizures   Viral encephalitis Cerebral malformations   Pyogenic meningitis Metabolic diseases   Tubercular meningitis Degenerative brain diseases   Neurocysticercosis Neoplasms Metabolic events Genetic disorders   Hypoglycemia   Hypocalcemia   Hypomagnesemia   Dyselectrolytemia (hypernatremia/hyponatremia) Vascular events   Cerebrovascular accidents Drug intoxication/side effects Vascular events   Thrombosis   Embolism   Hemorrhage Neoplasms Hypoxia/anoxia especially during delivery Head trauma Febrile seizures

The ILAE proposed a classification of epilepsies and epileptic syndromes in 1989. Earlier the epilepsies were classified as localization related epilepsies, generalized

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Figure 6.5.1 Hypsarrhythmia, a high voltage chaotic electroencephalogram pattern which changes, characteristic of infantile spasms

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Figure 6.5.2 Polyspike wave discharges suggestive of myoclonic seizures

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Figure 6.5.3 3/sec spike wave discharges suggestive of typical absence seizures

Figure 6.5.4 Epileptic focus—right frontal region  

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Figure 6.5.5 Periodic complexes seen in subacute sclerosing pan encephalitis

 

Figure 6.5.6 Video electroencephalogram. Simultaneous electroencephalogram and video recording

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Figure 6.5.8 Neurocysticercosis  

 

Figure 6.5.7 Structural malformation of central nervous system: agenesis of corpus callosum

 

Table 6.5.4 Classification of seizures Generalized: The epileptic discharge involves both cerebral hemispheres at the same time i

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•  Generalized tonic clonic seizures (earlier known as grand mal seizures): t starts with a tonic phase characterized by a generalized stiffening of the whole body, followed by rhythmic to and fro contractions of extremities. There may be a tongue bit in the tonic phase, with urinary or stool incontinence, and froting during the clonic phase •  Tonic seizures: There is sudden but sustained contraction of various muscle groups or the whole body. They may result in a drop attack if the patient is standing. There are often underlying other neurological abnormalities, and other types of seizures •  Atonic seizures: There is sudden loss of muscle tone of head and neck, trunk or limbs. Drop attack may result. These are also often associated with underlying other neurological abnormalities and other types of seizure may occur •  Clonic seizures: There are rhythmic jerking contractions and relaxation of various muscle groups •  Myoclonic seizures: Sudden contraction of a muscle or muscle group. They can be single, or occur in clusters. They may be simply myoclonic, or myoclonic atonic or myoclonic tonic •  Absence seizures: There is a short period of alteration of consciousness:   –  Typical absence: Start and end abruptly. There is no fall, and after the brief period of alteration consciousness (few seconds only), the child resumes activity as if nothing has happened   –  Atypical absence: Onset is gradual, the patient has alteration of consciousness for a variable duration (may be minutes) and ending is also gradual. Postural changes can occur and they are often associated with other seizure types and neurological abnormalities and mental retardation   –  Absence with special features: Eyelid myoclonus, myoclonic absence Focal or partial: The epileptic discharge starts in a focus of the brain in one hemisphere (focal or localization related seizures)



 



Without impairment of consciousness/responsiveness Simple partial seizures (SPS) With impairment of consciousness/responsiveness Complex partial seizures (CPS) Secondarily generalized seizures: both SPS and CPS may evolve to generalized seizures (which is a convulsive seizure): The seizure may start as a SPS and evolve to CPS. An AURA may often be the SPS before the CPS supervenes Associated motor movements (repetitive semipurposive movements like fiddling with clothes, rubbing, walking, repeating a word or phrase) called automatisms may occur during the period of impaired consciousness The terms simple and complex have now been removed as it is often difficult to assess impairment of consciousness especially in children, and they may simply be called focal seizures, and seizures may simply be described as focal seizures or focal motor seizures if there is a focal motor involvement Focal, generalized or unclear: Epileptic spasms  

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Nonepileptic events are events, which resemble seizures but are not the result of abnormal electrical discharges. They are also known as nonepileptic attack disorder, epilepsy imitators, epilepsy mimickers and pseudoseizures. These can also produce recurrent episodes of motor movement or apparent changes of consciousness or behavior that are also seen in children with epilepsy. Also disorders that mimic seizures are more likely to occur in children who have epilepsy, associated with abnormal EEG or to be relieved by antiepileptic drugs (AED) making their diagnosis more difficult.

 

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Twenty to thirty percent of all patients reporting to epilepsy clinics are found to have NEE. As many as 30% of patients with NEE have real seizures as well. Nonepileptic events and epilepsies both present at all ages and in many different forms. Therefore many conditions can mimic epilepsy at different stages of a child’s life.

Nonepileptic events can be divided into two groups: NEE

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1. Physiological : These are various physiological phenomena, which resemble seizures on observation or when described by parents. 2. Psychogenic : These are seen mostly in children more than 5 years of age and are either conversion reactions or malingering.

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epilepsies and unknown whether localization related or generalized. Typically, to classify an epilepsy into an epileptic syndrome, some information is required (Table 6.5.5), which may or may not be available. Practically, it is best to use the age-wise approach in classifying the epilepsies (Table 6.5.6).



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able 6.5.6 Genetic and developmental epilepsy syndromes by age of onset (according to International League Against Epilepsy) Neonatal period •  Benign familial neonatal seizures •  Early myoclonic encephalopathy •  Early infantile epileptic encephalopathy (Ohtahara syndrome) Infancy •  Migrating partial seizures of infancy •  West syndrome •  Myoclonic epilepsy of infancy •  Benign infantile seizures •  Dravet syndrome •  Myoclonic epilepsy in nonprogressive disorders Childhood •  Early onset benign childhood occipital epilepsy (Panayiotopoulos type) •  Epilepsy with myoclonic astatic seizures •  Benign childhood epilepsy with centrotemporal spikes •  Late onset childhood occipital epilepsy (Gastaut type) •  Epilepsy with myoclonic absences •  Lennox Gastaut syndrome •  Epileptic encephalopathy with continuous spike and wave during sleep including Landau Kleffner syndrome •  Childhood absence epilepsy Adolescence •  Juvenile absence epilepsy •  Juvenile myoclonic epilepsy •  Epilepsy with generalized tonic clonic seizures only •  Progressive myoclonus epilepsies Relation with age less specific •  Autosomal dominant nocturnal frontal lobe •  Familial temporal lobe epilepsies •  Autosomal dominant partial epilepsy with auditory features •  Generalized epilepsies with febrile seizures plus •  Familial focal epilepsy with variable foci •  Reflex epilepsies   –  Idiopathic photosensitive occipital lobe        –  Visual sensitive epilepsies   –  Primary reading epilepsy   –  Startle epilepsy Seizure disorders that are not traditionally given the diagnosis of epilepsy: •  Benign neonatal seizures •  Febrile seizures

Table 6.5.5 Information required for classifying as an epileptic syndrome •  Seizure type (s) (seizure semiology plus electroencephalogram pattern) •  Age of onset •  Developmental status •  Etiology •  Anatomy •  Precipitating factors •  Prognosis (occasionally)

History and Clinical Examination History and clinical examination can give clues to the correct diagnosis. A description of event, especially an eyewitness account is very important in obtaining a correct diagnosis. A review of home videos is often the most important aid to diagnosis. The event should typically be suggestive of some

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Pathophysiology: The spell is actually a reflex rather than a behavior problem as was thought earlier. They are of two types: 1. Cyanotic (more common): There is forceful expiration during crying, a respiratory pause (breath holding) resulting in hypoxia and cyanosis. 2. Pallid: Vagal stimulation following a painful stimulus or during pause in respiration during expiration, results in cardiac asystole, hypoxia and pallor.

Age-Based Approach Consider the types of seizures in a particular age group, and if the event does not match the type of seizures occurring in that age group, one should review the NEE in that age group (Table 6.5.7). For example, myoclonic jerks during sleep in a neonate may be confused with myoclonic seizures; daydreaming in a school going child may be confused with complex partial seizures.

leading to forceful crying. They occur in children 6 months to 2 years of age and disappear by 6 years age. Males are more commonly affected than females in a ratio of 3:1. Family history may be present in one-fourth of the cases.



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type of seizure. Developmental delay and neurological deficits are more likely to be associated with true seizures, but may also be associated with NEEs.

Attempts to Observe the Event This is possible if the event occurs at a particular time or is precipitated by something, e.g. breath holding spells: try to make the child cry. If psychogenic seizures are suspected, the event may be induced by suggestions.

Ancillary Testing: Electroencephalogram/Video Electroencephalogram

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Ancillary testing is done when there is doubt about the diagnosis of NEE despite history and clinical observation of the patient. Sometimes true seizures and NEEs may coexist making differentiation between the two very difficult.

Clinical presentation: The child holds his/her breath following a sudden painful stimulus and becomes pale or becomes cyanosed after a prolonged expiration while crying. He/she then loses consciousness for a brief period, usually less than a minute. There may be stiffening of the whole body, followed by a few clonic jerks making the event appear like a seizure. He/she gradually regains consciousness with return of normal color, and may remain drowsy or sleep for sometime. The attack may occur many times in a day.

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Common onepileptic vents Breath Holding Spells Breath holding spells are stereotypic events that occur in response to a painful stimulus or an adverse emotional event

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anagement: Is as follows: Counseling regarding the benign nature of the condition is a must to alleviate anxiety Diverting the child’s attention at the onset of crying can abort an attack

 

Table 6.5.7 Nonepileptic events at different ages Neonates—2 years Early childhood Abnormal movements Abnormal movements During sleep During sleep Benign neonatal sleep myoclonus Sleep myoclonus When awake Sleep myoclonus Chorea When awake Tics Masturbation Paroxysmal choreoathetosis Jitteriness clonus Abnormal behavior Stereotypies During sleep Myoclonic movements Sleepwalking Spasmus nutans Night terrors Opsoclonus Nightmares Abnormal breathing Confusional arousals phenomena When awake Recurrent apneic attacks Panic/rage attacks Breath holding spells Delirium Loss of consciousness/awareness Daydreaming Others Benign paroxysmal vertigo Migraine

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Late childhood and adolescence Abnormal movements Psychogenic “seizures” Loss of consciousness/awareness/ tone Psychogenic “seizures” Syncope Narcolepsy/cataplexy Others Fears and phobia

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Some children have low hemoglobin levels, therefore iron therapy may help in decreasing the frequency of attacks In case of severe multiple attacks, piracetam in doses of 50 mg/kg/day in three divided doses may be given, and can significantly decrease the frequency of attacks.

 

Table 6.5.8 Features of psychogenic nonepileptic events •  May be precipitated by an emotional event •  All episodes may not be similar •  No history of injury despite fall •  Memory of events during the episode may be present sometimes •  Thrashing movements are side to side rather than flexion extension, and appear to vary with time •  Waxing and waning of movements •  Screwing up the eyes when attempts are made to examine then, and uprolling of eyes on attempts to passively open the eyes •  When hand is raised up it falls on the side rather than on the face •  There is usually no frothing, but saliva may trickle out from the mouth. Voluntary tongue bite may occur •  No urinary incontinence; but may occur occasionally •  Patient appears to periodically be focused and interact with surroundings •  Attack terminates with a particular action, e.g. sprinkling water on the face holding legs together or rubbing hands •  Duration: Variable but is often prolonged •  Patient may start crying before, during or after the attack. Sometimes, tears may just flow. 

Benign Neonatal Sleep Myoclonus







This is a myoclonus that is sometimes seen in neonates at age of 1–2 weeks, up to 6 months of age. It comprises of repetitive jerking or myoclonic movements of the different body parts, and occurs only during sleep. Awakening the baby terminates the attacks. The baby remains neurologically normal. They may be mistaken for seizures and put on AEDs to which there is no response. EEG and video EEG are normal.





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Both forms may be difficult to differentiate from true epilepsy, just on the basis of history alone. It is important to try to observe an episode to discern whether it is a true seizure or a psychogenic one. A video EEG is required if any doubt remains about the existence of seizures. Some clues to psychogenic seizures are given in Table 6.5.8. Once diagnosed, children should undergo neuropsychological testing and counseling. Most children/parents would opt for discontinuing the drugs. A trial of placebo may be given. Sometimes true seizures coexist with psychogenic seizures when it becomes extremely difficult to differentiate true from psychogenic seizures, leading to either under treatment or overtreatment.





Syncope is a transient loss of consciousness, resulting in loss of tone and a fall, from which the patient makes a spontaneous recovery. Presyncope is the period just before consciousness is lost. It consists of a lightheaded feeling, weakness and unsteadiness. It may result in a drop attack. Twenty percent of children suffer from one or more attacks of syncope before the age of 15 years, but most of the syncopal attacks are benign in children. Syncope can be differentiated from seizures by taking a detailed history. If there is a doubt, then the tilt table test can be done, which involves putting the patient in 70° position after strapping to a table, and checking vital parameters and symptoms of syncope in that position. Cardiac syncope should be suspected if the syncope occurs during exercise or when lying down. If the child has vasovagal syncope, the child should avoid situations that precipitate the attack. During an attack, the clothes should be loosened and the patient should be made to lie down for some time. No attempt should be made to give mouth to mouth respiration.





1. Unresponsiveness with no motor activity 2. Unresponsiveness with varying degrees of motor activity, ranging from just shivering to thrashing around violently.

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Most seizures terminate spontaneously without treatment or after administration of a fast acting anticonvulsant drug. Status epilepticus (SE) means that seizures continue for a prolonged period. The International League Against Epilepsy defines SE as seizures that continue for more than 30 minutes or recurrent seizures for more than 30 minutes without recovery of consciousness in between the attacks. • Practical definition: Any patient who is brought with seizures to the hospital or whose seizures last for more than 5 minutes is to be treated as SE • efractory : If seizures fail to respond to appropriate first and second line drug treatment and persist for more than 60 minutes. SE



Psychogenic seizures are events that resemble seizures and occur due to emotional or psychological reasons. There is no accompanying epileptiform discharge in the brain. They are usually a conversion reaction, but may be a form of malingering as well. Twenty to thirty percent of children attending epilepsy units may have psychogenic seizures. They are seen only after the age of 5 years. Psychogenic seizures are mainly of two types:

cute eizures and tatus pilepticus

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Psychogenic Seizures

Certain ypes of eizures and pileptic yndromes

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Table 6.5.10 Diagnostic evaluation of status epilepticus All cases •  Blood biochemistry: Glucose and electrolytes, and other metabolic parameters •  Blood gases assessment Associated fever •  Blood counts •  Cerebral spinal fluid exam •  Urine examination •  Necessary cultures Studies on case to case basis •  Electroencephalogram •  Neuroimaging •  Drug levels 

Overall incidence is 50 patients per 100,000 population per year. Status epilepticus in children is most likely in those less than 3 years of age. Seventy percent of children less than 1 year with epilepsy may have SE.

Classification of Status Epilepticus A

ccording to seizure type: For example, generalized tonic clonic, partial, absence • ccording to the clinical presentation: – Convulsive status: When the seizures have a predominant motor component, e.g. GTCS, clonic, tonic, myoclonic, epilepsia partialis continua, seizures in one half of the body – Nonconvulsive status: Absence, complex partial SE, continuous spike waves during slow wave sleep. A

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Incidence

Etiology Etiology of status is essentially the same as that of seizures and epilepsy (Table 6.5.1). However, certain factors can precipitate seizures and SE in a person with epilepsy (Table 6.5.9).

All parents must be taught home management of seizures with a benzodiazepine (nasal/buccal midazolam, rectal diazepam or sublingual lorazepam). The child should be put on long-term anticonvulsants if he is found to have EEG abnormality, abnormal neuroimaging or is far from medical facility, parents are not educated or confident about home management of seizures.

Prognosis •

•

The success of treatment of SE depends on how quickly the seizure is brought under control. The principles of management are well defined, but the protocols vary. What is important is that every medical care facility must have a very clear protocol or drill in the management of SE. One does not have to wait for 30 minutes to set into motion the treatment protocol for SE. Goals of management are to stop the seizure activity as soon as possible and prevent brain damage and systemic complications, and at the same time to support airway-breathing-circulation, carry

 

Table 6.5.9 Precipitating factors of seizures/status epilepticus in chronic neurological disorders Febrile illness Inadequate antiepileptic drugs (substandard brands/different compositions) Sudden discontinuation of antiepileptic drugs Sleep deprivation/fatigue/emotional upset Central nervous system stimulants like theophylline

F

M

Management

Follow-Up Advice

Mortality is 1–2% in developed countries. Improvement in prognosis of convulsive SE is due to more effective and prompt treatment orbidity: ong-term complications include epilepsy, focal neurological deficit, post-status encephalopathy and mental retardation. Recurrence of SE can occur in up to 13% cases. l

Convulsive SE can be life-threatening and also cause permanent neuronal damage after 1.5–2 hours of seizure activity due to excessive glutamate production leading to excessive neuronal depolarization, rise in intracellular sodium and calcium, cerebral edema and finally cell damage and death. Systemic changes include hypoxia, hypotension and hyperpyrexia. Metabolic derangements like acidosis, hypoglycemia and hyperkalemia can result in cardiac, respiratory and renal failure.

ebrile eizures S

Pathophysiology

out a diagnostic evaluation (Table 6.5.10) and treat the underlying condition. A suggested management protocol is shown in Table 6.5.11.

Definition These are seizures, which occur between 3 months to 5 years of age, associated with fever but without evidence of intracranial infection or defined cause for the seizure, and without any history of seizures earlier.

Epidemiology Two to four percent of all children below the age of 5 years suffer from febrile seizures (FS). Incidence is equal in both sexes. Twenty-five to forty percent children with FS have a family history of FS. Any infection that causes fever can cause FS. In view of the high incidence of family history, children with FS are said to have a genetic predisposition to FS.

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Types of Febrile Seizures

Febrile seizures are generalized tonic, clonic or tonic-clonic seizures, occasionally hypotonic, but never myoclonic. If focal seizures occur they may be unilateral, and may be followed by Todd’s paralysis suggesting a focal origin of the seizures.

Febrile seizures are of two types (Table 6.5.12).

Diseases of Central ervous ystem

Type of Seizures in Febrile Seizures

Investigations •

EEG is not required for the diagnosis or management of FS, whether simple or complex, even when they

 

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Table 6.5.11 Suggested protocol for management of status epilepticus or any patient presenting with acute seizures Time Action 0–5 minutes Observe Initial observation and management •  Seizure activity; diagnose SE, assess patients condition Airway •  Suction secretions •  Administer oxygen •  Insert nasal airway Breathing •  Intubate and provide ventilator support if required (this may done at any time throughout the management process) Circulation •  Start intervenous line, draw samples for blood sugar and biochemistry. Glucose may be estimated by a glucometer.   Start two lines if possible •  If hypoglycemic or glycemic status unknown: IV glucose 2 ml/kg—6 months 25% glucose, less than 6 months 10% glucose Monitoring •  Vital signs monitoring especially pulse oximetry • Continue maintaining airway breathing circulation monitoring 5–15 minutes • Drug administration Stabilization, monitoring and ABC support No IV access: IV line established: •  Diazepam rectally 0.5 mg/kg •  Lorazepam 0.1mg/kg (max 5 mg) at 2 mg/min Drug administration •  Midazolam intranasal /buccal 0.2–0.4 mg/kg, OR intramuscular – 0.1–0.2 mg/kg. •  Midazolam at 2 mg/min 0.1–0.2 mg/kg Start first line drug: •  Lorazepam sublingual 0.1 mg/kg OR Any benzodiazepine. •  Diazepam 0.2 mg/kg (max – 10 mg) at 5 mg/min Repeat twice if seizures do not stop in 5 minutes (Rapid onset of action but short acting ) Dose can be repeated twice if seizures do not stop Followed by •  Fosphenytoin IM—20 mg/kg phenytoin after 5 minutes equivalent (PE). Divide in half and give two separate injections for more rapid action No response, seizures recur or initial seizures more than 10 minutes: 15–35 minutes Phenytoin (PHT) Monitoring and ABC support 20 mg/kg@ 1 mg/kg min IV infusion (solution only in saline as PHT is incompatible with dextrose or calcium) OR Drug administration Fosphenytoin (FOS) 20 mg/kg of PE @ 3 mg/kg/min (150 mg/min) Second line drug (solution in dextrose or saline) (1.5 mg of FOS = 1 mg of PHT) Phenytoin/fosphenytoin (Slower onset of action but longer acting) •  Continue maintaining airway breathing circulation monitoring 35–60 minutes •  Repeat phenytoin/fosphenytoin (Established SE)   5 mg/kg 2 doses to max dose of 30 mg/kg •  Start third agent—phenobarbitone/midazolam infusion Monitoring and ABC Support   –  Phenobarbitone 20 mg/kg @ 2 mg/kg/min IV     OR Shift to ICU   –  Midazolam drip—0.2 mg/kg bolus, followed by infusion of 0.2–2 mg/kg/hour     OR Drug administration   –  Valproate injection—20 mg/kg bolus over 5 minutes, then maintain at 5 mg/kg/hour for 6 hours Repeat second line drug in smaller dose •  PLUS  •  Give mannitol Mannitol infusion to reduce cerebral edema if there are sign of raised intracranial pressure— Start third line drug 5 mL/kg over 10 minutes in all patients if seizures persist for more than 30 minutes

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After 60 minutes (Refractory stage) Monitoring and ABC support ICU care EEG monitoring

More than 60 minute •  Continue maintaining airway breathing circulation monitoring (Ventilator support is required at this stage) •  Continuous EEG monitoring if available •  Continuous infusion of midazolam in increasing doses till seizure control OR Pentobarbital: loading dose: 20 mg/kg over 1 hour followed by a maintenance infusion of 0.25–5 mg/kg/hour OR Thiopentone: loading dose: 5–10 mg/kg over 2–5 minutes, maintenance 2–10 mg/kg/hour OR Propofol: loading dose 1–3 mg/kg, maintenance 2–10 mg/kg/hour

Drug administration: Induce coma

Remember •  In children most SE is symptomatic, hence investigation thoroughly to find etiology. •  LP should not be done in a convulsing patient. •  There is no place of oral administration of drugs in acute seizures; where IV access is a problem rectal/buccal/nasal routes should be used. •  Most children can be managed successfully with BZP/PHT. •  Fosphenytoin is preferred if cost is not an issue. (Cost of Fosphenytoin is 3 times cost of phenytoin; 10 kg child—cost of phenytoin loading approx Rs 25, cost of Fosphenytoin—Rs 75.) •  Start the next drug/s only after full loading doses of PHT/PB have been given. •  Give the full loading dose in one dose as this is more effective, rather than suboptimal doses many times. •  For hypotension, inotropes may be required. •  Choice of drug depends on cost and availability, as well as the ICU and monitoring facilities. It is better to give valproate rather than phenobarbitone and midazolam rather than pentobarbitone if ventilation facility is not available. •  After seizure control: Discontinue drug infusion at 12 hours. If seizures recur reinstate drug and try weaning off at 12 hourly intervals. •  Continue maintenance doses of PHT and phenobarbitone 12–24 hours after loading dose administration. •  End point of treatment: n EEG—no electrographic seizures or burst suppression pattern; if no EEG monitoring is available—clinical seizure control. •  Prognosis depends on how fast the seizures are controlled. o





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Abbreviations: SE, Status epilepticus; EEG, Electroencephalogram; BZP, Benzodiazepines









MTS

R

isk of epilepsy: Overall risk of epilepsy following FS is 2–5%. Preventing FS does not decrease the risk of epilepsy • isk of mesial temporal sclerosis ( ): There is a strong association between the development of refractory temporal lobe epilepsy/MTS and complex FS (especially prolonged or focal.) However, it remains unclear whether the prolonged FS is the cause of MTS, or whether a pre-existing MTS predisposes the child to have prolonged FS.

Mental and Neurological Development Mental and neurological development remains normal if it was normal before onset of FS.

Mortality Mortality is not increased in children with FS as compared to the normal population.

West yndrome S

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–

•

are recurrent. An abnormal EEG does not change the management of FS, and is therefore not recommended as part of the assessment of a child with FS. Neuroimaging is not required in simple FS but may be done in: – Micro/macrocephaly, neurocutaneous syndrome or pre-existing neurological deficit – Persistent postictal neurological deficit after the FS – Recurrent complex FS.

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Table 6.5.12 Types of febrile seizures Simple Complex •  Less than 15 minutes duration •  More than 15 minutes duration   and/or   and •  Focal features present including •  No focal features s/o focal Todd’s paralysis origin of seizure •  Only one attack in one febrile   and/or •  More than one attack in one episode of fever febrile episode

Management of attack of first FS and subsequent long-term management of FS is shown in Flow chart 6.5.1.

Risks Following FS

350

isk of recurrence: Thirty-five percent of all children will have recurrence after the first FS. Management/ prevention of recurrences is shown in Figure 6.5.9 R

•

This is an epileptic syndrome with three essential features: 1. Characteristic seizures called infantile spasms: The child has a sudden spasm of the body in which the head, neck or trunk undergoes a contraction, resulting in either flexion (flexor spasms), but sometimes extension (extensor spasms) or flexion of one part and extension of the other (mixed spasms). The severity of the spasms can be very mild when parents may notice only a mild

Management

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Diseases of Central ervous ystem

Flow chart 6.5.1 Algorithm for management of febrile seizures

Source: Reproduced from Indian Journal of Pediatrics Special Supplement on Epilepsy 2007

Pathophysiology

Onset is most common around 3–4 months of age, and they may remit with treatment or spontaneously by around 2 years age, or they may remain uncontrolled and evolve into other syndromes (Lennox-Gastaut syndrome) or seizure types (tonic, atonic, atypical absences or myoclonic).

•

It is postulated that the hypsarrhythmia and spasms originate from the brainstem.

Investigations • N

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Electroencephalogram has diagnostic findings in this syndrome euroimaging: MRI is the imaging modality of choice. It may show CNS malformation or evidence of an earlier CNS insult Biochemical investigations to look for inborn errors of metabolism.

Treatment Following options are available: • teroids: ACTH or prednisolone • igabatrin: Especially in infantile spasms due to tuberous sclerosis or symptomatic infantile spasms • ther anticonvulsant drugs: Valproate, benzodiaze 351 pines, topiramate or levetiracetam ­

Almost any CNS insult can result in infantile spasms. Tuberous sclerosis is often associated with infantile spasms.

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Etiology

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vibration to severe resulting in complete folding over the body. They occur in clusters, and each cluster has many jerks. They are maximum on getting up from sleep or when falling asleep (infantile spasms may be used synonymously with West syndrome by many people). 2. Electroencephalogram findings of hypsarrhythmia, which is a high voltage completely chaotic EEG, which changes every second with spikes from multiple foci. 3. Developmental regression with onset of seizures. In many cases developmental delay pre-exists.

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Pyridoxine should be tried early in all children in whom a clear cause for spasms has not been identified Epilepsy surgery for focal cortical lesions should be considered if the child has not shown a response to three trials of different AEDs. E

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Childhood bsence pilepsy



This is idiopathic generalized epilepsy with a genetic basis. Onset is at 4–8 years, girls are more affected than boys.

carbamazepine and valproate) in management of common epileptic disorders including generalized tonic clonic as well as focal seizures is nearly similar. The decision regarding specific drug depends upon: • The type of seizures and epileptic syndrome • Side effects • Cost and • Lifestyle of the patient. In our set up in view of low cost, ease of administration and low side effects, phenytoin is the drug of choice. Monotherapy should be the rule. Polytherapy should be avoided because of drug interactions, and subsequent alteration of drug efficacy.

These include typical absence seizures with sudden loss of consciousness, associated with automatisms in the form of lip smacking, eye blinking and hand picking. The seizure terminates suddenly as child resumes activity as if nothing happened. Many attacks occur every day. The attacks can be precipitated by hyperventilation. Child is neurologically normal.

Electroencephalogram Electroencephalogram shows 3 Hz spike wave discharges on a normal background. Hyperventilation precipitates 3 Hz discharges on EEG and the seizure clinically.

Response to treatment is very good. Seizures remit in most children by 10–12 years of age. However, many children may develop infrequent generalized tonic clonic seizures. E

anagement of pilepsy T

Drug herapy Decision Making: Should Antiepileptic Drugs Be Started?





The most important consideration in management of epilepsy is the possibility of recurrence of the seizure. Drug treatment is considered only when recurrent seizures are confirmed. The decision should be taken after counseling the parents, especially after a first seizure. Generalized tonic clonic seizures: Recur in only around 40% cases; hence, first episode of generalized tonic clonic seizure does not require treatment with long-term AEDs. Exceptions to this rule include; the first episode was a SE where the patient resides in a place, which is far off from medical facility or parents are overanxious and unable to administer home treatment of acute seizures. Partial, absence, atonic and myoclonic seizures: Because of high rates of recurrence of seizures, treatment is indicated in these seizure types.

Choice of Antiepileptic Drugs Choice of antiepileptic drugs has been described in detail in Table 6.5.13 for details. The efficacy of the four 352 first line antiepileptic drugs (phenytoin, phenobarbital,

Changing Antiepileptic Drugs Start the second drug in a small dose, and build it up to a dose effective in controlling seizures. Taper off the second drug as above.

Principles of Combination Therapy • • • •

Prognosis

Use drugs with different mechanisms of action Drugs should have large therapeutic index Few side effects Keep in mind drug interactions: Combination may cause increased toxicity or decreased efficacy.

Drug Level Monitoring Drug levels may be estimated in certain specific situations (Table 6.5.14), but this is not usually required. Drug dosage should be decided by clinical control of seizure or appearance of side effects. Drugs whose levels are useful include phenytoin, carbamazepine, phenobarbitone and valproate.

Follow-up Parents should be instructed to maintain a seizure diary (Flow chart 6.5.2) containing details of seizure type, duration and frequency. Initial follow-up should be: • After 4 weeks • If breakthrough seizures occur and • If side effects occur.

Valproate and ethosuximide.

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Start an AED in a small dose and build up gradually to an optimal dose. It is best to calculate a target dose, and start with one-third of that, and increase by one-third every week till target dose is reached in case of drugs with short half-lives like carbamazepine and valproate. Phenytoin and phenobarbitone may be started with the full optimum dose at the start. If seizures continue, increase gradually till maximum tolerated dose is reached or seizure is controlled. reating a relapse: Restart the same drug in the same dose as was effective in controlling seizures earlier.

Treatment

Starting Antiepileptic Drugs

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Seizures

Subsequent follow-up (if seizures are controlled): three monthly.

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Carbamazepine

Focal seizures Generalized tonic clonic seizures

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Idiopathic generalized epilepsies— Childhood absence epilepsy, juvenile myoclonic epilepsy, infantile spasms, Lennox Gastaut syndrome

Broad spectrum, effective against any seizure type

Valproate

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Neonatal seizures Status epilepticus Tonic clonic Focal seizures Clonic febrile seizures

Phenobarbitone

 

Table 6.5.13 Drugs used in treating epilepsy A. Conventional antiepileptic drugs Drugs Indications Phenytoin Focal seizures GTCS

Suspension: 100 mg/5 mL Tablets 200, 400, 600 mg Sustained release tablets are also available 200 mg, 500 mg

Tablets 200, 400 mg Syrup 200 mg/5 mL

Tablets 30 mg Syrup 30 mg/5 mL

Tablets 100 mg

Preparation Suspension 30 mg/5 mL 125 mg/5 mL

Sustained release preparation: Two divided doses 10–30 mg/kg/day Three divided doses

Three divided doses

20–40 mg/kg/day Doses up to 80 mg/kg/day may be used provided there are no side effects

Single dose or two divided doses

3–5 mg/kg/day

In two divided doses

Dose 5–8 mg/kg/day

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Rash Bone marrow depression Steven Johnson syndrome

Hepatotoxicity Drowsiness Lethargy Weight gain, Hyperammonemia Teratogenicity

Sedation Hyperkinetic behavior Dependence

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Side effects toxicity Gum hypertrophy, Rash Steven Johnson syndrome Toxicity Ataxia Nystagmus Blurring of vision

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The suspension is thick and settles at the bottom, it needs to be shaken thoroughly

Not to be used in absence and myoclonic, atonic and atypical absence seizures

Start with low dose

Precaution in children less than 1 year of age

Since it has a long half life, the drug may be started with the target dose

Avoid phenytoin in children if cost is not a factor Younger children require higher doses

Make sure about which preparation the patient is using because of wide variation in the concentration in different preparation

Since it has a long half life, the drug may be started with the target dose

Remarks Younger children require higher doses

Diseases of Central ervous ystem

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Myoclonic seizures, atonic, tonic, atypical absence

Add on drug for any seizure type

Clonazepam

Clobazam

Broad spectrum, add on drug. Multiple seizure types

Lamotrigene

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Add on focal/generalized epilepsy West syndrome, Broad spectrum add on drug for epilepsy with multiple types of seizures, e.g. Lennox Gastaut syndrome

Monotherapy: Refractory partial seizures in children more than 12 years of age

Monotherapy: Infantile spasms especially those due to tuberous sclerosis Add on: Refractory focal seizures

Vigabatrin

B. Newer antiepileptic drugs Oxcarbazepine Same as carbamazepine

Intermittent use in Febrile seizures, or seizures due to known precipitating causes

Myoclonic seizures

Nitrazepam

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With valproate start with 0.15 mg/ kg/day Increase to 0.3 mg/kg/day Monotherapy 0.3 mg/kg/day Increase to 0.6 mg/kg/day With enzyme inducing drug start with 0.6 mg/kg/day increase to 1.2 mg/kg/day

Tab 25 mg, 50 mg, 100 mg

Tab 500 mg

Suspension

8–10 mg/kg/day in two divided doses Target maintenance – 30 mg /kg/ day Maximum 50 mg/kg/day Start with 40 mg/kg/day Target maintenance dose 80–100 mg/kg/day Max 120–150 mg/kg/day

Tab 150 mg, 300 mg, 600 mg

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0.5 mg/kg/day one two divided doses

Tabs 5 mg, 10 mg, 20 mg

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0.03–0.1 mg/kg/day two three divided doses

0.5 mg/kg/day two divided doses

Tabs 0.5 mg, 2 mg

Tab 5 mg, 10 mg

Rash Headache Drowsiness

Visual field defects Blindness

Fewer side effects like allergies and bone marrow suppression

Drowsiness Hypotonia Ataxia Drowsiness Hypotonia Ataxia Drowsiness Hypotonia Ataxia less than other benzodiazepines

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Level is affected by other antiepileptic drugs

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Perimetry/fundoscopy regularly to check for visual complications Use with care with valproate

Not easily available/manufactured in India.

Drug level monitoring is not required

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Gabapentin

Levetiracetam

Topiramate

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Add on for refractory focal epilepsy without generalization Neuralgias

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Add on Focal/generalized epilepsy West syndrome, Broad spectrum add on drug for epilepsy with multiple types of seizures, e.g. Lennox Gastaut syndrome Add on for myoclonic seizures Focal seizures Primary generalized seizures

Monotherapy: Focal or generalized epilepsy

Tab 100 mg, 300 mg, 400 mg,   600 mg

Tab 250 mg, 500 mg, 750 mg 20 mg/kg/day increase weekly Increase to 60 mg/kg/day In two divided doses Start with 10–15 mg/kg/day Target dose less than 5 years 40 mg/kg/day More than 5 years 30 mg/kg/day Three divided doses

Start with 10 mg/kg/day

Max dose: 8 mg/kg/day

Tab 25 mg, 50 mg, 100 mg, 200 mg Start with 0.5 mg/kg/day Increase to 5 mg/kg/day

Worsens myoclonus and absences Headache Anorexia Drowsiness Behavior problems

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Safe drug for children No drug interactions with other antiepileptic drugs

Good drug with few drug interactions

Headache Anorexia Drowsiness Behavior problems

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Drowsiness Ataxia, Metabolic acidosis Hyperammonemia especially with valproate

Diseases of Central ervous ystem

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Date

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ntiepileptic drugs (

Name

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Type 2





ypes of seizure: (in case the child has multiple types of seizures)

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Flow chart 6.5.2 A sample seizure diary

Type 4

Ds) Timing

Type of seizure Time of onset Time of control Precipitating factor (in case any identified)

Routine AED given Any AED given to Remarks Yes/No control acute seizure

Instructions: A separate page has to be made every month. Any skipping of doses/alteration of AED is to be recorded. In case of multiple types of seizures, each seizure type should be assigned a number, and the number be noted. Remarks: Anything unusual to be brought to the doctor’s notice.

Refer to Pediatric Neurologist

 

Table 6.5.14 Indications for drug level monitoring Uncontrolled seizures despite adequate doses of the correct antiepileptic drugs (through levels) Breakthrough seizures Antiepileptic drugs toxicity (peak levels) In polytherapy Change in antiepileptic drugs dose or regimen Other systemic disease altering drug metabolism or excretion To check compliance



(This diary should preferably be made in the language used locally)

• • • •

E

Counseling

Patients should be advised to allow the child to continue a normal lifestyle. School teachers should be informed about the nature of disease and should be specifically told not to be biased against these children. Some caution is advocated in possibly dangerous circumstances like cycling, swimming and activities near fire particularly in the first year of remission.

Drug esistant pilepsy E

Stopping Antiepileptic Drugs Before tapering, the parents must be counseled about the risk of relapse after tapering. • The drug must never be stopped abruptly; it must be tapered gradually over 4–12 weeks 356 • If patient is on multiple drugs, taper one drug at a time, wait for 1 month and then taper the next drug.

ifestyle

R

Duration of Treatment Duration of treatment is usually 18–24 months seizure free period. Increasing duration of AEDs therapy beyond 2 years does not decrease the risk of relapse. Certain other epilepsies may warrant earlier stopping, e.g. benign centrotemporal epilepsy, acute symptomatic epilepsy due to inflammatory granulomas.

xplain Disease

Parents should be informed about the nature of the disease and chances of recurrence with and without treatment. Some epilepsies are inherently refractory to treatment, and the poor outcome in such cases should be explained to the parents at the outset. L

Indications for Hospitalization • Status epilepticus • To observe the seizure type • Distinguish between seizure and NEE • Serious adverse reactions • To check compliance.

Children less than 2 years Uncontrolled seizures Suspected syndromes Multiple seizure types.

Drug resistant epilepsy may be defined as failure of adequate trials of two tolerated and appropriately chosen and used AED schedules (whether as monotherapy or in combination) to achieve sustained seizure freedom.

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• Drug preparations/brands must not be changed in a well-controlled patient. • Parents and older children must be counseled about all aspects of epilepsy and its management before starting treatment. • Caregivers must be taught home management of seizures with a benzodiazepine (rectal diazepam/ nasal or buccal midazolam). The procedure must be demonstrated with normal saline before sending the patient home.

AE

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• Seizures are the clinical manifestation of abnormal excessive paroxysmal discharges in the brain, while epilepsy is recurrent seizures without an immediate precipitating cause. • There are many different types of seizures depending on the part of the brain involved. • Investigation for epilepsy is carried out to find out the etiology of epilepsy as well as to identify and classify the type of seizures, epilepsy or epileptic syndrome. • Though EEG can help in diagnosis as well as classification of epilepsy, it must always be interpreted in the clinical context. • All attempts must be made to rule out NEE before starting treatment, as well as when there is poor response to first line antiepileptic drugs. • Cost factor must be taken into account before deciding on the AED to be started.



essages

1. Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia. 2010;51:676-85. 2. Kalra V. Management of childhood epilepsy. Indian J Pediatr. 2003;70:147-51. 3. Kotagal P, Costa M, Wyllie E, et al. Paroxysmal Nonepileptic Events in Children and Adolescents. Pediatrics. 2002;110:e46. 4. Kwan P, Sander JW. The natural history of epilepsy: an epidemiological view. J Neurol Neurosurg Psychiatry. 2004;75:1376-81. 5. Ma L, Yung A, Yau E, et al. Clinical Guidelines on Management of Prolonged Seizures, Serial Seizures and Convulsive Status Epilepticus in Children. HK J Paediatr (New Series). 2010;15:52-63. 6. National Institute for Clinical Excellence. The Epilepsies: The Diagnosis and Management of the Epilepsies in Adults and Children in Primary and Secondary Care. London. 2004 URL: http://www.nice.org.uk/nicemedia/ live/10954/29531/29531.doc Accessed July 21, 2011. 7. Shinnar S, O’Dell C. Treatment Decisions in Childhood Seizures. In: Pellock JM, Bourgeois BFD, Dodson WE, Nordli DR, Sankar R (Eds). Pediatric Epilepsy—Diagnosis and Therapy, 3rd edition. New York: Demos Medical Publishing; 2008. pp. 403-12. 8. Singhi P. Seizures and Epilepsy in Children: A Practical Guide, 1st edition. Delhi: Noble Vision; 2008. 9. Udani V. Pediatric Epilepsy: an Indian Perspective. Indian J Pediatr. 2005;72:309-13.

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anagement

Options include: • ewer Ds • pilepsy surgery: To remove epileptogenic foci • etogenic diet: The diet induces ketosis by high fat and low carbohydrate diet. Ketosis has an anticonvulsant effect in certain types of epilepsies • agal nerve stimulation: A device (the impulse generator) is implanted under the skin in the chest with a coil around the vagal nerve. It is activated in case of an impending seizure by passing a magnet across it. The impulses generated stimulate the vagus nerve and control the seizure.

Diseases of Central ervous ystem

A child with drug resistant epilepsy needs to be reworked up to: • Confirm true seizures • Confirm correct seizure type and epileptic syndrome • Confirm adequate correct and doses of AED.

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Headaches and Migraines in hildren Munni Ray

This common neurological disorder has both a high incidence and prevalence and the burden of this disease impacts not only the child but also the family including school performance, social life, mental health and quality of life. Bille reported that 75% of children complain of a significant headache by the age of 15. Migraine was reported in 3.9% of children aged 7–15 years, which increased from 1.7% in 7-year-old to 5.3% in 15-year-old. It was commoner in boys aged less than 7 years whereas in adolescents, girls had a higher prevalence. E

tiopathogenesis

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linical eatures F

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Headaches in children can either be primary such as migraine or tension type headaches or secondary. Secon dary headaches by definition have a cause and effect association with a specific etiology, whereas primary headaches are intrinsic to the nervous system. The etiopathogenesis of the different types of head aches in children is dependent upon the five different temporal patterns of headaches. The primary headaches are of generally the acute recurrent variety like migraine whereas the chronic nonprogressive type is like tension type headaches (TTH) and chronic daily headaches. The acute and the chronic progressive types of headaches occur generally due to secondary causes and they primarily present in the emergency. The list of etiologies, which present as secondary headaches, is provided in Table 6.6.1. The major pathophysiologic basis of life-threatening causes of acute or chronic progressive headaches is raised intracranial pressure. The biological basis of the primary headaches at a molecular level is yet uncertain and different etiopathogenetic theories like neurovascular theory, release of neuropeptides and chanellopathies have been cited.

The diagnosis of pediatric headaches is challenging as children have limitations in describing their symptoms. Moreover, one individual may have more than one disorder. An orderly approach is required for the proper diagnosis. Crucial elements include a thorough history (based on the information given by the child primarily and then by 358 the parents) supplemented by general, neurological and



Table 6.6.1 Secondary causes of acute headache Causes Proportion of disease contribution to acute headache in emergency room (%) Viral illness 40–70 Sinusitis 1–6 Post-traumatic headache 5–7 Meningitis/encephalitis 2–9 Streptococcal pharyngitis 5–10 Brain tumor 2–3 Postictal headache 1–4 Intracranial hemorrhage 1 Sinus venous thrombosis <<1 Ischemic stroke <<1 Intracranial cyst rupture <<1 Ventriculoperitoneal <<1 shunt malfunction  

pidemiology

psychological evaluation, as well as laboratory testing and neuroimaging in selected patients. The headache history is crucial and the questions enquired are highlighted in Table 6.6.2. The “red flags,” which suggest the possibility of secondary headache are: first or worst headache ever in life, recent headache onset, increasing severity or frequency, occipital location, headache awakening from sleep associated with severe vomiting and that associated with straining. Once these features are identified, the pediatrician must conduct the work up indicated and thereby diagnose any secondary headache disorder that is present.

Table 6.6.2 Helpful questions for obtaining headache history •  When did the headache begin? •  How did the headache begin? •  What is the temporal pattern of the headaches? •  What is the headache frequency? •  How long does the headache typically last? •  Do the headaches happen at any particular time or circumstance? •  Is there an aura or prodrome? •  Where is the pain? •  What is the pain like? •  Are there associated symptoms? •  What do you do during the headache? •  Would I know you had a headache if I saw you? •  What makes the headache better or worse? •  Are there any symptoms between headaches? •  Are there any other health problems? •  Are you taking medications? •  Is there a family history of headaches? •  What do you think is causing the headaches?  

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Headaches in children and adolescents are common, and a steady alarming increase in their incidence has been attributed to the rapidly changing untoward lifestyle habits.



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Diagnostic studies are seldom required unless risk factors are identified. Nonetheless, many families and physicians feel compelled to embark on investigations for children with headaches but unwarranted investigations may be

  

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Modalities of iagnosis

  

 

Assessment of psychosocial background is of immense importance. The evaluation process should be completed with scales for depression, anxiety, etc. and family interview. The impact of the headache on a child’s life must be part of the evaluation using PedsQL .4.0 and PedMIDAS.



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Psychological xamination

 

 

This includes examination of: • Cervical spine • Vascular evaluation for skull bruits • Ears • Temporomandibular joint • Nerves including supraorbital nerves, occipital nerves, and examination of nerves IX through XII • Eyes • Sinuses • Teeth.

 

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Headache xamination

Table 6.6.3 International Classification of Headache Disorders II criteria for pediatric migraine without aura and episodic tension type headaches Criteria for pediatric migraine without aura: a.  At least five attacks fulfilling criteria B–D below b.  Headache attacks lasting 1–72 hours c.  Headache has at least two of the following characteristics:   •  Unilateral location, may be bilateral, frontotemporal (not occipital)   •  Pulsing quality   •  Moderate or severe pain intensity   •  Aggravation by or causing avoidance of routine physical activity (e.g. walking and climbing stairs) d.  During the headache, at least one of the following:   •  Nausea, vomiting or both   •  Photophobia and phonophobia, which may be inferred from behavior e.  Not attributed to another disorder Criteria for episodic tension type headaches: •  At least 10 episodes fulfilling 2–4 •  Headache lasting 30 minutes to 7 days •  Two or more of the following:   –  Pressing/tightening quality – Mild to moderate severity – Bilateral   –  Not aggravated by routine activity •  Both of the following:   –  No nausea or vomiting – Phonophobia or photophobia is absent  

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The general examination should include vital signs, growth parameters, head circumference, skin examination and ophthalmological assessment. Although a frequent parental concern, headaches caused by poor visual acuity are easily identified by most patients. In the overwhelming majority of patients, serious medical and neurologic disorders can be excluded by a detailed history and examination. Children with headaches related to serious pathology have demonstrable neurologic signs and the three important features are: papilledema, sensorial alteration and paralysis.

 



Physical xamination

counterproductive as it can undermine ones attempts at reassurance. Routine laboratory studies and performance of lumbar puncture are not recommended. If the history/ physical examination raises concern about meningitis or encephalitis, a lumbar puncture will be necessary. In headaches caused by pseudotumor cerebri, the lumbar puncture may be both diagnostic and therapeutic. Electroencephalography is not indicated as it is unlikely to determine an etiology or distinguish migraine from other types of headaches. Neuroimaging on a routine basis is not indicated in children with recurrent headaches and a normal neurologic examination. Physicians should consider imaging in children with an abnormal neurologic examination or in whom red flag alerts like associated seizures, a recent onset of severe headaches, a change in headache type, or associated features to suggest neurologic dysfunction are present. The routine use of neuroimaging may lead to the discovery of incidental benign abnormalities, which may cause undue alarm, and headaches may wrongfully be attributed to these incidental findings. In the emergency, setting a computed tomography of the head is preferred and a plain scan is highly sensitive in acute hemorrhage whereas MRI is the investigation of choice otherwise. Once the secondary headache disorders are ruled out the primary headaches like migraine and tension type headache, etc. are diagnosed as per criteria laid down by the International Classification of Headache Disorders (ICHD) laid down in 2004 (Table 6.6.3).

iseases of en ral ervous ys e

In the absence of secondary headache, the clinician proceeds to diagnosing a primary headache disorder. If the headache is atypical or difficult to classify, the possibility of secondary headache should be reconsidered. Useful strategies to help improve headache diagnosis in children might be the following: • Take history with sufficient time and patience, and with age-appropriate terminology • Ask the patient (assisted by parents) to keep an appropriate headache diary (e.g. depicting headache characteristics, associated symptoms, triggers) over a period of weeks and the degree of disability as well as medication usage. The assessment of headache severity in children should be done using combination of pain rating scale and visual analogue scale according to age and cognitive levels of subjects.

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The mainstay of treatment of secondary headaches is to manage the underlying cause. The priority of a pediatrician managing a child with primary headaches is to reassure confidently that the headaches are not caused by a lifethreatening etiology. Management of pediatric primary headaches is complex, and nonpharmacological therapy is the first line of treatment (Fig. 6.6.1). Maintaining a headache diary may be remarkably therapeutic. Noting triggers in the diary and their careful avoidance is important. Other approaches include appropriate sleep hygiene, regular physical activity and limiting caffeine. Behavioral therapies like relaxation techniques and biofeedback have shown good efficacy. Psychological interventions aim to reduce psychosocial stressors, provide more social support for families and help the patient to improve his coping abilities. These techniques are useful in children with both migraine and TTH. Pharmacologic approaches to migraine include rescue and prophylactic medications. Both ibuprofen (10 mg/kg)

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Treatment

and acetaminophen (15 mg/kg) are safe and efficacious as rescue medications in managing acute attacks when given early and in appropriate doses. Parents should be cautioned to limit the use of these drugs to a maximum of 2–3 times/week to avoid medication overuse headaches. Nasal sumatriptan is the only serotonin receptor antagonist, which has been useful in managing acute headaches in adolescents. For prophylaxis of migraine in children, the recommended drugs are propranolol (2–4 mg/kg/d), flunarizine (5 mg/d), valproate (20–40 mg/kg/d) and topiramate (1–10 mg/kg/d), cyproheptadine (0.25–1.5 mg/ kg/d) and amitriptyline (10–25 mg/d). These drugs are to be used in those who have frequent attacks (1–2 attacks/ week) or disabling headaches (PEDMIDAS score > 30) with the aim to lower the frequency to 1–2 attacks per month and disability for at least 4–6 months.

Prognosis Almost half of childhood headaches persist into adulthood, and long term follow-up studies have indicated that there

 

Flow chart 6.6.1 Practice guidelines for evealuation and management of a child with headaches

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• Pediatric headaches are common. • Secondary headaches usually present in emergency and they should be promptly diagnosed and managed. • Majority of recurrent headaches are primary in nature.

1. Bille BS. Migraine in school children. A study of the incidence and short term prognosis, and a clinical psychological and electroencephalographic comparison between children with migraine and matched controls. Acta Paediatr. 1962;51:16-151. 2. Brenner M, Oakley C, Lewis D. The evaluation of children and adolescents with headache. Curr Pain Headache Rep. 2008;12:361-6. 3. Headache classification subcommittee of the International Headache Society. The International classification of headache disorders: 2nd edition. Cephalalgia. 2004;24:9-160. 4. Hershey AD. Recent developments in paediatric headache. Curr Opin Neurol. 2010;23:249-53. 5. Kienbacher C, Wöber C, Zesch HE, et al. Clinical features, classification and prognosis of migraine and tension type headache in children and adolescents: a long term follow-up study. Cephalalgia. 2006;26:820-30. 6. Lewis DW, Ashwal S, Dahl G, et al. Practice parameter: evaluation of children and adolescents with recurrent headache. Neurology. 2002;59:490-8. 7. Termine C, Özge A, Antonaci F, et al. Overview of diagnosis and management of paediatric headache. Part II: therapeutic management. J Headache Pain. 2011;12:25-34.

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International Classification of Headache Disorders II has improved the identification of childhood migraines. Recent studies have highlighted the presence of osmophobia as an important associated feature in children with migraines and presence of cutaneous allodynia is under evaluation. Use of headache drawings in evaluation of children has greatly improved the diagnostic aspect. Identification of comorbidities in childhood headaches like obesity, epilepsy, allergy, emotional and sleep disorders, etc. influences management choices, overall outcome and response. Almotriptan has been recently recommended for treatment of headaches in adolescents.

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As migraine is a disorder with genetic, basis prevention of development is unlikely, although use of biobehavioral techniques as well as prophylactic medications may help in reducing attacks.

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• Appropriate identification by using headache history, clinical examination and headache diary analysis helps in appropriate diagnosis using ICHD-II. • Biobehavioral therapy along with pharmacological managements are to be used to reduce school absenteeism, headache induced disability and improve quality of life.

Prevention

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is a tendency to transform from one subtype of headache to the other.

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Movement isorders Anoop Verma

Table 6.7.1 Types of movement disorders and their phenome­ nology

1. Hyperkinetic MD, e.g. tics, chorea, ballismus, dystonia, myoclonus, stereotypies and tremor 2. Hypokinetic MD referred as akinetic/rigid syndrome, e.g. Parkinsonism. These are rare in children. When faced with a MD, some key questions need to be asked: • Is the pattern of movements normal or abnormal? • Are the movements hyperkinetic or hypokinetic? • Are the movements paroxysmal or continuous? • Has the MD changed over time? • Can the movements be suppressed voluntarily? (e.g. tics) • Is the abnormal movement heralded by a premonitory sensation or urge? • Is there any clinical clue of focal neurological deficit or systemic disease? • Is there any family history of similar disorder? (e.g. dominant or recessive) • Is there any history of hypoxic ischemic encepha­ lopathy or neonatal hyperbilirubinemia? (e.g. athe­ tosis and dystonia) • Is there any history of precipitating factors? (e.g. drugs, infections or muscular exercise) • Does the MD abate with sleep?

 

A movement disorder (MD) is typically defined as dysfunction in the implementation of appropriate targeting and velocity of intended movements, dysfunction of posture, the presence of abnormal involuntary movement, or the performance of normal appearing movements at inappropriate or unintended times. Movement disorders are divided into two major categories:

Movement disorder

Brief description

Chorea

Slow, large amplitude involuntary movements of proximal more than distal muscles

Athetosis

Slower writhing irregular movements predominantly distal

Tardive dyskinesia

Movements of mouth and face, usually drug induced

Dystonia

Co-contraction of agonist and antagonist, which cause twisting and repetitive movements or abnormal postures

Hemiballismus

Violent flinging movements, which are irregular affecting one side

Myoclonus

An extremely brief contraction of a muscle group leading to involuntary purposeless jerk of affected limb

Ataxia

Inability to control movements and typically is caused by cerebellar dysfunction

Tics

Rapid, involuntary, briefly suppressible, repetitive, nonrhythmic and stereotyped movements Simple motor tics are typically sudden, brief and meaningless movements that usually involve only one group of muscles, such as eye blinking, head jerking or shoulder shrugging Complex motor tics are typically more purposefulappearing and of a longer nature. They may involve a cluster of movements and appear coordinated

Tremor

Rhythmic oscillation about a certain point or position involving one or more body part

Stereotypies

Repetitive, patterned involuntary movements that have no apparent function







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The basal ganglia consist of five large subcortical nuclei, e.g. caudate nucleus, putamen, globus pallidus, substantia nigra and subthalamic nuclei. They participate in controlling the movement, but do not have either direct input or output with the spinal cord; rather they interact with the prefrontal and premotor cortices and therefore influence the planning and initiation of movement. The disease process selectively involves these structures resulting in various types of MDs; the details at neurotransmitter level are beyond the scope of this article (Table 6.7.2).

A qualitative appreciation is required to diagnose MDs. Various types of MDs and their brief descriptions are given in Table 6.7.1. D

Pathophysiology of Movement isorders Most MDs have their origin in the basal ganglia dysfunction, which is based on their organization and function within the complex information circuits of the brain, although virtually the entire nervous system is engaged in motor control, e.g. upper motor neuron, lower motor neuron, cerebellar circuitry, basal ganglia circuitry, motor association cortex and sensory system.

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Type of movement disorder

Metabolic Causes

Caudate nucleus

Chorea

Tremors may be the most prominent manifestation of various metabolic causes (Wilson disease and phenyl­ ketonuria, hypoglycemia, hyperthyroidism, deficiencies of magnesium and thiamine). It is a feature of many neurodegenerative disorders or cerebellar disease.

•

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•

• • • •

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isorders with horea as the Predominant Manifestation Sydenham’s Chorea (Chorea Minor or Saint Vitus Dance)

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This is a disease characterized by rapid, uncoordinated jerking movements affecting primarily the face, feet and hands. It results from childhood infection with Group A beta hemolytic Streptococcus and is reported to occur in 20–30% of patients with acute rheumatic fever. Chorea movements can occur with degenerative/ metabolic disorders and dyskinetic cerebral palsy.

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It may also manifest as toxicity to drugs and toxins (amphetamines, caffeine, corticosteroids and alcoholism and tobacco withdrawal).

isorders with ystonia as the Predominant Manifestation D

Primary Dystonia •

diopathic torsion dystonia ( T1 dystonia): It is the most common form of primary dystonia and is inherited as an autosomal dominant trait. The typical phenotype consists of childhood onset limb dystonia, which gradually progresses over subsequent years to become generalized, affecting trunk and limb muscles. The diagnosis rests on clinical presentation with normal perinatal history, normal intelligence and no biochemical abnormalities. Confirmation is usually by genetic analysis. • opa responsive dystonia ( ): The most important type is DYT5. Segawa disease has a characteristic diurnal variation. Symptoms improve on awakening and are worse later in the day. Although uncommon, the importance of DRD lies in its dramatic and sustained response to levodopa. The clinical presentation is similar to DYT1 dystonia, with childhood limb onset dystonia and gradual progression to generalized dystonia, with mild parkinsonism in some patients. Confirmation is by mutation analysis. DY

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Movement disorders disappear during sleep, seizures persist or may worsen. Movement disorders have more stereotyped appear­ ance and are more persistent than seizures. Seizures are often characterized by loss of consciousness or awareness whereas MD is not. Seizures are accompanied by epileptiform activity in EEG whereas MD is not.

Drugs and Toxins

D





ifferences from pilepsy

It is a slowly progressive neurological disorder characterized by a tremor of the arms or hands that is apparent during voluntary movements, such as eating and writing.

DRD

•

The first step is to categorize the abnormal movement into one of the common types (Table 6.7.1). Examine whether the abnormal movements interfere with voluntary movements. Tics and stereotypies are distinct motor behaviors, e.g. limb chorea, facial tics, other oral movements of lip and tongue biting can be present in neuroacanthocytosis. Tics and obsessive compulsive disorders can be associated with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. Repetitive stereotyped hand movements, such as wringing and/or repeatedly putting hands into the mouth, occur in Rett syndrome. Fixed muscle contractures, jerks and spasms seen after peripheral trauma need to be distinguished from dystonia and myoclonus. The neurological examination needs to be tailored to the clinical history. For MDs that are situation specific, home videos can provide useful information.

Familial Essential Tremor

I

•

pproach to iagnosis

D

•

Bradykinesia

E

A

Substantia nigra

Ballismus

Secondary Dystonia There are several causes of secondary dystonia particularly infections, trauma, metabolic disorders and degenerative disorders; these must be considered in appropriate settings.

Tic isorders D







Dystonia

Subthalamic nucleus

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Putamen

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Level of involvement

D

isorders with Tremor as the Predominant Manifestation

 

Table 6.7.2 Level of involvement in various types of movement disorders

Simple Motor Tics Simple motor tics are typically sudden, brief and meaningless movements that usually involve only one group of muscles, such as eye blinking, head jerking or shoulder shrugging.

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It is an inherited neuropsychiatric disorder with onset in childhood. It is characterized by multiple physical (motor) tics and at least one vocal (phonic) tic. These tics characteristically wax and wane, can be suppressed temporarily, and are preceded by a premonitory urge. D

Miscellaneous isorders Stereotypies and Self-Injurious Behavior Some stereotypies are simple rhythmic movements, e.g. body rocking, waving, flapping the hands, staring, and touching whereas others like head banging can be self injurious. -

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Tourette’s Syndrome

Lesch-Nyhan Syndrome

Chorea Chorea can result from the use of phenytoin, lamotrigine, amphetamines, antihistamines, antipsychotics and metoclo­ pramide. Tardive Syndromes Tardive syndromes are a group of delayed onset abnormal involuntary MDs induced by drugs. Tardive dyskinesia has a slow onset and characterized by rhythmic involuntary movements of tongue, face, and jaw usually after long antipsychotic drug use. Tardive dystonia (usually of the face and neck), akathisia (during neuroleptic or even afterward), tics (Tardive Tourettism), myoclonus (of the neck or upper arms) and tremor can also result from chronic antipsychotic use.

Acute Dystonic Reactions (Figs 6.7.1A and B) Acute dystonic reactions can be induced by dopamine de­ pleting drugs, e.g. antihistamines, antipsychotics, antiemet­ ics (domperidone, metoclopramide or prochloperazine) tet­ rabenazine, and antimalarials. The dystonia usually occurs on the first day of drug exposure and affects the head, neck and trunk muscles with neck retraction, tongue protrusion, trismus and oculogyric crisis. It is treated with anticholiner­ gics (benztropine) or benzodiazepines.

a

Tremor Tremor may be caused by many drugs such as amphetamine, albuterol, terbutaline, caffeine, carbamazepine, valproic acid, ephedrine and pseudoephedrine. It is reversible once the cause has been removed.

Management horea For symptomatic treatment, tetrabenazine, pimozide benzodiazepines, haloperidol or valproate can be used. All children with Sydenham’s chorea are to be treated as if they had acute rheumatic fever with penicillin for 10 days to eradicate active streptococcal infection and prophylactic C

D

rug nduced Movement isorders I

D

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-

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-

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Lesch Nyhan syndrome, an X linked recessive disorder of purine metabolism, is characterized by mental retardation, spasticity, extrapyramidal symptoms and intense self mutilation (e.g. lip biting) with intact pain sensation. These patients have elevated uric acid levels. The self mutilating behavior improves with carbidopa levodopa, naltrexone and serotonin re uptake inhibitors.

Akathisia Akathisia (restlessness) is induced by antidepressants, antipsychotics, antihistamines, calcium channel blockers, carbamazepine or metoclopramide. If the offending drug cannot be stopped, propranolol or benzodiazepines may alleviate the symptoms.

B  

Figures 6.7.1A and B Acute dystonic reaction. (A) Neck retraction; (B) Oculogyric crisis caused by metoclopramide

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Precautions

Indications

0.05 mg/kg/d Increase gradually up to 0.2 mg/kg/d, max 10 mg/d)

Prolong QT interval Cardiac arrhythmia

Gilles de Tourette syndrome

Haloperidol

Initial: 0.25–0.5 mg/d Increase by 0.25–0.5 mg weekly Maximum 0.15 mg/kg/d

Liver, kidney disease

Choreiform movement epilepsy Rheumatic chorea Thyrotoxicosis Hemiballismus Gilles de Tourette syndrome

Tetrabenazine

Dosage for children not established Suggested half of adult dosage Adult dosage 12.5 mg bid Increment of 12.5 mg every 5–7 days Maximum 3 mg/kg/d

Pregnancy Lactation Depression Patient on levodopa, reserpine

Chorea Hemiballismus Myoclonus Bucco-lingual dyskinesia In certain dystonias

Trihexylphenidyl

Begin with 0.5 mg/d < 4 years 1 mg/d > 4 years Increase 1 mg every 5 days till benefit or side effect

Glaucoma Sick sinus syndrome Cardiac failure Tachycardia

ITD Myoclonus Drug-induced MD Torticollis

S t

DRD Dystonia Parkinson state

m

L-dopa - Carbidopa Start 1 mg/kg/d; up to 5 mg/kg/d

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Dosage

Pimozide

N

Drug

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Table 6.7.3 Summary of drugs used in movement disorders

Less than 6 years of age—5 mg/kg/d oral Porphyria Hepatic failure May increase every 5–7 days by 5 mg/ MAO’s kg/d 6–12 years: nitially 10 mg/kg/d; increase by 5 mg/d at weekly intervals Usual dose: 10–30 mg/kg/d

Chorea Athetosis Ballismus Paroxysmal kinesogenic dyskinesia

Sodium valproate

Start 5–10 mg/kg/d, up to 15–30 mg/kg/d Liver disease Above 20 kg–400 mg/d SLE Porphyria

Chorea Athetosis Ballismus

Clonazepam

Initial: 0.01–0.03 mg/kg/d in 2–3 to divided doses Increase 0.25–0.5 mg/d every 3–5 days Maximum dose 0.2 mg/kg/d

Hypersensitivity to benzodiazepine

ITD Torticollis Myoclonus Startle syndrome

Propranolol

1–2 mg/kg/d

Avoid in cardiac failure, asthma

Tremors



i

Carbamazepine

Abbreviations: ITD, Idiopathic torsion dystonia; MD, Movement disorders; DRD, Dopa-responsive dystonia; SLE, Systemic lupus erythematosus

D

It is managed by small doses of levodopa, which rapidly and completely relieve the symptoms.

S

Tics and Tourette syndrome do not require treatment as their natural history is one of exacerbation and remission. The parents must be told that tics are not a sign of progressive neurological illness and are made worse by stress and will diminish when ignored. The drug treatment in selected cases includes pimozide, clonidine, fluphenazine and haloperidol. D

I

rug- nduced Movement isorder -

Drug induced movement disorder is best managed by stopping the offending drug and supportive care. The acute drug induced dystonia are usually self limiting or respond to treatment with benztropine. Table 6.7.3 shows a summary of dugs commonly used in the management of MDs. -

opa- esponsive ystonia R

D

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Management is usually ineffective. High dose anticholinergic drug therapy (trihexyphenidyl, 30 mg/d) may be useful. Other drugs used are baclofen, benzhexol, carbamazepine and benzodiazepines. All juvenile onset dystonic patients deserve a trial of L dopa. Botulinum toxin may be used in focal dystonia.

Tics and Tourette yndrome

D

diopathic Torsion ystonia D

I

long acting penicillin therapy until a minimum age of 21. Steroid treatment has also been shown to be of benefit. In lupus associated chorea, the control of the underlying disease with high dose steroids is recommended.

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1. Fenichel GM. Movement Disorders, chapter 14. Clinical Pediatric Neurology, 4th edition, 281; 2001. 2. Fernandez Alvarez E. Movement disorders in children: recent advances in management. Indian J Pediatr. 2009;76:531 6. 3. Grosset KA, Grosset OG. Prescribed drugs and neuro­ logical complication. J Neurol Neurosurg Psychiatry. 2004;75(suppl_3):iii2 8. 4. Jarman PR, Wood NW. Genetics of movement disorders and ataxia. J Neurol Neurosurg Psychiatry. 2002;73:II22 6. 5. Nygaard TG, Wooten GF. Dopa responsive dystonia: some pieces of puzzle are still missing. Neurology. 1998;50: 853 5. 6. Rojahn J. Self injurious and stereotypic behavior of noninstitutionalized mentally retarded people: prevalence and classification. Am J Ment Defic. 1986;91(3):268 76. -

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• Establishing phenomenology is the key to diagnosis to MD. • Every type of MD has its own characteristic, and combinations of them are also not rare, try to find the dominant one and existence of others also. • Presence of neurological and non neurological causes of abnormal movement, epilepsy and epilepsy mimic also have to be considered. • After having reached to clinical based MD type, proceed for diagnostic work up to locate the cause behind and accordingly plan for treatment. • Home videos can aid diagnosis in paroxysmal MDs.

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ncephalitis and ncephalopathies E

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Diseases of Central ervous ystem

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Several groups of viruses can invade the brain to cause encephalitis. Some of these like arboviruses, Herpes simplex, rabies, etc. are “neurotropic,” i.e. they have a predilection for the brain while others like measles, mumps and influenza only occasionally invade the brain. • Arbo or ‘arthropod borne’ viruses: e.g. Western equine, Eastern equine, Venezuelan equine, Japanese, St Louis, West Nile and Murray valley encephalitis viruses. These viruses are naturally transmitted between insects and vertebrate animals that decide the geographical habitat and seasonal occurrence of the infection • Herpesviruses: herpes simplex 1 and 2, varicella zoster, Ebstein-Barr, cytomegalovirus, human herpesvirus-6, B virus • Enteroviruses: polioviruses, coxsackie, echo, enteroviruses 70 and 71 • Orthomyxoviruses: influenza viruses • Paramyxoviruses: measles, mumps, parainfluenza, Nipah virus. • Adenoviruses • Rhabdovirus

pidemiology

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Japanese encephalitis (JE) is the commonest VE in Asia and causes the maximum number of cases worldwide. Arboviruses have their own specific geographical distribution depending on the activity of their insect vectors, and tend to cause epidemics or outbreaks. For example, JE transmission occurs between the mosquito Culex tritaeniorrhynchus, a rice field breeding mosquito and the pig. Man is an incidental “dead end” host. Rabies is prevalent in most countries of the world. Herpes simplex encephalitis (HSE) is the commonest form of sporadic encephalitis in western countries. Mumps, measles and rabies encephalitis have been largely eradicated from many developed countries due to effective vaccination programs. Japanese encephalitis and rabies are public health problems in India.

Pathogenesis The illness begins with the entry of the infecting agent and replication at an extraneural site. Most viruses reach the nervous system hematogenously and the probability of encephalitis depends on the degree of viral amplification at the extraneural site and the ensuing viremia. Other viruses gain access to the brain by the neuronal route. For example, the rabies virus replicates locally at the site of animal bite, then enters the nerve endings and travels retrograde via axons to the brain. Upon reaching the brain, the virus replicates in neurons and may lead to cell death. There are varying degrees of parenchymal and meningeal inflammation, edema and necrosis. Some viruses may have a predisposition to involve specific areas of the brain such as temporal lobe in herpes simplex and hippocampus in rabies.

Clinical eatures F

iral ncephalitis E

V







The term “encephalitis” means inflammation of the brain parenchyma, either a part or all of the “encephalon”. It is an important cause of death and permanent neurologic disability in both children and adults. Most commonly, encephalitis has an infectious cause. Actual invasion by a viral agent causing direct neuronal injury is the most common cause of encephalitis, when it is called “viral encephalitis” (VE). Nonviral agents can also produce inflammation of the brain parenchyma. Encephalitis and meningitis are overlapping syndromes. Pathologically, some degree of both meningeal and parenchymal inflammation is found in most patients with viral and nonviral invasion of the brain. Therefore the term “meningoencephalitis” is often used. Direct injury by invasion may result in acute, subacute or chronic manifestations. Sometimes the inflammation is not due to invasion but is an indirect immunologically mediated injury. Noninflammatory diffuse cerebral dysfunction is termed as “encephalopathy”; common causes include metabolic, toxic or ischemic. Encephalopathy can be acute or chronic. The term encephalopathy is also used for altered mentation due to any cause. The term acute febrile encephalopathy is used for a febrile illness with altered sensorium of 2 weeks or less duration in a previously well child. It may have infectious (including VE) and noninfectious causes.

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Rashmi Kumar

Clinical manifestations depend on whether the brain parenchyma or meninges are predominantly involved producing an encephalitic or meningitic syndrome respectively. The same virus may produce a meningitic picture in one and encephalitic picture in another patient. The severity of manifestations may vary widely either as a mild febrile illness associated with headache to a severe disorder with convulsions, coma, neurological deficits and death. Usually the onset is abrupt with fever and declining mental status. There may be irritability, agitation, screaming spells, confusion, delirium, drowsiness, stupor or coma. Headache may be complained of in older children.

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lood Counts

In the acute stage, blood counts usually reveal a polymorphonuclear leukocytosis. Low platelets counts and high packed cell volume in patients from endemic areas may point towards dengue infection. E

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Cerebrospinal luid xamination

amples for iral Culture V

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This is an essential investigation but should be done when considered safe. Cerebrospinal fluid in VE typically shows a pleocytosis of up to 300 cells/mm3, which can be either predominantly lymphocytic or polymorphonuclear, with normal to slightly raised protein and normal sugar level. Cerebrospinal fluid pleocytosis (> 5 cells/mm3) is present in more than 95% cases of acute VE and exceeds 500 cells/mm3 in 10% cases of AVE. The CSF in acute VE is indistinguishable from aseptic or viral meningitis.

Samples for viral culture from respiratory secretions, throat 368 swab, CSF, blood, urine and stool taken as early as possible

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erological nvestigations in cute erum for pecific g ntibody evel

Japanese encephalitis is commonly diagnosed by the antibody capture ELISA for IgM antibody in acute phase serum and CSF. R

Polymerase Chain eaction

ests for abies R

T

Polymerase chain reaction (PCR) is being developed to provide a rapid and accurate diagnostic tool for a host of pathogens and is the mainstay of diagnosis. This is widely used for diagnosis of HSE with high sensitivity (> 90%) and specificity (100%).

euroimaging of rain B

N

No single test is sufficient for antemortem diagnosis of human rabies. Saliva can be tested by virus isolation or reverse transcription followed by PCR (RT-PCR). Skin biopsy specimens are examined for rabies antigen in the cutaneous nerves at the base of hair follicles. Immunoflourescent staining of corneal smears and skin biopsy specimen do not have a high yield. Serological assays are not suitable for diagnosis of rabies as virus-specific antibodies in serum tend to appear on average 8 days after the onset of clinical symptoms. The fluorescent antibody test is considered the gold standard for the diagnosis in animals’ postmortem.

Neuroimaging of brain is now a standard investigation in patients with suspected VE. Neuroimaging is often normal, may reveal cerebral edema and diffuse low attenuation, patchy hypodensities or specific abnormalities as in HSE. Cranial neuroimaging may also be useful in ruling out other treatable intracranial disorders and acute disseminated encephalomyelitis (ADEM). Magnetic resonance imaging is the procedure of choice. Characteristic abnormalities are found in HSE, which shows early changes of focal edema in the medial aspects of the temporal lobes, orbital surfaces of the frontal lobes, insular cortex and cingulate gyrus (Fig. 6.8.1). In infants and young children however, more widespread changes may be seen. In JE, neuroimaging shows distinct hypodensities in the thalamus, basal ganglia and brainstem. E

nvestigations

in the illness should be collected in appropriate transport media and sent to the reference laboratory.

lectroencephalography

Electroencephalography shows diffuse slow waves as a nonspecific finding in VE. In HSE, characteristic changes of 2–3 Hz periodic lateralized epileptiform discharges originating from the temporal lobes are seen in less than half the cases in later stages. In practice, the diagnosis of encephalitis is presumptive, based on clinical assessment and exclusion of other possibilities. Specific virological investigations are complex, time consuming and expensive. Even in advanced centers,

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Typical features include an initial stage of fever, headache and vomiting lasting for less than a week followed by convulsions, coma and neurological deficits with or without signs of meningeal irritation. Severe cases may be associated with life-threatening rise in intracranial tension, decerebration or flaccid coma. Typically this stage lasts for 7–10 days after which, there is gradual recovery with or without sequelae. Some patients may have a biphasic course. Occasionally VE can be subacute in onset or present as stroke, a movement disorder or a behavioral disturbance (as seen with HSE). Chronic encephalitis can present like a degenerative brain disorder. Examination should include a search for skin rashes often seen with enteroviral encephalitis, measles, dengue and varicella zoster. Parotitis often occurs with mumps. Concurrent upper respiratory infection is characteristic of influenza. Patients with rabies may have the characteristic hydrophobia or aerophobia. A constellation of fronto– temporal signs with aphasia, personality change and focal deficits or focal seizures is characteristic of HSE. Rabies may present as an ascending paralysis simulating GuillainBarre syndrome. Japanese encephalitis is associated with prominent extrapyramidal signs in the form of rigidity and abnormal movements, especially in the convalescent stage. Even when the diagnosis of VE is made, identification of the etiologic agent is a daunting task. Neurological signs do not reliably identify the underlying etiology despite the propensity of certain neurotropic viruses to affect specific focal areas of the brain. Geographic and seasonal factors, history of recent travel, contact with animals, animal bite, occupation and immune status of the patient need to be considered.

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Figure 6.8.1 MRI brain in herpes simplex encephalitis showing temporal lobe changes

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Postinfectious or Postvaccinal cute Disseminated ncephalomyelitis

pecific herapy E

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Nonviral agents, which can cause encephalitis include: • acteria: – Pyogenic and tuberculous meningitis – Mycoplasma pneumoniae – Listeria monocytogenes

ncephalopathies

Clues must be sought to differentiate encephalopathy from encephalitis, but the distinction is not always possible on clinical grounds. General features of encephalopathies are: • Absence of fever or meningeal signs • Absence of focal neurologic signs or focal seizures • No peripheral leukocytosis • Normal CSF • Diffuse slowing on electroencephalography • Normal imaging studies.

onviral nfectious ncephalitis I

N

Specific therapy is recommended in encephalitis due to herpes group of viruses. Acyclovir in a dose of 15 mg/kg administered as an intravenous infusion over 1 hour every 8 hours for 14 days (21 days in immunocompromised) is indicated in HSE. Success of antiviral therapy depends on early institution of therapy. Acyclovir is also recommended for varicella-zoster encephalitis. Oseltamivir can be considered for influenza encephalitis. Trials with α-interferon and nasogastric ribavirin in JE in children have revealed no benefit.

ther Causes of cute ebrile ncephalopathy E

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Supportive treatment is the mainstay of therapy for a child with presumed VE. A severe case should be managed in an intensive care unit. Measures include maintenance of airways, breathing and circulation, hydration, electrolyte status and control of pyrexia and convulsions. It is prudent to use appropriate parenteral antibiotics to cover for meningitis. Raised intracranial tension should be controlled with mannitol infusion (0.25–1.0 g/kg every 4–6 hours), intravenous furosemide or intermittent positive pressure ventilation to keep arterial CO2 tension between 25 and 30 mm Hg. Proper nursing care must be given. The role of steroids in acute VE is debatable. Theoretic arguments exist for and against their use. A study that evaluated high dose dexamethasone in JE found no benefit of steroid therapy.

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upportive reatment

This is a postinfectious immune inflammation, common postinfectious causes being measles, rubella, mumps, varicella zoster, influenza A and B, Rickettsia and Mycoplasma pneumonia; while vaccines associated with this syndrome include rabies, vaccinia, measles and yellow fever. The illness is monophasic with altered consciousness, convulsions and multifocal neurological signs affecting cerebellum, optic nerves, long tracts, spinal cord and peripheral nerve roots. Fever is usually absent at the onset of symptoms. A history of a viral exanthema or vaccine in the recent past is usually available. Cerebrospinal fluid may reveal a mild pleocytosis. Characteristic plaque like lesions are seen scattered in white matter, at times in deep gray matter and other areas of the neuraxis (Fig. 6.8.2). Treatment options include high dose pulse steroids, intravenous immunoglobulins and plasmapheresis. The initial presentation of multiple sclerosis can be indistinguishable from ADEM.

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reatment T

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etiological diagnosis is possible in only a small proportion of clinically suspected cases.

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Spirochetes: syphilis, Leptospirosis, Lyme disease Brucellosis Legionella Salmonella typhi Cat scratch disease (Bartonellosis) ickettsia ungi: Cryptococcus, Histoplasma, Aspergillus, mucormycosis, Candida, coccidioidomycosis Protozoa: Plasmodium, Trypanosoma, Naeglaria, Acanthameba, Toxoplasma gondii, schistosomiasis, echinococcus granulosus etazoa: Trichinosis, echinococcus, cysticercus, schistosoma Human slow viral infections: SSPE, progressive rubella panencephalitis, Creutzfeldt-Jakob disease, Kuru, pro gressive multifocal leukoencephalopathy. HIV-AIDS itself causes subacute or chronic encephalitis but the associated immunosuppression may predispose to encephalitis by other pathogens.

Diseases of Central ervous ystem

– – – – –

The presence of fever in itself is not sufficient to make a diagnosis of infective or inflammatory encephalitis since encephalopathy may be precipitated by systemic 369 infection or sepsis without cerebral inflammation (infective encephalopathy) or some other cause of fever may coexist.

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is yellow to white because of high triglyceride content and biopsy reveals diffuse microvesicular fatty infiltration without any evidence of inflammation or necrosis. Reye’s syndrome has been reported from different parts of India. O

Prognosis and utcome Even when meningoencephalitides are not fatal, they have the potential to cause permanent neurological handicap in the child. Therefore, the treatable infections must be energetically treated. The outlook is somewhat better with the noninflammatory encephalopathies.

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Chronic ncephalitis and ncephalopathies

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This syndrome of acute encephalopathy with fatty infiltration of the liver usually presents with a history of a preceding viral infection (upper respiratory infection in 90%; varicella in 5–7%). A strong association exists with preceding intake of salicylates. Abrupt onset of protracted vomiting is followed by delirium, combative behavior and stupor. Most children have a mild course but rapid progression to seizures, coma and death may occur. Mild hepatomegaly and hypoglycemia are common. Hepatic 370 dysfunction is suggested by raised liver enzymes (more than threefold), raised serum ammonia and abnormal coagulogram but serum bilirubin is usually normal. Liver

ibliography 1. Chaudhuri A, Kennedy PG. Diagnosis and treatment of viral encephalitis. Postgrad Med J. 2002;78:575-83. 2. Glaser CA, Honarmand S, Anderson LJ, et al. Beyond viruses: clinical profiles and etiologies associated with encephalitis. Clin Infect Dis. 2006;43:1565-77. 3. Kalra V. Acute febrile encephalopathy. In: Gupta V, Gupta D (Eds). Practical Paediatric Neurology, 2nd edition. New Delhi: Arya Publications; 2008. p. 112. 4. Kumar R. Viral encephalitis and encephalopathies. In: Singh M (Ed). Medical Emergencies in Children, 4th edition. New Delhi: Sagar Publications; 2006. pp.324-33. 5. Prober CG. Central nervous system infections. In: Behrman RE, Kleigman RM, Jenson HB, Stanton BF (Eds). Nelson Textbook of Pediatrics, 18th edition. Pennsylvania: WB Saunders Co; 2008. pp. 2512-23.

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• Encephalitis and encephalopathies are important causes of hospital admissions among children in India. • Encephalitis refers to inflammation of brain parenchyma and can be caused by a large variety of infections. • Encephalopathy or noninflammatory diffuse cerebral dysfunction can be caused by several toxic and metabolic causes. • These conditions have the potential of permanent neurologic handicap in the survivors. • Specific treatment is available for many nonviral infections and HSE.

Dengue ncephalopathy The occurrence of neurological manifestations in dengue infections has been recognized for long. Dengue infection may produce a picture of acute febrile encephalopathy with or without rash, swelling (non-pitting edema on face and body), bleeding manifestations, low platelet count and deranged liver function without frank jaundice. The cause of encephalopathy in dengue was believed to be vasculitis with fluid exudation, cerebral edema, hypoperfusion and hyponatremia. However, recently the neurotropic potential of dengue virus with virus invasion of the brain producing “encephalitis” has been well documented primarily from studies in Southeast Asia.

ey



•



•

Infectious encephalopathies: these include infectious disorders associated with encephalopathy without actual invasion of the brain parenchyma. Important causes include cerebral malaria, enteric encephalopathy, dengue encephalopathy, shigellosis and sepsis syndrome Fever from any cause associated with metabolic or toxic encephalopathy can produce a picture of acute febrile encephalopathy. Examples of such metabolic/toxic causes include Reye’s syndrome, dyselectrolytemia, diabetic, uremic or hepatic coma, poisoning and heat stroke Fever from any cause associated with a structural lesion in the brain such as tumor or vascular insult.



•

Some viral encephalitides are chronic and may present like a neurodegenerative disorder. These include subacute sclerosing panencephalitis, progressive rubella panencephalitis, HIV, toxoplasma and human slow virus infections, Kuru, progressive multifocal leukoencephalopathy and Creutzfeldt-Jakob disease. Diffuse cerebral dysfunction can follow asphyxia, trauma, vascular insult, CNS infection and metabolic disorders (hypoglycemia, hyponatremia, inborn errors of metabolism). Degenerative brain disorders and epileptic encephalopathies also present as chronic encephalopathy.



 

Figure 6.8.2 MRI brain in acute disseminated encephalomyelitis showing plaque like lesions in deep white matter

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Diseases of Central ervous ystem

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cute Bacterial

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eningitis

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Bacterial meningitis may be sporadic or epidemic, it commonly occurs in infants and children although it can occur at any age. In developed countries, a substantial reduction of H. influenzae (Hib) and pneumococcal meningitis has occurred because of widespread immuni zation. However, these organisms continue to cause menin gitis in many developing countries. Poor socioeconomic conditions, overcrowding, malnutrition and HIV, further contribute to the high incidence of meningitis in developing countries. Hib meningitis occurs usually in children between 3 months to 3 years of age. Pneumococcal meningitis occurs throughout childhood and is particularly seen in children with pneumonia, otitis media, sinusitis, CSF leaks, head injury, sickle cell disease and thalassemia major. Meningococcal meningitis occurs mainly in school age children and young adults. Meningitis caused by Hib, Pneumococcus and Meningococcus is rare in the first 3 months of life because of transplacental transfer of protective maternal antibodies.

E

tiology The three major causative organisms in children are Hemophilus influenzae, Neissera meningitides and Streptococcus pneumonia and in neonates, Gram-negative bacilli, group B streptococci and Listeria monocytogenes. The causative organisms vary mainly with the age (Table 6.9.1), nutritional and immune status of the child and associated clinical conditions.

pidemiology



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Infections of the central nervous system are serious diseases that are associated with high mortality and morbidity. Early diagnosis and appropriate management are extremely important. The presentation of various CNS infections is often nonspecific and includes fever, headache and altered sensorium, at times seizures and focal neurodeficitis. Clues from a detailed history, epidemiology, examination and appropriate investigations are required for a precise diagnosis. Central nervous system infections include: • eningitis: Acute, subacute or chronic • cute encephalitis: Diffuse or focal • Encephalopathy with systemic infections • Postinfectious syndromes Several organisms including bacteria, viruses, parasites and fungi can cause CNS infections. In this chapter bacterial meningitis, brain abscess and neurocysticercosis (NCC) are discussed.

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Pratibha Singhi

Pathogenesis Bacterial meningitis occurs through the hematogenous route in most cases. Inhaled bacteria adhere to the nasopharyngeal mucosa, evade mucosal host defense mechanisms and enter the blood stream, and then the CSF by penetrating the blood brain barrier (BBB). This is facilitated by various neurotropic and virulence factors.

 

Table 6.9.1 Common causative organisms for bacterial meningitis in various age groups Age Causative organisms Initial antibiotics and doses (mg/kg/day) < 1 month

Gram-negative bacilli (E. Coli, pseudomonas), Group B streptococci, Listeria monocytogenes

1–3 months

Hemophilus influenzae. B Streptococcus pneumoniae Neissera meningitides Gram-negative bacilli, Group B streptococci Listeria monocytogenes Hemophilus influenzae. B Streptococcus pneumoniae Neissera meningitides

> 3 months

Key: * In places with aminoglycoside resistant Gram-negative organisms ** In places with ceftriaxone resistant pneumococci *** If ceftriaxone not affordable

Ampicillin 50–100; q6–8h plus Gentamicin 2–2.5; q8h or *Cefotaxime 100; q8h Ceftriaxone 100; q24h or Cefotaxime 100; q8h plus ampicillin

Ceftriaxone/or cefotaxime plus ** Vancomycin 15; q6h or *** Ampicillin and chloramphenicol

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Clinical Presentation



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As early diagnosis of meningitis is extremely important, it should be suspected in any child with lethargy, unconsci ousness, inability to feed, stiff neck and seizures. It is important to note that the absence of fever or meningeal signs does not exclude the diagnosis of bacterial meningitis.

Differential Diagnosis The differential diagnoses according to presentation include: • cute onset fever and meningismus: Aseptic meningitis, pneumonia with right upper lobe involvement, retropharyngeal abscess and cervical lymphadenitis • Coma: Encephalitis, Reye’s syndrome, metabolic problems, hepatic encephalopathy, intoxications and other causes of nontraumatic coma. Cerebral malaria is an important differential diagnosis in endemic regions. Blood films for malarial parasites should be taken in children with splenomegaly and anemia • ocal signs: Cerebral abscess, herpes encephalitis, intracranial bleeds and other space occupying lesions; get urgent neuroimaging • ubacute presentation: Tubercular, fungal and parasitic meningitis.

Laboratory Diagnosis

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• Cerebrospinal fluid examination: CSF examination is essential for the diagnosis of meningitis. Lumbar puncture (LP) should be done as early as possible in all cases of suspected meningitis and also in the following: – Neonates and very young infants who present as nonspecific sepsis – Children with febrile seizures: up to 18 months of age, or if the child looks ill or is on previous antibiotics. –

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Typically meningitis presents acutely with fever, headache, vomiting, altered sensorium, stiff neck, and in some cases, seizures and photophobia. The child may have a preceding upper respiratory infection, pneumonia or otitis media. Fever may be absent in very small infants, in severely malnourished or immune compromised children, and in children on previous antibiotic therapy. Younger children may not be able to complain of headache but may be irritable. Seizures may be the presenting feature in almost a third of children with meningitis; they may be recurrent and prolonged. Impairment of sensorium at presentation may be minimal, but worsens gradually with progression of the disease. In some cases of meningococcal meningitis a fulminant course with sepsis, shock, (WaterhouseFriderichsen syndrome) rapidly progressive cerebral edema and raised intracranial pressure (ICP), evolving over a few hours may occur. On examination, neck rigidly and other signs of meningeal irritation are seen. These include: • ernig’s sign: With thighs flexed on abdomen, passive extension of knee produces pain in the back • Brudzinski’s sign: Passive flexion of neck produces flexion of both lower limbs • ripod sign: In the sitting position, the child supports himself with both arms extended behind the back, which is kept straight • nee-kiss sign: The child cannot bend forward to kiss his knees.

Diagnosis

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The inflammatory exudate covers the brain and cerebral blood vessels, causes vasculitis and thrombosis; ischemia may lead to cerebral infarction. Cerebral edema may be marked and may lead to cerebral herniation. Neuronal damage finally occurs.

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europathology

Meningeal signs may be minimal or absent in neonates and young infants, and in malnourished and deeply comatose children. In infants, a bulging fontanel is an important sign of meningitis. Symptoms and signs of raised ICP (headache, vomiting and respiratory abnormalities) may appear within 24–28 hours. Papilledema at presentation is uncommon and if present, a CT scan must be done to exclude a mass lesion or a complication. Focal signs may be due to subdural collection, cortical infarction or cerebritis. Associated findings such as a maculopapular or petechial rash in meningococcal infections, otitis media or pneumonia in pneumococcal infections, and pustular skin lesions in staphylococcal infections may be seen. In neonates, meningitis may be present with nonspecific symptoms of sepsis with poor feeding, lethargy, fever, vomiting, irritability, high-pitched cry and at times seizures. The anterior fontanel may be level or full and in some cases, there may be enlargement of head with separation of sutures.

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Non-hematogenous spread of bacteria into the CSF can also occur from contiguous sites of infection such as otitis media, sinusitis and mastoiditis or through direct communication of the subarachnoid space (SAS) with the skin or mucosa as in head trauma, dermal sinuses and through infected CSF shunts. Bacterial multiplication and autolysis in the SAS leads to the release of bacterial components that trigger a strong inflammatory response. Several inflammatory cytokines and chemokines including interleukins and tumor necrosis factor (TNF) are produced that in turn lead to the release of other inflammatory mediators, including platelet activating factor, matrix metalloproteinases (MMP), nitric oxide and free oxygen radicals that lead to disruption of the BBB. Leukocytes pass from the blood into the CSF leading to CSF pleocytosis, and further release of various toxic mediators that adversely affect the cerebral blood flow and cerebral metabolism, and contribute to the development of cerebral edema.

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Organism Identification

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• Cerebrospinal fluid Gram stain: It is quick, reliable and inexpensive, positivity depends on the number of organisms in the CSF—at least 105 colony forming units/ mL of CSF is required. The yield is markedly increased by examining fresh centrifuged sediment of the CSF. • cridine orange: It stains the nucleic acid of some bacteria so that they appear bright red orange under a fluorescent microscope. It stains the intracellular bacteria better than the Gram stain and may be positive even when the Gram stain is negative. • Cerebrospinal fluid culture: A positive CSF culture is the gold standard for organism identification. High positivity (≈ 75%) reported from developed countries is not seen in developing countries because of prehospital antibiotic therapy, delayed plating, inadequate storage and transport of CSF. • apid diagnostic tests: Rapid diagnostic tests detect bacterial antigen by counter-current immunoelectro phoresis, enzyme linked immunosorbent assay (ELISA) and latex agglutination tests. They are helpful in providing early diagnosis, and in differentiating viral from bacterial meningitis. A negative test does not exclude bacterial meningitis. These tests are expensive and are not routinely used. • ultiplex polymerase chain reaction assays: PCR can rapidly detect a large number of organisms; however, they are not available in most developing countries. • amples from other sites of infection: Samples from other sites of infection such as pleural fluid, cellulitis, otitis, aspiration of petechiae in suspected meningococcemia, and urine in young infants should also be collected for organism identification. • ther nonspecific tests: Nonspecific tests such as raised peripheral white blood count, C-reactive protein, CSF lactate and procalcitonin have limited specificity. O

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Table 6.9.2 shows the CSF characteristics helpful in differentiation of acute bacterial meningitis from aseptic and tubercular meningitis. Occasionally, an initial polymorphonuclear response can be seen in viral meningitis and an initial lymphocytic response in bacterial meningitis. The CSF sugar is normal in most cases of viral meningitis, but may be low in some cases; however, it is rarely below 20 mg/dL.

Diseases of Central ervous ystem

• Contraindications of P include: – Raised ICP – Focal neurological symptoms or signs – Shock/cardiorespiratory instability – Thrombocytopenia (platelet count < 40,000/mm3)/ coagulation disorder – Local infection at LP site. Appropriate antibiotics should be given early in all cases of suspected meningitis even if the LP is delayed. Early antibiotic administration for 24 hours does not significantly alter the CSF cellular response but may decrease the yield on culture and on Gram stain. CT scan before the LP is not routinely needed; it is indicated in children with focal neurological symptoms or signs, papilledema, critically raised ICP or suspicion of a mass lesion. CT is normal in most cases of bacterial meningitis, including those with subsequent herniation; a normal CT does not rule out raised ICP. Typically the CSF pressure is raised, there is polymor phonuclear leukocytosis, decreased glucose and increased protein concentration. The cell count may vary from a few to hundreds to over a thousand leukocytes; almost 90% cases have a CSF cell count over 100/mm 3. In developing countries the reported CSF cell counts are not very high in most cases. A cloudy CSF under pressure is almost diagnostic of bacterial meningitis. Cell count should be done within half an hour of CSF collection. In normal children, the CSF has 0–5 mononuclear cells/ mm3; polymorphonuclear cells are very rarely seen. Presence of a single polymorphonuclear cell in the clinical setting of meningitis should be considered significant. In neonates the upper limit of normal extends to 20–30 WBCs/mm3; however the mean CSF cell count is generally 5–10 WBCs/mm3. The CSF glucose levels are less than 40 mg/dL in more than half the cases; a CSF to serum glucose ratio of 0.4 or less is 80% sensitive and 98% specific in children above 2 months of age. In neonates a CSF to serum glucose of less than or equal to 0.6 is abnormal. The blood glucose should be collected before the LP. At times the CSF can be completely normal in early stages of bacterial meningitis, particularly in neonatal meningitis; a repeat LP after few hours may show abnormalities; antibiotic therapy must therefore be started in all cases with a strong suspicion of bacterial meningitis.

 

Table 6.9.2 Cerebrospinal fluid characteristics in various types of meningitis Types of meningitis

Cell count

Polymorphonuclear Lymphocytes cells

Protein (mg/dL)

Bacterial Partially treated

Cerebrospinal fluid appearance Cloudy Clear

Glucose

Few 100 to > 1000 5 - Few 100

+++ ++

+ +

Raised 100 to > 500 ↓↓ Raised 100–500 ↓

Tubercular Viral

Clear Clear

< 500 10–500

+

+++ ++

Raised 100–500 N (< 50) or raised up to 100

↓ N

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Antibiotic Therapy

Prognosis Coma, raised ICP, status epilepticus, shock and respiratory depression are important predictors of mortality and morbidity. Neurologic sequelae including hearing loss, hydrocephalous, spasticity, visual and cognitive deficits and developmental delay are common.

Prevention To prevent secondary meningitis, children with Hib or meningococcal meningitis should be isolated for 24 hours.





This should be broad enough to cover all the likely pathogens according to the age of the child and the prevalent epidemiology and resistance patterns of organisms. Once the organism is isolated on culture, and its susceptibility is determined, antibiotic therapy is targeted accordingly. If no organisms are isolated, the initial antibiotics should be continued for at least 7–10 days. The standard recommendation for the duration of antibiotics is 10–14 days for S. pneumoniae and H. influenza, and 7 days for N. meningitides. Shorter durations of antibiotic therapy (5 days) have also been found effective. A minimum of 3 weeks of antibiotics are required for Gramnegative, staphylococcal, meningitis and for neonatal meningitis. With proper treatment, the CSF culture and Gram stain become negative within 24–48 hours and the CSF glucose normalizes over 72 hours. The increase in cells and proteins may persist for several days. A repeat LP either during treatment or at the end of therapy is not routinely

­

Appropriate IV antibiotics and supportive therapy should be started as soon as possible. Close monitoring is essential to detect and manage any acute life threatening complications such as shock or raised ICP. Ideally this is done in a pediatric intensive care unit (PICU) until the child is stable. In resource poor countries, at least the severely ill children should receive intensive care.

Airway, breathing and circulation must be maintained. Shock, raised ICP, seizures and status epilepticus must be urgently and appropriately managed. Enough fluids should be given to maintain normovolemia, normal blood pressure and thereby adequate cerebral perfusion. Electrolyte imbalances should be promptly corrected. • Corticosteroid therapy: Early dexamethasone therapy (0.15 mg/kg/6 hourly × 4 days) has been recommended in developed countries as it reduces mortality, severe hearing loss and neurological sequelae in cases of Hib and pneumococcal meningitis. However, no beneficial effect of corticosteroids has been found in children from low income countries and thus they are not recommended • ral glycerol: Oral glycerol for the first 48 hours (6g/kg/ day q6hour) may reduce neurological sequelae • ther therapies for modulation of inflammatory pathways: Other therapies for modulation of infla mmatory pathways such as isoform of nitric oxide synthase, inhibition, endothelin agonists, antioxidants, neurotrophin, glutamate antagonist, TNF neutralization, MMP inhibition, caspase inhibition are still experimental • he role of intravenous immunoglobulin: The role is limited to children with immune deficient states and in some cases of neonatal meningitis. O

Management

Supportive Treatment

O



If treated properly children improve within 48–72 hours and the fever comes down within 4–5 days. Persistent fever (> 10 days) may be due to thrombophlebitis, subdural effusions, spread of infection (such as pneumonia, arthritis or osteomyelitis), drug fever and rarely resistant organisms. The common complications are listed in Table 6.9.3. CT scan during therapy is indicated in a child who does not show clinical improvement, has sudden unexplained deterioration, new onset seizures or focal neurologic signs, signs of raised ICP, persistent fever or enlarging head. Subdural effusions, infarct, hydrocephalus, cerebritis or cerebral abscess may be detected. MRI detects parenchymal complications earlier than CT. Ultrasound of the head is helpful in neonates and in infants with open fontanel.

needed unless there is appearance of new symptoms or signs.

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Course and Complications

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Late onset seizures Subdural empyema Infarcts, cerebritis and brain abscess Hydrocephalus Cranial nerve involvement Sensorineural deafness Diabetes insipidus Spread of infections to distant sites (pneumonia, pericarditis, arthritis and osteomyelitis)

• Hib meningitis: Rifampicin (20 mg/kg/day twice daily for 4 days) for all household contacts if there is at least one unvaccinated contact less than 4-year-old. Rifampicin for the index case before discharge if ampicillin and/or chloramphenicol were used, as they do not eradicate H Influenzae; it is not needed if ceftriaxone was used • eningococcal disease: Rifampicin (10 mg/kg 12 hourly for 2 days) for household and day care contacts. Ceftriaxone single IM dose (125 mg for children < 12 years and 250 mg for older children and adults). Ciprofloxacin 500 mg or azithromycin 500 mg single dose in adults • Primary prevention: It is possible by immunization against the common pathogens causing meningitis. M

 

Table 6.9.3 Complications of bacterial meningitis

Chemoprophylaxis

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Streptococci, staphylococci, Gram-negative organisms, anaerobic bacteria and several unusual organisms may cause brain abscess. In neonates Gram-negative organisms particularly Citrobacter diversus and Proteus mirabilis are common. The causative organisms of the abscess are determined mainly by the underlying/predisposing condition. In about one-third of cases, polymicrobial sepsis is seen.

Pathogenesis









Brain parenchyma gets infected by the hematogenous route, contiguous spread from an adjacent infection, trauma or a neurosurgical procedure. The predisposing conditions and likely organisms are shown in Table 6.9.4. Following hematogenous infection, the pathogens localize in the poorly vascularized areas of the brain such as the gray-white junction and cause cerebritis. The inflammation and edema progress through four stages in 4–6 weeks: 1. Early cerebritis (1–3 days) 2. Late cerebritis (4–9 days) 3. Early fibroblastic capsule formation (10–14 days)





Clinical presentation is variable; usually it is subacute with fever, headache, vomiting, altered sensorium, seizures, neck rigidity and focal neurodeficitis depending on the site of the abscess. Occasionally the presentation may be acute if the abscess ruptures in the ventricles. Papilledema, sixth nerve palsy and occasionally cerebral herniation syndromes may occur secondary to raised ICP. Neonates and young infants present with nonspecific features of irritability, lethargy, poor feeding, seizures, bulging fontanels and an enlarging head; focal signs are rare. Differential diagnosis includes tumors, focal encephalitis such as herpes, and other focal suppuration.

N

Etiology

Clinical Presentation

S

It is rare in developed countries (0.3–1.3 per 100,000 people per year), but not uncommon in developing countries.



Epidemiology

Diagnosis •

euroimaging: Typically brain abscess appears as a characteristic ring enhancing lesion with central hypodensity and surrounding edema on CT (Fig. 6.9.1). In early cerebritis, the ring enhancement may be incomplete and a double contrast CT may be helpful in defining the capsule. The MRI is more sensitive than CT in diagnosis of cerebritis • rganism identification: It is done by Gram stain and culture of the aspirate. Blood cultures are positive in less than 25% cases with hematogenous infections N

A

Bacterial Brain bscess

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A

Brain abscess is a focal infection of the brain parenchyma, which may be bacterial, tubercular, fungal or parasitic.

4. Late capsule formation (> 14 days) when a dense fibrous capsule is formed. Most brain abscesses occur in the cerebral hemispheres, some in the cerebellum and brainstem, depending on the etiology. Multiple scattered abscesses are common with hematogenous infections; those secondary to direct spread are usually single and occur in contiguous brain parenchyma.

Diseases of Central ervous ystem

Brain bscess

 

Table 6.9.4 Predisposing conditions for brain abscess and likely organisms Predisposing conditions for brain abscess Likely organisms Hematogenous spread Cyanotic congenital heart disease particularly tetralogy of Fallot Streptococcus viridans, Staphylococcus aureus, Microaerophilic streptococci, Haemophilus species Subacute bacterial endocarditis Streptococcus viridans, Microaerophilic streptococci, Staphylococcus aureus, Haemophilus species Chronic pulmonary infection Streptococci, staphylococci, anaerobic bacteria Orofacial infections Anaerobic bacteria, streptococci (aerobic and anaerobic), Staphylococcus aureus Sinus infections Streptococci (aerobic and anaerobic), Staphylococcus aureus, Haemophilus species, anaerobic bacteria, Pseudomonas Malnutrition and immunocompromised status Staphylococcus aureus, Gram-negative organisms, Anaerobic organisms, unusual organisms Direct spread Chronic otitis, mastoiditis Streptococci (aerobic and anaerobic), Staphylococcus aureus, Haemophilus species, Proteus, anaerobic bacteria, Pseudomonas Infected dermal sinuses, epidermis cysts and encephalocele Staphylococcus aureus, Staphylococcus epidermidis, streptococci, enterobacteriaceae Complication of meningitis Organisms causing the underlying meningitis particularly Gram-negative staphylococci

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abscess into the ventricular system and low Glasgow coma scale (GCS) at presentation. Delayed treatment is associated with significant neuromorbidity.

d

Prevention

T

N

b

Early treatment of orofacial and dental infections, and antibiotic prophylaxis for children with cyanotic congenital heart disease undergoing procedures associated with bacteremia; and after penetrating skull injury or craniotomy are some helpful measures.

eurocysticercosis

Neurocysticercosis caused by infection of the CNS with encysted larvae of Taenia solium is a common cause of acquired epilepsy in many developing countries.

Pathogenesis

E

lectroencephalogram: It may show focal slowing, spikes or periodic lateralizing discharges • he underlying source of infection: It should be identified by a detailed history, examination and appro priate investigations. ­

T

•

Management

S

­

A

Management involves appropriate antibiotics and surgical drainage or excision of the abscess. Urgent decompression is required in cases with critically raised ICP. • ntibiotics: Antibiotics alone are used in early cerebritis, very small abscesses (< 2 cm) or abscesses in deep seated/critical areas of the brain. A broadspectrum combination to cover anaerobic, Gramnegative, Gram-positive and staphylococcal species is used until a specific organism is identified. Ceftriaxone/ cefotaxime, metronidazole and vancomycin are generally used. Penicillin and chloramphenicol can be used if cephalosporins are not affordable. Subsequent antibiotics are tailored to the organism identified. Antibiotics in highest doses are given IV for at least 6 weeks • In children with marked cerebral edema, IV cortico steroids are used for a short period to reduce cerebral edema and raised ICP • upportive management: Supportive management for raised ICP, seizures and general PICU care is the same as for any critically ill child. There is no scientific evidence to recommend the use of prophylactic anticonvulsants. Proper treatment of the source of infection should be done.

Prognosis Early adequate management is associated with 90% 376 cure rate. Poor prognostic factors include multiple large abscesses, underlying cyanotic heart disease, rupture of

Neurocysticercosis is acquired through the feco-oral route, by eating food contaminated with T. solium eggs that are passed in feces of persons with intestinal Taeniasis (which occurs by eating undercooked pork infected with cysticerci). In the human intestine the eggs hatch to release larvae that penetrate the intestinal mucosa, and migrate throughout the body to produce human cysticercosis. Most mature cysts are found in the CNS, skeletal muscle, subcutaneous tissue and the eyes. Cycsticerci often live asymptomatically within host tissues for years, (vesicular cysts) evading host response after which they degenerate (colloidal or granular nodular stage) and cause symptoms.

Clinical

M

 

Figure 6.9.1 CT showing large abscesses

anifestations

Neurocysticercosis is classified into parenchymal and extraparenchymal (ventricular, cisternal, ophthalmic or spinal). The latter is uncommon in children. Most children present with single degenerating parenchymal cysts, some with multiple cysts.

Parenchymal Neurocysticercosis Parenchymal neurocysticercosis usually presents after 5 years of age, some cases are seen in preschoolers and even in infants. • Seizures occur in 70–90% of cases; usually they are partial (84–87%), and of short duration. Status epilepticus occurs in 2–32% cases • Almost a third of children have headache and vomiting. Papilledema and focal neurodeficits are uncommon • Cysticercal encephalitis with severe acute raised ICP may rarely occur in children with innumerable cysts and extensive cerebral edema.

Extraparenchymal Neurocysticercosis Extraparenchymal neurocysticercosis is rare in children as compared to adults, and may present as arachnoiditis, obstructive hydrocephalus or chronic meningitis. Spinal cysticercosis may present as transverse myelitis or other

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aboratory ests

N

Cysticidal Therapy



Serologic tests have a low positivity (17–25%) particularly for single lesions. Both ELISA and the enzyme linked immuneelectro-transfer blot assay are more sensitive in cases with multiple brain lesions than in those with single-lesions. Stool examination for tapeworms, blood counts and X-rays of skeletal muscles are not useful. Biopsy of subcutaneous nodules can corroborate the diagnosis. Cerebrospinal fluid is normal in most cases but may show increased cells and proteins and hypoglycorrhachia in NCC meningitis.

Carbamazepine or phenytoin are used for seizure control, usually for a period of 1 year seizure free interval if the lesion has disappeared on follow-up CT and longer if the lesion is persistent or calcified. Prednisolone 1–2 mg/kg orally or IV dexamethasone for 3–5 days are used if there is edema or features of raised ICP.

S

­



reatment





Diagnosis is with neuroimaging. On CT the commonest finding is a “single”, small (< 20 mm) ring or disc enhancing lesion with surrounding edema (SSECTL) (Fig. 6.9.2). The scolex appears as a bright, high-density eccentric nodule in these cysts and is pathognomonic of NCC. It represents the degenerating stage (colloidal) of the cyst. Some children may have 2–3 or multiple lesions; disseminated NCC with numerous cysts – “starry sky” appearance is typical of NCC (Fig. 6.9.2). Calcified cysts are few millimeters in size, single or multiple and generally without any surrounding edema. Extraparenchymal NCC: Hydrocephalus, enhancement of tentorium and basal cisterns due to arachnoiditis and occasionally infarcts, may be seen. MRI is better for identification of scolex and visualization of extraparenchymal cysts.

T

Diagnosis

raised ICP, progressive focal neurodeficit, CT lesion more than 20 mm, lobulated irregular shape, and marked edema causing midline shift favor the diagnosis of tuberculoma. Also tuberculomas are often seen in the base of the brain whereas NCC lesions are seen near the gray-white junction of the cortex. Sophisticated imaging techniques like proton magnetic resonance spectroscopy and 3D constructive interference in steady state are being tried to distinguish NCC from tuberculoma. Mantoux test, chest X-ray and other tests should be done for exclusion of tuberculosis. Other DD include microabscess, low grade astro cytoma, cystic cerebral metastasis, toxoplasmosis and fungal lesions. Since NCC is pleomorphic, it should be considered in the differential diagnosis of seizures and other neurological disorders.

Diseases of Central ervous ystem

spinal cord syndromes. Ophthalmic cysticercosis can cause visual deficits and limitation of eye movements.



In cases where the scolex is not well seen, the differential diagnosis mainly includes tuberculoma. Presence of

­

Differential Diagnoses

Albendazole (15 mg/kg/day, 4 weeks) or praziquantel (50 mg/kg/day for 15 days) has been found effective for destruction of vesicular cysts. It is also associated with higher and faster resolution of SSECTL. However, whether cysticidal therapy improves long-term seizure control is debatable. Albendazole is the drug of choice as it is more effective than praziquantel, less expensive and better tolerated. Cysticidal therapy is contraindicated in cases with: • Markedly raised ICP particularly in disseminated NCC • In ophthalmic NCC, as the host inflammatory response may cause sudden elevations of ICP/damage to the eye • Such cases should be treated with corticosteroids alone. Cysticidal therapy is not indicated for calcified lesion(s) as the parasite is already dead. Shunt placement may rarely be required for hydro cephalus. Ventricular cysts can be removed endoscopically. As NCC is a pleomorphic disease, treatment needs to be individualized.

Follow-Up A repeat CT is generally done after 3–6 months to determine whether the lesions have resolved.

Outcome

 

Figure 6.9.2 CT scan of the head in a child with neurocysticercosis showing a cyst with a scolex

Outcome depends on the type of NCC, cyst location and numbers. Single lesions disappear within 6 months in over 60% cases, and risk of seizure recurrence is low. Cases with multiple lesions and calcifications have frequent seizure 377 recurrences.

vip.persianss.ir

























1. Best J, Hughes S. Evidence behind the WHO Guidelines: hospital care for children--what are the useful clinical features of bacterial meningitis found in infants and children? J Trop Pediatr. 2008;54:83-6. 2. Moorthy RK, Rajashekhar V. Management of brain abscess: an overview. Neurosurg Focus. 2008;24:E3.





Bibliography





T

b

• Early diagnosis and administration of appropriate antibiotics are essential to reduce morbidity and mortality of bacterial meningitis. • Infants and neonates usually do not have typical signs and symptoms of meningitis. • Lumbar puncture should be done in all cases of suspected meningitis (unless contraindicated) and in all neonates with sepsis. • Supportive management for raised ICP and seizures along with adequate fluid and electrolyte therapy are extremely important. • Clinical presentation of brain abscess is often atypical in children; neuroimaging must be done in suggestive settings.



essages



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3. Nigrovic LE, Malley R, Kuppermann N. Cerebrospinal fluid pleocytosis in children in the era of bacterial conjugate vaccines: distinguishing the child with bacterial and aseptic meningitis. Pediatr Emerg Care. 2009;25:112-7. 4. Peltola H, Roine I. Improving the outcomes in children with bacterial meningitis. Curr Opin Infect Dis. 2009;22:250-5. 5. Prasad K, Kumar A, Gupta PK, et al. Third generation cephalosporins versus conventional antibiotics for treating acute bacterial meningitis. Cochrane Database Syst Rev. 2007;CD001832. 6. Salinas R, Prasad K. Drugs for treating neurocysticercosis (tapeworm infection of the brain). Cochrane Database Syst Rev. 2002;2:CD000215. 7. Scarborough M, Thwaites GE. The diagnosis and management of acute bacterial meningitis in resource-poor settings. Lancet Neurol. 2008;7:637-48. 8. Singhi P, Singhi S, Newton C, et al. Central Nervous System Infections, In: Nichols DG (Ed). Rogers Textbook of Pediatric Intensive Care, 4th edition. Philadelphia: Wolters Kluwer/ Lippincott Williams and Wilkins; 2007. pp. 1353-99. 9. Singhi P. Neurocysticercosis. The Adv Neurol Disord. 2011;4(2):67-81. 10. Therapy of suspected bacterial meningitis in Canadian children six weeks of age and older – summary. Pediatr Child Health. 2008;13:309-10. 11. Tsou TP, Lee PI, Lu CY, et al. Microbiology and epidemiology of brain abscess and subdural empyema in a medical center: a 10-year experience. J Microbiol Immunol Infect. 2009;42(5):405-12. 12. Van De Beek D, de Gans J, Mclntyre P, et al. Corticosteroids for acute bacterial meningitis. Cochrane Database Syst Rev. 2007;CD004405.

Prevention is possible by ensuring proper hygiene and sanitation, and animal husbandry.

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Diseases of Central ervous ystem

6.10

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tupor

Stupor is a condition of unresponsiveness, similar to deep sleep, from which the patient can be aroused only by vigorous and repeated stimuli. Even when aroused, communication is by monosyllabic sounds and simple behaviors and as soon as the stimulus ceases the stuporose subject lapses back into the unresponsive state.



Coma is a state of unconsciousness in which the eyes are closed and sleep-wake cycles are absent. There is no understandable response to external stimuli or inner need and the patient neither utter understandable responses nor accurately localize noxious stimuli. It is differentiated from:

•

V

•

Lethargy, drowsiness caused by a condition other than sleep Stupor, a state of somnolence in which a patient can be transiently aroused Delirium, a state of confusion in which attention, concentration and memory can be impaired.

egetative tate S

•

Vegetative state (VS) consists of: •

• •

No evidence of sustained, reproducible, purposeful or voluntary behavioral responses to visual, auditory, tactile or noxious stimuli No evidence of language comprehension or expression Intermittent wakefulness manifested by the presence of sleep-wake cycles (i.e. periodic eye-opening).

N



S

Minimally conscious state is defined as a condition of severely altered consciousness in which the patient demonstrates minimal but definite behavioral evidence of self or environmental awareness.

Brain Death Brain death is defined as the permanent absence of all brain functions including those of the brainstem. Brain-dead patients are irreversibly comatose and apneic with absent brainstem reflexes. E

Coma

inimally Conscious tate

tiology

Coma is caused by wide variety of causes (Table 6.10.1). They are broadly classified into traumatic or nontraumatic. In nontraumatic coma, infections are the commonest cause of coma. In the experience from the authors’ center, out of 100 children with nontraumatic coma, 60% were due to infections, 19% had toxic-metabolic causes, 10% had status epilepticus and 7% had intracranial bleed.

Clinical ips to Differentiate Coma by tiology T

S

Clouding of consciousness describes states of reduced wakefulness characterized by impaired attention and memory. Patients may be distractible, hyperexcitable and irritable with slow thought processes.

E

Clouding of Consciousness

S

Definitions

Vegetative state may be a transient, persistent or permanent condition. Transient VS lasts less than 4 weeks and is often associated with a favorable outcome. The term persistent is applied when VS lasts longer than 4 weeks, regardless of etiology. Vegetative state is considered permanent (i.e. irreversible) after 3 months following nontraumatic brain injury and after 12 months following traumatic injuries. M

Coma is a common childhood neurological emergency that can have a devastating outcome. It can occur from trauma or a wide range of nontraumatic causes. The incidence of nontraumatic coma is 30/100,000 children per year and that of traumatic coma is 670/100,000.

Detailed and clear history is important to approach a case of coma. History of accidental or non-accidental trauma differentiates between traumatic and nontraumatic coma. Presence of fever points towards an infective cause of coma though fever may precipitate a metabolic cause of coma too. Infants with systemic infection and coma can present with hypothermia. History of drowning, choking, aspiration, drug/toxin exposure or dog bite should be elicited. Coma due to inborn error of metabolism can occur at any age but symptoms of failure to thrive; neurodevelopmental delay and seizures with history of consanguinity may precede encephalopathy. A child with history of seizures may be having nonconvulsive status.

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Table 6.10.1 Causes of coma

E











Focal lesion –  Intracranial bleed; arteriovenous malformation –  Stroke –  Accidental/non-accidental head injury –  Brain abscess –  Focal encephalitis (Herpes) Diffuse lesions –  Accidental/non-accidental head injury –  Infections: bacterial, malaria, enteric, Shigella, rickettsia –  Postinfectious: acute necrotizing encephalopathy –  Vascular: venous thrombosis –  Diffuse hypoxic injury: postcardiac arrest, shock –  Metabolic causes   -  Electrolyte disturbances: sodium   -  Acid base abnormality   -  Endocrine: hypoglycemia, diabetic ketoacidosis   -  Inborn error of metabolism   -  Infections   -  Hepatic failure –  Renal failure –  Hydrocephalus –  Hypertensive encephalopathy –  Nonconvulsive status –  Postictal –  Drugs, toxins and poisoning

T

b

d

•            •                                     

valuation of a Child with Coma

E



Coma is a medical emergency and requires multidisciplinary approach going. It includes simultaneous assessment, evaluation and treatment. Stabilization of any child with coma is a priority. Patency of the airway and adequate breathing should be ensured as a comatose child is more prone to aspiration because of loss of protective reflexes. Any child having GCS less than eight should preferably be intubated. If breathing is not adequate, mechanical ventilation should be initiated. Hemodynamic status should be monitored and fluid bolus be (20 mL/kg) given on evidence of shock. Hypoglycemia, if present, should be treated, hematological, biochemical and acid-base status should be assessed and derangements corrected. Evidence of internal and external injuries must be sought and any temperature instability must be treated. If seizures are present, anticonvulsants must be given and treated accordingly.

xamination

Vitals All vitals should be recorded as they can give a vital clue. Hypertension can cause hypertensive encephalopathy or may be a Cushing’s response to raised ICP. Seizures, retinal

hemorrhage and pulmonary edema can occur secondary to hypertension. Hypotension may be seen in shock, myocardial dysfunction or adrenal insufficiency and can lead to decreased cerebral perfusion. Fever may indicate infection. Tachycardia may be because of early shock, sepsis or fever. Bradycardia may be in response to raised ICP. Tachypnea with lung findings may indicate respiratory focus. Silent tachypnea may be metabolic because of acidosis due to diabetic ketoacidosis, drug/toxin, uremia, etc.

General Examination Skin/mucosal membranes should be examined for anemia, icterus, rash, skin bleeds, purpura, and neurocutaneous markers. Look for any evidence of trauma in the form of hematoma, fracture or bruises. Measure head size for microcephaly, palpate fontanels, look for sutural separation and auscultate head for any bruit. Height and weight must be measured to rule out failure to thrive.

Systemic Examination Cardiac examination is important to look for any evidence of heart lesion, which may lead to stroke, palpate abdomen for hepatosplenomegaly which may be present in various infection or metabolic disorders and respiratory examination is helpful to detect underlying pneumonia or empyema.

Neurological Examination Careful neurological examination is important to localize the cause and the lesion. Prior administration of neuromuscular drugs or anticonvulsants may hamper the examination.

Grading of Coma Level of consciousness need to be recorded objectively and the most common scale used is GCS but it cannot be used in younger children, especially in children less than 3 years of age. Modified GCS has been recommended for these young children and has been endorsed by the British Paediatric Neurology Association. Each component of the score should be reported separately as compared to summed up score (e.g. GCS 5, 7 or 12) as it has been shown that summed up scores cannot be equated with clinical assessment.

Eye Findings Examine pupillary reaction to light, direct and consensual. Pupillary reaction correlates with the severity of coma. Preserved pupillary reaction despite other brainstem abnormal signs, indicate toxic/metabolic

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anagement

S

M

Management of the comatose child starts as soon as the child presents to the physician (Table 6.10.3). Maintain the airway, breathing, circulation as discussed above. Steroids have no role in TBI. But, they are useful in acute disseminated encephalomyelitis, tubercular meningitis and enteric encephalopathy. Decompressive craniectomy should be considered in cases of severe TBI or refractory raised ICP. Adequate nutrition should be provided in all cases of coma and some cases may need to be fed through nasogastric tube.

Prognosis and utcome O

­

nvestigations

Comatose child may need a variety of investigations. The list is exhaustive and some may be needed in all and some may be tailored according to the differential diagnosis (Table 6.10.2). If LP is contraindicated, the most appropriate therapeutic agents should be started. CT scan is the most common neuroimaging available and is the first line investigation. CT and MRI complement each other in traumatic brain injury (TBI). While CT helps in diagnosing conditions, which require urgent surgical treatment like bleed; MRI helps in diagnosing acute axonal injury. Always discuss with neuroradiologist to plan the investigation, which is best for the patient and is cost effective.

Motor Examination Examine bulk, tone, posture, asymmetry and reflexes in motor system. Decerebration is usually a reflection of raised ICP and central herniation. Decortication and decerebration can result from metabolic, toxic and structural “causes” of coma. Flaccidity and areflexia are grave signs in a comatose child. Focal seizures, if present, may help in localization. Myoclonic jerks are seen with anoxic and hepatic encepha lopathy. Dystonia or dyskinesia in a comatose child without antecedent history of a neurometabolic disease may be present in Japanese B encephalitis, tubercular meningitis and inborn errors of metabolism or phenothiazine, phenytoin or metoclopramide toxicity.

Diseases of Central ervous ystem

cause. Unilaterally fixed and dilated pupil is evident of transtentorial herniation, provided topical administration of mydriatics has been ruled out. Corneal reflex gets diminished/absent in children with deep coma. Presence of nystagmus may be because of ongoing status, barbiturate or phenytoin poisoning. Persistent ocular deviation may be due to hemispheric or brainstem dysfunction or ongoing status. Ophthalmoplegia, ocular bobbing, convergent or divergent spasms, episodes of lid retraction and spontaneous blinking usually suggest brainstem dysfunction. Extraocular movements should be tested with the doll’s eye maneuver. Papilledema and retinal hemorrhages can be ruled out on fundus examination.

N

Pattern of Respiration

A

A

A

­

S

• Normal • Cheyne- tokes: Cerebral hemispheres, rarely, upper pons • Central neurogenic hyperventilation: Brainstem teg mentum • pneustic: Mid or low pontine dysfunction • taxic: Medulla • pnea: Medullary dysfunction.

Other Neurological Signs Neck rigidity is present in meningitis, herniation or trauma. Meningeal irritation can also be assessed by Brudzinski’s and Kernig’s sign. Raised ICP can lead to various herniation syndromes, which can be subfalcine, transtentorial or transforaminal.

The outcome of coma depends on the etiology, depth and duration of impaired consciousness. Mortality in these children has varied between 25% and 35%. Factors, which predict increasing mortality, are usually infants or small children (< 3 years), poor pulse volume, abnormal respiratory pattern and apnea, abnormal pupillary size and reaction, abnormal extraocular movements, absent corneal reflex, abnormal motor muscle tone and m-GCS less than eight. All children with nontraumatic coma should be given aggressive multidisciplinary rehabilitation program till 12 months before giving any outcome. T

Abnormal respiratory patterns help in localization of the disease. The different patterns are:

ontraumatic Coma

raumatic Coma

Children with trauma show much better outcome than their initial evaluation suggests. Severity of trauma and poor socioeconomic status are predictors of poor outcome. Refractory raised ICP also predict poor outcome.

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Table 6.10.2 List of investigations Sample

Patients

Indications

Complete blood count

All

Infection

Blood sugar

All

Hypoglycemia/hyperglycemia

Serum electrolytes

All

Metabolic disturbances

Calcium, phosphate

All

Metabolic disturbances

Liver function tests

All

Hepatic encephalopathy, metabolic, toxic, infections

Renal function tests

All

Uremic encephalopathy, infections, metabolic, toxic

Arterial blood gas

All

Acidosis

Ammonia

All

Metabolic, toxic, infections

Lactate

All

Infections, metabolic, toxic

Culture

Specific

Infections

Peripheral blood film for malaria

Specific

Cerebral malaria

Viral markers

Specific

Viral encephalitis

Leptospira serology

Specific

Leptospirosis

Weil Felix test

Specific

Rickettsial infections

Widal test

Specific

Enteric encephalopathy

Toxicology screen

Specific

Poisoning

Enzyme studies

Specific

Metabolic, neurodegenerative, syndromic

Culture

Specific

Infections

Reducing substances

Specific

Metabolic disorders

Toxicology screen

Specific

Poisoning

Ketones

Specific

Metabolic, diabetic ketoacidosis

Cell count, protein, sugar, culture

Specific

Infections

Viral markers

Specific

Viral encephalitis

Tuberculosis workup

Specific

Tubercular meningitis

Blood

Urine

Cerebrospinal fluid

Fungal culture, serology, galactomannan Specific enzyme immunoassay

Infections

Neuroimaging CT head (Contrast/plain)

All; except documented uncomplicated metabolic causes such as diabetic ketoacidosis, hypoglycemia

Trauma, infections, bleed, tumor, vascular cause

CT angiography

Specific

Vascular cause

MRI

Specific

Infections, acute disseminated encephalomyelitis, acute necrotizing encephalopathy of childhood, neurometabolic disorders

Conventional electroencephalogram

Specific

Seizure, nonconvulsive status, infections

Continuous electroencephalogram

Specific

Seizures, comatose children on paralysis

Electrophysiological studies

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Table 6.10.3 Management of coma General management •  Head in midline, normothermia, 30° head end elevation, euvolemia and adequate sedation and analgesia •  In impending herniation, hyperventilation and mannitol (0.25–1 g/kg)/3% hypertonic saline (0.1–1.0 mL/kg/hour) are drug of choice •  Target ICP < 20 mm Hg or CPP > 50 mm Hg.

Seizures

•  Benzodiazepines (IV diazepam/lorazepam at 0.1 mg/kg) followed by IV phenytoin loading dose at 20 mg/kg over 30 minutes •  Nonconvulsive status may be present and should be looked through subtle clinical signs or continuous EEG

Specific management

Hypoglycemia

Hypoglycemia/hyperglycemia

•  Head in midline, normothermia, 30° head end elevation, euvolemia and adequate sedation and analgesia •  In impending herniation, hyperventilation and mannitol (0.25–1 g.kg)/3% hypertonic saline (0.1–1.0 mL/kg/hour) are drug of choice •  Target ICP < 20 mm Hg or CPP > 50 mm Hg

Seizures

•  Benzodiazepines (IV diazepam/lorazepam at 0.1 mg/kg) followed by IV phenytoin loading dose at 20 mg/kg over 30 minutes •  Nonconvulsive status may be present and should be looked through subtle clinical signs or continuous EEG

Infections

•  •  •  •  • 

Drug poisoning

•  Specific antidote



S









N











Raised ICP













Bacterial: broad spectrum antibiotics Herpes: acyclovir Cerebral malaria: antimalarials (quinine/artesunate derivatives) Rickettsia: oral doxycycline or IV azithromycin TBM: antitubercular treatment

1. Bansal A, Singhi SC, Singhi PD, et al. Nontraumatic coma. Indian J Pediatr. 2005;72:467-73.





Bibliography















2. Kirkham FJ. Non-traumatic coma in children. Arch Dis Child. 2001;85:303-12. 3. Seshia SS, Bingham WT, Griebel RW. Coma in childhood. Handbook of Clinical Neurology. 2008;90:329-50. 4. Sharma S, Kochar GS, Sankhyan N, et al. Approach to the Child with Coma. Indian J Pediatr. 2010;7:1279-87. 5. Singhi PD, Bansal A, Ramesh S, et al. Predictive value of electroencephalography and computed tomography in childhood non-traumatic coma. Indian J Pediatr. 2005;72: 475-9. 6. Singhi S, Singhi P, Baranwal AK. Bacterial meningitis in children: critical care needs. Indian J Pediatr. 2001;68:737-47. 7. Society of Critical Medicine, The World Federation of Pediatric Intensive and Critical Care Societies and the Paediatric Intensive Care Society UK. Guidelines for the acute medical management of severe traumatic brain injury in infants, children, and adolescents. Pediatr Crit Care Med. 2003;4(suppl.):S1-S75. 8. Stevens RD, Bhardwaj A. Approach to the comatose patient. Crit Care Med. 2006;34:31-41. 9. Wong CP, Forsyth RJ, Kelly TP, et al. Incidence, aetiology, and outcome of non-traumatic coma: a population based study. Arch Dis Child. 2001;84:193-9.



• Coma is a medical and neurological emergency. • Broadly it can be divided into traumatic or nontraumatic coma. • Causes of nontraumatic coma are quite varied. • The basic principles of management include rapid assessment and stabilization, detailed history and clinical examination to assess depth of coma, localization of lesion in the central nervous system and possible clues to etiology, and treatment includes general and specific measures. • Because coma has a high rate of mortality and morbidity in children, and the clinician may be unsure of the outcome very early in the course, it is important to have strategies to define prognosis.



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Abbreviations: ICP, Intracranial pressure; CPP, Cerebral perfusion pressure; EEG, Electroencephalogram; TBM, Tuberculous meningitis

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C



hildhood rain Tumors

Primary brain tumors are the most common solid tumors and the second most common malignancy of childhood following leukemia, accounting for almost 35% of total childhood malignancies. Overall mortality is around 45%. Annual incidence in developed countries is around 28 cases per million children less than 19 years of age. Childhood brain tumors differ significantly from adults in reference to their location, clinical presentation, tendency to disseminate early, histological features and their biological behaviors. Astrocytoma and embryonic tumors are more common in children, whereas metastases, glioma and meningioma are seen predominantly in adults. Manifestations and outcome depend upon location, degree of resectability and response to adjuvant therapy. Advanced treatment modalities like stereotactic radiosurgery (SRS) and intralesional chemotherapy have increased the life span and improved the quality of life of these children. E

tiology

Genetic instabilities have been implicated in the pathogenesis of brain tumors. In medulloblastoma, common cytogenetic abnormalities observed are isochromosome17q, deletion at 6q and 9q. Hereditary syndromes like neurofibromatosis, von-Hippel-Lindau disease and ataxia telangiectasia are associated in about 5% of brain tumors. Craniopharyngiomas arise from persistent remnants of craniopharyngeal pouch. Primitive neuroectodermal tumors arise from primitive embryonic tissue. Environmental factors like high dose radiations and viral infections have also been implicated in the causation of brain tumors.

Pathophysiology and lassification C

pidemiology

Brain tumors can be classified according to location, histological criteria and degree of malignancy (Tables 6.11.1 and 6.11.2). The terms “benign” and “malignant” often are misleading when applied to brain tumors. Malignant tumors such as medulloblastoma may be curable in up to 80% of children who are older than 3 years if radically removed and are not disseminated at diagnosis. Conversely, some benign tumors can disseminate (up to 4% of cases in low-grade astrocytoma), and may be quite difficult to eradicate. Table 6.11.1 Anatomical classification of brain tumors Site of involvement Brain tumor Infratentorial (43.2%) Astrocytoma Medulloblastoma Brainstem glioma Ependymoma Dermoids Epidermoids Teratoma Chordoma Supratentorial (40.9%) Craniopharyngioma Primitive neuroectodermal tumors Glioma Pineoblastoma Leukemia Lymphoma Choroid plexus papilloma Germ cell tumors Multiple sites and spinal Astrocytoma cord (15.9%) Glioma Ependymoma Leukemia  

E

Kamer Singh Rana



t

t

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Table 6.11.2 Brain tumors based on degree of malignancy Grade Prognosis Intracerebral Grade 1 (Benign) Favorable with removal Cerebellar astrocytoma, Gangliocytoma only Choroid papilloma Pinealoma Hemangioblastoma Grade 2 Favorable additional Extraventricular ependymoma (Semi benign) therapy required Isomorphic astrocytoma Anisomorphic pinealoma Grade 3 Guarded, additional Polymorphic(Semi malignant) therapy required Gangliocytoma Ependymoma Plexus papilloma Grade 4 (Malignant) Poor Glioblastoma Medulloblastoma

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Extracerebral Neurinoma Meningioma craniopharyngioma Ventricular ependymoma Polymorphic pituitary adenoma

Polymitotic meningioma Polymitotic neurinoma

Meningeal sarcoma

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Figure 6.11.1 Post-gadolinium T1 weighted transverse MRI image of brain showing a well-defined heterogeneously enhancing mass lesion in the right cerebellar hemisphere. Biopsy proven case of cerebellar astrocytoma

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Supratentorial tumors are commonly seen within first year and after 10 years of age, whereas between 1 year and 10 years of age, infratentorial tumors are more common. Hospital based prevalence data from India based on WHO classification suggests that the most common childhood brain tumors in descending order are astrocytoma (34.7%), medulloblastoma and craniopharyngioma. Neurological symptoms related to brain tumors are general and local. General symptoms are from increased intracranial tension (ICT) that results from progressive enlargement of tumor in the limited cranial vault, obstruction of CSF and brain edema. Local symptoms are due to the effects of the tumor on contiguous areas of the brain. Small strategically located tumor can be devastating by compressing the vital structures. Compression of the large vascular channels results in cerebral anoxia. Expanding mass also produces various herniations by creating pressure gradient in different compartments causing secondary brain dysfunction because of overcrowding, stretching and rupturing of blood vessels, edema and pressure over vital structures, notably cranial nerves and vital centers in the brainstem.

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Surgery remains the mainstay of treatment (Table 6.11.3). Total resection cannot be accomplished in many cases, but

Figure 6.11.2 Post-gadolinium T1 weighted sagittal MRI image of brain showing a well-defined intensely enhancing mass lesion expanding the fourth ventricle and displacing the brain stem anteriorly. Biopsy proven case of medulloblastoma  

Computerized tomography is the imaging modality of choice in an emergency. Most tumors enhance with contrast material. Magnetic resonance imaging with gadoliniumdiethylenetriaminepentaacetic acid is generally preferred diagnostic mean (Figs 6.11.1 to 6.11.4). It is better in delineating benign masses from malignant growths, inflammatory and infectious conditions and normal brain tissue. Tumors in the posterior fossa, temporal lobe, sellar and chiasmatic regions are also best visualized with MRI. Positron emission tomography and MR spectroscopy have a role in characterization of brain tumors, in follow-up and differentiation from other nonmalignant conditions.

partial resection is useful to reduce the bulk of tumor thus permitting destruction of remaining malignant cells by irradiation and chemotherapy. Radiotherapy can be used either as an adjuvant to surgery or for definitive therapy. Many pediatric brain tumors are radiosensitive. One of the newer modalities is SRS involving a radiation procedure called Gamma Knife surgery. This treatment precisely focuses radiation beams to the tumor, delivers radiation beams in the exact size and 385 shape of the tumor with the aid of brain imaging techniques.

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Clinical signs and symptoms depend upon tumor’s location, size and child’s age. Aggressively growing tumors are associated with early and severe symptoms, whereas initial signs and symptoms of slow-growing tumors are subtle. Subtentorial tumors, obstructing CSF pathway present with features of raised ICT such as early morning headache, vomiting, bradycardia, hypertension, visual disturbances, papilledema, mental changes and gait disturbances. Intraaxial masses like pontine glioma present with features of multiple cranial nerves palsy. Supratentorial tumors present with seizures and focal neurological deficit. In younger children before closure of skull sutures, these tumors manifest as progressively enlarging head size.

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Addition of chemotherapy has increased median survival rates for high-risk medulloblastoma and highgrade astrocytoma. Newer strategies have been designed to concentrate chemotherapy agents directly in to the tumor. Recent advances in chemotherapy include primarily supportive care measures such as the use of hematopoietic growth factors and autologous stem-cell harvesting and reinfusion. These measures shorten the duration of myelosuppression, allowing administration of higher and more frequent doses of chemotherapy. Endocrine dysfunctions can develop before and after removing midline tumor, after craniospinal radiation or chemotherapy. Complete endocrine work up before surgery for midline tumors is essential for better outcome. Children with tumors in the vicinity of hypothalamic-pituitary axis are prone for fluids and electrolytes abnormalities during perioperative period. All children (except those having Cushing’s disease) with midline tumors in the vicinity of pituitary hypothalamic axis are administered hydrocortisone 100 mg every 6–8 hourly during surgery and postoperative period for 3 days. Hydrocortisone is continued if serum cortisol levels are low. Endocrinal follow-up after resection of a craniopharyngioma and other midline masses and cranial irradiation for a long time is recommended. Prophylactic antiepileptic drugs like intravenous phenytoin 10 mg/kg as slow loading followed by 4–8 mg/kg/day are recommended during perioperative period. Psychological assessment is essential as these children are more prone for cognitive and behavioral problems. Neurological manifestations of brain tumors in children depend upon the age of the child, size and location of the tumor and can be so varied that at times diagnosis is missed. To avoid this dangerous situation, one must be aware of the pathophysiology of childhood brain tumors.

 

Figure 6.11.3 Post-gadolinium T1 weighted coronal MRI image of brain showing a well-defined rim enhancing lesion in the third ventricle. Biopsy proven case of third ventricle ependymoma

 

Figure 6.11.4 FLAIR coronal MRI images of brain showing an ill-defined mass lesion expanding the pons. Biopsy proven case of pontine glioma

 

Table 6.11.3 Common childhood brain tumors Type of tumor Salient features Astrocytoma Originate from astrocytic neuroglial cells. Commonest site is cerebellum. Commonest association is with NF1. Peak age of presentation is 5–9 years. Histologically can be classified into four different subtypes. Grade 1 shows low mitotic activity and is the most common variety. Glioblastoma multiforme (WHO grade IV) causes rapid and extensive invasion of surrounding tissue. Principal treatment is gross total resection. Postoperative radiotherapy is indicated in recurrence. Chemotherapy has a limited role. Medulloblastoma

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Accounts for 40% of all posterior fossa tumors. Highly invasive embryonic neuroepithelial tumor. Morphologically similar tumors arising in other central nervous system locations are called primitive neuroectodermal tumors. Ataxia-telangiectasia is a known common association. Male to female ratio is 2:1 and the peak age is 2–4 years. It has the greatest propensity for extraneural spread, especially to bone and bone marrow. Treatment includes gross near total resection with reduced dose posterior fossa radiotherapy followed by chemotherapy. The overall event free 5 year’s survival is 60–70%. Benign tumors arise from remnants of the Rathke’s pouch. Commonest site is parasellar region. Often infiltrate surrounding critical structures. They have bimodal age distributions with peaks at age 5 years and 15 years. Clinical symptoms are visual dysfunctions, endocrine abnormalities, raised intracranial tension, behavioral and cognitive dysfunction. Symptoms of endocrine dysfunction are present in 80–90%. Treatment strategies include intracavity chemotherapy, resection, radiation therapy and stereotactic radiosurgery. Growth hormone deficiency is seen in 75% of children with craniopharyngioma followed by gonadotropins (93%). Diabetes insipidus develops in two-third cases.

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1. Capodano AM. Nervous System: medulloblastoma. Atlas Genet Cytogenet OncoHaematol. 2000. Available from www. AtlasGenetics oncology.org/tumors/MedulloblastomaID5065. html. 16 Mar2011 2. Di Rocco C, Massimi L, Caldarelli M, et al. Cerebral tumors in children less than one year of age. Neuro-Oncology. 2004;6:419. 3. Dyer S, Prebble E, Brundler M, et al. Genomic imbalance in high and low grade astrocytomas. Neuro-Oncology. 2004;6:405. 4. Jain A, Sharma MC, Suri V, et al. Spectrum of brain tumors in India: a multi-institutional study. Neurol India. 2011;59:20811.

5. Kim KE, Kim KU, Kim DC, et al. Cytogenetic characterization of central nervous system tumors: the first comprehensive report for a single institute in Korea. J Korean Med Sc. 2009;24(3):453-60. 6. Louis DN, Ohgaki H, Wiestler OD, et al. The 2007 WHO Classification of tumors of central nervous system. Acta Neuropathol. 2007;114(2):97-109. 7. Pomeroy SL, Tamayo P, Gaasenbeek M, et al. Prediction of central nervous system embryonal tumors outcome based on gene expression. Nature. 2002;415:436-42. 8. Vance LM. Perioperative management of patients undergoing pituitary surgery. Endocrinol Metab Clin N Am. 2003;32:355-65. 9. Veeravagu A, Lee M, Jiang B, et al. The role of radiosurgery in the treatment of craniopharyngiomas. Neurosurg Focus. 2010;28:E11.

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aised ntracranial Pressure Sunit Singhi

Pathophysiology Monro-Kellie doctrine states that in a noncompliant skull vault, ICP is the sum total of pressure exerted by the brain (≈ 80%), blood (≈ 10%) and CSF (≈ 10%). The volume of brain tissue increase without a significant change in ICP only if there is an adaptive reduction in CSF and cerebral blood volume but when these adaptations have been exhausted, ICP increases exponentially.

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Clinical symptoms and signs of raised ICP are highly variable and depend on the nature and location of the primary brain insult, and the rate of increase in ICP. In awake patients, irritability, headache, vomiting, confusion and decreased alertness, neck retraction and tense fontanel on palpation may be presenting features. Papilledema, though a reliable sign of raised ICP, is usually absent in acute conditions. In unconscious/comatose patients, raised ICP should be suspected in all patients with head injury, meningitis encephalitis, liver disease and diabetes mellitus. The clinical features strongly favoring raised ICP are abnormal posturing (decerebration or decortication), abnormal pupillary dilatation, hypertension, bradycardia, irregular breathing, sixth nerve palsy and papilledema. CT scan signs of brain swelling are predictive of increased ICP, but the CT scan may be normal even in the presence of documented raised ICP.

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Raised intracranial pressure is a life threatening condition that is commonly seen in emergency with both traumatic and nontraumatic neurological illnesses. Unless recognized and treated early, it may cause secondary brain injury due to reduced cerebral perfusion pressure (CPP), and progress into herniation syndrome and death.



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Management Goals and Principles of Therapy The immediate goal is to prevent progression to herniation or to reverse the herniation if present, and then to maintain adequate CPP. The principle therapeutic measures include maintaining normoxia and normocarbia, avoiding factors that aggravate or precipitate raised ICP namely fever, hypoxia, hypoglycemia, hypotension and any noxious stimulation, treatment of underlying cause whether intracranial or

The normal range for ICP varies with age. The usual normal range is considered as 5–15 mm Hg. In new born term infants, it is 1.5–6 mm Hg, in young children 3–7 mm Hg and in older children 10–15 mm Hg. Intracranial pressure more than 20 mm Hg is considered as intracranial hypertension requiring treatment. For all practical purposes, if symptoms and signs of raised ICP are present, one should consider that ICP is more than 20 mm Hg and treat accordingly. Sustained ICP values more than 40 mm Hg indicate severe life threatening raised ICP.

 

    

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Table 6.12.1 Common causes of raised intracranial pressure Increase in brain volume •  Cytotoxic edema: encephalitis, meningitis, head injury, Reye’s syndrome, vasogenic edema: hypoxic ischemic injury (hypoventilation, shock), ischemic stroke/infract, metabolic encephalopathy – hyperpyrexia, hepatic failure, lead intoxication •  Space-occupying lesions: hematomas, tumors, abscesses Increases in blood volume •  Venous obstruction: cerebral venous thrombosis •  Vasodilatation: due to hypoxia, drugs or hypercapnia •  Status epilepticus Increases in cerebrospinal fluid volume •  Obstructive hydrocephalus, communicating hydrocephalus •  Impaired reabsorption: subarachnoid hemorrhage. Increased production: tumors Idiopathic or benign intracranial hypertension 

Common causes of raised ICP with respect to patho physiology are shown in Table 6.12.1.

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Cerebral perfusion pressure is the pressure at which brain is perfused. It provides an indirect measure of adequacy of cerebral blood flow (CBF). It is calculated as the difference between mean arterial pressure (MAP) and ICP (CPP = MAP – ICP). Generally accepted minimal CPP values necessary to prevent ischemia are as follows: infants/toddlers: more than 40–50 mm Hg; children: more than 50–60 mm Hg. Cerebral perfusion pressure less than 40 mm Hg is a significant predictor of mortality in children with TBI. Autoregulation maintains a steady CBF within a CPP range of 50–150 mm Hg. It is lost at CPP values less than 50 mm Hg. Once autoregulation is lost, CBF and cerebral blood volume become dependent on changes in systemic blood pressure.



Cerebral Perfusion Pressure

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Start 100% oxygen with nonrebreathing mask and if needed use bag valve mask ventilation to ensure adequate oxygenation. Short-term hyperventilation is required in patients with signs of impending herniation (unequal pupils, posturing).

Maintain euvolemia use isotonic fluids. If there are signs of poor perfusion, give a bolus of normal saline 20 mL/kg. Maintain good blood pressure to achieve desired CPP, if needed, by using fluid and vasoactive agents (dopamine, nor-epinephrine). Colloids are not recommended.

General Management

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• Head position: Elevate head end of bed by 30° and keep head in neutral position to promote venous drainage. • Temperature: Keep below 38°C. If child is febrile, use paracetamol 15 mg/kg/dose and surface cooling. • edation and analgesia: Use midazolam 1–3 µg/kg/ min, morphine 0.1 mg/kg/dose q6hour and titrated to achieve a level that the patient responds to commands only and is asleep. • Glucose control: Keep random blood sugar around 150 mg/dL. Hypoglycemia (< 60 mg/dL) and hyperglycemia (> 180 mg/dL) should be avoided. • eizure prophylaxis: Use phenytoin; 20 mg/kg IV loading, followed by 5–8 mg/kg/day for the first 7 days for seizure prophylaxis in patients with severe head injury, focal symptoms and signs and CNS infections. • Use lidocaine 1 mg/kg/dose 5 minutes before endotracheal suctioning and procedure. Do not repeat within 2 hours. • Gastrointestinal (G ) bleed prophylaxis: Use antacid 1 mL/kg/dose q8hourly or pantoprazole 1 mg/kg/dose q12hourly, (if GI bleed is present use pantoprazole). • nemia: Maintain Hb concentration around 10 g/dL to help cerebral oxygen delivery.

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• Hypertension: Characteristically increase in systolic pressure is common in response to raised ICP. Generally it is left untouched in acute raised ICP unless underlying cause is hypertensive encephalopathy. Treatment is reasonable in patients with evidence of rapidly worsening brain edema on CT scan, and those with a persistent extreme surge in blood pressure. If it is decided to treat hypertension, vasodilating drugs, such as nitroprusside, nitroglycerin and nifedipine, should be avoided; these could increase ICP. Sympathomimeticblocking drugs (esmolol, labetalol) or centrally acting alfa-receptor agonists (clonidine) are preferred because they reduce blood pressure without affecting ICP. F

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Airway In unconscious patients, airway patency should be ensured by positioning the patient on the side and suctioning of the oral secretion. Oro or nasopharyngeal airways can be used. Endotracheal intubation and assisted ventilation are needed in patients with a modified Glasgow Coma Score less than or equal to eight, signs of respiratory distress, declining O2 saturation, irregular respiratory efforts, inadequate chest movements or central cyanosis.

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Table 6.12.2 Therapeutic modalities to reduce raised intracranial pressure General measures and first tier therapy •  Head in neutral position, 30° elevation •  Ensure oxygenation: normoxia and normocarbia (PaCO2 ‡ 35 mm Hg) •  Ensure adequate circulating volume – normovolemia •  Maintain normal BP •  Ventilation to achieve PaCO2 = 35 mm Hg •  Osmotic diuretic; mannitol 0.25–0.50 /kg IV over 20 min, repeat s.o.s. OR Hypertonic (3%) saline infusion: 10 mL bolus, 0.1–1.0 mL/kg/hour infusion •  Dexamethasone: 1–2 mg/kg IV q6hours - cytotoxic cerebral edema (brain abscess, granuloma, tumor) •  Cerebrospinal fluid drainage: obstructive hydrocephalus •  Prevent all events that increase intracranial pressure Fever - hypothermia, Pain - adequate sedation–analgesia, Seizures anticonvulsant, Loud noise, Invasive stimuli Second tier therapy •  Profound hyperventilation (PaCO2 30–35 mm Hg) •  Barbiturates coma: thiopental or pentobarbital •  Moderate hypothermia (32–34°C) Third tier therapy •  Decompressive craniectomy or temporal lobectomy •  Hyperventilation to PaCO2 < 30 mm Hg (use transiently)

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extracranial, maintain adequate MAP (more than 50th centile for given age and gender) with help of fluid and, if needed, vasoactive therapy and bringing ICP down with hyperosmolar therapy and other measures. Therapeutic modalities to treat raised ICP are shown in Table 6.12.2 and an overall approach in Flow chart 6.12.1.

irst Tier-Treatment

After initial general measures, if signs of raised ICP persist, use first tier therapy.

Mild Short-Term Ventilation Mild shot-term ventilation should be undertaken if danger of impending herniation is present (see above under breathing). Monitor for reversal of unequal pupils, posturing and improvement in mentation, after that target a PaCO2 ≈35 mm Hg. There is no role for prophylactic hyperventilation.

Heavy Sedation Use morphine and midazolam, and titrate the dose to achieve a state where child is asleep, and has sluggish response to glabellar tap. 389

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Flow chart 6.12.1 Approach to management of raised intracranial

 

Abbreviations: ICP, Intracranial pressure; GCS, Glasgow coma scale; CSF, Cerebrospinal fluid; MABP, Mean arterial blood pressure; PICU, Pediatric intensive care unit

Osmotherapy (Mannitol, Hypertonic Saline)

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• Mannitol: (2.5 mL/kg of 20% mannitol) given as a rapid infusion reduces blood viscosity, and improves microvascular CBF, cerebral oxygenation and CPP with reduction in cerebral blood volume initially. Within 15–30 minutes, it reduces ICP through direct osmotic effect on neural cells with reduction in total brain water, and reduced CSF production. If further dose is required, use 1.25–2.5 mL/kg/dose. Do not repeat mannitol in less than 4 hours. Monitor the urine output and take care of hypovolemia. Mannitol is contraindicated in decompensated shock, oliguria, anuria and heart failure. • Hypertonic saline (3% H ): Hypertonic saline creates an osmotic force to draw water from the interstitial space of the brain parenchyma into the intravascular space. It promotes rapid CSF absorption, increases 390 cardiac output, and expands intravascular volume

thereby augmenting the CPP with a positive inotropic effect. Usual loading dose is 10 mL/kg followed by 0.1–1 mL/kg/hour. In cerebral edema, the initial serum sodium goal is commonly set at 145–155 mEq/L and is intensified up to 160 mEq/L, if clinically indicated. Monitor serum sodium and creatinine every 6 hours. It is contraindicated if serum sodium is more than 150 mEq/L, and/or osmolality is more than 320 mosmol/L. Therapy must be tapered after 24 hours of continued infusion to prevent rebound raise of ICP. • Mannitol versus hypertonic saline: It is unclear which of these two therapies is superior for reduction of ICP. A recent systematic review found that HS appears to achieve a greater reduction in ICP than other osmotic agents in head injury patients. In a study of nontraumatic encephalopathies, there was less mortality with use of HS as compared to mannitol.

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Corticosteroids are commonly used for primary and secondary brain tumors to decrease vasogenic edema. The most commonly used regimen is IV dexamethasone 0.15 mg/kg/dose every 6 hours (maximum 16 mg/day). Routine use in head injury is not recommended.

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1. Bansal A, Singhi SC, Singhi PD, et al. Non traumatic coma. Indian Pediatr. 2005;72:467-73. 2. Gwer S, Gatakaa H, Mwai L, et al. The role for osmotic agents in children with acute encephalopathies: a systematic review. BMC Pediatr. 2010;10:23-30 3. Knapp JM. Hyperosmolar therapy in the treatment of severe head injury in children: mannitol and hypertonic saline. AACN Clin Issues. 2005;16(2):199-211. 4. Mayer MJ, Megyesi J, Meythaler J, et al. Acute management of acquired brain injury part II: an evidence-based review of pharmacological interventions. Brain Inj. 2010;24(5):706-21. 5. Singhi P, Singhi S, Baranwal AK. Bacterial meningitis in children: critical care needs. Indian J Pediatr. 2001;68:737-47. 6. Singhi SC, Tiwari L. Management of intracranial hypertension. Indian J Pediatr. 2009;76 (5):519-29. 7. Thompson AE, Salonia R. Airway management. In: Fuhrman BP, Zimmerman JJ, (Eds). Pediatric Critical Care, 4th edition. Philadelphia: Elsevier Saunders; 2011.



Monitor continuously for all vital parameters (temperature, heart rate, respiratory rate and blood pressure) and level of consciousness (hourly), neurological status, brainstem signs, oxygenation (SpO2), EtCO2, ICP, and CPP. Also assess adequacy of sedation and analgesia, input and output and bowel sounds. After a dose of mannitol, monitor the urine output hourly. Random blood sugar should be monitored at least every 6 hours, and if hypoglycemia or hyperglycemia is present, monitor blood sugar every 1–2 hours. Serum sodium



Monitoring

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Random blood sugar, iCa2+, serum electrolytes, hemogram, blood culture and febrile encephalopathy work up.



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A febrile child with raised ICP should receive empiric ceftriaxone (50 mg/kg IV q12hourly), acyclovir 30 mg/ kg IV in three divided doses 8 hourly as infusion over 1–2 hours for herpes encephalitis, and IV quinine if child is a resident of Plasmodium falciparum endemic area, and has hypoglycemia and anemia.

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• Raised intracranial pressure is a life threatening condition; unless recognized and treated early, it may progress into herniation syndrome and death. • Symptoms and signs are neither sufficiently sensitive nor specific, hence a high index of suspicion and vigilance are needed for early recognition. • Immediate goal of management is to prevent/reverse herniation and to maintain good CPP. • The therapeutic measures include stabilization of airway, breathing and circulation, along with neutral neck position, head end elevation by 30°, adequate sedation and analgesia, minimal stimulation and hyperosmolar therapy (mannitol or 3% saline). • Short-term hyperventilation (to achieve PCO2 ≈30 mm Hg) using bag ventilation can be resorted to if signs of impending herniation are present.

Antibiotics/Antiviral Agents

Obtain neuroimaging (CT/MRI) in all patients with raised ICP soon after stabilization. CT will readily identify intracranial bleed, hydrocephalus, cerebral edema, compartmental shifts, infarct, abscess or intracranial space occupying lesions. Initial normal CT does not rule out an evolving lesion of an infection or raised intracranial pressure. In HSE, CT head is abnormal in approximately 50% of cases but may be normal in the first 4–5 days.

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should be monitored every 4–6 hours, if 3% saline is used. Electroencephalogram should be monitored to look for nonconvulsive seizure if child is comatose.

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The reported incidence rates are 3–8 per 100,000 children per year. Arterial ischemic strokes (AIS) constituted 80% of cases. Neonates are at significantly increased risk for ischemic stroke compared with older infants and children. At all ages, there is an unexplained male predominance for ischemic stroke. E

Stroke is defined as an acute neurologic deficit conforming to a vascular territory lasting for more than 24 hours. Stroke can result from rupture of a vessel (hemorrhagic stroke) or occlusion of artery (arterial ischemic) or a vein/ venous sinus (sinovenous thrombosis). An acute onset of focal neurological deficit may not always be due to vascular derangement but may result from other causes, also referred to as “stroke like syndrome”. These include metabolic disorders, tumors, postictal Todd’s palsy, etc. Cerebrovascular disease in children is most frequently associated with several conditions, many of which are genetic. In addition, the brain of a child is immature and has more plasticity than adult brain, so recovery and final outcome are better in younger patients than adults.

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The common causes of ischemic and hemorrhagic strokes are summarized in Table 6.13.1. The most frequently reported risk factors for stroke in children include cardiac

Table 6.13.1 Common causes of stroke in children Hemorrhagic stroke Ischemic stroke A.  Vascular malformation A. Heart disease   •  Arteriovenous malformations   •  Congenital heart disease   •  Aneurysm   •  Rheumatic heart disease   •  Angiomas   •  Infective endocarditis B.  Hematological   •  Complication of cardiac surgery   •  Leukemia B.  Hematologic disorders   •  Thrombocytopenia   •  Sickle cell anemia   •  Hemophilia   •  Leukemia   •  Disseminated intravascular coagulation   •  Polycythemia C.  Trauma   •  Protein C, protein S and antithrombin III   •  Falls deficiency   •  Shaken body syndrome   •  Antiphospholipid antibodies   •  Birth trauma C.  Vascular disease D.  Prematurity   •  Moyamoya disease   •  Vasculitis Infective   •  Pyogenic   •  Tuberculosis   •  Fungal   •  Varicella   •  AIDS Noninfective   •  Systemic lupus erythematosus   •  Polyarthritis nodosa   •  Takayasu arteritis D.  Hereditary metabolic   •  Homocystinuria   •  Raised lipoprotein (a)   •  MELAS E. Trauma   •  Blunt cervical arterial trauma   •  Arterial dissection F.  Miscellaneous   •  Hypotension

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Cerebral sinovenous thrombosis (CSVT) commonly occurs in the setting of acute illnesses, e.g. sepsis or dehydration and head and neck infections. The main neurologic manifestations of sinovenous thrombosis in children are altered sensorium, headache and focal neurologic signs such as hemiparesis and cranial nerve palsies. Signs of raised ICP typically develop gradually over hours and days. Underlying risk factors including prothrombotic states may “predispose” the patient to thrombosis, while acute illnesses often act as triggering factors. S

Hemorrhagic troke The hemorrhage can be parenchymal or extracerebral. Onset is apoplectic in hemorrhagic stroke with loss of consciousness and seizures. Signs of raised intracranial pressure and mass effect are usual. There may be meningismus if there is subarachnoid hemorrhage. E

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This is the most common clinical type of stroke seen accounting for nearly two-thirds of children with stroke. Anterior circulation is affected in more than 80% of patients and middle cerebral artery is the most common vessel involved. It typically presents with acute onset of neurological deficit such as hemiparesis with or without seizures. In older children with involvement of dominant hemisphere, aphasia is a prominent feature. Seizures indicate cortical involvement in patients with lesions at

Table 6.13.2 Differential diagnosis of stroke •  Inflammatory granuloma •  Acute disseminated encephalomyelitis •  Migraine •  Intracranial infections •  Cerebral tumors •  MELAS •  Neonatal seizures •  Post-leukoencephalopathy syndrome  

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The clinical features at presentation vary with age of the patient, the type of stroke and extent of involvement. Embolism produces a rapidly evolving clinical picture, with maximum involvement within a few minutes. Thrombosis is slower in development and may progress either intermittently or progressively during a period of hours or days. There may be a prodromal period of days to weeks, consisting of febrile upper respiratory infections or frontal headache contralateral to the hemiparesis. There are three clinical distinct syndrome of stroke: (1) AIS; (2) cerebral sinovenous thrombosis (CSVT) and (3) hemorrhage.

The diagnostic evaluation in a patient with stroke is aimed at confirming the diagnosis of cerebrovascular disease, defining extent and type of stroke (ischemic or hemorrhagic), determining the vascular territory (large vessel or small vessel) and identifying the underlying etiology of stroke. The strokelike picture can be seen in variety of conditions (Table 6.13.2). A patient presenting with stroke should be investigated in a systematic fashion. All patients coming with acute onset neurological deficit should first undergo neuroimaging. MRI is the investigation of choice since CT cannot pick up an infarct in early stage. In case MRI cannot be done, a plain CT scan is mandatory. This will help to differentiate between infarction and hemorrhage and rule out other diagnosis. The advantage of MRI is that MR angiography and MR venography can be done at the same time if necessary. This helps to elucidate noninvasively the vascular anatomy of cerebral vessels and demonstrates stenosis or occlusion in ischemia and vascular malformation in cases with hemorrhage. Imaging of the

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internal capsule, there is dense hemiplegia with facial nerve palsy of upper motor neuron type. Infarcts in posterior circulation and large infarcts involving middle cerebral artery may present with alteration of sensorium. Focal signs may be absent in neonates or young infants, in whom seizures may be the only manifestation of clinical stroke.

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disorders, coagulation disorders, iron deficiency anemia, sickle cell disease, infection, Moyamoya vasculopathy, arterial dissection, and other rare genetic disorders. Risk factors in children with AIS are definable in approximately 80% of cases, are age-related, and differ significantly from adults. Embolic stroke secondary to congenital heart disease is a frequent cause of stroke during childhood. Infections of CNS, e.g. acute bacterial meningitis and tuberculous meningitis are common causes of stroke in children in tropical countries. Occlusion of blood vessels by perivascular exudates and endarteritis are the underlying cause of vascular occlusion. Varicella has been identified as an important risk factor for childhood stroke and is reported to account for a significant proportion of ischemic strokes. The stroke may occur weeks to months after varicella infection. Cervicocerebral arterial dissections have been increasingly recognized as a cause of stroke. Arterial dissections may occur in internal carotid artery or vertebral artery. Cervicocerebral dissections are often preceded by some form of trauma to the neck. Moyamoya disease is characterized by progressive stenosis and occlusion of the cerebral arteries at the circle of Willis. In response to the stenosis, an abnormal network of small collateral vessels develops, creating the characteristic “puff of smoke” appearance on angiograms. Iron deficiency anemia is a risk factor for stroke in children. The possible underlying mechanism includes thrombocytosis leading to hypercoagulable state and anemic hypoxia. Risk factors for cerebrovascular disease are outlined in Table 6.13.1.

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All patients with AIS should be started on aspirin (1–5 mg/ kg/day) to prevent future recurrences. This is given for a period of 1–2 years. R

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ibliography 1. Amlie-Lefond C, Sébire G, Fullerton HJ. Recent developments in childhood arterial ischaemic stroke. Lancet Neurol. 2008;7(5):425-35. 2. Dlamini N, Billinghurst L, Kirkham FJ. Cerebral venous sinus (sinovenous) thrombosis in children. Neurosurg Clin N Am. 2010;21:511-27. 3. Lopez-Vicente M, Ortega-Gutierrez S, Amlie-Lefond C, et al. Diagnosis and management of pediatric arterial ischemic stroke. J Stroke Cerebrovasc Dis. 2010;19:175-83.



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Early rehabilitation of children with stroke is essential as its proper application may well determine ultimate motor function. As soon as possible after admission, the child should have an evaluation of: • Ability to feed safely • Communication • Positioning requirements • Risk of pressure ulcers. A comprehensive assessment of speech and language should be made and speech therapist should be involved in the rehabilitation program.



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In acute stage, maintaining perfusion and homeostasis is the first priority. Signs of trauma and raised intracranial pressure should be looked for and appropriately managed. On presentation it is essential to make the distinction between hemorrhagic and ischemic stroke, since the former may require neurosurgical intervention. Tissue plasminogen activator is the only approved treatment for acute ischemic stroke in adults. Experience with thrombolysis is limited in children, and hence not recommended as of date. Anticoagulation should be considered in children with: • Confirmed extracranial arterial dissection associated with AIS • Cerebral venous sinus thrombosis provided there is no significant hemorrhage • Cardioembolic stroke. The treatment for hemorrhagic stroke in children depends on the cause and the condition of the patient. Treatments for vascular malformations include surgery, endovascular embolization and radiosurgery. Other therapy in acute phase of stroke depends upon the underlying cause. Patients with sickle cell disease benefit from blood transfusion or exchange transfusion. Antibiotics are required if there is suspicion or evidence of

Prevention of ecurrence

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infection such as septic CSVT. Iron supplementation is given in patients with iron deficiency anemia. After stabilizing the patient, a thorough search should be made for the underlying cause responsible for the event and specific treatment should be instituted for the underlying etiology. Revascularization surgery should be considered in patient with Moyamoya disease to prevent recurrences.



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cervical and proximal intracranial arterial vasculature should be performed in all children with AIS. After confirming the existence of infarct or hemorrhage, one should investigate further to determine the etio logy of stroke. All patients should have a chest x-ray, electrocardiogram and echocardiogram as underlying heart disease is a very common cause of stroke in the pediatric population. Cerebrospinal fluid analysis is mandatory in a stroke patient with unexplained fever or signs of central nervous infections. Patients with unexplained stroke should be screened for prothrombotic states.

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6.14

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tiology

Many conditions or diseases can be associated with floppiness. A list of such disorders based on published

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data is shown in Table 6.14.1. They can be grouped into CNS disorders, neuromuscular disorders (NMD), genetic disorders, metabolic disorders (mostly inborn errors of metabolism) and miscellaneous disorders. Certain systemic disorders like septicemia, meningitis, encephalitis, bulbar poliomyelitis, acute transverse myelitis, acute severe malnutrition and hypokalemia can cause acute onset hypotonia; however these are usually not labeled as floppy infant but are diagnosed according to the primary disease. Central nervous system disorders account for 60–80% of floppy infants whereas NMDs are seen in 10–30% and genetic disorders in about 20% cases. Most common CNS disorder is perinatal asphyxia and its sequel. The most common NMD is spinal muscular atrophy (SMA) and the most common genetic disorders are Down and Prader

The term floppy infant literally means an infant who is extremely hypotonic. Clinically the condition refers to an infant with generalized hypotonia presenting at birth or in early life. The onset of floppiness in these infants is usually subacute to chronic that continues to persist. Floppy infant, often termed floppy infant syndrome, is not a disease but a clinical condition associated with a large number of diseases and disorders. They usually present with floppiness, diminished motor activity and/or certain complications like feeding difficulty and pneumonia. Even if they present with complications, floppiness remains the predominant feature.

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Table 6.14.1 Diseases associated with or causing hypotonia in floppy infants Genetic disorders (syndromes) Central nervous system disorders Down syndrome Malformations Prader-Willi syndrome Ponto-cerebellar hypoplasia Trisomies Holoprosencephaly Metabolic disorders (mostly inborn errors of metabolism) PIN stress and sequel Aminoacidopathy Birth anoxia and hypoxic ischemic encephalopathy Hyperphenylalaninemia from deficiency of the cofactor BH4 Birth trauma Homocystinuria due to defects in methylcobalamin formation Intracranial hemorrhage Maple syrup urine disease due to deficiency of E3 subunit Hypotonic CP Multiple carboxylase deficiency - infantile form Neuromuscular disorders Isolated 3-methylcrotonyl cocarboxylase deficiency Anterior horn cell disease Methylmalonic acidemia Spinal muscular atrophy type I and II Non-ketotic hyperglycinemia, neonatal form Polyneuropathy Mevalonic aciduria Guillain-Barré syndrome Propionic acidemia Bulbar poliomyelitis Methylmalonic aciademia Hereditary motor and sensory neuropathy type III (DejerineGlutaric aciduria type I Sottas, HMSN) Canavan disease Congenital hypomyelinating neuropathy Lipid metabolism disorders Neuromuscular junction disorders Infantile Refsum disease Myasthenia - transient neonatal and congenital forms Zellweger Syndrome Infant botulism Leigh disease Developmental disorder of muscle Late onset metachromatic leukodystrophy Myotubular myopathy Miscellaneous disorders Nemaline rod myopathy Hypothyroidism Central core disease Congenital laxity of ligaments Mini core and multicore disease Ehler–Danlos syndrome Congenital muscle fiber-type disproportion (CMFTD) Marfan syndrome Benign congenital hypotonia Muscular dystrophy Myotonic muscular dystrophy Congenital muscular dystrophy (CMD) Fukuyama disease Walker-Warberg syndrome Muscle-Eye-Brain disease Metabolic myopathy Pompe disease (Glycogenosis type II)

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Etiology of floppy infant is diverse; there cannot be a set of routine investigation for the condition. Investigations have to be guided by clinical suspicion based on history and clinical examination. A useful approach to investigation is to try to categorize the possible cause, i.e. CNS, neuromuscular, genetic, metabolic or miscellaneous disorder and then proceed accordingly. However, it may not always be possible to pin-point the etiology on clinical ground as several signs and symptom are shared by many diseases, especially NMDs. If CNS cause is suspected, there is hardly any need for extensive investigation as diagnosis in most cases can be arrived at based on history and examinations, i.e. sequel of birth anoxia. Imaging is often done to confirm any brain pathology if clinically suspected. If NMD is suspected, certain investigations are needed to establish the etiology. These are serum muscle enzymes (commonly CPK), nerve conduction velocity studies, electromyography, muscle biopsy and genetic studies. CPK is usually raised in muscular dystrophies. Nerve conduction















The workup of floppy infants is aimed at finding the causes that are quite diverse. A systematic approach through good history, thorough examination and etiology-oriented diagnostic investigation is necessary. In history, emphasis should be given on bad obstetrical history, prenatalintranatal-neonatal stress, postneonatal problems, development, past and family history. Neurological examination needs to be through with special emphasis on tone, power, reflexes, sensation and development. The most important areas in examination of a floppy infant are tone and power of muscles. Classic signs of hypotonia in a floppy infant include: • Hypotonic posture: infant assuming a frog-leg posture with hands and legs everted and externally rotated • Sparse/diminished motor movement of the extremities • Very little resistance on passive movement of the joints • Head lag • Body assuming the posture of inverted “U” on ventral suspension. The severe the hypotonia the prominent are these signs. Hypotonia in floppy infants is usually accompanied by motor weakness that needs careful assessment to rule out NMDs. Power in floppy infant is examined by: • Observation of movement, spontaneous and on stimulation • Using the standard pull-push technique at joints giving varying resistance (kinetic power) • By trying to move a limb held static by the infant and feeling the resistance (static power). Attempt should also be made to find whether weakness is proximal or distal. Proximal weakness is more common in myopathies and muscular dystrophies, and distal weakness is more common in peripheral neuropathies. Certain features in history and examination can give valuable clues to etiology and should be looked for in all cases of floppy infant. Some such features are given in Table 6.14.2. At the end of the examination, efforts should be made to find as to which etiological group the particular case belongs to, i.e. CNS, neuromuscular, genetic, metabolic or miscellaneous disorders (Table 6.14.1). These will help in proper selection of investigations. Central nervous system cause should be suspected in presence of:

History of prenatal, intranatal, neonatal and postneonatal problem • Weakness relatively less severe compared to the degree of hypotonia • Brisk tendon reflexes • History of seizures • Cognitive dysfunction with or without hearing and visual deficits. Neuromuscular disorder should be suspected in presence of: • Profound motor weakness proportional to the severity of hypotonia • Decreased or absent tendon reflexes • Relatively preserved cognitive function • No history of seizure. Genetic cause should be suspected in presence of: • History of bad obstetrical history • Consanguinity • Positive family history • Dysmorphism • Specific clinical features of diseases associated with floppiness and mental retardation (Table 6.14.1). Metabolic [Inborn errors of metabolism (IEM)] cause should be suspected in presence of: • Bad obstetrical history • Consanguinity • Positive family history • Dysmorphism and certain feature characteristic of IEM like vomiting, feeding difficulty, lethargy, recurrent dehydration, acidosis, seizures, coma, respiratory abnormality, organomegaly, rash and failure to thrive.

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Willi syndromes. Metabolic and other disorders as causes of floppy infant are relatively uncommon. Some disorders like perinatal insult, Guillain-Barre syndrome, infant botulism and certain inborn errors of metabolism can have acute and stormy presentation. However, the course is usually protracted and prolonged and hypotonia continues to remain as a predominant feature.

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velocity is useful in differentiating whether the weakness is neurogenic or myopathic. Nerve conduction velocity is essential for diagnosis of Guillain-Barré syndrome and useful in botulism. Electromyography is essential when myopathy is suspected. Electromyography also has special utility in diagnosis of myasthenia and myotonic dystrophy and

1. Bassam BA. Floppy infant. In: Katirji B, Kaminiski HJ, Preston DC, Ruff RL, Shaprio BE (Eds). Neuromuscular Disorders in Clinical Practice. Boston: Butterworth-Heinemann; 2002. pp. 1311-18. 2. Birdi K, Prasad AN, Prasad C, et al. The floppy infant: retrospective analysis of clinical experience (1990-2000) in a tertiary care facility. J Child Neurol. 2005;20:803-8. 3. Bodensteiner JB, Riggs JE, Schocher Jr. SS. Congenital myopathies. In: Katirji B, Kaminiski HJ, Preston DC, Ruff RL, Shaprio BE (Eds). Neuromuscular Disorders in Clinical Practice. Boston: Butterworth-Heinemann; 2002. pp. 111427. 4. Connolly AM, Iannaccone ST. Anterior horn cell and cranial motor neuron disease. In: Swaiman KF, Ashwal S, Ferriero DM (Eds). Pediatric Neurology, 4th edition. Mossy: Elsevier; 2006. pp. 1859-85. 5. Dua T, Das M, Kabra M, et al. Spectrum of floppy children in Indian scenario. Indian Pediatr. 2001;38:1236-43. 6. Paro-Panjan D, Neubaeur D. congenital hypotonia: is there an algorithm? J Child Neurol. 2004;19:439-42. 7. Peredo DE, Hannibal MC. The floppy infant: evaluation of hypotonia. Pediatr Rev. 2009;30:e66-76. 8. Prasad AN, Prasad C. Genetic evaluation of the floppy child. Semin Fetal Neonatal Med. 2011;16:99-108. 9. Prasad AN, Prasad C. The floppy infant: contribution of genetic and metabolic disorders. Brain Dev. 2003;25:457-476.

      

             

 

     

Abbreviations: IEM, Inborn errors of metabolism; CMFTD, Congenital muscle fiber-type disproportion; CMD, Congenital muscular dystrophy; SMA, Spinal muscular atrophy; GBS, Guillain-Barré syndrome; HMSN, Hereditary motor-sensory neuropathy.

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botulism. Imaging of muscles (i.e. ultrasound and MRI) has also been used to diagnose dystrophic muscles, although nonspecific. Muscle biopsy with special staining is needed to arrive at the definitive diagnosis of myopathies. Molecular genetic studies are now becoming almost essential for most of the NMDs as several diseases are confirmed with certainty using this technique, since muscle biopsy findings on many occasions are overlapping. DNA markers are commonly studied. Genetic studies are relatively easy and less invasive; its value has been clearly established in SMA where the causative abnormality is the survival motor neuron (SMN) gene mutation. In conditions where genetic abnormalities have been clearly defined, as in SMA, genetic studies are preferred first. Spinal muscular atrophy is the most common cause of floppy infant. The current recommendation is that when NMD is suspected, SMN gene should be studied first. If positive, there is no need of muscle biopsy. If negative, muscle biopsy is undertaken. Genetic studies thus have obviated muscle biopsy, which is difficult in infant. Whenever genetic or metabolic causes are suspected, appropriate genetic/metabolic studies are undertaken. For dysmorphism and suspected syndromes, karyotyping and DNA-based molecular diagnostic studies are usually undertaken. Workup for metabolic causes is usually started with screening tests in blood and urine followed by confirmatory tests like amino acidograms, analysis of enzymes and metabolites. Investigations for disorders in the miscellaneous category are based on clinical suspicion.

Diseases of Central ervous ystem

Table 6.14.2 Clinical clues to possible diagnosis in a floppy infant A Historical findings and diagnostic clues:   •  Miscarriage, consanguinity (genetic and metabolic disorder)   •  Decreased fetal movement (myotubular myopathy, nemaline rod myopathy)   •  Polyhydramnios (myotubular myopathy)   •  Maternal myasthenia (myasthenia gravis)   •  Maternal myotonia (myotonic muscular dystrophy)   •  Constipation (botulism) B. General physical examination findings and diagnostic clues:   •  Dysmorphism (genetic disorders and syndromes, some IEMs)   •  Dolichocephaly (CMFTD, nemaline rod myopathy)   •  Macrocephaly (Canavan disease)   •  Inverted V-shaped upper lip (myotonic muscular dystrophy)   •  Tented upper lip (Fukuyama muscular dystrophy)   •  Unslanting palpebral fissure (Zellweger syndrome)   •  High arched palate (myotubular myopathy, CMFTD, nemaline rod myopathy, myotonic muscular dystrophy)   •  Cleft palate (nemaline rod myopathy)   •  Joint contractures (CMFTD, CMD, central core disease, Ulrich’s anomaly)   •  Scoliosis and kyphoscoliosis (SMA, central core disease, minicore disease, multicore disease)   •  Arthrogryposis (nemaline rod myopathy, CMD, congenital hypomyelinating neuropathy)   •  Pes cavus (central core disease)   •  Subluxation of hip (CMFTD)   •  Undescended testes (myotubular myopathy) C. Neurological examination findings and diagnostic clues:   •  Visual impairment (muscle eye brain disease, Walker-Warburg syndrome)   •  Ocular anomalies (muscle eye brain disease, Walker-Warburg syndrome)   •  Impaired corneal reflex (botulism)   •  Third nerve palsy (botulism)   •  Ptosis (myasthenia gravis, myotubular myopathy)   •  Facial nerve palsy (botulism)   •  Bulbar palsy (bulbar poliomyelitis, GBS, botulism, nemaline rod myopathy)   •  Hypotonia disproportionate to weakness (benign congenital hypotonia, CMFTD, myofibrillar myopathy)   •  Fasciculation (SMA)   •  Insensitivity to pain (HMSN III, congenital hypomyelinating neuropathy) D. Other system examination findings and diagnostic clues:   •  Cardiomyopathy (Pompe disease, myofibrillar myopathy)   •  Cardiac anomaly (central core disease, minicore disease)   •  Hepatomegaly (Pompe disease)

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Neuromuscular isorders in hildren Sheffali Gulati

Neuromuscular disorders can be due to disorder anywhere in the motor unit. It comprises of neuronopathy (primary disorder of anterior horn cell), neuropathy (primary disorder of axon or its myelin), neuromuscular junction disorders and myopathy (primary disorder of muscle). Fundamental tools to differentiate these disorders include a detailed medical history including a family history and a carefully performed physical examination. Table 6.15.1 enumerates key features to differentiate between these disorders. Weakness and hypotonia are common features of motor unit disorders. Normal tone requires an intact CNS as well. Cerebral (central) hypotonia differs from peripheral hypotonia (due to motor unit disorders) by having preserved

muscle stretch reflexes, preserved power, associated seizures, dysmorphic features and malformations of brain or other organs. Table 6.15.2 shows common etiologies of peripheral and central hypotonia. D

Muscle isorders Table 6.15.3 enumerates the muscle disorders categorized according to the age of presentation. C



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The congenital myopathies usually present with floppy infant syndrome. Occasionally, they may manifest in

 

Table 6.15.1 Key features to differentiate between motor unit disorders Site of involvement

Proximal (P) vs. distal (D) involvement

Muscle stretch reflexes

Electrophysiological studies

Muscle biopsy

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Absent

Evidence of denervation, fasciculations

Type grouping

Nerve

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Depressed/absent

Abnormal nerve conduction studies, Denervation Denervation pattern potentials on electromyogram

Neuromuscular junction

Variable

Normal

Repetitive nerve stimulation-abnormal decrement/increment

Muscle

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Low amplitude short duration polyphasic motor Usually characteristic unit action potential on electromyogram

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Table 6.15.2 Differential diagnosis of hypotonia Mixed hypotonia

Chromosomal disorders Prader-Willi syndrome Trisomies Static encephalopathies Cerebral malformations Perinatal insult Neurometabolic Acid maltase deficiency Biotinidase deficiency GM1/GM2 gangliosidoses Peroxisomal disorders Infections Sepsis/meningitis Intrauterine infections Benign congenital hypotonia Genetic defects Lower syndrome Familial dysautonomia

Anterior horn cell Spinal muscular atrophy Neuropathies Giant axonal neuropathy Congenital hypomyelinating neuropathy Charcot-Marie-Tooth disease Neuromuscular junction disorders Myasthenia gravis Botulism Myopathies Central core disease Myotubular myopathy Nemaline rod myopathy Congenital fiber type disproportion myopathy Metabolic myopathies Muscular dystrophy Dystrophinopathies Myotonic dystrophy Facio-scapulo-humeral dystrophy Congenital muscular dystrophy Emery-Dreifuss muscular dystrophy

Hypothyroidism Acid maltase deficiency Hypoxic ischemic encephalomyopathy Familial dysautonomia Infantile neuronal degeneration Motor unit disease with superimposed asphyxia Mitochondrial disorders

                     

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Table 6.15.3 Muscle disorders based on age of presentation Muscular dystrophies: Duchenne Becker Emery-Dreifuss Facio-scapulo-humeral Limb-girdle Congenital Congenital myopathies: Nemaline Centronuclear Central core Endocrine-metabolic disorders: Hypokalemia Hypocalcemia Hypercalcemia Glycogen storage disease: Acid maltase deficiency Inflammatory myopathies: Dermatomyositis Polymyositis (rarely) Lipid storage disease Carnitine deficiency Mitochondrial myopathies  

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Muscle disorders presenting in childhood

Congenital myotonic dystrophy Congenital myopathies: Centronuclear myopathy Congenital fiber-type disproportion Central core disease Nemaline myopathy Congenital muscular dystrophy Glycogen storage diseases Acid maltase and phosphorylase deficiencies Lipid storage diseases Carnitine deficiency  

Muscle disorders presenting at birth

ongenital Muscular ystrophies D

They usually present at birth. The affected infant shows hypotonia, weakness or arthrogryposis (Fig. 6.15.1). Diagnosis

is supported by elevated CPK levels, dystrophic myopathic features on muscle biopsy, and exclusion of common myopathies of newborn. Congenital muscular dystrophies (CMD) are divided into syndromic and nonsyndromic (Table 6.15.4). Merosin negative CMDs are more severe as compared to merosin positive CMDs. Syndromic CMDs have associated cerebral involvement. No specific treatment is available. D

Muscle ystrophies Muscle dystrophies are characterized by progressive clinical course. Common ones are described below.

Dystrophinopathies

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Dystrophinopathies are a group of disorders resulting from mutations in the dystrophin gene (located on the short arm of X chromosome in the Xp21 region). • uchenne muscular dystrophy: It is the most common dystrophinopathy with an incidence of 1 in 3,500 live male births. • ecker muscular dystrophy: Its rarer allelic variant, differs from Duchenne muscular dystrophy (DMD) by

 

Table 6.15.4 Classification of congenital muscular dystrophies

 

Figure 6.15.1 Uhlrich’s muscular dystrophy - distal hyperextensible joints

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Non-syndromic congenital muscular dystrophies Merosin deficient (Ch 6q22-23) Merosin positive: Uhlrich disease (Collagen VI deficiency) (Fig. 6.15.1), rigid spine syndrome (SEPN1 gene) Syndromic congenital muscular dystrophies Fukuyama congenital muscular dystrophies (Ch 9) Muscle-eye-brain disease (Ch 1) Walker-Warburg syndrome (Ch 9q34)  

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later childhood or even adulthood. Clinically, they are indistinguishable from one another. Common types include centronuclear, nemaline rod and central core disease. CPK is usually normal. Histopathology is diagnostic. Usually they have a benign course with nonprogressive hypotonia and weakness. Sometimes, they may present with early onset respiratory distress and feeding difficulties. Malignant hyperthermia may be associated with central core disease. Treatment is usually symptomatic.

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iagnosis: The serum creatine kinase levels are greatly elevated (> 10 times). It has no correlation with severity of the disease or response to treatment. Other muscle enzymes are also elevated. The levels decrease as the muscle mass is lost with the progression of the disease. • Mutation analysis is the standard for diagnosis, carrier detection and fetal diagnosis. Commonly available tests (PCR and Southern Blot) are able to pick up mutations (mainly deletions) in around 60% of cases. Now multiplex ligation-dependent probe amplification is being used with increased detection rates. • Muscle biopsy may be required in deletion negative cases and also to differentiate between DMD and BMD. • Management: Management of a child with DMD is briefly outlined in Table 6.15.5. • ther common dystrophies: Other common dystrohies besides dystrophinopathies are summarized in Table 6.15.6.

Limb Girdle Muscular Dystrophy Limb girdle muscular dystrophy (LGMD) is a group of clinically heterogeneous syndromes consisting of different specific disease entities. The individual disorders in this group are characterized by progressive muscular weakness predominantly involving proximal (girdle) muscles of the limbs. Even within a particular subtype of LGMD or among the affected members of the same family, age at onset and rate of disease progression are variable. The susceptibility to complications (cardiomyopathy, arrhythmias, respiratory insufficiency) is variable among LGMD type. They can be autosomal dominant or autosomal recessive. Common LGMD subtypes include sarcoglycanopathies, calpainopathy, caveolinopathy, dysferlinopathy, etc.

Metabolic Myopathies The metabolic myopathies are a group of muscle disorders resulting from failed energy production related to defects in glycogen, lipid or mitochondrial metabolism. Affected older children and adults present primarily with exercise intolerance, weakness and myoglobinuria; newborns and infants present with severe multisystem disorders. In patients with glycolytic/ glycogenolytic defects, symptoms are induced by either brief

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Figures 6.15.2A and B Duchenne muscular dystrophy. (A) Calf hypertrophy; (B) Valley sign  

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its later age of onset (usually > 6 years of age), more prolonged unaided ambulation (> 15 years), more incidence of myalgias, occasional rhabdomyolysis following exercise and cardiac findings, which are “out of proportion” to limb weakness. Both of them form two ends of a spectrum. • Genetics: Deletion of more than or equal to one exon is the most common mutation seen (~ 65%). In around 90% boys with DMD, the “out of frame” mutation disrupts the normal dystrophin transcription resulting in almost undetectable dystrophin. The “in frame” mutations result in production of some abnormal molecular weight dystrophin leading to Becker muscular dystrophy (BMD) phenotype. • linical features: Children with DMD often have delayed motor milestones. Gait disturbances often become apparent at 3–4 years of age. Waddling gait, Gower sign and calf muscle hypertrophy (Figs 6.15.2A and B) are classical findings at this stage. Neck flexor muscle weakness is seen early. Other muscles may also show hypertrophy. The progression of weakness may plateau between 3 years and 6 years of age. Subsequently there is increasing gait difficulty, contractures and increased lumbar lordosis. Natural history studies have shown the age at loss of independent ambulation in untreated DMD to be between 8.8 years and 10.5 years. After loss of ambulation, there is worsening kyphoscoliosis, increasing upper limb weakness and bulbar dysfunction. • Weakness of intercostal and diaphragmatic muscles with spinal deformity compromises respiratory function. Cardiomyopathy and arrhythmias are the major cardiac manifestations in DMD. The cause of death in DMD patients is usually a combination of respiratory insufficiency and cardiomyopathy. Other clinical features of DMD may include variable degree of intellectual disability and impaired gastric motility. • More than 90% of female carriers are asymptomatic. However, few may have variable degree of weakness with elevated creatine kinase levels. Full DMD phenotype may be present in case of complete inactivation of normal X chromosome. Increased risk of cardiomyopathy may be seen in female carriers.

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Chronic treatment: The aims of treatment for MG patients should be to induce and maintain complete clinical or pharmacological remission with minimal adverse effects. • Nonimmune modulatory: pyridostigmine • Immune modulatory: steroids, steroid sparing agents and thymectomy (Table 6.15.9).

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auses: Disease progression, stressor/illness, withdrawal of chronic treatment, use of contraindicated medication (Table 6.15.10). A close differential diagnosis is cholinergic crisis due to over dosage of acetylcholinesterase (AChE) inhibitors. • hort-term immunotherapy: IVIG 2 g/kg over 2–5 days and plasmapheresis. • upportive care: Temporary NPO or nasogastric tube feeding to prevent aspiration. Close respiratory monitoring and provide ventilatory support if necessary. • holinergic crisis: Cholinergic symptoms and signs may include diarrhea, urinary incontinence, miosis, bronchospasm, salivation and lacrimation. If patient is in crisis, withhold AChE inhibitor. S

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Juvenile myasthenia gravis is an autoimmune disorder of synaptic transmission. Circulating acetylcholine receptor (AChR) antibodies interfere with fixation, placement or survival of nicotinic AChR. Muscarinic receptors are not affected, therefore, pupillary and autonomic responses are spared. The salient features of JMG are given in Table 6.15.7. Various tests used in diagnosis of JMG are discussed in Table 6.15.8.





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Physical therapy •  Effective stretching and appropriate positioning at various joints, assistive devices to prevent contractures, avoid high resistance strength training Surgery •  Persistent contractures, spinal fusion Steroids •  Standard of care •  Usually started in children more than 2 years of age with static or declining function •  Most effective dose 0.75 mg/kg/d of prednisolone •  Deflazacort (0.9 mg/kg/d) may be preferred in children with excessive weight gain with prednisolone or with pre-existing behavioral problems •  Non-ambulatory Duchenne muscular dystrophy children: low dose (0.3-0.6 mg/kg/d) prednisolone may be started with aim of preserving upper limb strength, reducing progression of scoliosis and delaying the decline in respiratory and cardiac function •  Before starting steroids: adequate immunization (pneumococcal/ influenza/varicella); screening with chest X-ray and Mantoux test •  Monitoring of children on steroid therapy: screening for side effects of steroids (cushingoid features, obesity, hirsutism, acne, behavioral changes, polyuria/polydipsia, GERD/PUD, fractures, color of urine after exercise) •  At each visit, monitor weight/height/body mass index, blood pressure and blood sugar •  Annual SMR staging •  Annual ophthalmologic evaluation •  Pulmonary function tests (6 monthly in non-ambulatory; annually in ambulatory patients) •  Echocardiography (once in 2 years < 10 years of age; annually > 10 years) •  Serum calcium, phosphate, 25(OH) Vitamin D (biannually) •  DEXA scan annually •  Respiratory and cardiac care •  Management of gastrointestinal problems •  Psychosocial management Newer therapies •  Exon skipping, gene therapy, cell therapy

2. Congenital myasthenia gravis 3. Transient neonatal MG in an infant born to a myasthenic mother.

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Table 6.15.5 Management of a child with Duchenne muscular dystrophy

isometric exercise, such as lifting heavy weights, or by less intense but sustained dynamic exercise. With disorders of lipid metabolism, the abnormalities are usually induced by prolonged exercise and prolonged fasting. Investigations include serum CPK, urine myoglobulin, serum ammonia, TMS, GCMS, electrophysiological studies, forearm ischemia exercise test, muscle biopsy and molecular studies. D

Neuromuscular Junction isorders



Neuromuscular junction disorders comprise of presynaptic, synaptic and postsynaptic disorders. The cardinal features of these disorders are a waxing-waning course and easy fatigability, which improve after rest. In infants and children, three forms of myasthenia gravis (MG) are characterized: 1. Juvenile myasthenia gravis [JMG (autoimmune)] similar to adult type

In a case of suspected peripheral neuropathy, the pediatrician first should confirm that the patient has a disorder of the peripheral nerve, determine the type (axonal or demyelinating) and anatomic distribution of nerve involvement, find out the predominant symptom (motor/ sensory/autonomic), consider and test for the possible etiologies and determine the optimal treatment options. Flow chart 6.15.1 shows an overview to approach to a child with suspected peripheral neuropathy.

Hereditary Neuropathies Charcot-Marie-Tooth Disease It is the common hereditary neuropathy and comprises of a heterogeneous group of inherited, non-metabolic neuropathies. Salient features include positive family history, long slowly progressive course, foot deformities, no 401 definite sensory symptoms but prominent sensory signs.

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Table 6.15.6 Other muscle dystrophies Muscular dystrophy

Underlying defect

Clinical features

Myotonic dystrophy type 1 (AD)

Abnormal expansion of [CTG]n repeats in the DMPK gene (chromosome 19)

Congenital form: respiratory failure, poor feeding, hypotonia, facial diplegia, clubfoot and gastroparesis, decreased fetal movements and polyhydramnios in mother Late onset form presents during adolescence; myotonia, facial weakness, distal limb weakness, cataracts, frontal baldness, endocrinopathies, cardiac arrhythmias and disturbed gastrointestinal motility

Facio-scapulo-humeral muscular dystrophy (AD)

D4Z4 deletion on 4q35

Age of onset variable; the disease may start with asymptomatic facial weakness followed sequentially by scapular fixator, humeral, truncal and lower extremity weakness; slowly progressive; extraocular and bulbar muscles are spared; contractures are rare; side to side asymmetry of muscle weakness is typical; extramuscular manifestations include deafness, Coats’ disease, atrial arrhythmias and restrictive respiratory disease (Figs 6.15.3A to C)

Emery-Dreifuss muscular dystrophy Type 1: X-linked Type 2: AD Type 3: AR

Type 1: Ch Xq28 (STA) Type 2 and 3: Ch 1q11-q23 (LMNA)

Triad of early contractures, slowly progressive muscle weakness and cardiac conduction defects

Oculopharyngeal muscular dystrophy (AD)

PABPN1 gene symbol. Ch locus 14q11.2

Initial features are ptosis and dysphagia followed by proximal lower limb weakness and external ophthalmoplegia

Abbreviation: DMPK, dystrophia myotonica-protein kinase

Clues from history •  Slowly progressive course with relapsing-remitting tendency with variable or fatigable weakness •  Perinatal: reduced fetal movements, polyhydramnios, arthrogryposis •  Infancy: hypotonia, weakness, weak cry, feeding difficulties, recurrent apneic episodes •  Childhood: difficulty in chewing or swallowing, fatigability or hoarse voice, diplopia especially on sustained gaze or continuous activity like reading, weakness of jaw, orthopnea secondary to diaphragmatic weakness; limb girdle weakness Clues on neurological examination •  Eye signs: ptosis (may be asymmetric); Peep sign (on attempting to tightly close eyes, after few minutes the cornea gets exposed due to inability to sustain contraction of orbicularis oculi), ophthalmoparesis •  Facial weakness: compensatory wrinkling of forehead (due to hypercontracted frontalis to maintain eye opening), expressionless facies, Snarl on trying to smile; inability to close the jaw •  Other cranial musculature: Bulbar weakness, tongue may show triple longitudinal furrowing •  Skeletal musculature: proximal limb weakness, tachypnea/shallow respiration

•  Edrophonium testing: a rapid acting, short duration cholinesterase inhibitor. Effects are seen within 10 seconds and persist till 120 seconds; positive: transient resolution of the clinical signs (ptosis/ ophthalmoplegia/dysarthria); diagnostic dose is 0.1–0.2 mg/kg [may be repeated every minute to a total maximum dose of 5 mg (weight < 34 kg) or 10 mg (weight > 34 kg)]; should be done in a monitored setting with available atropine and cardiorespiratory resuscitation kit •  Infants: edrophonium is not recommended for use in infants due to high risk of arrhythmias and short duration of action which precludes objective assessment. Neostigmine (Prostigmine methylsulphate) by intramuscular injection (Figs 6.15.4A and B); slower in action, response anticipated in 10–15 minutes and maximum in 30 minutes, a more objective assessment of response can be made; dose used is 0.125 mg/kg in an infant and 0.04 mg/kg in an older child. If the result is equivocal or negative, the dose may be repeated in 4 hours •  Ice pack test: may be helpful for the diagnosis of ocular myasthenia; should only be interpreted as positive when there is clear and unequivocal improvement in ptosis following a 2-minute application of an ice pack to the affected eyelid •  Electrophysiological testing: repetitive nerve stimulation test: The fatigability of neuromuscular transmission is demonstrated by a decrement of more than 10% in compound muscle action potential after repetitive nerve stimulation (2–5 Hz). Single fiber electromyography may show increased jitter or variation in contraction time in muscle fibers •  Serum antibodies: Acetylcholine receptor antibodies may be positive; positivity rates are lower in peri and pre-pubertal children (50–60%). Anti-MuSK antibodies may be demonstrable in 40% seronegative myasthenia gravis patients •  Muscle biopsy: not indicated routinely •  X-ray Chest or CT of anterior mediastinum may be show thymoma/ thymic hyperplasia •  Thyroid profile should always be done in suspected juvenile myasthenia gravis patients 









 





 













One should keep in mind that in large families with known hereditary neuropathies, only 20% of affected family members seek medical attention because of symptoms. One should enquire in detail before arriving at a conclusion regarding family history: difficulty with running, sports or military activities, high arched feet or flat feet, hammer or curled-up toes, claw hands, wasting of muscles, foot troubles, foot ulcers, use of orthosis, arthritis 402 or poliomyelitis (incorrect diagnosis), difficulty in walking on heels and toes.

 

Table 6.15.8 Diagnosis of myasthenia gravis

 

Table 6.15.7 Presentation of juvenile myasthenia gravis

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Mechanism of action

Dose

Indications

Monitoring/Precautions

Pyridostigmine

AChE inhibitor

1-7 mg/kg in 5 or 6 divided doses 30 minutes before meals Maximum dose: 300 mg Dose of IV pyridostigmine is 1/30th of oral dose

First-line for all JMG patients

May use glycopyrrolate/atropine for muscarinic side effects

Corticosteroids

Exact mechanism unknown; immunosuppressive; reduces anti–AChR antibody level

In non-acute setting start at low dose (@ 0.5 mg/kg/d); dose can be gradually increased as tolerated; Once in remission, ↓ dose gradually Acute setting-pulse steroids

Cases unresponsive to pyridostigmine and acute settings

Monitor for side effects

Azathioprine

Purine antimetabolite inhibits T cell proliferation

1–3 mg/kg/d as single dose; may be increased by 0.5–1 mg/kg/day every 4–8 weeks

May be used as steroid sparing drug; may be used alone also

CBC, hepatic function monthly Withhold treatment if counts < 3000; reduce if < 4000/ mm3

IVIG

Blocks Fc receptor of antibodies

Acute setting: 2 g/kg/d IV over 2 or 5 days Maintenance: 1 g/kg/d X 2 days every 4–8 weeks

May be used in myasthenic crises or as maintenance therapy if child unresponsive to other immunemodulatory therapy

Monitor for side effects

Plasmapheresis

Removes AChR antibodies from circulation

Acute setting: 3–5 exchanges every other day; number may depend on the severity Maintenance: 3–5 exchanges/ months

May be considered in children who failed to respond to AntiAChE

Monitor for side effects

Thymectomy

Immuno-modulator

-

Necessary in thymoma; may be considered in nonthymomatous hyperplasia; thymectomy within 2 years of diagnosis results in a higher rate of remission

Undertaken with caution in very young children due to the occurrence of immunological abnormalities





Genetic testing is important for the accurate diagnosis and classification of hereditary neuropathies. The genetic testing should be guided by the clinical phenotype, inheritance pattern (if available) and electrophysiological features. Detailed discussion of peripheral neuropathies is out of scope of this chapter. The common immune mediated neuropathies are described briefly below as they are commonly encountered in the clinical practice.

nt S t m

It is a common cause of acute flaccid paralysis in children. Many subtypes have been described and include acute inflammatory demyelinating polyradiculoneuropathy, acute motor axonal neuropathy, acute motor and sensory neuropathy, acute sensory neuronopathy, acute pandysautonomia and the Miller-Fisher syndrome. About two-thirds of GBS cases have an antecedent infection within 6 weeks prior to symptom onset, generally an upper respiratory tract infection or gastroenteritis. The clinical manifestations include an acute onset symmetrical ascending weakness (both proximal and distal) with frequent facial weakness and respiratory weakness in one-fourth of cases. Dysautonomia is also common. The axonal forms of GBS exhibit a more rapid and severe course. The weakness reaches a nadir at 2–4 weeks after symptom onset with progressive recovery over weeks to months. Guillain-Barré syndrome is usually a monophasic illness but about 7–16% of patients suffer recurrent episodes of worsening after an initial improvement. 403

Absolutely contraindicated: Curare, penicillamine, Botox, IFN-α Relatively contraindicated: –  Antibiotics: Fluoroquinolones (ciprofloxacin. levofloxacin, etc.) –  Macrolides (erythromycin, azithromycin, etc.) –  Aminoglycosides (gentamicin, tobramycin, etc.) –  Quinine –  Class IA antiarrhythmic (procainamide, quinidine, lidocaine, etc.) –  Magnesium –  Use with caution: Ca-channel blockers, lithium, statins, steroids

Guillain-Barré Syndrome



 

•  •             

ral Nervous ys e

Table 6.15.10 Medications exacerbating myasthenia gravis

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Drug

iseases of e

Table 6.15.9 Management of juvenile myasthenia gravis

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Flow chart 6.15.1 Approach to peripheral neuropathy

Abbreviations: CMT, Charcot-Marie-Tooth; MLD, Metachromatic leukodystrophy; ALD, Adrenoleukodystrophy; AIDP, Acute inflammatory demyelinating neuropathy, CIDP, Chronic inflammatory demyelinating neuropathy; AMAN, Acute motor axonal neuropathy; MFS, Miller-Fischer syndrome; SCA, Spinocerebellar ataxia; FA, Friedrich’s ataxia; HNPP, Hereditary neuropathy with pressure palsies; HSAN, Hereditary sensory autonomic neuropathy

a

C

Figures 6.15.3A to C Facio-scapulo-humeral muscular dystrophy. (A) Inability to close eyes completely; (B) Forward sloping of shoulders with straight clavicles; (C) Scapular winging on attempted forward flexion  

404

B

concentration (80%) with the mononuclear cell count being either normal (albumin-cytologic dissociation) or less than 50 cells/mm. Both electrophysiological studies and CSF analysis may be normal in the first week of the illness. The common differential diagnosis is given in Table 6.15.11. Immunotherapy is the main stay of treatment. IVIG (2 g/ kg) or plasmapheresis done within 2–4 weeks of symptom

­



The diagnosis depends on classical clinical picture, electrophysiological findings and CSF examination. Electro physiology may reveal absent F-responses or H-reflexes, reduced CMAPs or SNAPs (in axonal forms), prolonged distal latencies, reduced conduction velocities, abnormal temporal dispersion and conduction blocks (in demyelinating types). Cerebrospinal fluid analysis may reveal raised CSF protein

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S

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C

iseases of e

a

Figures 6.15.4A and B Juvenile myasthenia gravis. Neostigmine challenge test - (A) Pre and (B) Post test; also note the asymmetric ptosis

 

Table 6.15.11 Common differential diagnosis of Guillain-Barré syndrome Muscle disorders

Neuromuscular junction Neuropathies disorders

Central nervous system disorders

Inflammatory myopathy Periodic paralysis Hypokalemia Infections

Myasthenia gravis Eaton-Lambert syndrome Botulism

Acute myelopathy Acute anterior poliomyelitis Brainstem stroke Brainstem encephalitis

Diphtheric neuropathy Acute intermittent porphyria Traumatic neuritis Vasculitic neuropathy

 

Table 6.15.12 Clinical spinal muscular atrophy subtypes Spinal muscular atrophy subtype

Age at onset

Usual highest function achieved

Natural age at death

Type I (severe, Werdnig-Hoffman disease)

0–6 months

Never sit

< 2 years

Type II (intermediate)

7–18 months

Sit, never stand

> 2 years

Type III (mild, Kugelberg-Welander disease)

> 18 months

Stand and walk

Adult

Spinal muscular atrophy is the most common anterior horn cell disorder encountered in children. It will be discussed briefly below. A

S

pinal Muscular trophy Spinal muscular atrophy (SMA) is characterized by degeneration of motor neurons of the spinal cord, which





results in hypotonia and muscle weakness. Spinal muscular atrophy is divided into three clinical types (Table 6.15.12). Ninety-six percent children with 5q13 linked SMA shows SMN1 gene deletion or gene conversion from SMN1 to SMN2. Four percent patients have intragenic SMN1 mutations. Type 1 disease presents with profound hypotonia and flaccid weakness (Fig. 6.15.5). Respiratory weakness, poor swallowing and tongue fasciculations are common. Aspiration pneumonia is an important cause of morbidity and mortality. Children with type II disease are usually able to sit unaided. They may develop kyphoscoliosis, tremors (polyminimyoclonus), poor swallowing and respiratory insufficiency. Type III patients are usually able to walk. They may mimic LGMD or myopathy. Treatment is usually supportive. Various therapeutic 405 strategies, being evaluated, are enlisted in Table 6.15.13.

D

nterior Horn ell isorders C

A

onset is recommended. The treatment is warranted in non-ambulatory patients but their role in mildly affected GBS patients who are mobile is uncertain. Patients who have not responded to initial IVIG treatment may benefit from a second course of IVIG. General supportive care includes cardiorespiratory care, physical therapy, nutritional management, management of neuropathic pain, bladderbowel care and prevention of deep vein thrombosis.

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ibliography

• Detailed history and examination, in a child with suspected neuromuscular disease, is essential to localize the lesion in the motor unit. • Family history with pedigree drawing is imperative to reach appropriate diagnosis. • Investigations must be planned judiciously while managing children with neuromuscular disorder. • Never miss potentially treatable conditions like neuromuscular junction disorders which may mimic















ey Messages



K



SMN1 gene replacement: Gene therapy SMN2 activation: Histone deacetylase inhibitors, hydroxyurea Promotion of exon 7 inclusion: Anti-sense oligonucleotides Stabilization of SMN protein: Aminoglycosides Cell replacement: Cell therapy Neuroprotection: Riluzole, gabapentin



•  •  •  •  •  • 



 

Table 6.15.13 Therapeutic approaches in spinal muscular atrophy

1. Bushby K, Finkel R, Birnkrant DJ, et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis and pharmacological and psychosocial management. Lancet Neurol. 2010;9:77-93. 2. Darras BT, Friedman NR. Metabolic myopathies: a clinical approach; Part I. Pediatr Neurol. 2000;22:87-97. 3. Darras BT, Friedman NR. Metabolic myopathies: a clinical approach; Part II. Pediatr Neurol. 2000;22:171-81. 4. England JD, Gronseth GS, Franklin G, et al. Evaluation of distal symmetric polyneuropathy: the role of laboratory and genetic testing (an evidence based review). Muscle Nerve. 2009;39:116-25. 5. Jackson CE. A clinical approach to muscle disease. Semin Neurol. 2008;28:228-40. 6. Joint Task Force of the EFNS and the PNS. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy. Report of a Joint Task Force of the European Federation of Neurological Societies and the Peripheral Nerve Society. J Peripher Nerv Syst. 2005;10:220-8. 7. Moxley III RT, Tawil R. Channelopathies: myotonic disorders and periodic paralysis. In: Swaiman KF, Ashwal S, Ferriero DM (Eds). Pediatric Neurology, Principles and Practice, 4th edition. Elsevier; 2006. p. 2085. 8. Tawil R, van Der Maarel SM. Facio-scapulo-humeral muscular dystrophy. Muscle Nerve. 2006;34:1-15.



 

Figure 6.15.5 Frog like posture in a child with spinal muscular atrophy type II

B

t

t

common muscle disorders. They may also have potentially fatal complications if unrecognized. • Genetic counseling and pre-natal diagnosis are important in selected clinical scenarios. When we come across families with multiple sibs affected with common conditions like SMA and DMD, the medical fraternity carries the blame for not offering appropriate genetic counseling and pre-natal diagnosis.

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ental etardation and utism R

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Cerebral Palsy,

Diseases of Central ervous ystem

6.16

MS Mahadeviah

Cerebral palsy at present is broadly classified to spastic dyskinetic, mixed, ataxic and hypotonic.

pastic diplegia: It refers to the spasticity predomi­ nantly of the lower extremities with minimal or no involvement of upper extremities. The major causes include prematurity, ischemia and infections leading to periventricular leukomalacia. These children have relatively better cognitive functioning.

•

pastic hemiplegia: It refers to involvement of left or right side of the extremities; upper usually greater than lower. Spastic hemiplegia has the best prognosis for ambulation; but is more prone to develop seizures. In 20–30% the pathology is contralateral infarcts.

•

pastic quadriplegia: It refers to equal involvement of all the four extremities with generalized spasticity. They have considerable clinical manifestations of drooling, difficulties in feeding, seizures along with speech, hearing, visual and intellectual disabilities. The most common pathologies are periventricular leukomalacia and multicystic cortical encephalomalacia. The prognosis for independent ambulation is poor.

E

tiology



At present 75–80% of causes of CP point to antenatal factors, which are responsible for abnormal development of brain. Main etiological factors in 10–20% of children with CP are intrapartum asphyxia and exposure to maternal infections such as chorioamnionitis, sepsis, urinary tract infections and fever with elevated levels of cytokines. Prematurity, especially infants weighing less than 1,000 g is a major risk factor resulting in intraventricular hemorrhage and periventricular leukomalacia. Perinatal and neonatal causes such as sepsis, neonatal seizures, cerebral ischemia and low Apgar scores are present in substantial number of children with CP.

Clinical Features The most common presentation of CP is delay in motor development such as head control, sitting, standing and walking. All types of CP are characterized by abnormal muscle tone, reflexes or motor development and coordination. Other features include asymmetrical reaching for objects, abnormal movements and postures. Associated manifestations include delay in speech, visual difficulties, intellectual disability and seizures.

•

S

S

•

S

Spastic type of CP accounts for 70–75% of the cases with CP. Spastic CP is further classified to spastic diplegia, spastic hemiplegia, spastic quadriplegia, spastic monoplegia and spastic triplegia, as described below.

Definition of Cerebral Palsy Cerebral palsy describes a group of permanent disorders of the development of movement and posture causing activity limitation. It is also attributed to nonprogressive disturbances that occurred in the developing fetal or infant brain. The motor disorders of CP are often accompanied by disturbances of sensation, perception, cognition, communication and behavior, epilepsy and secondary musculoskeletal problems. Cerebral palsy excludes motor disorders of spinal, peripheral nerve, muscular or mechanical origin. Although it is stated that there is no explicit upper age limit, CP usually refers to the first 2–5 years when there is active growth of the brain.

N

Spastic Cerebral Palsy

S

Cerebral palsy (CP) as it is commonly known is the commonest cause of physical disability in children. It encompasses a group of nonprogressive and noncontagious disorders causing physical disability mainly in the various areas of body movement. In spite of all the progresses in newborn care its prevalence remains at 2–2.5 per 1,000. The prevalence in India is not definitively established. Although CP is described as a static encephalopathy, the neurological features may change over the time.

Classification

S

Cerebral Palsy

pastic monoplegia and triplegia: These are rare.

Dyskinetic Cerebral Palsy These include athetoid or choreoathetoid children with dyskinetic CP presenting with hypotonia, head lag, variable tone, drooling, tongue thrust, rigidity and dystonia. In the past dyskinetic CP was common with neonatal hyperbilirubinemia secondary to Rh incompatibility, which may still be a cause in developing countries. Other factors include severe birth asphyxia, lessons in basal ganglia and mitochondrial disorders.

Differential Diagnosis It is important to rule out disorders of motor disability. Detailed history and examination should be directed to rule out progressive neurological disorders (degenerative), muscular disorders (myopathies and muscular dystrophies), spinal cord tumors and genetic syndromes.

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ental etardation ( ntellectual Disability) M

I

At the present state of the art of medical practice, an MRI scan of the brain is necessary. Ophthalmic evaluation, hearing tests, speech and language evaluation, psychological educational evaluation, EEG and other investigations should be done depending on the clinical profile.

Definition

Counseling the Parents

Prevalence

anagement

Intellectual disability affects the population in varying proportions; however, 75% of these cases fall under mild intellectual disability. Severe intellectual disability accounts to less than 5% of the population of affected children.

-

Counseling the parents is the greatest challenge the professional faces. It is important to teach the parents regarding the activities of daily living such as feeding, bathing, dressing and follow up of therapy that is being done by the physiotherapist and occupational therapist. Frequent follow up, addressing the special needs of children and parents should be the most important service provided by the center.

-

-

Management of children with CP involves a multidisciplinary team, which should include a developmental pediatrician, physiotherapist, occupational therapist, orthotic specialist, orthopedic surgeon, psychologist, educational specialist, speech pathologist and social worker along with consultants in neurology, psychiatry, ophthalmology, assistive technology and otolaryngology as necessary.

Mental retardation (MR) is defined as “significantly sub average general intellectual functioning, existing concurrently with deficits in adaptive behavior and mani­ fested during the developmental period that adversely affects a child’s educational performance,” according to the US Special Educational Plan, The Individuals with Disabilities Education Act. Many consider the use of the term “MR” as offensive and the term intellectual disability or intellectually challenged is now preferred by most advocates in most English speaking countries.

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nvestigations

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Pathogenesis

Management includes prevention of contractures, which is the main goal of physiotherapist and orthopedic surgeon.

Surgical Procedures

-

tiology

Intellectual disability (MR) is multifactorial in etiology. The causes include socioeconomical to genetic, metabolic, endocrine and infectious disorders, and induced by toxins and trauma. Mild forms, which are the most common one, occur four times greater in women with poor education and socioeconomic population. A list of common causes of intellectual disabilities is given in Table 6.16.1.

Clinical eatures F

-

Surgical procedures such as tendo achilles lengthening, adductor tenotomy, psoas transfer and soft tissue release to prevent dislocation of hip. Posterior rhizotomies are useful in selected cases with spastic diplegia.

Mild intellectual disability (MR): IQ level 50–70 Moderate intellectual disability (MR): IQ level 35 50 55 Several intellectual disability (MR): IQ level 25 35 40 Profound intellectual disability (MR): IQ level below 20–25. -

• • • • E

Physiotherapy

Classification

-

Some of the common drugs used are muscle relaxants such as lioresal, baclofen, dantrolene sodium and benzo­ diazepines. One of the most popular drugs that is used to relieve spasticity is botox (botulinum toxin), which when injected to specific muscle groups is effective in reducing spasticity. However, it is important to have specific evaluations for such therapies because of the cost involved. Levodopa and carbamazepine are recommended in children with dystonia and rigidity.

-

Drugs

There are no specific pathological correlates for intellectual disability. The more severe the intellectual disability, greater are the chances of finding abnormalities in the brain. These include reduction in brain volume (microcephaly), disorders of cell migration, heterotopias, polymicrogyria, pachygyria and dendritic changes.

Prognosis Cerebral palsy is a lifelong disorder and hence parents and adolescents require constant counseling. Independent ambulation is the dream of every parent. Children with hemiplegia and diplegia have better prognosis than children with quadriplegia. Anticipatory guidance should be provided regarding ambulation and education for future planning. A gross motor function classification system 408 provides the best guidance to clinician for prognosis.

Any dysmorphic feature such as microcephaly, macrocephaly and facial features as present in Down syndrome and Turner syndrome should raise suspicion of intellectual disability. Developmental delay involving milestones such as head control, sitting, standing, walking and talking are the earliest presentations. Special attention should be paid to speech and language development. Children with mild intellectual disability may later present with scholastic backwardness with global difficulties in learning.

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Parental causes •  Consanguinity •  Maternal age and nutrition •  Infections •  Toxemias •  Metabolic diseases - diabetes mellitus •  Drugs - alcohol (fetal alcohol syndrome) Perinatal and neonatal •  Prematurity •  Low birth weight •  Fetal distress and asphyxia •  Difficult labor •  Multiple births •  Sepsis •  Seizures •  Hyperbilirubinemia Postnatal •  Malnutrition •  Infections - viral and bacterial (TORCH, HIV) •  Trauma resulting in head injury •  Child abuse and neglect Genetic, chromosomal and dysmorphic syndromes •  Down syndrome •  Klinefelter syndrome •  Turner syndrome •  Fragile X syndrome •  X-linked mental retardation •  Williams syndrome •  Cornelia De-Lange syndrome •  Neurocutaneous syndromes (tuberous sclerosis) •  Neurofibromatosis Inborn errors of metabolism •  Phenylketonuria •  Galactosemia •  Mucopolysaccharidosis Endocrine •  Hypothyroidism and iodine deficiency

nvestigations

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M

anagement

S

Since intellectual disability is a lifelong condition, manage­ ment requires a multidisciplinary team that consists of a pediatrician, psychologist, education specialists, speech pathologist, social worker and occupational therapist. Consultants should include pediatric neurologist, psychi­ atrist and ophthalmologist. The key to the success of management depends on the inclusion of parents as equal partners in management. Early diagnosis in infancy is important. Medical professionals should pay attention to parents’ concerns regarding child’s development. A definitive diagnosis of developmental delay, if not the definitive cause can easily be done in the majority of cases by 2 years. Delay in neck control by 6 months, sitting by 12 months, walking by 18 months and talking by 2 years should alert every pediatrician of the possibility of intellectual disability.

Drugs There is no scientific evidence for the use of medications to improve brain functions. Perhaps the only drug that successfully cures MR is thyroxine for hypothyroidism if initiated in the newborn period. Antiepileptic drugs such as phenobarbitone, phenytoin, carbamazepine, valproates are used to treat various seizure disorders which are present in children with intellectual disability.

The list is endless. To make a broad statement, any adverse effect on the developing brain from conception to 18 years can cause intellectual disability.

• Primary prevention: These include counseling regarding proper maternal and infant nutrition, healthcare, prenatal immunization with rubella vaccine, folic acid supplements, genetic counseling and if indicated prenatal screening for malformations. The specific measures for children include proper nutrition, health education in school and universal immunization. • econdary prevention: Early diagnosis and rehabili­ tation frequent developmental screening. • ertiary prevention: Research and liaisons with governmental agencies for proper funding and support to the families. T

S

Prevention

According to the Diagnostic and Statistical Manual of Mental Disorders (DSM IV), three criteria must be met for a diagnosis of MR: (1) an IQ below 70; (2) significant limitations in two or more areas of adaptive behavior (as measured by an adaptive behavior rating scale, i.e. communication, self help skills, interpersonal skills and more) and (3) evidence that the limitations became apparent before the age of 18. An accurate medical history is the most important part of the diagnosis. The history should include prenatal, perinatal, postnatal, developmental, dental and visual, general health, school performance and behavior. Detailed history about family should include parental education, family income, socioeconomic status, history of the intellectual disability, epilepsy, genetic disorders and mental health. -

-

Diagnosis



N

Ideally newborn screening for thyroid function and metabolic disorders should be done depending on the clinical diagnosis and age of the child. Further investigations such as cranial CT scans, MRI of brain, EEG, hearing, speech and language studies, ophthalmic, psychological and psycho educational evaluations should be performed.



 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A.             B.                 C.          D.                    E.       F.   

Diseases of Central ervous ystem

A detailed physical examination should note general physical appearance, dysmorphic features, neurocutaneous markers, eye contact, detailed developmental and neuro­ logical examination should be done.

Table 6.16.1 Common causes of intellectual disability

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Since 75–80% of children with intellectual disability have mild degree of MR, attaining independent living and fair educational skills are good.

developmental disorders with considerable genetic etio­ logical factors.

tiology

Monozygotic twins have 90% concordance rates and dizygotic twins 30%. Many genetic syndromes including fragile X syndrome, Turner syndrome, Prader Willi, Angelman syndrome, tuberous sclerosis, neurofibromatosis and few more seem to have features of autism in some of the cases. Prenatal, perinatal and postnatal factors do not play a role in the etiology of autism.

Mild Mental Retardation

-

Given excellent rehabilitation, these children with MR who have minimal impairment in sensory motor area can hardly be differentiated from normal population. They develop good social and communication skills. Academic skills up to fifth to sixth standard can be achieved by teenage years. As adults they can be self supportive and can lead independent lives. They however need to be supervised and assisted during social and economic stress.

Prevalence

-

Moderate Mental Retardation

Prevalence rates have changed dramatically from 4–6/10,000 of early 60s to 40–60/10,000 according to recent reports. This increase seems to be due to many factors. • Autism is one of the spectrums • Better awareness among the parents and professionals • Availability of better clinical services • Perhaps a real increase, the exact cause of which is not known.

They constitute 10% of children. Most of them can acquire communicative skills, which can be provided by vocational training. They however have limited academic skills. They face considerable difficulties in adolescent period because of lack of social skills and peer relationships. As adults they will require sheltered workshops and need supervision.

F

n U

Pervasive Developmental Disorders

Pervasive developmental disorders, which include autistic disorders, Asperger syndrome, Rett syndrome and child­ hood disintegrative disorder (Heller syndrome) are of particular importance to the pediatrician as there seem to be an increasing prevalence in recent times. These disorders are characterized by marked impairment in many areas of child development. The common features include impairment in reciprocal social interactions, communication and the presence of stereotyped behavior, interest and activities. A

utism

-

-

Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. The diagnostic criteria require that symptoms become apparent before a child is 3 year old. It is perhaps the commonest of the pervasive

Pathophysiology and euroanatomical indings N

They constitute only 1–2%. These children have identifiable neurological and genetic diagnosis. With intense training they can develop some communication skills. However, they will require home care with individual supervision and treatment of associated conditions.

Occurrence of seizures points to the involvement of cerebral cortex. Anatomic changes are also noted in anterior cingulated gyrus—an area of brain associated with feelings, thoughts and decision making. Deficits in reticular activating system as well as abnormalities in prefrontal and temporal lobe are also common. However, these are not necessarily consistent findings. I

-

ti e

Profound Mental Retardation

Childhood autism has its manifestations usually at around 18–24 months of age and is well established by 3 years of age. The signs usually develop gradually, but some autistic children first develop more normally and then regress. Essential features are impairment of social interaction, communication and imagination and restricted interests and repetitive behavior. Deviant social skills include poor eye contact, gaze avoidance and failure to respond when name is called. Failure to gesture, point, lack of reciprocal smile, solitary play, hand flapping, making unusual sounds, and delay in acquisition of speech and language are the major features for the diagnosis of childhood autism.

nvestigations

Diagnosis is based on behavior and not by tests, cause or mechanism. There are specific psychological tools used to assess the child. Additional tests such as speech and language evaluation, psychological, educational, psychiatric assessments, EEG and MRI of brain may be necessary because of the comorbidities such as epilepsy, intellectual disability (MR), communication deficits and behavioral oddities.

They constitute 3–5% of children. Some of the children can profit to a limited extent by academic input. They should concentrate on acquiring self care skills. Adult years have to be spent at home or community homes.

G R

Clinical eatures

V d

Severe Mental Retardation

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1. American Psychiatric Association. DSM 5 development. 2010. 2. Denckla MB, James LS. An update on Autism: a developmental disorder. Pediatrics. 1991;87(Suppl 5). 3. Francis K. Autism Interventions: a critical update. Dev Med Child Neurol. 2005;47:493 9. 4. Nelson KB. The epidemiology of cerebral palsy in term infants. Ment Retard Dev Disabil Res Rev. 2002;8:146 50. 5. Palisano R, Rosenbaum P, Walter S, et al. Development and Reliability of a system to classify gross motor function in children with cerebral palsy. Dev Med Child Neurol. 1997;39:214 23. 6. Rutter M, Scopler E. Autism and pervasive developmental disorders. Concepts and diagnostic issues. J Autism Dev Disord. 1987;17:159 86. 7. Stromme P, Hagberg G. Etiology in severe and mild mental retardation: a population based study of Norwegian children. Dev Med Child Neurol. 2000;42:76 86. 8. The Definition and Classification of Cerebral Palsy. Dev Med Child Neurol. 2007;49:1 44. -

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Autism is not a progressive neurological disease and hence improvement will occur in all areas over the period of intervention. Children who start out with good speech and language skills to begin with and good cognition will do better. Many will grow up to have gainful employment and independent listing. Twenty five percent of cases of autism are of the regressive type.

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ett yndrome

Rett syndrome is a disorder of early development of brain. Rett syndrome is caused by mutations in the gene MECP2. Infants have normal head size till 6 months of age and then decrease is noted in brain growth. Major clinical features are the hand writing movements and loss of purposeful use of hands. Autistic behavior is noted at 2–3 years of age. Children with Rett syndrome develop seizures. Death occurs in adolescence usually in the third decade from cardiac arrhythmias.



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Asperger syndrome differs from autistic disorder in that there are no delays in language. Single words are spoken at 2 years and phrases at 3 years and no delays are noted in cognitive development. These children have appropriate self help skills and adaptive behaviors. However, there is impairment in social interaction, restricted, repetitive behavior, interest and activities. Asperger syndrome may manifest later than autistic disorder. Social interaction becomes more noticeable in school age. Major milestones may be delayed and children with Asperger syndrome exhibit clumsiness. Asperger syndrome is a lifelong disorder and is more common among males.

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Management requires a multidisciplinary team consisting of developmental pediatrician, psychologist, educational specialist, speech pathologist, occupational therapist, psychiatrist social worker and most importantly a behavioral therapist. Present interventions include the following: • Psychoeducational and behavioral – Teach–treatment and education of autistic and related communication handicapped children – Applied behavioral analysis – Alternative communication – Social skills teaching – Parental involvement • Psychopharmacological – Conventional antipsychotics – Selective serotonin reuptake inhibitors – Beta blockers – Mood stabilizers • Less traditional or complimentary (which are of doubtful value) – Megavitamin therapy – Gluten and casein free diet – Sensory and auditory integration. Autism is perhaps the most difficult developmental disability and requires all the skills to communicate and counsel the parents. It is a lifelong disability causing severe anxiety, physical and mental exhaustion. Parents need all the help and support that professionals can give for many years. Majority of the children require special education because of intellectual disability. Seizure disorders should be appropriately treated with antiepileptic drugs. Psychiatrist should actively be involved in evaluation and follow up when medications are prescribed.

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Karyotyping is advised to rule out genetic syndromes such as fragile X syndrome.

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Sunil Karande Learning disabilities (LD) and attention deficit hyperactivity disorder (ADHD) are two common neurodevelopmental disorders that occur in up to 5–10% of children.

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Learning disability is a group of neurodevelopmental disorders, which manifest in childhood as persistent difficulties in learning to efficiently read (dyslexia), write (dysgraphia) or do mathematical calculations (dyscalculia) despite normal intelligence, conventional schooling, intact hearing and vision, adequate motivation and sociocultural opportunities.

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A history of language delay, or of not attending to the sounds of words (trouble playing rhyming games with words, or confusing words that sound alike), along with a family history, are important red flags for dyslexia. Children with LD present with persistent “academic problems” such as reading slowly and incorrectly, skipping lines while reading aloud, making repeated spelling mistakes, untidy/ illegible handwriting with poor sequencing and inability to perform even simple additions and subtractions. These children invariably fail to achieve school grades that are commensurate with their intelligence.

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A conclusive diagnosis of LD cannot be made until the child is about 7–8-years old. Unlike children having LD, some children are “normal late developers” who by the age of 7–8 years on their own outgrow their learning problems. An evaluation for LD should be considered for all children presenting with learning problems in preschool/school. A 412 multidisciplinary team comprising of pediatric neurologist, counselor, clinical psychologist and special educator is needed to assess each child referred for poor school performance. The sequence of evaluations done is as follows:

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Learning disability is believed to be a result of functional disruption in neural systems and is genetically inherited. Dyslexia or “specific reading disability” is the most common and most carefully studied, affecting 80% of all those identified as learning-disabled. Children with dyslexia have deficits in “phonologic awareness”; viz. they have difficulty developing an awareness that words, both written and spoken, can be broken down into smaller units of sound and that in fact, the letters constituting the printed word represent the sounds heard in the spoken word.

Audiometric and ophthalmic examinations are done to rule out hearing and visual deficits, as they are common causes of poor school performance. Also, children with non-correctable hearing and visual deficits (of ≥ 40% disability) do not qualify for a diagnosis of LD, but are diagnosed as having “hearing impairment” and “visual impairment” respectively The pediatric neurologist then takes a detailed clinical history and does a detailed clinical examination to exclude medical causes, e.g. hypothyroidism, chronic lead poisoning; and neurological causes, e.g. cerebral palsy, Wilson disease; and to identify behavioral causes, e.g. ADHD, depression, conduct disorder (CD) or oppositional defiant disorder (ODD), of poor school performance The counselor takes a detailed interview of the parents/ family members to rule out that emotional problem due to stress at home/school is not primarily responsible for the child’s poor school performance The clinical psychologist conducts the standard Wechsler Intelligence Scale for Children test to determine that the child’s global intelligence quotient score is average or above average (≥ 85). This helps to exclude children having “borderline intellectual functioning” IQ score (71–84) also known as “slow learners” who also present with poor school performance The special educator assesses the child’s academic achievement by administering a standard educational test (e.g. Curriculum Based Test, Woodcock-Johnson Tests of Achievement) to assess the child’s performance in areas such as reading, spelling, written language and mathematics. An academic achievement of up to 2 years below the child’s actual school grade placement or chronological age is considered diagnostic of LD The child psychiatrist plays an important role in confirming the diagnosis of ADHD, a comorbid condition found in 12–24% of children with LD.

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Treatment The cornerstone of treatment of LD is remedial (special) education and it should begin early when the child is in primary school. Using specific teaching strategies and teaching materials, the special educator formulates an Individual Educational Program to reduce or eliminate the child’s deficiencies in specific learning areas of reading, writing and mathematics identified during the child’s educational assessment. The child has to undergo remedial education sessions twice or thrice weekly for a few years to achieve academic competence. However, even after adequate remedial education, subtle deficiencies in reading, writing and mathematical abilities persist.

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Table 6.17.1 Diagnostic and statistical manual of mental disorders-IV-revised criteria for diagnosing attention deficit hyperactivity disorder Behavior domains Inattention (9 criteria) Hyperactivity-impulsivity (9 criteria) Hyperactivity (6 criteria) 1. Careless with details 1. Fidgets with hands or feet or squirms in seat 2. Fails to sustain attention in tasks 2. Leaves seat when should be seated 3. Appears not to listen 3. Runs about or climbs excessively and inappropriately 4. Does not finish instructed tasks 4. Cannot play or engage in leisure activities quietly 5. Poor in organizing tasks 5. Always “on the go” or “driven by a motor” 6. Avoids tasks that require sustained mental effort 6. Talks excessively 7. Loses things Impulsivity (3 criteria) 8. Easily distracted by extraneous stimuli 1. Blurts out answer before question is completed 9. Forgetful in daily activities 2. Has difficulty awaiting turn 3. Interrupts or intrudes others’ conversations or games Note: Criteria for subtypes is 6/9 on either list, or for combined subtype, 6/9 on both lists - together with certain pre-requisites (see text)

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Its diagnosis is made by ascertaining whether the child’s specific behaviors meet the diagnostic and statistical manual of mental disorders-IV-revised criteria (Table 6.17.1). These criteria define three subtypes of ADHD: 1. ADHD primarily of the inattentive type (ADHD/I) 2. ADHD primarily of the hyperactive-impulsive type (ADHD/HI) 3. ADHD, combined type (ADHD/C). A child meets the diagnostic criteria for ADHD by documentation of: • Presence of at least six of the nine behaviors described in the inattentive domain (ADHD/I), or the hyperactive/ impulsive domain (ADHD/HI), or in both domains (ADHD/C), and these behaviors should be occurring “often” and to a degree that is maladaptive and inconsistent with the child’s developmental level • Presence of these behaviors in two or more settings (for example, at home and at school) for at least past 6 months

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Attention deficit hyperactivity disorder is a neuro developmental disorder characterized by persistent hyperactivity, impulsivity and inattention that significantly impairs educational achievement and/or social functioning.

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A history of being asked to leave preschool for disruptive behavior, or of being avoided by peers for play activities, along with a family history, are important red flags for ADHD.

It is well known that favorable outcome of LD is dependent on early diagnosis, regular remedial education for a few years, availing the necessary provisions, and a supportive home and school environment.

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The ”academic problems” of children with LD also have an adverse impact on their self-image, peer and family relationships and social interactions.

Every pediatrician can facilitate early detection of LD by enquiring about every child’s school performance during a consultation and guiding the parents for getting their child’s psychoeducational assessment done, when LD is suspected.

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Recent functional MRI brain studies indicate that the disorder may be caused by atypical functioning in the frontal lobes, basal ganglia, corpus callosum and cerebellar vermis. Pharmacological studies have also implicated dysregulation of frontal-subcortical-cerebellar catecholaminergic circuits (dopamine and norepinephrine neurotransmitter systems) in the pathophysiology of the disorder. Family studies have provided strong evidence that genetics plays a major role in conferring susceptibility to ADHD. Studies have indicated that low-birth weight and psychosocial adversity (for example, severe parental discord, low-social class, and foster placement) are predisposing risk factors for ADHD. F

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The management of LD in the more time-demanding setting of secondary school is based more on providing provisions (accommodations). These provisions, e.g. exemption from spelling mistakes, availing extra time for all written tests, dropping a language and substituting it with work experience, dropping algebra and geometry and substituting them with lower grade of mathematics and work experience, are meant to help the child cope up in a regular mainstream school.

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Between 18% and 35% of children with ADHD have one or more associated psychiatric disorders such as anxiety disorder, depression, ODD and CD. Also, up to 15–20% of children with ADHD have associated LD. It is known that children with combined LD and ADHD have more severe learning problems than children who have LD but no ADHD, and also more severe attention problems than children who have ADHD but no LD.

Treatment Optimal treatment of ADHD requires integrated behavioral and medical (combined) treatment.

Behavioral Therapy Parents are taught how to • Reinforce positive behaviors by praise or by using daily contingency charts (star or “happy face” charts) • Extinguish negative behaviors by active ignoring • Effectively punish for intolerable behaviors. Simple psychoeducational interventions at school such as seating the child near the teacher to minimize classroom distractions, or assigning a specific teacher to review daily assignments with the child are effective in improving the behavior and academic performance of affected children.

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Pediatricians should initiate an evaluation for ADHD when a child presents with symptoms that include academic underachievement and failure, disruptive classroom behavior, inattentiveness, poor self-esteem, or problems with establishing or maintaining social relationships. Those familiar with its management can even initiate the medication management, but will need to liaise with a child psychiatrist/developmental pediatrician when intolerable side effects or treatment failure occur or if comorbid conditions are suspected.

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It is well known that favorable outcome of ADHD is dependent on early diagnosis and treatment and a supportive home and school environment. If ADHD remains undetected the child may experience academic failure, rejection by peers, and develop low-self-esteem. Recent studies suggest that 30–60% of affected children continue to show significant symptoms of ADHD into adolescence and young adulthood. Adolescence may bring about a reduction in the over-activity but inattention, impulsiveness and inner restlessness remain. It is now well recognized that the presence of a child with ADHD results in increased likelihood of disturbances to family and marital functioning, disrupted parentchild relationships and increased levels of parent stress, particularly when ADHD is comorbid with ODD or CD.

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Medications Medications are not recommended for use in children who are below 6 years of age. Methylphenidate (MPH) and atomoxetine are the two drugs, which are being currently prescribed. Most children with ADHD improve on the stimulant MPH and maintain their improvement without intolerable adverse events. Short-acting MPH is now available in our country. Its behavioral effects begin within 30 minutes of oral administration and last for 3–5 hours. The daily dose should be individualized by titration and careful monitoring and it ranges from 5 mg to 20 mg twice daily to three times daily. Side effects include anorexia, stomach ache, headache, irritable mood, tics and sleep difficulties. These side effects are usually mild and responsive to dose adjustment and often abate with continuous use. Continuous use has been associated in some children with slowing of physical growth (approximately 1 cm/year during the first 1–3 years of treatment), which is transient and of unclear cause. In Western countries, long-acting MPH is available and it permits once-daily administration (18–54 mg) and its behavioral effects last for 10–12 hours. It is used to ensure compliance in children who feel embarrassed to take medication in school. Atomoxetine a non-stimulant highly selective nora drenaline reuptake inhibitor is a relatively new drug with efficacy comparable to MPH. The starting once-daily dose is 0.5 mg/kg/day and increased after 4 days to 1.2–1.4 mg/kg/day. Its most commonly reported adverse effects are transient and include dyspepsia, nausea, vomiting, decreased appetite and weight loss. In general, medication is best titrated against 414 desirable effects such as behavioral control, improved educational achievement and peer group relations, and development of intolerable adverse effects. Medication

omplications

ibliography 1. Biederman J, Faraone SV. Attention-deficit hyperactivity disorder. Lancet. 2005;366:237-48. 2. Demonet JF, Taylor MJ, Chaix Y. Developmental dyslexia. Lancet. 2004;363:1451-60.

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can be discontinued on Sundays and school holidays. Also, periodic (yearly) discontinuation for a brief period during summer vacations is often used to reaffirm the need for continuing medication.



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Presence of some symptoms of ADHD before 7 years of age Clear evidence of clinically significant impairment in academic or social functioning, or in both. These symptoms not occurring exclusively during the course of a pervasive developmental disorder, schizophrenia or another mental disorder.



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There is no definitive clinical picture as GDD is a symptom complex associated with a variety of conditions. Child invariably presents with significant delay in two or more major developmental domains. Expected features include microcephaly or occipitofrontal circumference 2 SD below the mean, dysmorphic features and identifiable neurological deficits. Global developmental delay from prenatal causes may be associated with growth retardation, multisystem involvement (congenital heart disease, hepatosplenomegaly, seizures, etc.). Associated sensory problems in hearing, vision and/disequilibrium reactions may be seen with a specific etiological yield. Adaptive problems and behavioral alterations are common in both prenatal and postnatal insults. A family history of miscarriages or difficulties in learning in family members and a history of intrapartum complications may be elicited in some children. A history of birth asphyxia, seizures and abnormal neurological findings in the newborn period and infancy are often predictors of GDD, especially in the presence of dysmorphism. Clinically identifiable features emerge as the child grows and follow-up evaluation of babies-at-work often points to an underlying condition. Clinical evaluation of the growing child with GDD must include a follow-up for global mental functions, particularly looking at the evolving capacities. These include: the degree/quality of awareness and alertness, orientation, intellectual functions including cognitive development, 415



There is a paucity of studies related to GDD in the population. The relatively new concepts and the prevailing controversies regarding terminology, coupled with the difficulties in ascertaining diagnosis in young children whose capacities are evolving, pose challenges to epidemiological studies. The exact incidence and prevalence in India is not known. The double burden of infectious diseases along with poverty correlates such as malnutrition and risks associated with urbanization, exposure of mothers and infants to toxic substances may contribute to the growing numbers of children with GDD in developing countries.



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Global developmental delay is defined as “a significant delay in two or more of the following developmental domains: gross/fine motor, speech or language, cognition, social/ personal-adaptive and activities of daily living (ADLs)”. In practice, however, the term GDD is usually reserved for children younger than 5 years of age, showing the symptom complex with an as yet undefined nosologic profile that includes poor cognitive and psychomotor functions, whereas the term “mental retardation” or “intellectual disability” is applied to older children when IQ testing is more reliable and valid.

Evidence from several studies during this decade points to the heterogeneous nature of the underlying diseases. Studies from China and India suggest that the predominant categories of cerebral dysgenesis, chromosomal disorders, multiple malformation syndromes, hypoxic ischemic encephalopathy and antenatal toxin exposures account for global functional delays in nearly two-thirds of children. At present time, our knowledge of the prime movers for observed etiology (e.g. gene responsible for a particular cerebral dysgenesis) may not be sufficient and one may be describing in pathogenic terms (e.g. periventricular leukomalacia and cerebral dysgenesis). However, an approach of conceptualizing etiology as a diagnostic aid that can translate into useful clinical information for prognosis and management is gaining momentum, consistent with practice parameters and guidelines proposed by the Child Neurology Society and the American Academy of Neurology.

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Developmental disabilities are a group of interrelated neurologic disorders occurring in childhood, characterized by delay, deviation or dissociation in streams of early child development. Developmental delay is simply a complaint referring to a condition whereby infants or young children do not achieve developmental milestones at the expected age. The impact of impairments responsible for the delay in the major streams of development including motor, perceptual, speech, cognition and behavior is seen as functional limitation and decreased ability of the child to participate in expected activities as one grows older. Deviation is said to be present when a child with developmental lag also shows abnormal or distorted features such as persistence of neonatal reflexes and inability to progress from one stage of development to another. Dissociation refers to developmental lag in some domains being more than in others. The quality or quantity of changes in performance/development appears locked in one stage in a certain domain and progressing in another over a period of observation. Global developmental delay (GDD) constitutes a subset of developmental disabilities.

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The basic screening may include thyroid profile testing, TORCH screen and MRI/CT scan of brain. One should consider referring children to care settings with good diagnostic facilities whenever etiological diagnosis is important to prognosticate and provide appropriate intervention. Neuroimaging and karyotyping may be done for all with dysmorphism and congenital anomalies. Metabolic testing (e.g. serum amino acids) and biochemical analysis are additionally undertaken in tertiary settings for specific management. A suggested approach as a diagnostic strategy linked to intervention for children with GDD is described in Flow chart 6.18.1. The contemporary approach to diagnostic assessment of children with developmental disorders is based on the guiding principle that diagnostic assessment is a “dead end” unless it generates a focus/plan for intervention.

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Establishing an accurate etiologic diagnosis is not always possible, nevertheless the diagnosis process is absolutely necessary for accurate genetic counseling and rehabilitative planning. Early diagnosis of GDD is possible by regular newborn follow-up and periodic evaluation for developmental lag in the first 2 years of life. A developmental assessment based on in-depth history and clinical examination is paramount. Quite often, a detailed developmental history including prenatal, perinatal, neonatal history and developmental patterns in infancy may suggest diagnosis. Evidence of regression and poor capacity for self-help/ADLS expected for the age calls for a detailed diagnostic evaluation. Tests for adaptive functioning and psychomotor development using standard developmental scales appropriate for the age must be undertaken. The Bayley Scales of Infant Development, Wechsler Scales (WPPSI-III), Vineland Adaptive Behavior Scale are some tests administered for the purpose in children less than 5 years of age. A diagnostic formulation in terms of maturation and development can also form the basis for the early intervention (EI) and identification of special education needs (SEN). The process also confirms diagnosis by ruling out conditions such as autism, ADHD, etc.

approach for a child with developmental disability during the preschool years to help overcome the developmental lag. In the resource-poor settings, EI or help in the early years starts as a high-risk follow-up clinic linked to primary care and extends to become a cost-effective family-centered model. Drawing from the fundamental neurodevelopment perspectives, the caregiver who is often a developmental therapist or a pediatrician, works to create a developmental setting in which the key to a child’s progress is mother-child participation. The basis for EI is that there are critical periods of development and interventions, to be most effective, should happen before those periods. The second reason is that the CNS has the feature of neuroplasticity or intrinsic ability of neural structure to form functional neuronal networks for new learning. Helping the child with GDD during the early years is critical for later development. Developmental gains may not always be measurable in quotients but some benefits are obvious. Early intervention prevents developmental decline and deviant patterns of development that are seen in GDD. Professional intervention is particularly effective in addressing the motor and sensory impairments and seizures that are often seen as comorbidities. Even in a child with severe impairment providing sensory inputs and appropriate experiences early in life contributes to information gains (early infant stimulation). Guidance to parents is a crucial component of EI. An early acceptance of the problem and an early involvement to help the child overcome the biological disadvantage helps parents understand their child better and cope with the difficult situations. In children with special learning needs from GDD, EI brings down inappropriate behaviors and improves social competence. The components for EI depend on the primary impair ment and can vary with the child’s needs. Developmental therapy focuses on mobility, manipulation and communi cation. In the presence of GDD without significant motor impairment, activities promoting sensory integration, balance and communication become important. Challenging behaviors (aggression, oppositional defiant behaviors) may require behavior management techniques as well as environment engineering. Medication is of little use, except for short term psychopharmacological management in select cases. Family counseling and respite care should be integral part of EI and management plan. Support care instituted early with interdisciplinary management should be multimodal to address the diverse needs of the child: health, education, recreation, social activities and direct efforts to ameliorate the effects of associated impairments and behaviors in order to improve functional outcomes and participation. A program for “early infant stimulation” is facilitated by early identification of problems at birth, or at discharge from nursery. Early and intensive support through home visits by health workers, and multicomponent stimulation programs

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global psychosocial functions or interpersonal skills to establish reciprocal social interactions, temperament, attention, energy and drive functions. Abnormalities in these areas constitute soft neurological findings for GDD and the developmental variability must alert the pediatrician to look for developmental deviations or dissociation.

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Flow chart 6.18.1 Diagnostic strategy linked to intervention for children with global developmental delay

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1. First LR, Palfery JS. The infant or young child with developmental delay. NEJM. 1994;330:478-83. 2. Majnemer A, Shevell MI. Diagnostic yield of the neurologic assessment of the developmentally delayed child. J Pediatr. 1995;127:193-9. 3. Pediatrician’s role in the development and implementation of an Individualized Education Plan (IEP) and/or and Individual Family Service Plan (IFSP). Pediatrics. 1999;104:124-7. 4. Shevell MI, Ashwal S, Donley D, et al. Practice parameter, evaluation of the child with global developmental delay: report of the quality standards subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. 2003;60:367-80. 5. Shevell MI, Majnemer A, Rosenbaum P, et al. Etiologic yield of subspecialists’ evaluation of young children with global developmental delay. J Pediatr. 2000;136:593-8. 6. Srour M, Mazer B, Shevell MI. Analysis of clinical features predicting etiologic yield in the assessment of global developmental delay. Pediatrics 2006:118:139. 7. Tang M, Lin C, Lin W, et al. The effect of adding a home program to weekly institutional based therapy for children with undefined developmental delay: a pilot randomized clinical trial. J Chin Med Assoc. 2011;74:259-66. 8. Tikaria A, Kabra M, Gupta N, et al. Aetiology of global developmental delay in young children: experience from a tertiary care centre in India. Nat Med J India. 2010;23::324-8.





In the field of developmental impairments, prevention includes prospective interventions to avert progression to disabilities. Prevention at the primary level is possible by efforts to 418 reduce the contributory illness and determinants of GDD and/or mental retardation. Good prenatal services and



Prevention

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obstetric care, good nutrition and administering measlesmumps-rubella vaccine to all girls, fortification of food with iodine, iron, folic acid, and general awareness campaigns for promoting health seeking behaviors, as well as screening for early identification, can go a long way in decreasing the magnitude of GDD. Approaches and interventions for prevention at various levels are summarized in Table 6.18.1. Primary prevention strategies remain the best for developing countries.



that are culture-sensitive and context-specific can promote developmental outcomes. The key care provider and the team of professionals (developmental therapist, speech therapist, pediatrician, clinical psychologist and other members) in a transdisciplinary/interdisciplinary mode of EI look to addressing risks and enhancing promotion of health and abilities as well as to prevent secondary problems through direct support to the child and the family.



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Table 6.18.1 Prevention of global developmental delay Level Approach Interventions Primary prevention (Preventing Health promotion •  Health education, especially for adolescent girls the occurrence of MR/GD) •  Improvement of nutritional status in the community, optimum health care facilities •  Improvements in pre, peri and postnatal care Specific protection •  Universal iodization of salt •  Rubella immunization for girls and women before pregnancy •  Folic acid administration in adolescence and early pregnancy •  Genetic counseling •  Prenatal screening for congenital malformation and genetic disorders •  Detection and care of high-risk pregnancies •  Universal immunization for children Secondary prevention (Health Early diagnosis and treatment •  Neonatal screening for treatable disorders Disease Progression) •  Intervention for babies ‘at risk’ for neurodevelopmental impairments •  Early detection of developmental delay and early intervention Tertiary prevention Disability limitation and •  Stimulation, training and education, and vocational opportunities (preventing complications and rehabilitation •  Mainstreaming/integration maximization of function) •  Support for families •  Parental self-help groups Source: Girimaji S et al. Mental Retardation: From Knowledge to Action (2001), WHO Document

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Section

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Diseases of Cardiovascular System

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Clinical Approach to Pediatric Cardiology: S Srinivasan Congenital Heart Disease: R Krishna Kumar Rheumatic Fever: Savitri Shrivastava Congestive Heart Failure: Diagnosis and Management: Anita Saxena Diseases of Endocardium, Myocardium and Pericardium: Srikanta Basu Cardiac Arrhythmias in Children: S Srinivasan

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Clinical Approach to Pediatric Cardiology S Srinivasan

The objectives of clinical examination of the cardiovascular system in newborns, young infants and older children are: 1. To ascertain without delay the presence of any life threatening critical congenital heart disese (CHD) that jeopardize the child’s survival 2. To institute appropriate resuscitative measures before referral 3. To identify the underlying cardiac conditions in terms of structural involvement 4. Its etiology-congenital/acquired, genetic (chromosomal/ dysmorphogenetic) 5. To assess its severity in terms of functional restriction 6. To document the presence or absence of other related complications and its impact on child’s nutritional, growth and developmental status.



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Cardiac Symptoms Symptoms of CHD can be very varied and subtle at times and may manifest anytime from fetal period to adulthood (Table 7.1.2). Many of these symptoms may not be the 420 presenting problem and therefore it has to be elicited by asking pertinent questions.

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History Taking The mother must be allowed to give her own account of the presenting symptoms, which compelled her to bring her child to medical attention and narrate the evolution of these symptoms from the time of their onset. Only open-ended questions must be used to get the most relevant and useful information. The historical points of interest, of course, will vary considerably, depending upon the age of the patient, and the presenting signs, symptoms and complaints. If the child is brought in a severe state of breathlessness or cyanosis or shock, precious time must not be wasted in taking elaborate history. Neonates with marked shortness of breath, cyanosis and pallor with lethargy need immediate attention, and clinical and investigative assessment to rule out life-threatening, acute cardiac emergency states, e.g. ductus dependent congenital cardiac lesions that restrict pulmonary or systemic blood flow. Other relevant and important details in history taking that have bearing on the diagnosis of the cardiac condition, its severity, and in planning treatment and counseling have been summarized in Table 7.1.1. Moreover, while taking the history, one should take note of the evolution of symptoms according to chronology, mode of presentation, duration, progression, severity, relieving factors, aggravating factors, associated symptoms and functional impairment.

Examination of an infant and young child needs a lot of tact, and the general principles of examining a child should be applied. Although it is an usual routine to follows a definitive order in clinical examination, in a young child, such an orderly examination may not be always possible because of their apprehensive and anxious nature. In a sleeping child, it is better to perform auscultation of the precordium for the nature of cardiac sounds and presence of murmurs and other sounds. Infants and young children must be comfortably seated in the mother’s lap with their dresses removed earlier before sitting in front of the examiner. The standard format of general physical examination has been summarized in Table 7.1.3. It is important to remember that vital signs should be examined first before undertaking detailed cardiac examination. The pertinent points to note are airway, breathing (rate, type and sign of distress), circulation (capillary filling time, details of pulse, blood pressure) and temperature.

Cardiac Examination Precordium

The objectives of inspection of the chest is to identify chest wall asymmetry if present, in the form of precordial prominence, pectus excavatum, carinatum, kyphosis, scoliosis, Harrison’s sulcus, etc., abnormal pulsations in the neck, suprasternal notch, parasternal region, epigastric region and over the back, the location of apical impulse—left side or right side, and scars of previous operative procedures.

Jugular Venous Pulse and Pressure The jugular venous pulse (JVP) waveform consists of three positive upstrokes—a, c and v and two negative waves—x descent after a and c waves and y descent after v wave. The abnormalities of various wave forms have been summarized in Table 7.1.4.

Arterial Pulse Pulse is the peripherally transmitted waveform of propa gated arterial blood from the aortic root along the arterial tree generated by systolic contraction of left ventricle. The travel speed of the arterial pulse wave is 10 times faster than that of the blood column. The importance of palpating the arterial pulse at various sites, e.g. both radials, femorals, brachials, popliteal, posterior tibials, dorsalis pedis, carotids and superficial temporal arteries should be kept in mind at the beginning of each clinical posting and perhaps throughout life so as to ensure that one does not miss coarctation of aorta and thromboembolic phenomena need to be repeatedly emphasized to the students at every ­

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History of functional limitations Treatment history

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Table 7.1.1 Important documentation of history relating to causative or precipitating factors History of abnormal facial features Many chromosomal disorders like Down’s syndrome, Turner’s syndrome, other trisomies and other genetic, metabolic or minor or major congenital and isolated malformations may indicate the presence of associated congenital heart diseases. malformations Past history Any physical symptoms, health problems, hospital visits or admissions in the past for recurrent chest infections, bacterial endocarditis, symptoms suggestive of rheumatic fever such as arthritis, abnormal movements, tuberculosis and delayed motor development, rashes, skin peeling in palms, soles, tips of fingers and toes, sore throat preceding onset of joint pains Antenatal history •  History of acute or chronic infections in various trimesters—fever, rashes •  Other maternal illness—metabolic disorders like gestational diabetes, autoimmune disorders like SLE •  Drugs—phenytoin, lithium, other anticonvulsants, etc. •  Substance abuse; alcohol, addictive drugs, etc. •  Exposure to irradiation, pollutants, others Birth history, Delayed crying and breath initiation, bluishness, sucking and feeding difficulty, lethargy, importance of finding out immediate postnatal and neonatal the gestational age, birth weight, need for resuscitation, need for breathing and oxygen support, prolonged stay history** in neonatal unit, need for tube feeding or intravenous fluids, type of medications given during neonatal stay in the hospital and subsequent to discharge Nutritional history Children with cardiac conditions with frequent heart failure or recurrent infections will have loss of appetite and their nutritional intake will be greatly compromised. History of growth and •  Growth impairment and failure to thrive in the first few years of life is commonly noted in moderate-to-severe developmental impairment cardiac structural lesions. Tall stature or short stature, delayed gross motor milestones have a bearing on underlying cardiac disease. •  In a child with tall stature, the possibility of Marfan’s syndrome must be considered. In a female child with short stature, Turner’s syndrome and associated coarctation of aorta must be ruled out. •  Moderate-to-severe congenital heart diseases will delay the gross motor milestones in relation to other areas of development. Chromosomal and dysmorphogenetic syndromes with associated heart diseases may exhibit global developmental delay. •  Record any of the following present in the family members: sudden death, SIDS, rheumatic fever, structural or congenital cardiac abnormalities in siblings, genetic or dysmorphogenic syndromes in the family •  The estimated recurrence risk of CHD is 2–6% when a previous sibling is affected, nearly 30% with two siblings affected and 3% if one of the parents is affected. School attendance and absenteeism, academic performance, inability to participate in games and sports activities Past and present treatment details

Personal/socioeconomic history

In a developing country with majority of the population being below the poverty line, long-term treatment facilities including surgical corrections at appropriate age may not be possible. Hence, children and adults at all ages may have congenital heart diseases with or without advanced complications like PAH. ** Preterms have higher incidence of PDA. These preterms also go into heart failure early in their first week with even moderate-sized defects with left to right shunts. Abbreviations: SLE, Systemic lupus erythematosus; SIDS, Sudden infant death syndrome; CAD, Congenital heart disease; PAH, Pulmonary arterial hypertension; PDA, Patent ductus arteriosus

Precordial Palpation The learning objectives of palpation of the precordium are: (1) to identify the site and type of apical impulse whether normal or abnormal, (2) to identify the presence of abnormal pulsations, heaves and thrills in specified precordial sites—left parasternal and epigastric regions, suprasternal notch, second left intercostal space (LICS) and (3) to ascertain enlargement of right ventricle, left ventricle or both, or dilatation of great arteries— aorta and pulmonary arteries.

Apical Impulse Apical impulse refers to the outermost and lowermost definitive palpable outward thrust of cardiac impulse

in the lower precordium imparted by the anterior movement of left ventricular (LV) apex during early systolic contraction of the left ventricle. Its location, amplitude, duration, size, character or contour must be recorded. In the first 3–4 years of life after birth, the normal location of the apical impulse is in the fourth LICS 1–2 cm lateral to the midclavicular line (MCL). Between 4–8 years, the location is in the fifth LICS on the MCL. Beyond 8 years, it lies in the fifth LICS 1–2 cm or half an inch medial to the MCL. The apex beat is shifted to the left in cardiomegaly, scoliosis, pectus excavatum and contralateral pneumothorax or effusion. It is shifted on the right side in cases of congenital dextrocardia, acquired dextroposition (heart pushed or pulled to the right side) and diaphragmatic hernia. Table 7.1.6 summarizes 421 different types of apical impulse.

posting of theirs. The various types of abnormal pulses have been depicted in the Table 7.1.5.

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Other Palpable Sounds The second heart sound (S2) may be palpable in pulmonary hypertension. The third heart sound (S3) may be rarely palpable in severe mitral regurgitation (MR) or dilated cardiomyopathy (DCM). The fourth heart sound (S4) is more often palpable in adults than in children in the following conditions: hypertrophic cardiomyopathy (HCM), severe aortic stenosis (AS), acute MR and long-standing hypertension. Suprasternal pulsations are seen and palpable in patent ductus arteriosus (PDA), AS, aortic regurgitation (AR), coarctation of aorta and aortic aneurysm. Pulsations in the parasternal area without a perceptible or palpable left parasternal lift is characteristic of right ventricular (RV) volume overload conditions like atrial septal defect (ASD),

tricuspid regurgitation (TR), moderate to large ventricular septal defect (VSD) without pulmonary arterial hypertension (PAH) besides hyperdynamic high output states. Epigastric pulsations are seen and the impulse is felt in RV volume overload states. Apart from these sounds, murmurs are also palpable in various areas.

Parasternal Heave Parasternal heave is both seen and felt by the ulnar border of the examiner’s hand over the left parasternal region Table 7.1.3 Proforma for general examination in a cardiac patient General appearance

Comfortable, consolable, state of distress

Posture/decubitus  

Table 7.1.2 Presentations of cardiac problems

Body build and proportion Nutritional and growth status

Anthropometry

Features of chromosomal/genetic/ Down’s syndrome, Turner’s dysmorphogenic syndromes syndrome, other trisomies, Williams syndrome, Noonan syndrome, etc. External isolated/multiple congenital external malformations

Short neck, webbing, polydactyly, syndactyly, camptomelia

Oral cavity, teeth and pharynx

Sore throat, caries

Skin

Rashes, erythema marginatum, nodules, desquamation

Joints

Rheumatic fever, rheumatoid arthritis

Abnormal movements

Chorea

Dependent edema

Sites–feet, legs, back, eyelids

Lymph nodes

Kawasaki’s disease, tuberculosis

Clubbing of fingers and toes

Cyanotic heart defects, bacterial endocarditis















Fetus (diagnosed by fetal echocardiography) •  Hydrops, arrhythmias, cardiomegaly Neonate and infant •  Heart failure (tachypnea with feeding or activities, labored breathing/ dyspnea, feeding difficulties, sweating on head), failure to thrive •  Cyanosis, circulatory failure, collapse, abnormal heart rate/rhythm, murmur, weak femoral pulses •  Noticeable excessive precordial activity or pulsations observed by mother, sleep disturbances, recurrent lower respiratory infections •  Dysmorphism, noncardiac congenital abnormalities Older child •  Heart failure (exercise intolerance, shortness of breath with activities), palpitation •  Increased precordial pulsations or prominence*, dizzy or fainting spells, syncope •  Chest pain on activity, recurrent lower respiratory infections, failure to thrive, murmur •  Hypertension, as a part of multisystem disease (rheumatic fever, Kawasaki’s disease), seizures (presenting as a complication of cyanotic heart disease), cyanotic spells, squatting

General health

Central cyanosis, differential cyanosis

 

Table 7.1.4 Abnormal JVP and its clinical interpretation “a” wave abnormalities Large “a” waves

Forcible contraction of right atrium against obstruction Tricuspid stenosis, RA myxoma at AV valve area Increased resistance offered by noncompliant right Severe PAH, PS (moderate-to-severe), RV cardiomyopathy, acute ventricle pulmonary embolism

Cannon or very large Contraction of right atrium against a closed tricuspid Tricuspid atresia, AV dissociation, complete heart block giant “a” waves valve

Absent “a” waves

Regular cannon waves

Junctional rhythm, isorhythmic AV dissociation

Irregular cannon waves

Complete heart block, classic AV dissociation, ventricular pacing, ventricular ectopics

Ineffective atrial contraction

Atrial fibrillation, marked sinus tachycardia

“v” wave abnormalities Large “v” waves

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Rapid and excessive RA filling

TR, TAPVD, ASD with MR

Abbreviations: JVP, Jugular venous pulse; AV, Atrioventricular; RA, Right atrial; PAH, Pulmonary arterial hypertension; PS, Pulmonary stenosis; RV, Right ventricular; TR, Tricuspid regurgitation; TAPVD, Total anomalous pulmonary venous drainage; ASD, Atrial septal defect; MR, Mitral regurgitation

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Table 7.1.5 Abnormal pulses Pulsus parvus Low-volume pulse with slow rise; its presence suggests the possibility of severe AS or severe low-output states like severe heart failure Pulsus tardus Slow rising pulse with a late peaking closer to the second sound and is reported in fixed LV obstructive lesions Hypokinetic pulse Weakly felt, small-volume pulse felt with difficulty in cases of low cardiac output states, such as shock, severe heart failure, myocarditis, cardiac tamponade, constrictive pericarditis, severe left heart obstructive lesions like MS and AS and aortic outflow obstructions like aortic arch syndromes and coarctation of aorta Hyperkinetic High amplitude, large-volume pulse with rapidly rising ascending wave felt in augmented high cardiac output states with (bounding) pulse decreased peripheral arterial resistance and wide pulse pressure, e.g. anxiety, exercise, fever, anemia, thyrotoxicosis, arteriovenous fistulas, beriberi, moderate MR, moderate-sized ventricular septal defects, AR, PDA Water hammer/ The pulse is elicited by suddenly and gently elevating the child’s arm above his/her shoulder while the radial pulse is continuously collapsing pulse felt by the palmar surface of the examiner’s hand instead of the usual three finger tips. It is a large-volume pulse with sudden and rapid upstroke with equally rapid downstroke. The term “water hammer” refers to a famous Victorian era English toy. Collapsing pulse indicates rapid and reverse diastolic run off into the left ventricle in AR and rapid run off to the peripheral vessels due to decreased systemic peripheral vascular resistance. AR, PDA, AP window, RSOV into the right ventricle and arteriovenous fistulas. Collapsing pulse in a cyanotic child suggests truncus arteriosus with truncal regurgitation, pulmonary atresia with AP collaterals, TOF with AP collaterals or PDA. Collapsing pulse is also felt in hyperkinetic states like anemia, fever, thyrotoxicosis, pregnancy and beriberi. Bisferiens pulse Pulse with two beats in a single systolic wave upstroke; when the examiner’s palpating finger feels two positive upward peaks during systole, it is termed as pulsus bisferiens, better appreciated over the carotids than radials. They indicate the presence of severe AR or AR with AS or HOCM. Corrigans pulse Prominently visible dancing pulsation over the carotids in AR Brisk/jerky pulse Pulse with a sharp, tapping upstroke with normal volume and downstroke is characteristic of HCM Anacrotic pulse It is felt in severe AS, is a small volume (low amplitude), slow rising (ana = up and crotos = beat) upstroke wave with late peaking. The anacrotic notch occurs during the early half of the ascent; earlier it is felt, severer is the AS. In severe MS, the notch is felt in the later half of the ascending limb. Dicrotic pulse It refers to pulse wave forms with two peaks in each wave, one in systolic ascending limb and the second prominent one in the descending limb of the wave during diastole. This is seen in cardiac conditions with low stroke volume and decreased peripheral arterial resistance—typhoid fever, LV failure, dilated cardiomyopathies and cardiac tamponade. Pulsus paradoxus It occurs when there is an exaggerated decrease in pulse volume and blood pressure more than 10 mm Hg recorded during inspiration. In normal individuals there is usually a normal physiological drop of systolic blood pressure during inspiratory phase ranging from 5 mm Hg to a maximum of 10 mm Hg, which may be appreciated by experienced clinicians on feeling the arterial pulse in the absence of tachycardia. Hence the term paradox used as adjective is not true. It is seen in cardiac tamponade, pericardial effusion, constrictive pericarditis, acute severe asthma and in conditions that obstruct superior vena cava return to right atrium as noted in anterior and superior mediastinal tumors. Pulsus alternans It refers to occurrence of alternating pulse of high and low amplitudes or volumes in the presence of normal rhythm and is indicative of moderate-to-severe LV failure. Pulsus bigemini, pulsus It refers to coupling of two or three beats followed by a pause with a stronger beat after the pause. It occurs in AV block and trigemini sinoatrial block with ventricular escape.

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Abbreviations: AS, Aortic stenosis; LV, Left ventricular; MR, Mitral regurgitation; AR, Aortic regurgitation; PDA, Patent ductus arteriosus; AP, Aortopulmonary; RSOV, Ruptured sinus of Valsalva; TOF, Tetralogy of Fallot; HOCM, Hypertrophic obstructive cardiomyopathy; HCM, Hypertrophic cardiomyopathy; MS, Mitral stenosis; AV, Atrioventricular

Table 7.1.6 Characteristics of apical impulse Tapping apical impulse Palpable S1 noted in MS; it represents a hypokinetic, underfilled left ventricle. Tapping apical impulse is also felt in ASD. Hyperdynamic apex Suggests LV dilatation seen in high cardiac output states, and ventricular volume overloads seen in MR and AR, VSD or PDA. In hyperdynamic apex, the apical impulse, besides being shifted outwards and downwards, has increased amplitude with brisk upstroke, is felt in more than one ICS, usually over two or three ICS exceeding 3 cm. It is ill sustained with the duration of impact between one-third and half of systole. Heaving apex It is said to be present when the systolic thrust is sustained and increased in duration almost like a wave felt for more than two-third of systole with increased amplitude and is confined to one ICS. It is indicative of pressure overload and LVH seen in AS, systemic arterial hypertension or coarctation of aorta. Retractile apical impulse Indicative of constrictive pericarditis where there is systolic retraction away from the chest wall, and forward or positive diastolic thrust. Double apical impulse It suggests AS with AR, HOCM, LBBB and in adults LV aneurysm. Triple or quadruple impulse may be felt in HOCM. Absence of apical impulse Dextrocardia, pericardial effusion, obesity, apex under the rib, emphysema or large pleural effusion on the left side Abbreviations: S1, First heart sound; MS, Mitral stenosis; ASD, Atrial septal defect; LV, Left ventricular; MR, Mitral regurgitation; AR, Aortic regurgitation; VSD, Ventricular septal defect; PDA, Patent ductus arteriosus; ICS, Intercostal space; LVH, Left ventricular hypertrophy; AS, Aortic stenosis; HOCM, Hypertrophic obstructive cardiomyopathy; LBBB, Left bundle branch block

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The first heart sound (S1) is produced by closure of mitral and tricuspid valves marking the beginning of systole. It is best heard over the apex and in mitral area. The S2 is produced by closure of semilunar valves of aorta and pulmonary arteries. The normal variable split of S2 is because the pulmonary component (P2) is normally heard 30 msec after the aortic component (A2) during inspiration (increased RV ejection time and pulmonary artery hangout interval) and within 20 msec during expiration. The S3 is low pitched,

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may be normally heard in early diastole and is caused by rapid ventricular filling. It may also be heard in athletes and pregnant women. If S3 occurs in a child with cardiac symptoms, one should suspect diastolic overload conditions or LV dysfunction (dilated left ventricle, decreased ejection fraction, constrictive pericarditis) or LV failure. The S3 gallop refers to an exaggerated sound with a cadence heard when significant tachycardia occurs with the above conditions. The S4 is often an abnormal sound and it is low pitched, late diastolic sound produced by forceful atrial contraction against certain degree of resistance and decreased ventricular compliance during late ventricular filling. The characteristics of various heart sounds have been summarized in Table 7.1.7.

 

Table 7.1.7 Characteristics of different heart sounds Intensity of S1

Cardiac conditions

Loud

Exercise, sinus tachycardia, short PR interval states like WPW syndrome, MS, tricuspid stenosis, atrial myxoma

Soft

Long PR interval, pericardial effusion, MR, TR, calcific MS, myocarditis and cardiomyopathy, proximal LBBB

Split S1

Ebstein anomaly, RBBB, large ASD

Intensity of S2 Loud S2

Soft S2

Increased A2: systemic hypertension, aortic root dilatation, L-TGA, TOF

Decreased A2: severe AS, AR, calcific aortic valve

Increased P2: pulmonary hypertension, ASD

Decreased P2: PS, TOF, TGA

Splitting of S2

Cardiac conditions

Wide (both A2 and P2 audible in inspiration and expiration)

Due to early A2 closure: VSD, MR Due to late P2 closure: PAH, PS, RBBB, pulmonary embolism, LV ectopic beat Increased hangout interval due to decreased impedance to pulmonary artery: ASD, PS, TAPVC, Ebstein, idiopathic dilatation of pulmonary artery

Wide and fixed split

ASD, severe RV failure

Paradoxical or reverse split

Delayed A2

P2, then A2 (split audible in expiration but not in inspiration)

Mechanical: AS, hypertension, CAD Electrical: Proximal LBBB; RV ectopics Decreased impedance to aorta: PDA, poststenotic dilatation in AS

Single S2

Absent A2: HLHS, aortic atresia Absent P2: Pulmonary atresia, truncus arteriosus, absent pulmonary valve Very soft/masked P2: TOF, TGA, Severe PS Synchronous A2 and P2: Severe PAH, PPH, Eisenmenger VSD

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LV overload states

MR, VSD, PDA

RV overload states

TR, ASD

LA S4 gallop

Aortic valvular stenosis, systemic arterial hypertension

Right atrial S4 gallop

PAH, PS, Ebstein’s anomaly, ASD, prolonged PR interval

Abbreviations: S1, First heart sound; WPW, Wolff-Parkinson-White; MS, Mitral stenosis; MR, Mitral regurgitation; TR, Tricuspid regurgitation; LBBB, Left bundle branch block; RBBB, Right bundle branch block; ASD, Atrial septal defect; S2, Second heart sound; A2, Aortic component of S2; L-TGA, Levotransposition of great arteries; TOF, Tetralogy of Fallot; AS, Aortic stenosis; AR, Aortic regurgitation; P2, Pulmonary component of S2; PS, Pulmonary stenosis; VSD, Ventricular septal defect; LA, Left atrial; PAH, Pulmonary arterial hypertension; LV, Left ventricular; TAPVC, Total anomalous pulmonary venous connection; RV, Right ventricular; CAD, Coronary artery disease; PDA, Patent ductus arteriosus; HLHS, Hypoplastic left heart syndrome; PPH, Primary pulmonary hypertension; S3, Third heart sound

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Table 7.1.8 Characteristics of organic heart murmurs Organic systolic murmurs Ejection

Mid/late systolic

MR TR VSD

AS PS ASD VSD

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Combination of defects

•  PDA •  Aortopulmonary window rupture of sinus of Valsalva into right ventricle or pulmonary artery •  Coronary arteriovenous fistulas •  Systemic arteriovenous fistulas •  Peripheral pulmonary artery branch stenosis •  ALCAPA Cyanotic •  Pulmonary arteriovenous fistulas •  Truncus arteriosus •  Blalock Taussig shunt

•  TOF •  Aortic coarctation •  Aberrant LCA with RCA collaterals

•  VSD + AR •  AR + AS •  MR + AR/TR + MR + AR

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Organic continuous murmurs

Abbreviations: MR, Mitral regurgitation; TR, Tricuspid regurgitation; VSD, Ventricular septal defect; AS, Aortic stenosis; PS, Pulmonary stenosis; ASD, Atrial septal defect; MVP, Mitral valve prolapse; AR, Aortic regurgitation; PR, Pulmonary regurgitation; MS, Mitral stenosis; TS, Tricuspid stenosis; PDA, Patent ductus arteriosus; ALCAPA, Anomalous left coronary artery from the pulmonary artery; TOF, Tetralogy of Fallot; LCA, Left coronary artery; RCA, Right coronary artery

Clicks, opening snap and pericardial friction rub are the other added sounds one should try to detect during auscultation.



Heart Murmurs Heart murmurs are audible sound waves in the range of 20 Hz–2,000 Hz that occur as a result of turbulent blood flow due to functional or structural hemodynamic alterations in the pattern of blood flow in the heart chambers across the valves or the atrial or ventricular septum or in the vessels as in coarctation of aorta, renal artery stenosis or pulmonary arteriovenous collaterals or malformations. When the presence of murmur over the precordium is appreciated by the student, it becomes essential to make a clinical decision whether the murmur is functional/ innocent or organic/pathological due to an underlying cardiac disorder. When one or more of the following are present, the murmur is likely to be pathologic and requires further evaluation: symptoms, cyanosis,

systolic murmur that is loud (grade 3/6, harsh and long in duration), diastolic murmur, abnormal heart sounds, presence of a click, and abnormally strong or weak pulses. The characteristics of organic heart murmurs have been summarized in Table 7.1.8.

Innocent Murmurs A murmur heard in a child without structural heart disease is termed innocent murmurs. The child has no cardiac related symptoms or other signs on careful history and physical examination, and basic investigations like chest X-ray, electrocardiogram (ECG) and echocardiogram are normal. A significantly large proportion of children have innocent murmurs beginning at 3–4 years of age. The characteristics of innocent or functional murmurs are usually the following: they are localized to specific areas, short, often early or mid-systolic, grade 1/6 or 2/6 (not associated with thrill) and vary in intensity with change in posture; decreasing in intensity when the child stands, sits up or strains during a Valsalva maneuver.

Other Abnormal Sounds

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1. Allen HD, Philips JR, Chan DP. History and physical examination. In: Moss AJ, Allen HD (Eds). Moss and Adams’ Heart Disease in Infants, Children and Adolescents, 7th edition. Philadelphia: Lippincott; 2008.pp.66-80. 2. Fyler DC, Nadas AS. History, physical examination, and laboratory test. In: Keane J, Fyler DC, Lock J (Eds). Nadas’ Pediatric Cardiology. Philadelphia: Saunders; 2006.pp.10116. 3. Geggel RL, Fyler DC (Eds). History, growth, nutrition, physical examination, and routine laboratory tests. Nadas’ Pediatric Cardiology, 2nd edition. Philadelphia: WB Saunders; 2008.

4. Park MK. Basic tools in routine evaluation of cardiac patients. In: Park MK (Ed). Pediatric Cardiology for Practitioners, 5th edition. Philadelphia: Mosby Elsevier; 2008.pp.3-39. 5. Roy DL. Cardiovascular assessment of infants and children. In. Goldbloom RB (Ed). Pediatric Clinical Skills, 3rd edition. Philadelphia: Saunders; 2003.pp.169-89. 6. Thompson WR, Mehrotra SM. Approach to heart diseases in children: cardiac history and physical examination. In: Abdulla Ra-id (Ed). Heart Diseases in Children: A Pediatrician’s Guide. New York: Springer; 2011.pp.3-16. 7. Tandon R. Bedside diagnosis of congenital heart disease. In: Bahl VK (Ed). Cardiology Update 2008. Cardiological Society of India. 2008.pp.484-90.

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Diseases of Car iovas ular ystem

7.2

Congenital Heart Disease R Krishna Kumar



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Congenital heart disease accounts for about 10% of infant deaths and nearly half of all deaths due to congenital malformations in developed countries. The prevalence of CHD diagnosed in the first 12 months is estimated at 6–8 per 1,000 live births. Of these, at least 25% are lifethreatening CHDs that require very early intervention. In India, for a population of 1.2 billion, it can be expected that there would perhaps be approximately 100,000 newborns born each year with CHD requiring some form of intervention early in life. It is estimated that only 3–5% of newborns and infants with CHD are receiving timely surgery in India. The vast majority of newborns with CHD escape timely detection. Congenital heart disease has a unique profile in India characterized by remarkable early attrition, late survival selected by natural history and significant numbers of older children with complications, such as pulmonary hypertension, overt (brain abscess and stroke) and covert (neurodevelopmental abnormalities) neurological damage. E



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This chapter will expand on the above mentioned points. A brief description of common CHDs has been included in a section at the end of the chapter.



1. The most important role of the pediatrician today is to ensure that, as far as possible, serious CHD should not be missed. This is especially true for the neonatal period and during infancy where maximal attrition from CHD occurs. 2. History, physical examination, chest X-ray and ECG are the traditional tools available to the pediatrician. With this it is usually possible to identify whether or not CHD is present except perhaps in the early newborn period where CHD diagnosis can be challenging. 3. Despite numerous anatomic possibilities, the physiologic categories of CHD are limited and can be understood. Understanding the basic hemodynamic and physiologic concepts are important because they have an important bearing on clinical picture, interpretation of echocar diographic reports, natural history and decision making on timing of surgical or catheter intervention. 4. The traditional diagnostic tools allow classification of physiologic categories in a significant proportion of babies. The limitations of the traditional tools in identifying the precise anatomy are substantial and this is exposed by the widespread use of echocardiography. 5. Numerous recent advances have dramatically changed the outlook of children with CHD. As a result some form of palliation or correction is feasible for most CHD provided this is undertaken in a timely fashion. 6. The improved understanding of CHD today suggests that management needs to be individualized or tailored to each patient. Today, it is possible to identify and determine the severity of all the specific lesions through echocardiography. Recognizing the numerous combinations and specific features with each lesion, each patient needs to be approached according to the specifics of the lesion(s). 7. It is increasingly evident that a substantial proportion of children with CHD have significant problems in other

organ systems. The pediatrician has an important role in identifying them because they have significant bearing on eventual outcomes and counseling of the family. 8. In spite of significant recent advances, long-term concerns after palliation and many forms of “correction” of CHD are significant and many of these children need life-long follow-up.

S



Congenital heart disease encompasses a broad and extremely diverse range of conditions that can manifest anytime from prenatal to late adulthood. In common parlance, CHD refers to structural heart defects that are present at birth. Conditions such as HCM and mitral valve prolapse may actually have a congenital basis but these are often discussed separately. In this chapter we will be discussing common structural defects that are present at birth. A practical approach lies in remembering the following:

tiopathogenesis

The link between etiology and embryogenesis of CHD is often very complex. A lot of recent research has focused on the chain of events in early embryogenesis of the heart and great vessels. As a result there have been dramatic conceptual upheavals. The details are beyond the scope of this chapter. In simplified terms, the pediatrician should recognize today that a growing proportion of patients with CHD have an identifiable genetic basis. Table 7.2.1 summarizes common genetic conditions that are associated with CHD. The association with acquired conditions and teratogens and occurrence of CHD has been summarized in Table 7.2.2.

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For many years, CHD has been broadly classified as cyanotic and acyanotic with certain specific subtypes in each category (Table 7.2.3). While broad classifications based on physiology works for many situations there are a number of patients who cannot be classified into common physiologic

categories. Additionally, there are often specific issues such as valve regurgitation that dictate the clinical presentation. The broad categories of CHD in Table 7.2.3 have limitations, and some patients may have a combination of lesions belonging to more than one category. For example, a child may have a large VSD with moderate pulmonary stenosis (PS) and mild pulmonary hypertension.

 

Table 7.2.1 Common genetic conditions that are linked to the occurrence of CHD Specific condition

Genetic basis

CATCH 22 syndrome

Microdeletion on long arm of chromosome 22, 22q11 Interrupted aortic arch, TOF, VSD, persistent truncus arteriosus, deletion; autosomal dominant inheritance double outlet right ventricle

Williams-Beuren syndrome

Microdeletion at chromosome 7q11.23 (Elastin gene Supravalvar AS, pulmonary arterial stenosis, aortic and mitral located in this segment); autosomal dominant inheritance valve abnormalities, adult systemic hypertension

Down syndrome

Chromosomal trisomy for chromosome 21 (rarely AV canal defect, perimembranous VSD, TOF, PDA Robertsonian translocation or mosaicism), sporadic mutation

Turner’s syndrome

Chromosomal (45, X karyotype and variants mosaicism, Predominantly left-sided lesions (BAV, coarctation); risk for structurally abnormal X chromosome) aortic root dilatation

Noonan’s syndrome

PTPN11 mutations in 50%; half of cases are de novo; PS (20–50%), HCM (20–30%), ASD autosomal dominant inheritance in the next generation

VATER association

No specific recurring etiology, sporadic; very small risk to VSD, TOF offspring

Holt-Oram syndrome

TBX5 mutation (70%); 15% familial, autosomal dominant Ostium secundum ASD, VSD, conduction defects inheritance

CHARGE

CHD7 mutation (60%) or deletion; most cases are de novo; Commonly right-sided lesions, branch pulmonary artery autosomal dominant inheritance stenosis and conotruncal lesions (TOF, VSD)

Alagille syndrome

Pulmonary valve, artery and branch pulmonary artery most JAG1 mutation (70%) or deletion (w5%); 50–70% of cases are commonly affected; TOF in 7–15% de novo; autosomal dominant inheritance

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Classification

Cardiac lesions

Abbreviations: CHD, Congenital heart disease; VSD, Ventricular septal defect; AS, Aortic stenosis; AV, Atrioventricular; TOF, Tetralogy of Fallot; PDA, Patent ductus arteriosus; BAV, Bicuspid aortic valve; PS, Pulmonary stenosis; HCM, Hypertrophic cardiomyopathy; ASD, Atrial septal defect

 

Table 7.2.2 Etiology of CHD: prenatal exposure to acquired factors Acquired condition

Association with CHD

Diabetes

A variety of forms of CHD are now linked with maternal gestational and pregestational diabetes. The list includes transposition, AV septal defects, VSD, hypoplastic left heart syndrome, cardiomyopathy and PDA

Febrile illnesses in the first trimester

Any febrile illness during the first trimester of pregnancy may have a two fold increase in the risk of CHD

Maternal rubella

Specific cardiac manifestations of rubella embryopathy include: PDA, pulmonary valve abnormalities, peripheral PS and VSD

Epilepsy

The association is perhaps as a result of the risk of CHD from anticonvulsant medications

Lupus (apart from typical symptoms Maternal SLE is associated with risk of complete heart block in the offspring of SLE it may be useful to ask for history of previous abortions) Phenylketonuria

Phenylketonuria is associated with greater than six fold increase in the risk of CHD (specifically VSD, TOF, PDA and single ventricle)

Vitamin deficiency

Multivitamin supplements including folic acid derivatives have been shown to protect against occurrence of CHD in two studies. Multivitamins may also reduce the risk of CHD associated with febrile illnesses in the first trimester

Prenatal exposure to medications in The list of medications known to be associated with a risk of CHD in the offspring includes: anticonvulsants, the first trimester NSAIDs, trimethoprim-sulphonamide, thalidomide and vitamin A congeners Occupational exposure

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Exposure to organic solvents, herbicides, pesticides and ionizing radiation may increase the risk of CHD in the offspring

Abbreviations: CHD, Congenital heart disease; AV, Atrioventricular; VSD, Ventricular septal defect; PDA, Patent ductus arteriosus; PS, Pulmonary stenosis; SLE, Systemic lupus erythematous; TOF, Tetralogy of Fallot; NSAIDs, Nonsteroidal anti-inflammatory drugs

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Examples

Acyanotic congenital heart disease Simple left to right shunts Pre-tricuspid

Partial anomalous pulmonary venous drainage, ASDs

Post-tricuspid Ventricular

VSD

Great artery

Aortopulmonary window, patent arterial duct, coronary cameral fistula, ruptured sinus of Valsalva

Combination of pre- and post-tricuspid

AV septal defect, left ventricle to right atrial communications

Obstructive lesions Cor triatriatum, obstructive lesions of the mitral valve apparatus

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Inflow: left-sided

Infundibular stenosis, pulmonary valve stenosis, branch pulmonary artery stenosis

Left ventricle

Subaortic membrane, valvular aortic stenosis, supravalvar aortic stenosis, coarctation of aorta

Miscellaneous lesions

Coronary artery abnormalities, congenital mitral and tricuspid valve regurgitation

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Outflow Right ventricle

Cyanotic heart disease Reduced pulmonary blood flow Intact interventricular septum

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Physiologic category

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Table 7.2.3 Broad physiologic categories of CHD

PA with intact ventricular septum, critical PS with right to left shunt at atrial level, Ebstein’s anomaly, isolated RV hypoplasia

Unrestrictive ventricular communication All conditions listed under VSD with PS or PA physiology;* Miscellaneous conditions

Pulmonary arteriovenous malformation, anomalous drainage of systemic veins to left atrium

Increased pulmonary blood flow Pre-tricuspid

Total anomalous pulmonary venous communication Common atrium

Post-tricuspid

All single ventricle physiology lesions without PS, persistent truncus arteriosus

Pulmonary hypertension

Shunt reversal after development of pulmonary vascular obstructive disease in any of the conditions associated with increased pulmonary blood flow (Eisenmenger physiology)

*VSD with PS or PA physiology: This includes all conditions with an unrestrictive interventricular communication and PS or PA. Included in this list are the following: Tetralogy of Fallot, double-outlet right ventricle, single ventricle, transposition with VSD, corrected transposition with VSD, AV septal defect and tricuspid atresia. Abbreviations: CHD, Congenital heart disease; ASDs, Atrial septal defects; VSD, Ventricular septal defects; AV, Atrioventricular; PA, Pulmonary atresia; PS, Pulmonary stenosis; RV, Right ventricular



Another way of understanding the physiology of CHD is to list various physiological perturbations (Table 7.2.4) that are commonly associated with CHD. Here again, it is evident that many defects have more than one physiological perturbation. The table is, however, useful in that it illustrates various mechanisms by which CHD produce clinical manifestations.

Physiology Here, the focus will be on illustrating selected key physiological concepts that are important to understand a large number of lesions. These include the following: S

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Pre- ricuspid ersus Post- ricuspid hunts Acyanotic heart disease with left to right shunts is traditionally classified as pre-tricuspid and post-tricuspid shunts.

Pre-Tricuspid Shunts Left to right shunts at the level of the atria are known as pretricuspid shunts. They include ASDs and partial anomalous pulmonary venous connection. The left to right shunt and the consequent excessive pulmonary blood flow is dictated by relative stiffness of the two ventricles. Since the right ventricle is relatively stiff (noncompliant) at birth and during early infancy, the shunt is small. Over the years, the right ventricle progressively enlarges to accommodate the excessive pulmonary blood flow. The pulmonary vasculature also becomes more capacious to gradually accommodate the excessive blood flow. This explains why ASD typically do not manifest with symptoms of pulmonary over circulation during infancy and childhood. The clinical signs are also easily explained by the physiology of pre- 429 tricuspid shunts. The diastolic flow murmur of ASD is across

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Physiological derangement

Hemodynamic consequences

Clinical consequences

Examples

Increased pulmonary blood flow

Inefficient circulation, pulmonary congestion, pulmonary hypertension

Failure to thrive, heart failure symptoms, tachypnea, frequent respiratory infections

All post-tricuspid shunts, some large pre-tricuspid shunts

Reduced pulmonary blood flow

Hypoxia in the presence of an ASD or VSD; Cyanosis, fatigue reduced cardiac output if both septa are intact

Mixing of systemic and pulmonary venous return (single ventricle physiology)

Some hypoxia will result but the exact oxygen saturation will be dictated by pulmonary blood flow. If pulmonary blood flow is increased (shunt ratio of 2:1 or more) saturations are usually above 85%.

Cyanosis of varying severity depending on pulmonary blood flow

All forms of univentricular hearts; double inlet left ventricle or right ventricle, tricuspid atresia, primitive hearts associated with asplenia and polysplenia

Unfavorable streaming and parallel circulation

Hypoxia tends to be severe unless pulmonary blood flow is significantly elevated

Severe cyanosis in the face of excessive pulmonary blood flow

All variations of TGA; double outlet right ventricle with subpulmonic VSD (Taussig-Bing)

Pulmonary venous hypertension

Pulmonary venous congestion with pulmonary arteriolar vasoconstriction and resultant elevation in pulmonary vascular resistance

Tachypnea from pulmonary edema, severe elevation in pulmonary vascular resistance translates into reduced pulmonary blood flow and increased cyanosis

Obstructed total anomalous pulmonary venous connection, cor triatriatum, congenital MS, mitral atresia with restrictive ASD, pulmonary venous stenosis

Elevated pulmonary vascular resistance

Inability to increase cardiac output during exercise or stress, increased right to left shunting across associated defects

Fatigue on effort, patients with defects in the atrial or ventricular septum will have increasing cyanosis

All conditions associated with increased pulmonary blood flow increase the risk for development of increased pulmonary vascular resistance

Left-sided AV valve regurgitation

LV volume overload, elevation in LA pressures, pulmonary venous congestion

Tachypnea, fatigue on effort

AV septal defects, corrected transposition, ASDs (5–10% have associated mitral valve prolapse and MR), congenital MR, anomalous coronary artery from pulmonary artery

Right-sided AV valve regurgitation

RV volume overload, elevated RA pressures, systemic venous congestion

Fatigue, right heart failure

Ebstein’s anomaly, congenital anomalies of tricuspid valve

LV hypertrophy

Elevated filling pressures resulting in left heart failure

Tachypnea from pulmonary venous congestion

All forms of LV outflow tract obstruction, hypertrophic cardiomyopathy

RV hypertrophy

Elevated right-sided filling pressures with systemic venous congestion

Right heart failure, liver enlargement, fluid accumulation (edema and ascites)

Advanced forms of RV outflow obstruction: critical PS, advanced pulmonary hypertension

Reduced coronary perfusion

LV dysfunction

Tachypnea, fatigue

Anomalous left coronary artery from pulmonary artery

Pulmonary valve regurgitation

Dilatation of branch pulmonary arteries with airway compression, RV dilatation

Respiratory symptoms in infants with TOF and absent pulmonary valve, fatigue on effort in patients with long-standing pulmonary valve incompetence

TOF with absent pulmonary valve

Aortic valve regurgitation

LV dilatation

Fatigue and palpitation

Bicommissural aortic valve in association with subpulmonic and some perimembranous defects

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Table 7.2.4 Physiological perturbations in CHD

All congenital heart defects that are associated with PS

Abbreviations: CHD, Congenital heart disease; ASDs, Atrial septal defects; VSD, Ventricular septal defect; PS, Pulmonary stenosis; TGA, Transposition of great arteries; MS, Mitral stenosis; AV, Atrioventricular; RA, Right atrial; LV, Left ventricular; LA, Left atrial; MR, Mitral re gurgitation; RV, Right ventricular; TOF, Tetralogy of Fallot

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Post-Tricuspid Shunts

This refers to a group of conditions where there is complete mixing of pulmonary and systemic venous returns. In addition to single ventricle (double inlet ventricle), a variety of conditions come under the category of single ventricular physiology. Atresia of one of the AV valves, severe hypoplasia of one of the ventricles, severe straddling of one of the AV valves over a large VSD are all examples of situations where there is mixing of pulmonary and systemic venous returns. The clinical manifestations are dictated by whether or not there is PS. In absence of PS, there is excessive pulmonary blood flow especially in infants because of the relatively lower PVR. As a result, the proportion of oxygenated blood from pulmonary veins that mixes with the systemic venous return is high. This results in minimal cyanosis and measured oxygen saturation may be in the 90s. However, the price for this preserved oxygenation is HF and development of permanent elevation of PVR [pulmonary vascular obstructive disease (PVOD)]. Over time, if the child survives infancy, PVR progressively increases with increasing cyanosis. Single ventricle and its physiologic variants can be associated with varying degrees of PS. Here the situation is quite similar to VSD-PS physiology except for relatively severe hypoxia because of free mixing of systemic and pulmonary venous return.

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Duct-Dependent esions An infant or a newborn with CHD that is dependent on the patency of the ductus arteriosus for survival can be termed as suffering form a duct-dependent lesion. Typically, these are newborns in which either the systemic blood supply is critically dependent on an open PDA [duct-dependent systemic circulation (DDSC)] or pulmonary blood flow is duct dependent [duct-dependent pulmonary circulation (DDPC)]. Closure of the PDA in DDSC results in systemic hypoperfusion (often mislabeled as neonatal sepsis). Examples of DDSC include hypoplastic left heart syndrome where the entire systemic circulation is supported by the right ventricle through PDA, interrupted aortic arch where the descending aortic flow is entirely through PDA. Severe coarctation and critical AS are also examples of DDSC. Closure of PDA in DDPC results in severe hypoxia and cyanosis in the affected newborn. Examples of DDPC include all forms of pulmonary atresia (irrespective of

This situation is characterized by a large communication at the ventricular level together with varying degrees of obstruction to pulmonary blood flow. Typically, this is in the form of subvalvar (infundibular), valvar, annular (small annulus) and occasionally supravalvar stenosis. The free communication between the two ventricles results in equalization of pressures. Severity of PS dictates the volume of blood flowing through pulmonary arteries and therefore amount of oxygenated blood returning via pulmonary veins. Severe PS results in right to left shunt across the VSD with varying degrees of hypoxia and, consequently, cyanosis. Cyanosis is directly proportionate to the severity of PS. Because the right ventricle is readily decompressed by the large VSD, heart failure (HF) is unusual. The best example of VSD-PS physiology is tetralogy of Fallot (TOF). In its least severe form, TOF is often not associated with cyanosis (pink TOF). Here PS is significant enough to result in a large pressure gradient across the right ventricular outflow tract (RVOT), but not severe enough to result in a reduction in pulmonary blood flow. Pink TOF is typically associated with a loud ejection systolic murmur because of a reasonable volume of blood flowing across the RVOT. As



D-P Physiology S

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Post-tricuspid shunts are different in that there is direct transmission of pressure from systemic to pulmonary circuit at the ventricular level (VSD) or great arteries (PDA and aortopulmonary window). For patients with large post-tricuspid shunts, symptoms begin in early infancy, typically after some regression of elevated pulmonary vasoconstriction in the newborn period together with progressive development of the pulmonary vascular tree. The excessive pulmonary blood flow returns to the left atrium and flows through the mitral valve resulting in an apical diastolic flow murmur that is a consistent marker of large post-tricuspid shunts. The left atrium and ventricle are dilated as a result of this extra volume. Elevation in pulmonary artery pressures is an inevitable consequence of large (or unrestrictive) post-tricuspid shunts and is labeled as hyperkinetic PAH. This needs to be distinguished from elevation of pulmonary vascular resistance (PVR) that results from sustained exposure to increased pulmonary blood flow.

ingle entricle Physiology



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the severity of PS increases, pulmonary blood flow declines and the intensity of murmur declines progressively. Other examples of VSD-PS physiology include double outlet right ventricle (DORV) with subaortic VSD and PS, corrected transposition with PS and atrioventricular (AV) septal defect with PS. These conditions are often indistinguishable from TOF at the bedside.

Diseases of Car iovas ular ystem

the much larger tricuspid valve and is therefore subtle or even inaudible. The S2 split is wide and fixed because of the prolonged “hang-out” interval resulting from increased capacitance of the pulmonary circulation. Pulmonary arterial hypertension is typically absent or at most mild. The presence of moderate or severe PAH in ASD is worrisome and may suggest the onset of irreversible changes in the pulmonary vasculature.

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Cyanosis

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Cyanosis may be peripheral or central. Peripheral cyanosis almost exclusively involves lips and extremities. Normal neonates may have bluish extremities that respond to warming or moving the extremities. Saturations of 90% or lower while breathing room air beyond the first 20 minutes are considered abnormal. Similarly, some infants may have peripheral cyanosis following exposure to cold. Central cyanosis involving the mucous membranes and trunk along with the lips and extremities strongly suggests the likelihood of CHD. Unfortunately, however, cyanosis often remains unnoticed. This is particularly true in the Indian context, where it is difficult to detect cyanosis due to

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Tachypnea (respiratory rates consistently more than 60/min in infants less than 2 months, greater than 50/min in older infants, greater than 40/min after 1 year) is a characteristic manifestation of HF in newborns (preterm newborns may normally have respiratory rates of up to 60/min). For infants, subcostal or intercostal retractions together with flaring of nostrils (alae nasi) are frequently associated with tachypnea. I

requent espiratory nfections

Respiratory infections that are frequent, severe and difficult to treat are common in infants with CHD associated with large left to right shunts resulting in increased lung blood flow. Not infrequently, heart disease may be detected for the first time during an episode of respiratory tract infection. S

Clinical tigmata of pecific yndromes S

The manifestations of CHD are different in a neonate, an infant or a child. It is often easy to recognize the presence of CHD in older children. In infants and particularly in newborns, manifestations of heart disease can often be subtle. Further, a number of conditions that do not involve the cardiovascular system can result in clinical manifestations that overlap with those resulting from heart disease. Notwithstanding these difficulties, it is possible to identify the presence of heart disease in most infants and newborns after careful clinical evaluation. The following clinical features should alert the pediatrician regarding the presence of CHD.

Difficult reathing

Evidence of presence of chromosomal anomalies or other syndromes that are known to be associated with CHD should alert the clinician to the presence of specific cardiac defects that are known to be associated with these conditions. The list of such conditions is a long one. Trisomy 21 is the most common chromosomal anomaly that is associated with heart disease. Other common examples include: trisomy 13, trisomy 18, Turner’s syndrome, Noonan’s syndrome, velocardiofacial and the Di-Georges’s syndrome (Table 7.2.1).

Cardiovascular xamination E

ecognition of Congenital Heart Disease

The parent of an infant with CHD may complain that the child has difficulty with feeds. This is usually a feature of an infant with congestive heart failure (CHF) resulting from CHD. The history may be of slow feeding, small volumes consumed during each feed, tiring easily following feeds and requirement of periods of rest during feeds. Not infrequently, no history of feeding difficulty may be obtained, but examination of the growth charts will reveal that the child’s growth rate is not appropriate for age. A recent decline in growth rate (falling off the growth curve) or weight that is inappropriate for age (< 5th percentile) may result from a large left to right shunt. Characteristically, growth retardation affects weight more that height.

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Unfavorable streaming refers to a situation where oxygen rich pulmonary blood flow is directed toward the pulmonary valve and poorly oxygenated blood toward the aortic valve. An extreme form of unfavorable streaming is the parallel circulation in transposition of great arteries (TGA) with intact ventricular septum. Here survival is dependent of the presence of a communication (ideally at atrial level) that allows mixing of pulmonary and systemic venous return. The presence of a VSD may improve the situation in TGA but significant cyanosis is usually present unless the pulmonary blood flow is torrential.

Difficult eeding and Poor Growth

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nfavorable treaming and Parallel Circulation

presence of a dark skin complexion. Further, cyanosis is often masked by anemia. When central cyanosis is suspected, its presence should be confirmed and severity quantified by measuring oxygen saturation using a skin oxymeter probe. Unfortunately, however, the availability of this instrument is limited to a few selected institutions.

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underlying heart defect) where the PDA is the predominant source of pulmonary blood flow. There are examples of pulmonary atresia where pulmonary blood supply is from major aortopulmonary collaterals. These children may survive even after the PDA closes. Critical PS (“nearlyatretic” pulmonary valve) can present as duct-dependent pulmonary blood flow. Neonates with duct-dependent physiology require prostaglandin E1 (PGE1) for survival. Early recognition of a duct-dependent situation allows early initiation of PGE1 and stabilization until definitive procedure can be accomplished.

A thorough and systematic cardiovascular examination provides valuable clues to the presence of heart disease. With practice, such an examination can be accomplished in a short time. For the pediatrician, a thorough familiarization

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Does the precordium feel normal?

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Are there visible precordial pulsations? Is the apex beat displaced, hyperdynamic or heaving? Is there a thrill palpable?

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The Checklist for Diagnosis of Congenital Heart Disease through Echocardiography 1. What is the visceral and atrial situs (solitus, inversus or ambiguous)? 2. What are the systemic venous connections like? Is the inferior vena cava intact? Is there a separate left superior vena cava? If so, how does it drain? 3. What is the relationship of the abdominal aorta to the inferior vena cava? 4. What is the appearance of the atria like? Is the atrial septum intact? Is there an ASD or a patent foramen ovale? If so, in what direction does blood flow? 5. How do the atria connect to the ventricles (concordant or discordant)? 6. Is it possible to identify two separate AV valves? 7. How are the AV valves in their appearance and function? 8. The ventricles: their size, shape and function? 9. Are various components of the interventricular septum intact? 10. Is there any outflow tract obstruction? 11. How do the ventricles connect to the great arteries? 12. What is the appearance and function of the semilunar valves? 13. What is the great artery relationship? 14. Are the branch pulmonary arteries in continuity? Is there any branch pulmonary artery stenosis? 15. What side is the aortic arch? What is its branching pattern? Is there a PDA or a coarctation? 16. What is the coronary artery anatomy? 17. How is the hemodynamics and physiology altered?

re the heart sounds normal?

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Is the pulse volume normal or increased? Is there a discrepancy of pulsation in any of the four extremities? A careful evaluation of pulsations in all extremities should always be a part of physical examination. Coarctation is readily diagnosed when weak femoral pulsations are detected in comparison to brachials or radials. When a discrepancy in pulses is suspected, four extremity blood pressure measurements should be obtained. An automated noninvasive blood pressure instrument is preferred over manual recording for four extremity blood pressure measurement.

Echocardiography has revolutionized diagnosis of CHD and its high diagnostic yield makes this investigation very cost effective in most situations. This statement is, however, only true if it is performed by an experienced individual who understands anatomy and physiology of CHD. In many children with CHD, a thorough evaluation is possible and all the questions addressed in the check list (below) can be answered. This is particularly true for infants and newborns in whom excellent images are readily obtained. Such patients can undergo a definitive procedure based on the information provided by the echocardiogram. Transesophageal echocardiography can supplement transthoracic studies. This is particularly true for patients with poor echocardiography windows that do not permit adequate imaging. Unlike adults, children undergoing transesophageal echocardiography often require general anesthesia. Echocardiography has a few inherent limitations, however. It consistently fails to define certain structures, such as the pulmonary artery branches beyond the hila of the lungs. Here cardiac computed tomography (CT) or cardiac magnetic resonance imaging (CMR) work well. Newer modalities such as three-dimensional echocardiography are in the evolving phase and, at present, do not add significant value to twodimensional echocardiography.

lectrocardiogram and Chest -ray





If there is a suspicion of heart disease on the basis of history or physical examination, an ECG and a chest X-ray should be obtained. The ECG should be interpreted keeping the age of the child in mind. Interpretation of the chest X-ray should involve evaluation of the cardiac silhouette and lung vasculature. The X-ray also provides information about the location of abdominal organs (for determination of the situs) and the aortic arch. Beyond the neonatal period, a normal ECG and chest X-ray makes the diagnosis of a hemodynamically significant heart defect unlikely. In the newborn, however, ECG and chest X-ray changes may take a few days to evolve. For the newborn, particularly in the first few days, a normal ECG and a normal X-ray does not rule out serious heart disease.





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Is it systolic or diastolic or both systolic and diastolic (diastolic murmurs always have a structural basis)? Is it loud (grade 3 or louder murmurs are seldom innocent)?



s (or are) there a murmur (or murmurs)? f so: I

I







Can the two components of the S2 be separated? Is there an additional heart sound in diastole (such as S3)? Are there any additional systolic sounds (ejection clicks)?



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re the arterial pulsations normal?

chocardiography

Diseases of Car iovas ular ystem

with what is normal is a useful initial step. It is useful to answer the following questions that can serve as a checklist for a preliminary cardiac examination. This checklist is not at all comprehensive and is designed primarily for answering the question: Does the patient have heart disease? It can also help identify the broad physiologic category of heart defect.

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urgery

Flow chart 7.2.2 Classification of common congenital heart operations

Abbreviations: ASD, Atrial septal defect, VSD, Ventricular septal defect; BT shunt, Blalock-Taussig shunt; ICR, Intracardiac repair; PA band, Pulmonary arterial band; PDA, Patent ductus arteriosus; TAP, Transannular patch; TOF, Tetralogy of Fallot; AV canal, Atrioventricular canal; TAPVC, Total anomalous pulmonary venous connection  

Surgery is still the best option for definitive treatment or palliation of most forms of CHD. A simple scheme of classification of surgery for CHD is shown in Flow chart 7.2.2. This classification is a practical one and is from the point of view of follow-up issues. A detailed description of all congenital heart operations is clearly beyond the scope of the chapter. Congenital heart operations are also broadly classified as open heart [requiring use of cardiopulmonary bypass (CPB)] and closed heart (not requiring CPB). Most corrective operations and many palliative operations fall under the category of open heart operations. These procedures are generally more significant and expensive undertaking because of the use of the CPB circuit and substantially larger number of disposable items. The morbidity of open heart operations is proportionate to the duration of exposure to CPB and the cross-clamp time (the period of time when heart beating is deliberately brought to a standstill through the use of cardioplegia).

has transformed the care of many children with CHD. Many simple defects such as secundum ASD, PDA, selected muscular VSD can now be closed in the catheterization laboratory. Additionally, balloon valvotomy is now the first line of treatment for congenital stenosis of the pulmonary and aortic valves. Additional details of catheter intervention procedures have been shown in Table 7.2.5. The advantages of catheter-based interventions are obvious and this has become an increasingly appealing option for many children. The procedures are far less traumatic than surgery,  

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To ensure the best possible results of management of CHD, it is necessary to assemble a team of specially qualified individuals who should ideally be a part of a comprehensive pediatric heart program. The details are shown in Flow chart 7.2.1. Definitive treatment for CHD requires the collaborative (and not competitive) use of surgery and catheter-based interventions. S

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Definitive reatment and Palliation

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Catheter nterventions for Congenital Heart Disease The scope of catheter interventions has grown by leaps and bounds in the last 2–3 decades and this treatment option

 

Flow chart 7.2.1 The constituents of a comprehensive pediatric heart program for optimal care of children with congenital heart disease (CHD). For the best and consistently reproducible results in newborn and infant heart surgery, the presence of such a team is vital

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Remarks Only defects in the fossa ovalis region with sufficient margins are suited for device closure

PDA

Coil or device closure

The vast majority of PDAs can be closed in the catheterization laboratory with the exception of large PDA in small infants

Muscular VSD

Device closure

Device closure is an option for relatively older infants and children (> 8 kg)

Membranous VSD

Device closure

This is controversial because of the small but definite possibility of heart block

Pulmonary valve stenosis

BPV

Treatment of choice for most forms at all ages; dysplastic valves in Noonan’s syndrome may not respond well to BPV

Aortic valve stenosis

Balloon aortic valvotomy Initial treatment of choice at all ages; eventually the dilated aortic valves may need surgical management

Branch pulmonary artery stenosis

Balloon dilatation with stenting

Stenting is often preferred to surgery in branch pulmonary artery stenosis

Coarctation of aorta

Balloon dilatation with or without stenting

Surgery is the preferred option in the newborn period because recurrence after balloon is very common. For older infants, balloon is a reasonable alternative. Older children and adolescents (> 10 years) may be offered stenting for a more complete relief. Neither balloon or stenting has a proven advantage over surgery.

Coronary artery fistula

Coil or device closure

Treatment of choice

Pulmonary arteriovenous malformations

Coil or device closure

Treatment of choice when discrete. For diffuse malformations, coil or device closure is not an option

Duct-dependent pulmonary circulation

Stenting of the PDA

Stenting can be offered in carefully selected cases as an alternative to the Blalock-Taussig shunt

Pulmonary atresia with intact ventricular septum

Perforation of the valve followed by balloon dilatation

Emerging as the procedure of choice in selected institutions with the facility and expertise

Ruptured sinus of Valsalva aneurysm

Device closure

A reasonable option in carefully selected cases

TGA

Balloon atrial septostomy

Short-term palliation before definitive surgery (arterial switch operation)

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Lesion ASD

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Table 7.2.5 Congenital heart defects amenable to catheter-based interventions

Abbreviations: ASD, Atrial septal defect; PDA, Patent ductus arteriosus; VSD, Ventricular septal defect; BPV, Balloon pulmonary valvotomy; TGA, Transposition of great arteries

nfective ndocarditis or ndarteritis

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Pulmonary arterial hypertension occurs commonly in the context of CHD. With increasing emphasis on early correction, the magnitude of the problem is on the decline in most developed nations. Unfortunately, because most children with CHD do not receive timely attention, this is still a problem of considerable magnitude in the developing world. The lesions that have the greatest likelihood include cyanotic heart disease with increased pulmonary blood flow. Here irreversible changes in pulmonary vasculature develops rapidly often during infancy itself. Therefore, it is particularly important to correct or appropriately palliate these lesions early (ideally within the first few months of

E

Pulmonary rterial Hypertension

Complications

E

A number of adverse complications occur as a consequence of CHD. For the sake of simplicity, we will focus on selected common complications.

life). Large acyanotic post-tricuspid shunts are also prone to early development of PAH and should be ideally corrected early, preferably within the first year. In pre-tricuspid shunts, PAH develops slowly and unpredictably. Most patients with ASD will have mild or no PAH throughout their lives. A small proportion develops accelerated changes in the pulmonary vasculature. Some of the key features responsible for the development of PAH have been summarized in Figure 7.2.1. I

accomplished with greater ease, allow rapid recovery and leave behind no scars.

Endocarditis can complicate CHD with a suitable substrate. This includes the presence of a region of significant turbulence created by high-pressure gradients. Examples include restrictive VSD and PDA, TOF (pulmonary valve) and other VSD-PS situations, and LV outflow tract obstruction. Some surgical operations (such as the BT shunt) are also associated with increased risk of infective endocarditis (IE) or endarteritis. Lesions with little or no turbulent flows, such as ASD are not associated with increased risk. Typically, the risk of endocarditis increases after dentition begins. Current guidelines do not routinely recommend antibiotic 435 prophylaxis for many conditions (including some of the

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Figure 7.2.1 Natural history of uncorrected CHD. This is a simplified representation showing the survival for most common congenital heart defects Abbreviations: ASD, Atrial septal defect; APW, Aortopulmonary window; AV canal, Atrioventricular canal; HLHS, Hypoplastic left heart syndrome, LR, Left to right; PDA, Patent ductus arteriosus; TAPVC, Total anomalous pulmonary venous connection; TGA, Transposition of great arteries; TOF, Tetralogy of Fallot

yocardial Dysfunction and

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yocardial Damage

Chronic volume overload results in ventricular enlargement and ventricular dysfunction that is typically revered after correction. A small proportion of patients with sever hypoxia also develop severe ventricular dysfunction involving both ventricles. Heart failure is mostly the result of hemodynamic consequences of increased pulmonary blood flow, mitral or tricuspid valve regurgitation and severe myocardial hypertrophy. Systolic dysfunction is a relatively less common 436 cause.

Polycythemia and its dverse Consequences A

This is affected in all forms of CHD and is particularly striking in large left to right shunts. Children with CHD show a high prevalence (59% in recent Indian studies) of significant malnutrition (weight is more affected than height) and this tends to improve after correction irrespective of the underlying lesion. However, catch up growth is slow especially if CHD is corrected late.

These have been listed in Table 7.2.6. They contribute substantially to morbidity in CHD. Chronic hypoxia, in utero hypoxia and hypoperfusion and open heart surgery (especially operations performed under total circulatory arrest) contribute substantially. Brain abscess is uniquely associated with cyanotic heart disease (typically beyond the age of 2 years) where the right to left shunt bypasses the pulmonary filter.

Older children with cyanotic CHD are prone to complications from a chronically elevated red cell turnover. These include symptoms of hyperviscosity, gout, renal failure and gall stones.

hythm Disorders and udden Death S

Growth and Nutrition

Neurologic and Neurodevelopmental Consequences

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above lesions). However, the importance of maintaining good dental hygiene in all children with CHD cannot be overemphasized.

Chronic enlargement of heart chambers predispose to tachyarrhythmia. Chronic right atrial (RA) enlargement (such as in ASD, Ebstein’s and severe TR) predisposes to atrial flutter. This can be persistent and refractory. Chronic RV enlargement predisposes to malignant ventricular

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Diseases of Car iovas ular ystem

Table 7.2.6 Management of hypercyanotic spells

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Immediate steps •  Check airway and start oxygen. If child is uncomfortable with mask or nasal cannula, deliver oxygen via tube whose end is held half to one inch away from nose. This corresponds to delivering 80% oxygen. •  Knee-chest position •  Sedate child with subcutaneous morphine (0.2 mg/kg/dose) or IM ketamine (3–5 mg/kg/dose). •  Obtain a reliable intravenous access. •  Sodium bicarbonate 1–2 mL/kg given as 1:1 dilution or can be diluted in 10 mL/kg of isolyte P, which is given bolus as the initial resuscitating fluid. •  Correct hypovolemia (10 mL/kg fluid bolus of isolyte P or dextrose normal saline). •  Keep the child warm. •  Correct anemia by packed cell transfusion. Hemoglobin levels < 12 g/dL merit correction through a blood transfusion in children with cyanotic spells. •  Start beta blockade. Beta blockade is fairly safe unless a specific contraindication like bronchial asthma or ventricular dysfunction exists. It should always be given with heart rate monitoring. Medications and dosages •  Intravenous metoprolol 0.1 mg/kg, given slowly over 5 minutes – Can repeat every 5 minutes for a maximum of three doses   –  Can be followed by infusion 1–2 µg/kg/min – Monitor saturation, heart rates and blood pressure   –  Aim to keep heart rate below 100/min. •  Intravenous esmolol 500 µg/kg over 1 minute as loading dose, 50 µg/kg/min for 4 minutes; if desaturation persists without a significant decrease in heart rate, the loading dose will need to be repeated and the infusion rate can be increased in 50 µg/kg/min increments until 300 µg/kg/min. This infusion should be maintained at the rate that produces the desired result. Esmolol is relatively expensive but has the advantage of being very short acting. •  Intravenous propranolol (0.1 mg/kg) If desaturation persists and there is still no significant trend toward improvement despite maximum beta blockage •  Start vasopressor infusion. Methoxamine given intravenously at dose of 0.1–0.2 mg/kg/dose or intramuscularly (0.1–0.4 mg/kg/dose). •  Phenylepherine 5 µg/kg as bolus and then 1–4 µg/kg/min as infusion •  If spells are persistent, consider paralyzing the child, elective intubation and ventilation and plan for surgery, which can be corrective or palliative (BT shunt) •  If convulsions occur, consider IV diazepam 0.2 mg/kg or IV midazolam 0.1–0.2 mg/kg/dose, as slow push. After a spell •  After a spell is successfully managed, a careful neurological examination is mandatory. In case of suspicion of neurologic insult during a spell, a CT scan is to be done to assess the presence and extent of cerebral infarcts. •  Initiate maximally tolerated beta blockade (propranolol 0.5–1.5 mg/kg/dose 8 hourly or 6 hourly). The dose can be titrated by the heart rate response. Beta blockade may help improve resting saturation and can decrease frequency of spells. •  Do a detailed segmental analysis by two-dimensional echo for complete diagnosis. •  Plan toward early corrective or palliative operation (depending on the age and anatomy). •  Continue therapeutic (if anemic) or prophylactic iron therapy (if not anemic). Prevention Parents of patients diagnosed to have a cyanotic congenital heart defect should be counseled if the possibility of occurrence of a spell is anticipated: •  Explain to them the circumstances when a spell may occur •  Avoid dehydration •  Rapid control of temperature whenever fever occurs •  Encourage early surgical repair. Obtaining IV access in a cyanotic child can precipitate spells. This can be avoided by sedating child with IM ketamine (3–5 mg/kg) and/or by using local anesthetic skin ointment (Emlap) before attempting for venous access or blood sampling. Abbreviations: BT shunt, Blalock-Taussig shunt; IV, Intravenous; IM, Intramuscular

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Cyanotic pells All patients with the VSD-PS physiology are prone to cyanotic spells. Cyanotic spells are due to an acute decrease in pulmonary blood flow, increased right to left shunt

and systemic desaturation possibly due to the following reasons: • Infundibular spasm due to increased circulating cate cholamines as a result of effort of feeding or crying. • Activation of mechanoreceptors in right ventricle due to decrease in systemic venous return or that in left ventricle due to decrease in pulmonary blood flow, leading to peripheral vasodilatation and fall in systemic vascular resistance producing increased right to left shunt and systemic desaturation. Same mechanism can 437 account for occasional episodes of bradycardia. ­

tachycardia (VT) and can precipitate sudden cardiac arrest in a small fraction of patients. This is starting to become a significant long-term concern after TOF repair where the pulmonary valve is rendered incompetent. Similarly LV hypertrophy and dysfunction are associated with higher than usual risk of malignant VT.

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Younger patients have a higher likelihood of spontaneous closure of defects. Most ASDs and most VSDs that are destined to close or become very small do so before the age of 3 years. PDAs have a tendency to close in the first 2–4 weeks after which they seldom close, particularly in a preterm infant.

Size of the defect

Larger defects have little likelihood of spon taneous closure. ASDs > 8 mm are unlikely to close spontaneously. Similarly, large unrestrictive VSDs are also unlikely to close.

Location of the defect

Only fossa ovalis ASDs have a tendency to close. Primum and sinus venosus type of ASDs do not close. Muscular VSDs have the highest likelihood of spontaneous closure. Perimembranous VSDs can also close spontaneously. Outlet (subpulmonic) VSDs may close by prolapse of the aortic valve with the risk of aortic regurgitation. Inlet VSDs and malalignment type of VSDs (such as those occurring in TOF) do not close spontaneously.

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urvival of Patients with Congenital Heart Disease The natural history of common forms of CHD is shown in Figure 7.2.1. This figure is an approximation but serves to illustrate the fact that without correction, many children with CHD (especially those with cyanotic CHD) will not survive beyond infancy or early childhood. This is dramatically altered by correction through surgery and in some situations through catheter interventions. Following surgical correction, the natural history of many CHDs is dramatically improved. Flow chart 7.2.2 is a useful guide to outcomes after common operations for CHD. With accumulating follow-up data, however, it is becoming increasingly apparent that many “curative” operations have important long-term sequelae. The best example is surgery for TOF. For many years it was thought that TOF repair was curative. A transannular patch that sacrifices the pulmonary valve and leaves behind severe pulmonary regurgitation 438 was not thought to be of major importance. However, after 25–30 years of experience, it is clear that most patients will

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Effect of likelihood of spontaneous closure

Age at evaluation

pontaneous Closure of Heart Defects

Abbreviations: ASDs, Atrial septal defects; VSDs, Ventricular septal defects; PDA, Patent ductus arteriosus; TOF, Tetralogy of Fallot

develop progressive RV dilatation with increased risk of late HF and sudden cardiac death. Similarly, there are growing long-term concerns after the arterial switch operation (aortic root dilatation, silent coronary occlusion), AV canal repair (AV valve regurgitation) and coarctation (residual hypertension, aortic aneurysm). Additionally, there are operations that involve placement of conduits (pulmonary atresia, Rastelli operations for TGAVSD-PS). These require replacement with growth. The Fontan operation, a final solution for all univentricular hearts (single ventricle physiology) is best described as palliative with several significant long-term concerns.

Some defects have a tendency toward spontaneous closure and this can influence the timing of intervention. The defects known to close spontaneously are ASD, VSD and PDA (during the first few months of life). The variables that influence likelihood of spontaneous closure include age at evaluation (the likelihood of spontaneous closure declines with age and most ASDs and many VSDs are unlikely to close after the first 3 years of age), size of the defect (smaller defects are more likely to close), location of the defects (fossa ovalis ASDs, perimembranous and muscular VSDs can close on their own). Table 7.2.7 summarizes the variables that influence spontaneous closure. It is important to recognize the possibility of spontaneous closure while interpreting echocardiogram reports in infancy.



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Table 7.2.7 Spontaneous closure of heart defects

Prevention Education of the lay public on the dangers of consanguinity, drugs and teratogens in the first trimester of pregnancy, widespread immunization against rubella can prevent CHDs to limited extent. However, since most CHDs do not as yet have an identifiable etiology, there is no effective strategy available for their prevention in the periconceptional period. Fetal echocardiography is emerging as a modality for CHD prevention after 14–16 weeks gestation. Fetal echo is best suited to diagnose relatively severe forms of CHD. Conditions that are involving major chamber discrepancy (such as hypoplastic left heart syndrome), single ventricles, and common AV canal can be identified in a simple screening protocol (the four-chamber view). With some refinement (outflow tract and three-vessel views), additional conditions such as TOF, large VSD, TGA, persistent truncus arteriosus can be picked up as well.

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Cyanotic spell is a pediatric emergency, which requires prompt recognition and intervention to prevent disabling cerebrovascular insults or death. A cyanotic spell needs to be taken seriously not just because of the immediate threat but also because it indicates the need for early operation. It is commonly seen below 2 years (peaks between 2 months and 6 months). The onset is usually spontaneous and unpredictable and occurs more often in early morning, although can occur anytime in the day. The infant cries incessantly; he is irritable and often inconsolable. Tachypnea is prominent and a cardinal feature. Typically these infants have a pattern of deep and rapid breathing without significant subcostal recession. Cyanosis deepens as the spell progresses. Later gasping respiration and apnea ensues, which leads to limpness and ultimately anoxic seizures. Spells can last from minutes to hours. Auscultation reveals softening or disappearance of pulmonary ejection murmur. The management of cyanotic spell has been summarized in Table 7.2.6.

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Based on anatomy, ASDs are classified as follows: • Fossa ovalis ASD: They are located in the central portion of the atrial septum in the position of foramen ovale. Only these defects are amenable to closure in the catheterization laboratory. • Sinus venosus ASD: They are located in the region of the superior vena cava-right atrium junction. These defects do not have a superior margin because the superior vena cava straddles the defect. • Ostium primum ASD: These defects are created by failure to seal the septum primum. They are in the lower part of the atrial septum and the inferior margin of the defect is formed by the AV valve. • Coronary sinus ASD: An unroofed coronary sinus is a rare communication between the coronary sinus and the left

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entricular eptal Defect ncidence

Ventricular septal defect accounts for 15–20% of all CHDs. It is the most common heart defect. A

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Fossa ovalis defects with good margins can be closed percutaneously in the catheterization laboratory with occlusive devices. Others require surgical closure. Closure is recommended before school entry to prevent late complications. Small defects (< 8 mm) can be observed. Spontaneous closure is well recognized in small defects that are diagnosed in infancy or early childhood.

ncidence

Atrial septal defects occur as an isolated anomaly in 5–10% of all CHDs.

reatment

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Heart failure is exceptional in infancy. Pulmonary hyper tension is also relatively rare. A small proportion of patients develop PAH. It appears that those who are destined to develop PAH do so relatively early (often in the second or third decade). Atrial septal defect closure is primarily recommended to prevent complications in late adulthood. These include atrial arrhythmias and HF. T

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Natural History and Complications

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The physiology of ASD is that of a pre-tricuspid shunt (see the section on physiology of CHD). The heart murmur in ASD originates from the pulmonary valve because of the increased blood flow through this normal-sized valve; therefore, the murmur is systolic in timing. An increased flow through the tricuspid valve may result in a diastolic rumble at the lower left sternal border. The dilated RV cavity prolongs the time required for depolarization of right ventricle resulting in delayed P2. This delay also results from the prolonged “hang-out” interval because of the very low resistance in the pulmonary circulation. Additionally, the large ASD tends to abolish respirationrelated fluctuations in systemic venous return to the right side of the heart, thereby the fixed S2.

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atrium, which produces a clinical picture similar to other types of ASDs.

Diseases of Car iovas ular ystem

The most significant challenge of fetal echocardiography lies in identifying the population at risk. The low incidence of CHD together with relatively small proportion of CHD that occur in “high-risk” pregnancies makes fetal screening of CHD and inefficient exercise. Further, the expertise and equipment required for accurate fetal echocardiography is scarce in regions with poorly developed facilities for pediatric heart care. Once a serious CHD is identified, it is vital to counsel the families carefully and thoroughly about the postnatal manifestations, natural history, surgical options and their long-term outlook. Before 20 weeks of gestation, medical termination of pregnancy (MTP) is an option. After legal period of MTP, fetal echocardiography enables directed delivery at a center with a comprehensive pediatric heart program. This overcomes the logistic challenges of transporting a newborn with CHD and allows prompt institution of treatment in the newborn period (such as PGE 1 for duct-dependent lesions). It is a common practice to recommend fetal echocardiography for future pregnancies after diagnosis of serious CHD in a child. This practice is likely to have a low yield because only 2–8% of CHD tend to recur. The highest chance of recurrence is with obstructive lesions of the left heart. The detection of certain specific chromosomal anomalies in a child should prompt an evaluation of parents to identify a carrier state. Examples of these conditions include partial deletion of chromosome 22 (22q-11 or the CATCH 22 syndrome), translocation variants of trisomy 21) through fluorescence in situ hybridization (FISH) or karyotyping. The growing list of single gene mutations that are known to be associated with CHD that can be detected through laboratory tests may enable precise counseling for a larger proportion of families where a child is affected with CHD.

natomy

The ventricular septum may be divided into a small membranous portion and a large muscular portion. The muscular septum has three components: (1) the inlet, (2) the trabecular and (3) the outlet septum. The trabecular septum is further divided into central, marginal and apical portions. A VSD may be classified into perimembranous, inlet, outlet, central muscular, marginal muscular and apical muscular defects.

Pathophysiology The physiology is that of a post-tricuspid left to right shunt. The magnitude of the shunt is determined by the size of the 439 VSD and the level of PVR. The lower the PVR, the greater the

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Patent Ductus rteriosus

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It is the persistence of normal fetal channel connecting the aorta and pulmonary artery and accounts for 5–10% of all CHDs. Functional closure of the ductus occurs within 12–24 hours after birth due to contraction of the medial smooth muscle. Anatomic closure occurs between 2–3 weeks and is produced by fibrosis of the ductal tissue. Prematurity is associated with delay in the process of closure of the ductus.

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natomical and Physiological Considerations

PDA needs to be understood in two circumstances: (1) as a source of pulmonary blood flow in cyanotic heart disease with reduced pulmonary blood flow and (2) as a cause of left to right shunts. In the former situation, the PDA tends to be vertical, often from the undersurface of the aorta, while in the latter it connects the roof of the main pulmonary artery with the proximal descending thoracic aorta. In this section, we will focus on the latter only. The PDA is programmed to close early in life. In cases where the ductus fails to close normally, blood will shunt from left to right into pulmonary artery and lungs. This occurs increasingly as the PVR drops and the pressure in the aorta exceeds that of pulmonary artery. The volume of shunted blood will increase pulmonary blood flow, increase venous return to left atrium and cause LA/LV

Persistent patency of ductus arteriosus in preterm infants is well recognized in the era of modern preterm care. The prevalence of PDA in babies less than 1,750 grams is 45% and it increases closer to 80% in very low-birth-weight babies weighing less than 1,200 grams. Patent ductus arteriosus with significant left to right shunt is associated with varied complications, such as necrotizing enterocolitis, intraventricular hemorrhage and chronic lung disease in preterm babies. Effective and timely treatment of PDA enhances preterm survival and reduces risk of complications. Studies showed that closure of hemodynamically significant PDA is beneficial but the timing and best method of closure is not clear. A hemodynamically significant duct is identified clinically by features of HF, bounding pulses, evidence of pulmonary over-circulation (tachypnea, tachycardia and continued requirement of mechanical ventilation). An easily audible murmur often accompanies the hemodynamically significant duct, but this is typically absent if the duct is large and unrestrictive. Echocardiography aids considerably in determining the hemodynamic significance of a PDA. A size of greater than 1mm/kg body weight is considered the minimum for the PDA to be of significance. Additional findings that suggest an important PDA include flow reversal in descending aorta and LA and LV enlargement.

Decisions to close a VSD is dictated by many considerations that include anatomic subtype, number and size of the defects, age at diagnosis, symptom status, comorbidity and logistics of follow-up. Infants with large defects should be referred to a center early for infant heart surgery. The consequences of delaying surgery in the hope that the defect will close spontaneously are, sometimes, quite devastating. They include pneumonia that is severe and refractory to treatment, severe malnourishment and premature pulmonary vascular disease. Catheter closure is usually unrealistic in early infancy because of technical challenges. The long-term results of surgical closure in infancy are excellent.

Clinical Circumstances Preterm Infants

Older Infants Older infants with PDA present like any other post-tricuspid shunts (such as VSD). T

T

reatment

volume overload. The flow in the PDA occurs throughout the cardiac cycle. This results in a murmur, which starts in systole after S1, peaks at S2 and continues in diastole. This is a continuous murmur. The passage of increased blood across the mitral valve produces a mid-diastolic murmur as in any other post-tricuspid shunt. The prolonged LV systole results in delayed closure of the aortic valve and a late A2. With large PDA, S2 may be paradoxically split. The excessive diastolic back flow from the aorta results in a low diastolic pressure and bounding pulses.

reatment

Three modalities of definitive treatment are available for PDA and they need to be tailored to anatomy and clinical circumstances. For the preterm infant, indomethacin or ibuprofen should ideally be the first line of treatment. The younger the gestational age of the infant, the lesser is the likelihood of a response to indomethacin or ibuprofen. Beyond 10 days postnatal age, the ductus rarely responds to indomethacin. In these circumstances, surgery should be considered. Catheter closure has emerged as a very promising option for all forms of PDA. Two methods are available. They include coil occlusion and closure with occlusive devices. Today, surgery is reserved for large ducts in small infants.

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magnitude of left to right shunt. In VSD, the left ventricle starts contracting before the right ventricle, and highpressure gradient is maintained between two ventricles throughout systole. Hence the murmur is pansystolic. Passing through a normal mitral valve, the relatively larger volume of blood results in a mid-diastolic murmur at the apex. This is a very useful clue indicating a large flow and operability of the lesion. Since the left ventricle has two outlets, it empties relatively early. This results in early A2. Since ejection into right ventricle and pulmonary artery is increased, P2 is delayed. Therefore the S2 is widely split but varies with respiration. In a large VSD with increasing PVR, S2 splitting becomes less and less obvious. It is single once PVR is significantly elevated because of the reduced “hangout” interval.

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Coarctation of orta

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Like in AS, PS may involve the valve or occur above or below the valve. Subvalvar or infundibular PS, (“doublechambered right ventricle”) results from hypertrophied muscle bundles within the RV cavity. In the common form of pulmonary valve stenosis, the valve is thickened with fused or absent commissures. This valve characteristically domes in systole; the resultant click is best heard during expiration when the excursion of the valve is exaggerated by a relatively underfilled RV cavity. Another form of pulmonary valve stenosis is the dysplastic valve (frequent in Noonan



Congenital Pulmonary tenosis

Isolated coarctation is more common in males (3:1) and characterized by narrowing of aorta typically located near aortic attachment of ligamentum arteriosum or PDA. It can be a localized or discrete narrowing or associated with long segment tubular hypoplasia of the segment proximal to the coarctation (isthmus). There are two types of presentations described: (1) symptomatic newborns or infants with HF, (2) relatively asymptomatic adolescent or young adults who may have “minor” symptoms in the form of headache, epistaxis and leg fatigue. Depending on severity of obstruction, the femoral pulses are both weak and delayed (due to delayed upstroke of arterial pulse in lower extremity sites) or absent. This is a valuable physical sign and an excellent screening test in newborns as well. In older children, a systolic murmur is present over descending aorta, distal to obstruction (in left interscapular region). Sometimes, a continuous murmur of collaterals between vessels arising from pre- and post-coarctation segment is present over the back of the chest. Hypertension with significant difference in upper and lower limb systolic blood pressures (> 20 mm Hg), which exaggerates on exercise, is an inevitable consequence in older children, and this accounts for most of the late morbidity. Additionally, vascular complications such as aortic dilatation with aneurysm formation, and berry aneurysms in cerebral vasculature are commonly seen. The ECG in symptomatic infant shows RVH while left ventricular hypertrophy (LVH) is present in older children and adult. Newborns with severe coarctation require surgery for 441 lasting relief. In older children, balloon dilatation is a less invasive option and in adolescents and adults, stenting of







The most common cause of congenital AS is bicommissural aortic valve. The partial or complete fusion of commissures between right-left or right noncoronary commissures results in variable degrees of severity of AS. Very severe stenosis presents early in newborn period with LV dysfunction and HF; less severe forms present later. Other forms of LV outflow tract obstruction are less common and include subaortic membrane and supravalvar AS. The latter is seen in association with the Williams-Beuren syndrome. The symptoms of AS are related to LV outflow obstruction and include effort angina, dyspnea, syncope and fatigue on effort. There is a significant risk of sudden death with sever AS especially in adolescent and young adults. The murmur of AS is loudest over the ascending aorta [i.e. upper right sternal border (URSB) or aortic valve area] and characteristically radiates to the carotid arteries. Constant systolic ejections click just after S1 is a consistent physical finding in bicommissural aortic valve. This is highly sensitive and specific in children and often better heard at the apex. The ECG is characterized by evidence of LV hypertrophy (voltage with strain in severe cases). Severe aortic valve stenosis can be relieved by balloon dilatation in the catheterization laboratory. Many of these patients require aortic valve surgery to deal with progressive AR. Other forms of AS require surgical relief.

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These lesions can be divided into two groups: 1. Ventricular outflow obstructive lesions, i.e. • Aortic stenosis • Pulmonary stenosis • Coarctation of aorta 2. Stenosis of AV valves/ventricular inflow tract: • Congenital mitral stenosis • Supramitral ring • Cor triatriatum • Tricuspid stenosis Features common in ventricular outflow obstruction are concentric hypertrophy of the chamber proximal to obstruction due to pressure overload and an ejection systolic murmur (ESM) due turbulent flow of blood through the obstruction.

syndrome) that is characterized by tethering of the leaflets to the adjacent main pulmonary artery with narrowing of the main pulmonary artery at the sinotubular junction. Supravalvular PS often refers to the narrowing of branch pulmonary arteries. Most patients are acyanotic and well developed. Newborns with critical PS are cyanotic and tachypneic. Majority of patients are asymptomatic in infancy and childhood. Dyspnea and fatigue are mild as long as the right ventricle maintains normal stroke volume at rest and augments its stroke volume with exercise. The murmur of PS is loudest over main pulmonary artery (i.e. second LICS) and is associated with systolic thrill. The intensity and length of ESM is directly proportional to severity of PS. Wide spitting of S2 is due to delayed closure of pulmonary valve. The pulmonary component of S2 is soft. An inconstant ejection click (louder in expiration) is also audible at the site of the murmur. The interval between S1 and click varies inversely with the degree of PS. The ECG shows right ventricular hypertrophy (RVH). Neonates with critical PS may show predominant LV forces because of associated hypoplasia of right ventricle. Balloon valvotomy, a relatively simple intervention, is now accepted as the standard treatment for valvar PS. While dysplastic valves have a characteristically suboptimal response, balloon is still attempted in them.

Diseases of Car iovas ular ystem

bstructive esions

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1. Allen HD, Shaddy RE, Driscoll DJ, et al. Moss Adams’ Heart Disease in Infants, Children and Adolescents, 7th edition. Philadelphia, USA: Kluwer/Lippincott William and Wilkins; 2008. 2. Kumar RK, Prabhu SS, Ahamed Z. IAP Specialty Textbook of Pediatric Cardiology. New Delhi: Jaypee rothers; 2008. 3. Kumar RK, Shrivastava S. Pediatric heart care in India. Heart. 2008;94;984-90. 4. Vaidyanathan B, Radhakrishnan R, Sundaram KR, et al. What determines nutritional recovery in malnourished children undergoing correction of congenital heart defects? Pediatrics. 2009;124:e294-9. 5. Vaidyanathan B, Sathish G, Mohanan S, et al. Clinical screening for congenital heart disease at birth: a prospective study in a community hospital in Kerala. Indian Pediatr. 2011;48:25-30. 6. Viswanathan S, Kumar RK. Assessment of operability in congenital cardiac shunts with increased pulmonary vascular resistance. Cathet Cardiovasc Interv. 2008;71: 665-70.

















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B

There is downward displacement of septal and posterior leaflets of the tricuspid valve into the RV cavity. A portion of right ventricle is incorporated in right atrium (atrialized right ventricle). This contracts asynchronously with the right ventricle resulting either in right to left shunting via a patent foramen ovale (majority) or HF (rare). Additionally, there is a leak through the severely deformed tricuspid valve. Presentation is variable and dependent on the severity of the involvement. Severe disease may manifest in the newborn period. Mild disease may resent for the first time in adulthood. Re-entrant arrhythmias are the frequent accompaniment and may result from accessory (bypass) tracts in the region of the displaced leaflets.





Among the cyanotic CHDs, TOF has a relatively favorable natural history that allows survival beyond infancy in about 75% of cases. As a result, it is the most common CHD encountered beyond the age of 1 year. The disease has been a subject of intense study over several decades. The physiology is that of VSD with PS and has been described earlier in this chapter. Anatomically, it is characterized by the classic tetrad: severe RV outflow obstruction, large VSD, aorta that overrides the VSD and RVH. Within this classic tetrad, there are numerous anatomical variations, most of which have an important bearing on treatment strategies. Corrective operation for TOF involves closure of the VSD and relief of the RVOT obstruction. There is growing emphasis on retaining the pulmonary valve during initial repair to prevent pulmonary regurgitation and its major late consequences (RV dilatation, arrhythmia, HF and sudden death). However, this is not often possible if the component(s) of the RVOT are small. Although corrective operation is feasible in very young infants, many centers opt for palliative options initially. Palliation is possible in the very young through the BlalockTaussig shunt, balloon dilatation of the pulmonary vale or stenting of the patent arterial duct (if present). Cyanotic spells are the major concern in severe TOF and the management and prevention has been elaborated upon in the section on complications.

bstein’s nomaly



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the coarctation segment can yield maximum reduction in gradient. Irrespective of the treatment modality chosen, all patients with coarctation should ideally be followed lifelong for hypertension and vascular complications that may occur in spite of relief of the obstruction.

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7.3

Savitri Shrivastava



Several studies have suggested that RF follows Group A streptococcal pharyngitis. Outbreaks of RF usually occur with epidemics of pharyngitis due to rheumatogenic strains of streptococci. Rheumatic fever and recurrences can be prevented with specific antimicrobial treatment. The most accepted postulation is that M proteins from the rheumatogenic strains share certain epitomes with cardiac myocytes and sarcolemmenal membrane protein. Antibodies produced in the host by these epitomes cross react with cardiac tissues and produce pancarditis (i.e. involving pericardium, myocardium and endocardium). The data is not clear if this host response is related to genetic programming, acquired alterations in host defense or immunological mechanisms. Pathologically, acute RF results in diffuse exudative and proliferative reaction resulting in infiltration with lymphocytes, polymorphonuclear leukocytes, histiocytes and eosinophils. In some areas, typical Aschoff nodules are formed with aggregation of multinucleated giant cells. These inflammatory changes are diffuse affecting heart, large joints, brain and subcutaneous tissue. Long-term sequelae occur as a result of involvement of endocardium of valvular and subvalvular region resulting in valvular heart disease. The most common involvement is of mitral valve (most common being MR) followed by aortic (AR is more common), tricuspid and very rarely pulmonary valve. Microscopically, there is edema, inflammatory cell infiltration and capillary proliferation. Inflammatory infiltrates are also frequently seen in myocardium with scanty injury and loss of myocardial fibers. Pericardial involvement results in fibrinous pericarditis, which may result in pericardial effusion which is serosanguinous. It usually resolves completely, never causing constrictive pericarditis. Small pericardial effusion is common but cardiac tamponade rarely occurs.

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Clinical eatures The classical clinical picture of RF consists of streptococcal sore throat followed 10 days to few weeks later by various manifestations of RF, although the history of acute streptococcal sore throat is available only in 50% of patients. The guidelines for the diagnosis of acute RF were originally suggested by Dr T Duckelt Jones in 1944, subsequently revised by the American Heart Association in 1965, updated in 1992 and latest revised and updated (Table 7.3.1) by WHO in 2003. The guidelines consist of major, minor and essential criteria. Two major or one major and two minor criteria are required in the presence of essential criteria to diagnose acute RF. It is important to emphasize that these guidelines are meant to help a physician in making a firm diagnosis of RF and do not mean that a physician should not use his/her clinical judgment in diagnosing acute RF in the absence of these criteria. Diagnosis of acute RF requires two major or one major and two minor manifestations and evidence of group A streptococcal infection.

tiopathogenesis

Acute RF with carditis results in valvular regurgitation most commonly of the mitral valve of variable severity. This is due to plastering and thickening of posterior leaflet, thickening and retraction of anterior leaflet and lack of normal coaptation. With aortic involvement, AR is the most common abnormality. Rarely, the tricuspid valve is involved; pulmonary valve is usually not involved in the acute attack.

Table 7.3.1 Revised Jones criteria for the diagnosis of acute rheumatic fever Major criteria

Minor criteria

•  Carditis

•  Arthralgia

•  Chorea

•  Previous rheumatic fever or rheumatic heart disease (RHD)

•  Erythema marginatum •  Polyarthritis

•  Fever

•  Subcutaneous nodules

•  Elevated erythrocyte sedimentation rate (ESR) or C-reactive protein or leukocytosis

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In early 20th century, there has been a marked decline in the prevalence of rheumatic fever (RF) in developed world. The earlier decline is related to the improved standards of living hygiene, health, literacy (particularly of females), medical facilities, etc. Further decline occurred with easy availability of penicillin to treat streptococcal throat infection. The reported incidence of RF in Indian series varies from 0.42–10.9 per 1,000 and the prevalence of rheumatic heart disease (RHD) using clinical criteria as reported varies from 0.56–11 per 1,000. Studies from some parts of India (Kerala/Chandigarh) suggest that there is a decline in the prevalence. Recent studies in India using echocardiography show a prevalence of RHD from 0.12–0.67 per 1,000.

•  Prolonged PR interval on ECG Essential criteria Evidence for recent streptococcal infection as indicated by: •  Increased levels of antibodies against streptococci •  Positive throat culture for Group A streptococcus •  Recent scarlet fever

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Noncardiac Manifestations of Rheumatic Fever

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rthritis: Rheumatic arthritis is a fleeting polyarthritis involving large joints like knees, ankles and elbows. Uncommonly smaller joints can be involved. The arthritis is typically migratory. The affected joints have redness, A

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inor Criteria

They are divided into clinical and laboratory.

Clinical ­

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ever: Usually present in 90% of patients, the tem perature usually goes up to 39.5°C. • rthralgia: Subjective joint pains without physical signs are labeled as arthralgias. Many Indian authors take it as major criteria. • History of previous RF or RHD. A

•



Laboratory •

Acute phase reactants consisting of polymorphonuclear leukocytosis, increased sedimentation rate and pre sence of C-reactive protein. The leukocyte count usually is between 10,000/cmm and 15,000/cmm. The sedimentation rate is almost always elevated during acute RF and remains so for 4–10 weeks in almost 80% of patients. In a small proportion of patients, it may remain elevated even beyond 12 weeks. C-reactive protein is a beta globulin, which is increased uniformly in all patients of acute RF. Absence of raised C-reactive protein goes strongly against the diagnosis of acute RF. Presence of C-reactive protein, however, is not diagnostic since it becomes positive in many infections. • lectrocardiogram: Prolonged PR interval is a nondiagnostic criterion since it can occur in many infections. Higher grades of block like second-degree ­

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The rheumatic carditis is a pancarditis involving pericardium, myocardium and endocardium. Carditis occurs in 34–90% of patients with acute RF. It is an early manifestation of RF so that by the time a patient seeks help, the patient already has evidence of carditis. Almost 80% of those patients who develop carditis do so within the first 2 weeks of the onset of RF. • Pericarditis: Pericarditis results in precordial pain, which may be quite severe. On auscultation, a pericardial friction rub is present. Clinical pericarditis is seen in approximately 15% of those who have carditis. The ECG may show ST and T changes consistent with pericarditis. As a rule, rheumatic pericarditis is associated with only small pericardial effusion and does not result in either tamponade or constrictive pericarditis. A patient of rheumatic pericarditis always has additional MR or AR murmurs or both. If after disappearance of the pericardial friction rub there are no murmurs, it is unlikely to be due to RF. • yocarditis: The features diagnostic of myocarditis are (1) cardiac enlargement, (2) soft S1, (3) protodiastolic (S3) gallop, (4) congestive cardiac failure and (5) Carey Coomb’s murmur. Carey Coomb’s murmur is a low pitched delayed diastolic mitral murmur heard during the course of acute RF. It tends to disappear after the myocarditis subsides. Most likely it is due to increased diastolic flow secondary to MR across inflamed rigid mitral valve. The disappearance can be explained by the decrease in the LV size following subsidence of myocarditis and better function of mitral valve— papillary muscle complex resulting in decrease in MR and subsidence of inflammation causing decrease in turbulent flow. • ndocarditis: Endocardial lesions are most important and tend to leave permanent scarring in most cases. The endocardial inflammation is most severe and common in the mitral and aortic valves, less common in the tricuspid valve and least in the pulmonary valve. The inflammation results in regurgitation murmurs. The most common finding of carditis is apical pansystolic murmur of MR occurring in 92–95% of patients. Aortic valve involvement results in early diastolic murmur of AR. Aortic valve is involved in 20–25% of cases; it is an isolated finding in only 5–8% of cases. Pathologically, tricuspid valve involvement is seen in 30–50% of cases. Clinical involvement of tricuspid valve in first attack of RF is extremely uncommon. Pulmonary valve involvement alone is almost never seen in acute RF.



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warmth, swelling, pain and limitation of movements. It is an early manifestation and occurs in 30–50% of cases in our country; there is no residual damage of the joints. • ubcutaneous nodules: Subcutaneous nodules appear as nontender, nonadhesive nodules varying in size from pin head to almond on body prominences like shin, wrist, elbow, knee, ankle, spine and occiput. They are late manifestations occurring around 6 weeks after the onset of RF, rarely as early as 3 weeks after the onset. In Indian series, their incidence is 5–20%. Usually they disappear in few days to few weeks rarely lasting even up to 1 year. Patients who have nodules always have carditis. Persistence of nodules is associated with chronic carditis. • Chorea: Chorea is characterized by purposeless jerky movements resulting in abnormal speech, muscular incoordination, dropping of articles, awkward gait and weakness. There is also emotional instability. Chorea is three to four times more common in females. It is a late manifestation occurring about 3 months after the onset of acute RF. It is reported to occur in 5–36% of cases. It is usually self limiting. • rythema marginatum: The rash is reddish, not raised above the skin and non-itching, with serpigenous margins. It starts as a red spot with a pale center, increasing in size to coalesce with adjacent lesions to form serpigenous margin. It increases by applying heat. Though specific but seen extremely rarely in India, probably due to dark complexion.

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ajor Criteria

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There is no specific treatment. Management is symptomatic combined with suppressive therapy (Table 7.3.2). In suppressive therapy, either aspirin or steroids can be used. The total duration of aspirin or steroid therapy is generally 12 weeks. With aspirin, the full doses are given for 10 weeks and then tapered off in next 2 weeks. Full doses of steroids are given for 3 weeks and then tapered very gradually in the next 9 weeks. The most commonly used steroid is prednisone. The dose is 60 mg/day for patients weighing more than 20 kg. This is continued for 3 weeks and then reduced to 50 mg/ day for 1 week and 40 mg/day for another week. Following this, the reduction in dose is by 5 mg/week. In patients

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Bed rest •  It is advised in all patients with carditis till activity subsides. •  Immobilization may have to be continued for 2–3 months especially in the presence of congestive failure. Diet •  Salt restriction is not necessary unless congestive cardiac failure is present. •  Easily digestible nutritious diet with vitamin supplements should be given. Antimicrobial therapy •  Penicillin: After testing skin sensitivity, procaine penicillin 400,000 units of, intramuscularly (IM), twice daily for 10 days followed by prophylactic injection of benzathine penicillin –  1.2 mega units every 21 days above 10 years of age. –  0.6 mega units 1 M every 15 days if the age is less than 10 years. •  Patients sensitive to penicillin should be advised to take erythromycin 20–40 mg/kg in two divided doses. Suppressive therapy Aspirin or steroids are given as suppressive therapy. •  For patients having carditis with congestive cardiac failure, use of steroids is generally mandatory. •  For carditis without congestive cardiac failure, one may use either steroids or aspirin; however, the author prefers use of steroids. •  For patients without carditis, it is preferable to use aspirin. Management of chorea •  Usually self limiting •  Complete physical and mental rest •  In resistant cases, phenobarbitone, 3–5 gm/kg/day •  Chlorpromazine, diazepam, diphenhydramine, haloperidol or promethazine can also be used to provide sedation.

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The essential criteria include evidence of recent strep tococcal infection. • The best out of these is the presence of antibodies against streptococci. The most common in use is the antistreptolysin “O” titer. Considerable confusion exists regarding the levels, which should be considered significant as the normal values differ significantly in different areas. Elevated levels of antistreptolysin “O” only indicate previous streptococcal infection and not RF. The higher the level, more the likelihood of a recent streptococcal infection; lower level considered “normal” do not necessarily exclude a recent streptococcal infection. Rising titers of antistreptolysin “O” is a strong evidence of a recent streptococcal infection. To increase the sensitivity, other antibodies can also be tested. Deoxyribonuclease B (anti-DNase B), antihyaluronidase (AH), streptozyme (SZ) are used by many centers. Single antibody sensitivity is 70%. With two antibodies tested, it rises to 90% and with three antibodies tested, it rises to 95%. With paired sera testing of single antibody, the sensitivity is 80% rising to 99% if paired sera of two antibodies are tested. • Positive throat culture for streptococci is relatively uncommon when a patient presents with acute RF. Positive throat culture cannot be equated with the diagnosis of RF. Positive throat culture means that streptococci are present in the throat. The patient may or may not have RF. • The third feature suggestive of the diagnosis of recent streptococcal infection is the history of recent scarlet fever. The desquamation of skin of palms and soles indicates that the patient has had scarlet fever within the previous 2 weeks. Scarlet fever is rare in India. • Rapid streptococcal antigen test was also tried but because of low sensitivity although high specificity, it was not found very useful.

Table 7.3.2 Treatment of acute rheumatic fever

weighing 20 kg or less, the dose is 40 mg/day for 2 weeks and then reduced by 5 mg/week. The dose of aspirin is 90– 120 mg/kg/day in four divided doses (if facilities for blood salicylate level estimation are available, the dose is modified to maintain a blood salicylate level of 20–25 mg/dL for 10 weeks and later tapered off over 2 weeks).

Prevention It would be ideal to provide primary prevention of RF. Primary prevention requires identification of streptococcal sore throat and its treatment with penicillin in the population. The treatment modalities have been summarized in Table 7.3.3. Table 7.3.3 Drugs for primary prophylaxis of acute rheumatic fever  

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ssential Criteria

Diseases of Car iovas ular ystem

AV block especially of the Wenckebach type may also be seen. Complete AV block is extremely rare as a manifestation of acute RF. Prolongation of QTc (corrected QT interval) is suggestive of myocarditis.

Drugs

Dose

Sore throat treatment (duration)

Benzathine penicillin G (deep IM injection) after sensitivity test (AST)

1.2 million unit (> 27 kg) 0.6 million unit (< 27 kg)

Single dose

Penicillin V (oral)

Children: 250 mg qid Adult: 500 mg tid

10 d 10 d

Azithromycin (oral)

12.5 mg/kg/day once daily

5d

Cephalexin (oral)

15–20 mg/kg/dose bid

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In pediatric cardiac practice, roughly 20–25% of cases in general have RHD, resulting in crippling valvular heart disease in many of them. Mitral valve is the most common valve involved in RHD. It may be regurgitant, stenotic or may have combined regurgitation and stenosis, combined mitral and aortic valve disease in the next common subset. Isolated aortic valve involvement is seen in only 2–8% of cases. Isolated rheumatic tricuspid valve disease does not occur. Tricuspid regurgitation—functional or organic is quiet common. Tricuspid stenosis occurs rarely and mostly with MS.

Clinical Features

In a child with MR, one should keep in mind other causes like mitral valve prolapse, cleft mitral valve, L-transposition with regurgitant left AV valve and connective tissue disorders.

Investigations lectrocardiogram: It reveals sinus rhythm and may be normal with mild MR. With increasing degree of MR, left atrial (LA) overload and LV volume overload is seen. Left atrial enlargement results in bifid P wave (P-mitrale). Left ventricular enlargement results in tall R waves in leftsided leads (I, aVL, V5, V6) with deep q waves indicating volume overload of left ventricle. In cases of severe MR, RV hypertrophy may be seen due to the development of pulmonary hypertension. • Chest -ray: Significant MR results in LA and LV enlargement with changes of pulmonary venous hypertension. • chocardiogram: It clearly shows the altered valve pathology, degree of LA and LV enlargement and function, and quantum of regurgitation. E

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Management Symptomatic patients with moderate-to-severe MR will need decongestive therapy [including angiotensin converting enzyme (ACE) inhibitors]. The patients should be carefully evaluated if the mitral valve could be repaired surgically. Patients with severe MR with decreasing LV ejection fraction need early surgical intervention. If the valve can not be repaired, they will need mitral valve replacement.

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Exertional fatigue and palpitation are common features. Exertional dyspnea and features of right-sided cardiac failure are late manifestations of severe grades of MR and LV failure. There is no tachycardia, tachypnea or basal rales unless significant LV overload/failure occurs. The pulse pressure is wide with significant MR. The cardiac size increases with increasing severity of MR resulting in LV hyperdynamic impulse downwards and outwards. There may be a palpable LVS3. The S1 may be soft, normal or loud. It may be masked by the murmur. The S2 is normal with mild MR; with severe grades of MR, it becomes wide variable split due to early A2 as LV systole is shortened due to part of stroke volume regurgitating in the left atrium. With severe MR and CHF, P2 446 becomes loud due to high pulmonary arterial pressures. Left ventricular S3 is generally audible with significant MR due to

Differential Diagnosis

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Chronic heumatic Heart Disease

increase in early diastolic filling. Moderate-to-severe degree of MR results in a low-pitched delayed diastolic murmur at the apex, which may be palpable as a diastolic thrill. A diastolic thrill is more commonly felt with MR than a systolic thrill. Systolic thrill is uncommonly felt at apex in MR as the blood is regurgitating in the left atrium, which is posteriorly placed. The diagnostic feature of MR is a pansystolic murmur best heard at the apex and radiating to the axilla. With significant MR, a low frequency delayed diastolic murmur is audible at the apex; the duration of murmur increases with increasing severity of MR. If MR is severe, the diastolic rumble is audible throughout diastole but has no presystolic accentuation in absence of MS. In patients with severe MR, there are also features of CHF like raised JVP and hepatomegaly.

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Its success depends on the awareness of parents regarding dangers of sore throat. Therefore, for primary prevention it is necessary to educate the community regarding the consequences of streptococcal sore throat. Logistically, it is difficult in our country since it requires (1) identification of sore throat, which is dependent on education of parents, (2) rapid laboratory confirmation of streptococcal infection of the throat and (3) medical help and availability of penicillin. Secondary prevention consists in giving long-acting benzathine penicillin intramuscularly. The dose is 1.2 mega units once every 3 weeks in patients above the age of 10 years or 0.6 mega units every 2 week below the age of 10 years. The injection is painful and some patient gets fever for 24–36 hours following the injection. As such, it is preferable to give the injection on a Saturday afternoon to avoid loss of studies for the child. In presence of carditis, ideally penicillin prophylaxis should continue life long. Less than ideal would be to continue it till the age of 35 years. If there is only polyarthritis but no carditis, usually the penicillin prophylaxis should be given for 5 years after the attack and subsequently all clinical attacks of streptococcal sore throat should be treated with penicillin. If there is allergy to penicillin (which is very rare in children), erythromycin can be used but this is not ideal.

Clinical Features In pediatric age group, male patients commonly have MS. The patient complains of shortness of breath on exertion initially. With increasing severity, this becomes more severe and the child becomes breathless on walking short distances. Subsequently, the child starts getting paroxysmal nocturnal dyspnea and breathlessness at rest. Later stages with development of severe pulmonary hypertension and TR features of CHF develop. The patient can also have

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lectrocardiogram: The rhythm is usually sinus; LA overload is seen. With increasing pulmonary hypertension, increasing degree of right axis deviation, RV hypertrophy (tall R wave in right-sided leads) and RA overload (tall peaked “P” wave) are seen. • Chest -ray: Heart size is usually normal, with development of TR and CHF. Cardiomegaly develops due to RA and RV enlargement. The left atrium is enlarged. Features of varying grades of pulmonary venous and arterial hypertensions are also seen. Two-dimensional echocardiogram with color flow mapping clearly shows the stenotic mitral valve; the mitral

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Differential Diagnosis

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Cor triatriatum, supramitral ring, congenital MS and LA myxoma are rare entities that can sometimes mimic the presentation of MS.

Management

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Salt restricted diet and diuretics are useful to reduce the pulmonary venous congestion. If there is evidence of cardiomegaly and CHF, digoxin is useful. Basically the mitral obstruction has to be relieved. Presently, balloon dilatation of mitral valve percutaneously is the method of choice. If it is not feasible, surgical closed mitral valvotomy is done. Both procedures have identical results. Both these procedures relieve the commissural fusion and to some extent the subvalvular fusion but chordae shortening and fusion are not relieved. If there is marked fibrosis of the valve and subvalvular apparatus, open surgical commissurotomy may be needed.

ortic egurgitation R

A



Investigations

valve area can be calculated. The gradient across the mitral valve is calculated by taking the velocity of the mitral inflow on Doppler. The peak velocity of TR gives the estimate of pulmonary arterial pressures.

Diseases of Car iovas ular ystem

hemoptysis or pulmonary edema due to severe pulmonary venous hypertension. On examination, there may be tachycardia and low pulse volume. Jugular venous pressure is normal with mild MS. With severe MS and TR, elevated JVP with prominent “V” wave (due to regurgitation of blood into right atrium) and rapid “Y” descent is seen (in the presence of TR without tricuspid stenosis). Enlarged and tender hepatomegaly, which may be pulsatile, if seen with significant TR, is seen. Respiratory rate with mild MS is normal; tachypnea develops with significant MS. Basal crepitations are also heard with significant MS. If the patient develops pulmonary edema severe respiratory distress, extensive rales and cyanosis are seen. Precordial examination reveals normal heart size in most cases. Cardiac enlargement is seen in the presence of CHF and TR. The apex beat is tapping; parasternal heave is present with the development of pulmonary hypertension. At this stage, P2 many also be palpable. Mild TR does not result in RV dilatation. Therefore, there is no parasternal pulsation. Significant TR results in RV dilatation resulting in parasternal lift. If the pressure in the right ventricle is elevated, parasternal pulsations can be seen and on palpation parasternal heave is felt. A systolic thrill is rarely felt along left or right sternal border. A diastolic thrill could be felt at the apex. On auscultation, the S1 is loud, S2 is normally split with loud pulmonary component, loudness depending on the degree of pulmonary hypertension. An opening snap—hallmark for the diagnosis of MS is audible at the apex at the beginning of diastole. The closure the opening snap to the A2, the severe is the MS. A low-pitched delayed diastolic rumble is audible at the apex with presystolic accentuation immediately after the opening snap. In the presence of significant TR, systolic pulsations can be felt over the liver, which enlarges with the development of CHF. A systolic murmur along the left sternal border increasing with inspiration or leg raising is the hallmark for the diagnosis of TR. With significant regurgitation, S3 can be heard in the tricuspid area; if the quantum of regurgitation is significant, a delayed diastolic murmur across tricuspid valve is heard. Rarely, an opening snap and presystolic accentuation of the diastolic murmur is heard if tricuspid stenosis is present.

Clinical Features Aortic regurgitation is common in male patients. The presenting symptom is usually palpitation and increased neck pulsations due to high stroke volume. Exertional fatigue and dyspnea develops in patient of significant AR, which become more prominent with the development of CHF. The pulse pressure is the best clinical parameter to asses the degree of AR. The wider the pulse pressure, severe is the regurgitation. The wide pulse pressure results in several signs (Table 7.3.4). It also results in prominent neck, suprasternal, peripheral and abdominal pulsations. The pulse shows a sharp rise and fall the so called water hammer pulse that becomes more evident on elevating the arm. Nodding of the head with cardiac cycle may be seen (de Musset’s sign). The increased pressure difference between the systolic pressure of upper and lower limbs is called Hill’s sign. Normally this difference is less than 20 mm Hg. With mild, moderate and severe regurgitation, it is 20–40 mm Hg, 40–60 mm Hg and greater than 60 mm Hg, respectively. Pistol shot sounds can be heard over large arteries with significant regurgitation. If slight pressure is applied over these arteries, a systolic murmur can be heard and if pressure is applied distally, a diastolic murmur is heard. This is called Durouzieu’s sign. Palpation of the precordium may be unremarkable with mild AR; with significant regurgitation, the cardiac impulse is displaced down and out and is of LV hyperdynamic type. The greater the amount of regurgitation, the bigger is the heart size. Rarely with severe regurgitation, the whole of

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Differential Diagnosis In a case of isolated AR, one should look for Marfan’s syndrome, Hurler’s syndrome and nonspecific aortoarteritis. The other Table 7.3.4 Peripheral signs of aortic regurgitation (AR) Corrigan’s pulse

Dancing carotids

De Musset’s sign

Head nodding

Quinke’s sign

Capillary pulsations over nail bed

Traube’s sign

Pistal shot sounds over femorals

Hill’s sign

Lower extremity blood pressure > upper extremity blood pressure > 20 mm Hg—Mild AR > 40 mm Hg—Moderate AR > 60 mm Hg—Severe AR

Management Mild AR is well tolerated. Significant AR causing LV dilatation may benefit with ACE inhibitors. If the left ventricle is progressively dilating and the patient is symptomatic or there is evidence of CHF, decongestive therapy along with ACE inhibitor should be started and patient planned for surgery, aortic valve repair or replacement. In most of these patients, the aortic valve repair is not possible and they end up with valve replacement. The improvement with surgery is remarkable but with prosthetic valve, the child has to take life-long anticoagulant therapy with its own inherent hazards.

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lectrocardiogram: The ECG may be normal with mild AR. If significant regurgitation is present, the ECG shows evidence volume overload of left ventricles—increased LV voltage with prominent “Q” waves and tall “T” waves. In patients with severe AR, particularly in presence of CHF, LA overload may also be seen. • -ray chest: In cases of mild AR, there is no cardiomegaly and aorta may be prominent. With increasing AR, heart size enlarges due to enlarged left ventricle. Changes of pulmonary venous hypertension develop with severe regurgitation and LV failure. • chocardiography: Two-dimensional and color Doppler echocardiography can confirm the diagnosis and also estimate the severity of AR, degree of LV enlargement and function. X

•

causes of AR like congenital aortic valve disease, rupture sinus of Valsalva or VSD with AR should be kept in mind.

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the precordium is pulsatile. The S3 may be felt over the LV apex. In some cases, a systolic thrill may be felt in second LICS. The S1 is soft, the S2 is normally split with mild-tomoderate regurgitation; it may be paradoxical with severe regurgitation particularly with LV failure. The murmur of AR is high pitched decrescendo diastolic starting with A2. A systolic ejection murmur is commonly heard in the aortic area conducted to the neck in cases with significant AR. Delayed diastolic rumble is heard in some cases of AR (Austin Flint murmur). Some of the other signs have been listed in Table 7.3.4.

Tricuspid regurgitation is commonly seen in patients of rheumatic mitral valve disease (20–50%). It can be functional or organic. If TR is present in absence of severe PAH, it is likely to be organic, but if PAH is present it can be either functional, organic or both.

Clinical Features There are no specific symptoms of TR except pain in right hypochondria and fatigue due to low cardiac output. The symptoms will depend on the lesion with which TR is associated. The signs diagnostic of TR are prominent “V” wave with rapid “Y” descent in JVP, systolic pulsations over liver, systolic murmur at lower left or right sternal border, increasing in severity with inspiration. It may sometimes be associated with a systolic thrill, enlarged right ventricle, S3, delayed diastolic rumble over tricuspid area. Tricuspid stenosis results in slow Y descent in JVP, diastolic rumble with presystolic accentuation in the tricuspid area and rarely an opening snap before the diastolic rumble. The other physical finding will be of the associated lesion; isolated tricuspid valve diseases of rheumatic etiology do not occur.

Investigations Electrocardiogram may reveal evidence of RA and RV overload pattern in addition to other changes due to the associated lesions. Significant TR results in cardiac enlargement due to dilatation of right atrium and right ventricle. Two-dimensional and color Doppler evaluation easily confirms tricuspid valve disease. The degree of regurgitation is estimated by color flow mapping.

Mueller’s sign

Systolic pulsation of uvula

Rosenbach’s sign

Pulsatile liver

Management

Gerhardt’s sign

Enlarged pulsatile spleen

Light house sign

Blanching and flushing of forehead

Landolfi’s sign

Alternating constriction and dilatation of pupil

Becker sign

Pulsations of retinal vessels

Presence of significant TR results in cardiomegaly and CHF, and the patients need decongestive therapy. The complete management will depend on the associated valvular lesions. Severe grades of TR results in dilatation of tricuspid annulus. If the tricuspid annulus is greater than 21 mm/m2,

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1. Grover A, Dhawan A, Lyengar SD, et al. Epidemiology of rheumatic fever and rheumatic heart disease in a rural community in northern India. Bull World Health Organ. 1993;71:59-66. 2. Gupta I, Gupta ML, Parihar A, et al. Epidemiology of rheumatic and congenital heart diseases in school children. J Indian Med Assoc. 1992;90:57-9. 3. Jones TD. The diagnosis of rheumatic fever. JAMA. 1994;126:481-4. 4. Kumar PK, Paul M, Francis TP. RHD in Indian: Are we ready to shift from secondary prophylaxis to vaccinating high-risk children? Curr Sci. 2009;97:397-404.

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ibliography

5. Massell BF, Chute CG, Walker AM, et al. Penicillin and the marked decrease in morbidity and mortality from rheumatic fever in the United States. N Engl J Med. 1988;318:280-6. 6. Misra M, Mittal M, Singh R, et al. Prevalence of rheumatic heart disease in school-going children of Eastern Uttar Pradesh. Indian Heart J. 2007;59:42-3. 7. Padmawati S. Rheumatic fever and rheumatic heart disease in India at the turn of the century. Indian Heart J. 2001;53: 35-7. 8. Sanyal SK, Thapar MK, Ahmed AH, et al. The initial attack of acute rheumatic fever during childhood in North India: a prospective study of the clinical profile. Circulation. 1974;49:7-12. 9. Shrivastava S, Subramanyam K, Tandon R. Severity of rheumatic mitral regurgitation in children. Indian J Pediatr. 1992;59:579-83. 10. Shrivastava S, Tandon R. Severity of rheumatic mitral stenosis in children. Int J Cardiol. 1991;30:163-7.

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it has to be repaired by annuloplasty in addition to the other valvular lesions at surgery.

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ongestive Heart ailure: iagnosis and Management

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auses of Heart ailure in nfants and hildren

Children can have diverse causes of HF depending on the age, geographical location and many other factors. The prominent causes of HF or ventricular dysfunction in children have been provided in Table 7.4.1. Table 7.4.2 enumerates the likely causes of HF by age at presentation. This is important as the symptoms and signs of HF can be confusing or fairly nonspecific in children. Heart failure presenting on the first day of life is commonly due to metabolic abnormalities and not CHD. Conditions producing fetal HF such as Ebstein’s anomaly or abnormal heart rate/rhythm are also causes of HF on day 1 of life. Obstructive and duct dependent lesions can present with HF or acute circulatory shock soon after birth. Heart failure due to left to right shunts occurs later (4–6 weeks) as the PVR falls, though large VSD, PDA, atrioventricular septal defect (AVSD) may present earlier. Children with isolated ASD are mostly asymptomatic; if an infant is diagnosed to -



Congestive heart failure is a complex syndrome resulting from multiple causes, which are different in children as compared to adults. This term is increasingly being replaced by heart failure, since peripheral congestion may not be present in all cases. Several definitions have been proposed for HF, which again reflects our less than complete understanding of this enigma. A commonly used definition is: “it is a pathophysiological state in which an abnormality of cardiac function is responsible for the failure of the heart to pump blood at a rate commensurate with the requirements of the metabolizing tissues, or does so only at elevated filling pressures”. In case of children, this requirement includes growth and development. Heart failure in infants and children is commonly secondary to congenital heart defects (shunts or obstructive lesions). Less common causes include cardiomyocyte dysfunction secondary to myocarditis/cardiomyopathies. Palliated CHD leading to HF is increasingly being recog­ nized.

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Table 7.4.1 Causes of heart failure in children by underlying pathology Cause

Comment

Volume overload (relative or absolute)

CHD with increased pulmonary blood flow (VSD, PDA, AVSD, TGA, truncus, TAPVC, etc.)* arteriovenous fistula or malformations, anemia, thyrotoxicosis ***

Obstructive lesions/atretic valves or great vessels

AS, PS, mitral valve atresia or stenosis, coarctation of aorta, aortic interruption**

Regurgitant lesions (MR/TR)

Congenital (e.g. as part of AVSD, Ebstein’s), acquired (e.g. RF/RHD), postoperative*

Myocyte dysfunction Primary

Inborn errors of metabolism, muscular dystrophies, DCM, drug-induced, hemoglobinopathies***

Inflammatory

Myocarditis, Chagas, HIV*

Hemodynamic

Obstructive or regurgitant lesions, HT**

Abnormal rate/rhythms

Tachycardiomyopathy, bradycardia, AV dyssynchrony***

Abnormal morphology

SV physiology**, ALCAPA

Ischemic

CAD (including premature CAD)***

Postoperative

Postbypass, SV surgeries, post-TGA repair**

Abnormal homeostasis

Hypothermia, hypoxia, hypocalcemia, hypoglycemia, sepsis*** (peculiar to neonatal period)

*: common **: uncommon ***: rare (may be common in specific age group/settings)

Abbreviations: CHD, Congenital heart disease; VSD, Ventricular septal defect; PDA, Patent ductus arteriosus; AVSD, Atrioventricular septal defect; TGA, Transposition of great arteries; TAPVC, Total anomalous pulmonary venous connection; AS, Aortic stenosis; PS, Pulmonary stenosis; MR, Mitral regurgitation; TR, Tricuspid regurgitation; RF, Rheumatic fever; RHD, Rheumatic heart disease; DCM, Dilated cardiomyopathy; AV, Atrioventricular; CAD, Coronary artery disease; SV, Single ventricle; ALCAPA, Anomalous left coronary artery from the pulmonary artery

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2–6 months

•  •  •  •  •  •  • 

•  Causes at 1–2 months •  Coarctation of aorta •  Aortic stenosis

Older children

•  •  •  •  • 

•  •  •  •  •  • 

Large VSD Large PDA AVSD Persistent truncus arteriosus Unobstructive TAPVC

RF/RHD CHD with complications Cardiomyopathies Severe PS with TR Palliated/postoperative CHD Tachycardiomyopathies

Abbreviations: VSD, Ventricular septal defect; PDA, Patent ductus arteriosus; AVSD, Atrioventricular septal defect; TAPVC, Total anomalous pulmonary venous connection; TGA, Transposition of great arteries; ALCAPA, Anomalous left coronary artery from the pulmonary artery; AS, Aortic stenosis; PS, Pulmonary stenosis; RF, Rheumatic fever; RHD, Rheumatic heart disease; CHD, Congenital heart disease; TR, Tricuspid regurgitation

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Epidemiology of HF in children is a difficult science given the fact that symptoms, etiology, diagnostic criteria and outcomes are quite heterogeneous. The annual incidence of CHD is about 8 per 1,000 (0.8%) of live births, of which one third are severe enough to warrant attention. Half of these result in HF. Rheumatic fever/rheumatic heart disease is an important cause of HF in children in developing countries like India. While the incidence and prevalence of RF and RHD are well documented, there are no data on presentation with HF in this group, although a significant majority of acute rheumatic carditis and established juvenile MS will present with features of HF.

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The cornerstones for rapid clinical diagnosis of HF in children are chest radiograph and an ECG.

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have ASD and is in failure, the likely diagnosis is the much more malignant CHD, total anomalous pulmonary venous connection (TAPVC). Heart failure secondary to CHD is unusual after the first year of life unless complicated by IE, anemia, infections or arrhythmias. Thus, older children (usually beyond 2 years) are likely to have other causes for HF like acute/chronic RHD, myocarditis, cardiomyopathies and postoperative CHD.

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Critical AS/PS Obstructive TAPVC Hypoplastic left heart Coarctation of aorta Adrenal insufficiency TGA with intact septum Day 1 causes

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The clinical features of HF in children vary according to the cause and age of the child. An important point to remember is that raised JVP, peripheral edema, effusions and chest crepitations are not seen in neonates and are unlikely in young children as a sign of HF. Chest crepitations, in fact, suggest the possibility of underlying chest infection, which so often accompanies HF in children especially in high pulmonary flow situations. Common clinical features of HF in children have been given in Table 7.4.3. These features are quite nonspecific in neonates and may resemble features of septicemia. Thus a high index of suspicion is required. Routine examination for lower limb pulses is very important otherwise coarctation of aorta will be missed. Coarctation of aorta is not a cause of HF beyond infancy and hence in such cases other diagnoses such as nonspecific aortoarteritis should be sought. One must also remember that neonates with coarctation of aorta or even interruption of aortic arch may have normal lower limb pulses due to PDA. Closure of PDA could be disastrous in these babies. Some of the other important clinical considerations are as follows: • Central cyanosis with HF should always be taken seriously in a neonate, especially if associated with soft or no murmur. • An ASD or VSD does not cause HF in first 2 weeks of life; prompt evaluation should be done for TAPVC or associated coarctation of aorta respectively. • A premature newborn with respiratory distress and a murmur is likely to have a PDA causing HF. • Rule out tachyarrhythmia as a cause of HF if heart rate is above 220 beats/min. • Associated extracardiac and chromosomal abnormalities may provide clues for diagnosis of CHD. • Older children with TOF or TOF physiology may develop HF due to complications such as anemia, IE, AR, large aortopulmonary collaterals.

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VSD PDA AVSD Aortopulmonary window Unobstructed TAPVC TGA and malposition complexes ALCAPA

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•  •  •  •  •  •  • 

Asphyxia Metabolic Systemic arteriovenous fistula Myocarditis Hematological

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Table 7.4.2 Common causes of heart failure by age at presentation

Chest radiograph should be done in all patients with suspected HF; an echocardiogram is not a substitute for radiograph. It enables diagnosis of cardiomegaly, quanti­ fication of pulmonary blood flow, presence of associated chest infection, pleural effusion, etc. as well as being pathognomonic in certain disease states. A cardiothoracic ratio of greater than 60% in neonates and greater than 55% in older children suggest cardiomegaly though expiratory films should be interpreted with caution. A large thymus can also give false impression of cardiomegaly in neonates and infants (Fig. 7.4.1). Cardiomegaly with increased pulmonary blood flow (pulmonary plethora), prominent main and 451

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Table 7.4.3 Clinical features of heart failure by age and associated findings Newborn/Neonates •  •  •  •  •  •  •  •  • 

Tachypnea Tachycardia Hepatomegaly Cardiomegaly Feeding difficulties Excessive sweating Subcostal recession Cyanosis and wheeze Shock

•  •  •  •  •  •  • 

Bounding pulses in arteriovenous malformations, PDA, truncus Asymmetric upper and lower limb blood pressure in aortic arch anomalies Central cyanosis in TGA, TAPVC, truncus, tricuspid atresia with no PS Differential cyanosis in PPHN and R-L shunt through patent ductus Multiple heart sounds in Ebstein’s Ejection systolic murmur in AS/PS Syndromic anomalies (Down’s, Noonan)

HLHS, coarctation of aorta, Interrupted aortic arch, critical AS, tachyarrhythmias, myocarditis

Infants •  •  •  •  •  • 

Poor feeding Lethargy Excessive sweating Tachypnea, tachycardia Slow weight gain Hepatomegaly

•  Precordial bulge, signs of pulmonary hypertension and less impressive systolic murmurs suggest larger L-R shunts •  Crepitations should alert to possibility of chest infection •  Cyanosis in TAPVC, TGA with VSD, AVSD, truncus •  Findings of CHF and cyanosis in suspected ASD suggest TAPVC •  Later onset of HF in infancy can be due to certain forms of TAPVC and ALCAPA

Older children •  •  •  •  •  •  •  •  • 

Poor weight gain Effort intolerance, orthopnea Cardiomegaly Gallop rhythm, murmurs Peripheral edema Basilar crepitations Fatigue Hepatomegaly Raised JVP

•  •  •  • 

Diastolic murmur in a child with known VSD suggests associated AR Pericardial rub in appropriate settings suggests acute RF Hypertension and unequal pulses or bruits suggest nonspecific aortoarteritis Findings of raised JVP, ascites and anasarca should lead to suspicion of constrictive pericarditis or restrictive cardiomyopathy

Abbreviations: PDA, Patent ductus arteriosus; TGA, Transposition of great arteries; TAPVC, Total anomalous pulmonary venous connection; PS, Pulmonary stenosis; PPHN, Persistent pulmonary hypertension of the newborn; AS, Aortic stenosis; HLHS, Hypoplastic left heart syndrome; VSD, Ventricular septal defect; AVSD, Atrioventricular septal defect; CHF, Congestive heart failure; ASD, Atrial septal defect; HF, Heart failure; ALCAPA, Anomalous left coronary artery from the pulmonary artery; AR, Aortic regurgitation; RF, Rheumatic fever; JVP, Jugular venous pulse

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Figure 7.4.1 A large thymus may give false impression of cardiomegaly in neonates and infants

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branch pulmonary arteries are features of significant left to right shunts (Fig. 7.4.2). Typical radiographs are rare, but if present are diagnostic of certain CHD, e.g. egg on side appearance in TGA (Fig. 7.4.3), normal heart size with ground glass lungs in obstructed TAPVC (Fig. 7.4.4), figure of 8 appearance in unobstructed TAPVC (Fig. 7.4.5) and so on.

lectrocardiogram

An ECG is a much underutilized investigation in children. It is often useful for diagnosing type of CHD and in tachyarrhythmia. Biventricular hypertrophy (Fig. 7.4.6) with volume overload of the left ventricle is seen in large VSD, the most common cause of HF in infants. Tachycardiomyopathy, a potentially reversible cause of HF, due to incessant supraventricular tachycardia (like ectopic atrial tachycardia) can only be picked up by ECG. Similarly bradyarrhythmias due to congenital complete heart block are detected on ECG (Fig. 7.4.7). Anomalous coronary artery from pulmonary artery (ALCAPA) produces a very specific pattern, pathologic q waves in anterolateral leads (Fig. 7.4.8). Left axis deviation in a child with large shunt lesion suggests

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Figure 7.4.5 Figure of 8 appearance in unobstructed total anomalous pulmonary venous connection (TAPVC)

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chocardiogram

An echocardiogram is invaluable in the diagnosis of HF. It confirms the presence of structural heart disease and aids in the management strategy. Echocardiogram is an operator dependent test and to avoid wrong diagnosis, it should always be interpreted in an integrated fashion with clinical, radiographic and ECG findings.

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AVSD as a cause of HF (Fig. 7.4.9). Rarely, hypocalcemia may cause LV dysfunction; ECG shows prolonged QTc interval with terminal T wave inversion (Fig. 7.4.10).

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Figure 7.4.3 Egg-on-side appearance in transposition of great arteries (TGA)

 

Figure 7.4.4 Normal heart size with ground glass lungs in obstructed total anomalous pulmonary venous connection (TAPVC)

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Figure 7.4.2 Features of significant left to right shunts: cardiomegaly with increased pulmonary blood flow (pulmonary plethora), prominent main and branch pulmonary arteries

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Figure 7.4.6 Biventricular hypertrophy with volume overload of the left ventricle seen in large ventricular septal defect (VSD)

 

Figure 7.4.7 Electrocardiogram detecting bradyarrhythmias due to congenital complete heart block

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with HF, especially neonates, where their abnormalities are an uncommon but reversible cause of ventricular dysfunction. Tests to screen for hypoxia and sepsis also constitute evaluation of HF in a newborn. Anti streptolysin O and C reactive protein are invaluable in work up for diagnosis of RF.

Management Key concepts in the management of HF in children are listed below: • Treatment of HF in children, like in adults, should consist of treatment of the cause, precipitating factors (like anemia, IE, infections, acute RF, noncompliance with drug or diet, arrhythmias, etc.) and treatment of the 454 congested state.

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Digoxin has a very narrow safety window in children and adults alike. It should be avoided in premature babies, those with renal compromised state and cases with acute myocarditis. Electrolytes (K+, Ca++, Mg++) should be carefully monitored to avoid potentiation of toxicity and development of arrhythmias (which are more often bradyarrhythmias in children). Generally initial total digitalization is not performed. One can start directly to oral maintenance dose at 10 µg/kg/day (the available digoxin elixir has 50 µg/mL, hence the dose is 0.1 mL/ kg twice daily). Continuous infusion of diuretics is recommended in cases of acute decompensated HF. Monitoring and supplementation of K+ is necessary at higher doses, as deficiency is associated with increased arrhythmic death. During early infancy, supplementation of potassium is usually not required up to 2 mg/kg of dose

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Figure 7.4.8 Anomalous coronary artery from pulmonary artery (ALCAPA) producing a very specific pattern, pathologic q waves in anterolateral leads

 

Figure 7.4.9 Left axis deviation in a child with large shunt lesion suggesting atrioventricular septal defect (AVSD) as a cause of heart failure

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Figure 7.4.10 Electrocardiogram showing prolonged QTc interval with terminal T wave inversion in hypocalcemia

Short term medical treatment is required for stabilization and alleviation of symptoms. This is a very common group because most of CHDs causing HF require surgical intervention. These children present with HF and frequently have comorbidities like sepsis or chest infection.

Children Requiring Long-Term Medical Therapy Several causes of HF in children require prolonged medical therapy. Examples include moderate sized VSDs, PDA, myocarditis/cardiomyopathy, etc. Therapy is also required for long term in residual defects following surgery and in valvular diseases where the risk benefit ratio is not in favor of surgery. -

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Infants with CHD Awaiting Surgery

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aorta, interruption of aortic arch, critical AS and TGA with intact septum and restrictive interatrial communication. These disorders require maintenance of duct patency with prostaglandin infusion till the time more definitive treatment can be employed. Because these children are very sick, they should be transferred to tertiary centers with expertise in their care after initial resuscitation and prostaglandin infusion (if required).

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for furosemide or equivalent. In cases requiring higher doses and in older children, a combination of loop diuretic and spironolactone (or other potassium sparing diuretics) may be preferred. Angiotensin converting enzyme inhibitors should be avoided in HF caused by lesions having pressure overload physiology, e.g. in AS, as they might interfere with compensatory hypertrophy. The incidence of ACE inhibitor induced cough is much less in children as compared to adults. One should avoid combining ACE inhibitors with spironolactone as there is a risk of hyperkalemia. Beta blockers should not be administered in acute decompensated HF. They should be started after stabilization and in low dose initially; the dose is uptitrated gradually. In neonates and infants, active fluid restriction is not recommended. Calorie supplementation, either by increasing the density of milk or giving commercially available high calorie formulas, is recommended. In older children, fluid and salt restriction are generally required. Children should be asked to avoid extra salt as is present in fries, chips, pizzas and other similar food items. S

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to ductus dependent CHD, such as tight coarctation of

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Advances in medical science have ensured a wide variety of evidence based and emerging therapies for the -

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Heart failure in children is a complex syndrome with heterogeneous etiology and presentation. Unlike adults, HF

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treatment or palliation of HF (Table 7.4.4). There are several newer agents, the roles of which are still investigational, in adults and in children. These include natriuretic peptides (e.g. nesiritide), calcium sensitizers (e.g. levosimendan), vasopressin antagonists (e.g. tolvaptan), renin inhibitors (e.g. aliskiren), endothelin antagonists (e.g. sitoxentan) etc. Some like oral phosphodiesterase inhibitors, anti inflammatory molecules, nitric oxide agonists and neuropeptidase antagonists have not proven useful or found to have excess side effects. Tables 7.4.5 to 7.4.7 outline the treatment of HF in children and dosages of common drugs used for the treatment in acute and chronic settings.

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Avoid hypothermia and hypoglycemia; check for hypocalcemia Maintenance of adequate oxygenation

Monitoring of blood gases if perfusion is poor Ventilate, if required, with modest PEEP to achieve PaO2 of 50–60 mm Hg and SaO2 of 75–85% to avoid pulmonary congestion

Adequate hydration

Stop oral feeds if severe tachypnea

IV access

IV and CVP lines (umbilical vein cannula)

IV inotropes for shock

Isoproterenol 0.5–2 µg/kg/min Dopamine 5–20 µg/kg/min Dobutamine 5–20 µg/kg/min Avoid digoxin or use cautiously

Milrinone

Inotrope and vasodilator Load with 25–50 µg/kg/min; maintain at 0.25–1 µg/kg/min

Diuretics

Furosemide 2–4 µg/kg PO/IV

Vasodilators

Captopril 0.1–1 mg/kg/day PO q 8 hourly Sodium nitroprusside 0.5–4 µg/kg/min IV Careful monitoring of blood pressure is necessary

Prostaglandin infusion for ductus-dependent lesions

Start at 0.1 µg/kg/min (up to 0.4 µg/kg/ min if no response), taper to lowest dose possible (0.005 µg/kg/min) Monitor for apnea; keep minimum required dose

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Heart transplantation has been used for the treatment of end stage heart disease in children for nearly 4 decades with first infant transplant done in late 1960s. Around 350 pediatric cardiac transplantations are done annually, representing about 10% of total cardiac transplantations. Majority of the transplantations are carried out for end stage heart disease due to cardiomyopathies. Other causes include CHDs like hypoplastic heart syndrome and other complex CHDs, single ventricle, palliated heart disease, etc. One year survival has approached 90%. However, given the fact that the surgery is done in few centers globally and the available donor hearts have remained static over last many years to few hundreds, it is clear that heart transplantation can be a solution for a minority only.

Supportive measures

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Table 7.4.5 Treatment algorithm for acute heart failure in neonates

A heightened interest has developed in stem cell therapy for HF. Several trials have been completed, or are ongoing in adults with HF, predominantly due to ischemic heart disease. Stem cell therapy is being investigated worldwide under experimental settings for children with refractory HF.

Abbreviations: PEEP, Positive end-expiratory pressure; IV, Intravenous; CVP, Central venous pressure; PO, Per os

 

Table 7.4.6 Oral dosages of common drugs used to treat chronic heart failure  

Table 7.4.4 Treatment options for chronic heart failure Established

Investigational

Pharmacotherapy •  ACE inhibitors •  Beta blockers •  Digoxin •  Diuretics •  Aldosterone antagonists •  Anticoagulants (with severe ventricular dysfunction) Cardiac transplantation Surgery Definite (for structural disease) Ventricular assist devices Extracorporeal membrane oxygenation Intermittent inotrope infusion (weekend pulsed dobutamine)

Pharmacotherapy •  Angiotensin receptor blocker •  Nesiritide •  Levosimendan Ventricular remodeling Cardiac resynchronization therapy Implantable cardiac defibrillator Stem cell therapy

Digoxin

10 µg/kg/day (in two divided doses for children < 5 years)

Furosemide

1–4 mg/kg/day (1–2 doses)

Spironolactone

2–4 mg/kg/day (two doses)

Captopril

Neonates: 0.4–1.6 mg/kg/day in three divided doses Infants and children: 0.5–4 mg/kg/day in three divided doses

Enalapril

0.1–0.5 mg/kg/day (two doses); avoid in neonates

Losartan

0.5 mg/kg/day once daily

Metoprolol

0.1–0.2 mg/kg/dose (two doses) and increase to 1 mg/kg/dose or maximally tolerated dose over weeks or months

Carvedilol

0.05 mg/kg/dose (twice daily) and increase to 0.4–0.5 mg/kg/dose (twice daily) or maximally tolerated dose

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in children is commonly due to structural heart disease and reversible conditions, thus lending it amenable to definitive therapy or short term aggressive therapy. Thus, the overall outcome with HF is better in children than that in adults. Clinical presentation of HF in younger children can be nonspecific requiring heightened degree of suspicion. In particular, some conditions that can present with acute

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Abbreviations: ACE, Angiotensin converting enzyme; ARB, Angiotensin receptor blocker

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Cardiac transplantation Ventricular assist device as bridge in case of delays or even ? destination



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Once or twice weekly dobutamine therapy Consider stem cell coronary infusion

1. Burch M. Heart failure in the young. Heart. 2002;88:198 202. 2. Gazit AZ, Oren PP. Pharmaceutical management of decompensated heart failure syndrome in children: current state of the art and a new approach. Curr Treat Options Cardiovasc Med. 2009;11:403 9. 3. Kay JD, Colan SD, Graham TP. Congestive heart failure in pediatric patients. Am Heart J. 2001;42:923 8. 4. Moffett E, Chang AC. Future pharmacologic agents for treatment of heart failure in children. Pediatr Cardiol. 2006;27:533 51. 5. Ramakrishnan S, Kothari SS, Bahl VK. Heart failure—definition and diagnosis. Indian Heart J. 2005;57:13 20. 6. Saxena A. ‘Working Group on Management of Congenital Heart Diseases in India’. Consensus on timing of intervention for common congenital heart disease. Indian Pediatr. 2008;45:117 26. 7. Shaddy RE, Boucek MM, Hsu DT, et al. Carvedilol for children and adolescents with heart failure: a randomized controlled trial. JAMA. 2007;298:1171 9.

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Add carvedilol in compensated HF, especially in cases with tachycardia



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Add ACE inhibitor. In case of ACE inhibitor-induced cough, switch to ARB like losartan Switch to nitrates if ACE inhibitor/ARB is not tolerated



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Start digoxin (not in myocarditis) Assess reversible and precipitating causes Assess the need for surgery/interventional procedure in case of structural heart disease



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In acute decompensation: bed rest, propped-up position, humidified oxygen Sodium and, if required, volume restriction

shock are important to recognize, as they can be effectively treated or palliated on an urgent basis. While the general principles of management are similar to those in adults, there is a dearth of evidence base in pediatric HF. It would require a judicious balance of extrapolation from adult medicine (thus avoiding generation of redundant evidence) and development of children specific treatments (thus recognizing the inherent differences in HF of children and adults) to optimize the outcomes in this challenging field.



 

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Table 7.4.7 Stepwise guide to management of heart failure

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Infective endocarditis is more common in adults as compared to the children, and accounts for 0.8–3.3 cases for each 1,000 admissions to hospital. The incidence in children and neonates may be rising due to increasing use of newer devices, indwelling catheters, increasing sophistication of resuscitative techniques especially in sick babies, and also due to overall improved survival. In India or in other developing countries, RHD still forms a significant proportion of cases with IE. In general, cardiac lesions with steep pressure gradients (VSD, PDA, left-sided valvular regurgitation) are associated with increased risk of IE. It is extremely rare in patients with ASDs. Tetralogy of Fallot bicuspid aortic valve and children who had undergone repair or palliation for cyanotic CHD are also at higher risk of IE. In newborn, endocarditis often involves right-sided structures and, the diagnosis may be difficult with a very high mortality rate.

tiopathogenesis

Gram-positive cocci are the most likely organisms, although gram-negative rods and fungi can cause IE. Streptococcus viridans is the most common causative agent followed by Staphylococcus aureus in children beyond the age of 1 year. This has been reported in Indian studies as well. However, S. aureus and fungus are more common in children where vascular indwelling catheter or prosthetic valve is used and in immunocompromised patients. The cardiac lesions consist of vegetations of fibrin, leukocytes, platelets and bacteria. Many clinical manifestations are related to destructive aspects of the infection or to embolization of portions of the vegetation. Endocarditis, particularly from Staphylococcus, may cause valvular damage, such as perforation of the aortic cusps or ruptured chordae tendinae of the mitral valve. Embolization may occur into the pulmonary or the systemic circulations and cause infarction, abscess or inflammation of various tissues. Emboli to the lungs, kidneys, spleen or brain are reported most frequently because in each location there are major clinical or laboratory findings of the phenomenon.

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The clinical presentation is insidious with prolonged fever, malaise, myalgia, anorexia, weight loss, pallor, arthralgia and headache. The classical signs like Janeway lesions, Osler’s node and Roth spot are rarely seen in children. The diagnosis should be suspected in any child with a significant cardiac murmur and a prolonged fever. Congestive cardiac failure may develop, especially if aortic or mitral valve regurgitation is created by the infection. Signs and symptoms of embolic phenomenon should be sought. Signs of recurrent pneumonia or a pleuritic type of pain may indicate embolization of infected material to the lungs. Signs of systemic embolization, such as splenomegaly, hematuria, splinter hemorrhages and central nervous system signs, should be sought in any febrile patient with a cardiac anomaly and, rarely the children may present with these signs acutely.

Diagnosis The diagnosis can be confirmed by obtaining the organisms from a blood culture. Usually three blood cultures should be taken aseptically within the first 12 or 24 hours and 2–3 mL of blood may be sufficient. Blood culture may be negative in nearly 7% of cases, although studies from India have shown that the percentage is much higher, which may be due to prior use of antibiotics, and insufficient sample of blood for culture specially in our set up. Nonspecific acute-phase reactants, such as ESR, C-reactive protein and rheumatoid factor are usually elevated; the tests may also be useful in following the progress of therapy. Echocardiography has become an important modality for the diagnosis of IE and is taken as a major criteria in the modified Duke’s classification (Tables 7.5.1 and 7.5.2). But it is important to remember that diagnostic yield of echocardiography is influenced by the image quality, size of vegetation (vegetation less than 2–3 mm may not be well seen by transthoracic echocardiography), location of vegetation and the experience of echocardiographer. The absence of valve changes or vegetations does not exclude endocarditis. Transthoracic echocardiography (TTE) is very sensitive in children due to better acoustic window but occasionally transesophageal echocardiography (TEE) is advised in situation when window is poor, in patients with prosthetic valve, grafts or conduits, rarely in aortic valve endocarditis or aortic root abscess. M

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Infective endocarditis is defined as the “endovascular microbial infection of cardiovascular structures,” involves infection of the endocardium or of the endothelium of the great vessels. This condition usually occurs as a complication of CHD or RHD, but rarely develops without pre-existing heart disease. It is associated with 16–25% mortality, and 20% patients require emergency surgery.



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Table 7.5.1 Duke’s classification with addition of the modified Duke’s criteria Major criteria A. Positive blood culture for IE •  Typical microorganism consistent with IE from two separate blood cultures as noted below: –  Viridans streptococci, Streptococcus bovis or HACEK group or Staphylococcus aureus –  Community-acquired enterococci in the absence of a primary focus •  Microorganisms consistent with IE from persistently positive blood cultures defined as: –  Two positive cultures of blood samples drawn > 12 hours apart, or –  All of three or a majority of four separate cultures of blood (with first and last sample drawn 1 hour apart) –  Single positive blood culture for Coxiella burnetii or anti-phase 1 IgG antibody titer greater than 1:800 B. Evidence of endocardial involvement Echocardiogram positive for IE (TEE recommended for patients with prosthetic valves rated at least “possible IE” by clinical criteria, or complicated IE paravalvular abscess; TTE as first test in other patients) •  Positive echocardiogram for IE is defined as: –  Oscillating intracardiac mass on valve or supporting structures, in the path of regurgitant jets, or on implanted material in the absence of an alternative anatomic explanation, or –  Abscess, or –  New partial dehiscence of prosthetic valve •  New valvular regurgitation (worsening or changing of pre-existing murmur not sufficient) Minor criteria

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•  Predisposition: predisposing heart condition or intravenous drug use •  Fever: temperature > 38.0°C (100.4°F) •  Vascular phenomena: ajor arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages and Janeway lesions •  Immunologic phenomena: lomerulonephritis, Osler’s nodes, Roth spots and rheumatoid factor •  Microbiological evidence: ositive blood culture but does not meet a major criterion as noted above¹ or serological evidence of active infection with organism consistent with IE •  Echocardiographic minor criteria eliminated ¹Excludes single positive cultures for coagulase-negative staphylococci and organisms that do not cause endocarditis Abbreviations: IE, Infective endocarditis; HACEK, Haemophilus species, Actinobacilius actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella species; TEE, Transesophageal echocardiography; TTE, Transthoracic echocardiography

in selected cases. If the patient is very ill, antibiotic treatment can be initiated empirically after the cultures are taken. However, in all the other cases, initiation of therapy should await the results of blood cultures. Exact treatment depends upon the organism isolated and its antibiotic sensitivities. Usually, penicillin (or vancomycin if sensitive to penicillin) and gentamicin are the preferred antibiotics that are administered parenterally. The total duration of therapy is for 6 weeks. Following completion of therapy, blood cultures should be obtained to verify eradication of the infection. American Heart Association has listed various regimens for IE in adults and the same can be followed in children with dose modification. Fungal endocarditis may be difficult to treat and may require surgery along with antifungals like amphotericin B for a duration of 6–8 weeks followed by oral antifungals like fluconazole for prolonged duration of time (may take up to a year). The indications of surgery in the acute phase have been listed in Table 7.5.3. The aims of the surgery are to repair the cardiac defects, eradicate infection and to prevent complications. Despite the availability of antimicrobials, endocarditis can lead to major complications (Table 7.5.4). Complications are more 460 likely to occur in patients with prosthetic valve, age less than

2 years, left-sided IE, fungal and staphylococcal IE, symptom continuing for more than 3 months and cyanotic CHDs.

Prophylaxis Antibiotics are recommended for the prevention of IE prior to certain medical and dental procedures. The guidelines by the American Heart Association have undergone changes in 2007. The cardiac conditions for which prophylaxis is recommended have been listed in Table 7.5.5. Presently it is recommended for all dental procedures that involve treatment of gingival tissue or periapical region of the teeth or oral mucosal perforation, for invasive procedures that involve incision or biopsy of respiratory mucosa, such as tonsillectomy and adenoidectomy. It is no longer recommended for genitourinary or gastrointestinal tract procedures solely for bacterial endocarditis prophylaxis. The application of these guidelines in Indian context is debated by various pediatric cardiologists. The drugs recommended are oral amoxicillin (50 mg/Kg), intravenous ampicillin, and those allergic to penicillin can take cefazolin, ceftriaxone, clindamycin, cephalexin, azithromycin or clarithromycin. The antibiotic should be given before the procedure and up to 2 hours after the procedure in those who did not take it earlier.

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Pathologic criteria Microorganism demonstrated by culture or histologic examination of vegetation, emboli, intracardiac abscess; or Active endocardial lesions on pathology examination Clinical criteria Two major criteria, or one major criterion and three minor criteria, or five minor criteria Possible IE One major criterion and one minor criterion, or three minor criteria

Embolic events: cerebral, pulmonary, renal, coronary Congestive heart failure Persistent bacteremia or fungemia Periannular extension of abscess Metastatic infection Glomerulonephritis/renal failure Mycotic aneurysm Arrhythmia or development of new heart block

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Table 7.5.4 Complications of infective endocarditis (IE)

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Table 7.5.5 Cardiac conditions for which antibiotic prophylaxis is recommended for dental, respiratory tract, infected skin, skin structures or musculoskeletal tissue procedures

Rejected •  Firm alternative diagnosis explaining evidence of IE; or •  “IE syndrome” resolved within 4 days of antibiotic therapy; or •  No pathological evidence of IE at surgery or autopsy within 4 days of antibiotic therapy; or •  Does not meet criteria for “possible IE” as above

 

Myocardial or periannular abscess Continued bacteremia after 2 weeks of antibiotic therapy Worsening of heart failure due to valvular regurgitation Embolic events Fungal endocarditis Prosthetic valve dysfunction

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•  Prosthetic cardiac valve or prosthetic material used for cardiac valve repair •  Previous IE •  Unrepaired cyanotic CHD, including palliative shunts and conduits •  Completely repaired congenital heart defect with prosthetic material or device, whether placed by surgery or by catheter intervention during the first 6 months after the procedure •  Repaired CHD with residual defects at the site or adjacent to the site of a prosthetic patch or prosthetic device (which inhibits endothelialization) •  Cardiac transplantation recipients who develop cardiac valvulopathy

Table 7.5.3 Indications for surgery in acute phase of infective endocarditis (IE)

Table 7.5.6 Etiology of myocardial damage  

•  •  •  •  •  • 

Diseases of Car iovas ular ystem

Table 7.5.2 Diagnosis of infective endocarditis (IE) according to the modified Duke’s criteria

Cardiomyopathy

­

Cardiomyopathy refers to a group of diseases of heart muscle that is not secondary to structural heart disease, hypertension or pulmonary vascular disease. These are categorized by WHO as dilated, hypertrophic, restrictive and arrhythmogenic right ventricular dysplasia—cardio myopathy. Factors identified as causes of myocardial damage have been shown in Table 7.5.6.

Dilated Cardiomyopathy Dilated cardiomyopathy is the most common type of heart muscle disease in children where both the ventricles are dilated with reduced contractility. The majority of cases of DCM are idiopathic.

Etiopathogenesis Three major factors, viz. preceding viral myocarditis, autoimmunity and underlying genetic predisposition have been implicated in the pathogenesis of myocardial damage in DCM. Injury to the myocardial cells is the initiating factor that leads to cell death. If considerable cell loss occurs, the myocardium fails to generate enough contractile force to produce adequate cardiac output and leads to

Infections

Metabolic, Endocrinal, Nutritional

Viral infections (myocarditis): Coxsackievirus B, human immunodeficiency virus, echovirus, rubella, varicella, mumps, EpsteinBarr virus, cytomegalovirus, measles, polio Others: Diphtheria, Mycoplasma, tuberculosis, Lyme disease, Psittacosis, Rocky Mountain spotted fever, Toxoplasma, Toxocara, Cysticercus, Histoplasma, coccidioidomycosis, Actinomyces

Pompe, Carnitine deficiency syndrome, hyperthyroidism, carcinoid, infant of diabetic mother, kwashiorkor, pellagra, thiamine deficiency, selenium deficiency

Familial—Hereditary

Coronary arteries

Mitochondrial myopathy syndrome, hypertrophic cardiomyopathy, Duchenne or Becker muscular dystrophies, Friedreich’s ataxia, Kearns-Sayre syndrome, other muscular dystrophies

Kawasaki disease, anomalous left coronary artery

Connective tissue— Granulomatous—Infiltrative Systemic lupus erythematosus, scleroderma, rheumatoid arthritis, sarcoidosis, amyloidosis, dermatomyositis, leukemia

Other Anemia, sickle cell disease, endomyocardial fibroelastosis, histiocytosis

Drugs—Toxins Doxorubicin, cyclophosphamide, chloroquine hemosiderosis

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Children with DCM usually present typically after HF. Cough, poor feeding, irritability and difficulty in breathing are usually the initial presenting symptoms. Older children complain of easy fatigability, dyspnea and palpitation, and rarely may present with pulmonary edema. Clinical examination may reveal displaced apical impulse, muffled heart sound with a prominent S3 or S4. Murmurs are usually not audible but rarely the murmur of MR or TR may be heard. The liver may be enlarged and in older children, other signs of venous congestion like neck vein congestion and peripheral edema may be observed. A short duration of symptoms (2–4 weeks) may suggest myocarditis. The infant or young child with the disease is often tachypneic, tachycardic with weak peripheral pulses, and has cool extremities and hepatomegaly. Blood pressure is low with a decreased pulse pressure, accentuated P2, murmurs of mitral and tricuspid regurgitation; murmurs may be inconspicuous initially if the patient presents with acute HF and cardiomegaly.

mmunoglobulins: Intravenous immunoglobulin (IVIg) has been used as an immunomodulator, which neutralizes pathogenic antibodies and suppress the ongoing process. Pediatric Cardiac Society of India in a consensus review (2009) has recommended IVIg in cases where symptoms are preceded by viral illness, or when history is short (< 3 months) or cardiac enzymes are elevated. • urgical procedures: Reduction cardiomyoplasty or Batista operation, and assist device and artificial heart are some procedures, which are often used as option to “bridge to transplantation procedure” and are very expensive. Cardiac transplantation is the final treatment for DCM with severe LV dysfunction and offers a 5-year survival benefit of 50–70%. I

•

Prognosis In a small proportion of pediatric patients, DCM may resolve completely. In few pediatric case series, the mortality from DCM at 5 years after presentation varied from 33% to 66%. In a large case series from AIIMS on 128 children, it was reported that 54% improved on medication and of these 24% became symptom free without medication. Thirty-five percent deteriorated despite therapy and 19% died. Female sex was only multivariate predictor of death. Overall the prognosis of DCM will improve only if various etiologies are understood and etiology-specific therapy is instituted. Table 7.5.7 List of investigations in DCM  

Clinical Features

not possible and many a times, various treatment modalities (immunoglobulins or carnitine) are administered without good evidence. The treatment modalities have been enlisted in Table 7.5.8.

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Findings and comments

Chest X-ray

Cardiomegaly and features of pulmonary venous congestion

Electrocardiogram

Low voltage waves, S-T segment depres sions with T wave inversion in the anterolateral precordial leads, prominent Q wave, changes suggestive of arrhythmias

Echocardiogram

Ejection and shortening fraction, quanti fication of MR, clots, thrombus and coronaries; rule out any structural heart lesion

creening of family members: With the advancement of molecular genetic techniques, prospective controlled studies on screening of family members have revealed a genetic transmission up to 20–30% cases with DCM and a prevalent autosomal trait. Due to limited awareness about the genetic predisposition, screening and echo of family members are not performed, but it is advisable in view of above findings.

Basic laboratory tests

Hemogram, ESR, glucose, urea, creatinine, LFT, electrolytes, calcium, phosphorous, ABGs

Metabolic screening

Blood lactate, serum ammonia, urinary ketones

Muscle enzymes

CPK, CPK-MB, cardiac troponin T

Treatment

Endomyocardial biopsy and viral culture

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The main aim for diagnostic evaluation for a patient with DCM is to identify the underlying etiology so that an etiologyspecific therapy can be planned. An additional purpose is to determine the extent of myocardial dysfunction and its complication like clot formation in the heart. Table 7.5.7 provides a list of useful diagnostic tests.

Treatment involves supportive management of CHF 462 (discussed in detail in the chapter on congestive cardiac failure). Ideally, etiology-specific treatment is recommended, but it requires clear proof of association of etiology, which is

­

Diagnosis

­

Investigations

Screening and echocar Screening of first degree relatives of the case diogram of family members ­

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CHF. Overstretching of the ventricles causes myocardial thinning, cavity dilatation, secondary valvular regurgitation and compromised myocardial perfusion. The resulting subendocardial ischemia perpetuates myocyte damage. Myocardial remodeling is an important contributor to worsening HF. Lost myocyte cells are replaced with fibrous tissue, thereby decreasing the compliance of one or more ventricles and adversely affecting performance. Aldosterone, angiotensin II, catecholamines, endothelins and mechanical factors, such as excessive myocardial stretch and ischemia, have been identified as mediators of remodeling. Altered gene expressions resulting in calcium-handling abnormalities, down regulation of myosin or conversion to the less active beta isoform, and abnormal beta-receptor signal transduction have all been identified at the molecular level in the chronically failing heart.

Not advised routinely and not very specific for identifying etiology

Abbreviations: DCM, Dilated cardiomyopathy; MR, Mitral regurgitation; ESR, Erythrocyte sedimentation rate; LFT, Liver function test; ABGs, Arterial blood gases; CPK, Creatine phosphokinase

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Diseases of Car iovas ular ystem

 

Table 7.5.8 Treatment options for DCM Treatment options

Comments

Digoxin

Can be given in myocarditis but loading dose is to be avoided

Furosemide + spironolactone

Helps in reducing systemic and pulmonary venous congestion

Beta blockers and carvedolol

Carvedolol is the most widely used and improves symptoms and LV failure. It should be considered in the absence of overt heart failure, particularly in the presence of tachycardia

Anticoagulation and aspirin

All children with DCM and severe LV dysfunction (EF < 30%) should ideally be anticoagulated and in the absence of monitoring INR, aspirin can be tried. Presence of LV thrombus is a strong indication for oral anticoagulation.

Carnitine

If metabolic screening suggest carnitine deficiency (elevated ammonia levels, high blood lactate or presence of urinary ketones), carnitine can be given.

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Benefits by reducing systemic vascular resistance. Initiate treatment with captopril and can be changed to enalapril.

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ACE inhibitors (Captopril, enalapril)

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Intravenous inotropes and vasodilators Dobutamine is the first choice in the stage of decompensation (dobutamine, dopamine, amrinone, milrinone)

Abbreviations: DCM, Dilated cardiomyopathy; ACE, Angiotensin converting enzyme; LV, Left ventricular; EF, Ejection fraction; INR, International normalized ratio

Hypertrophic Cardiomyopathy

Investigations

Hypertrophic cardiomyopathy is a condition in which myocardial thickness is increased. In contrast to DCM, the LV cavity has a normal or decreased size. During systole, the hypertrophied myocardium bulges into the LV outflow tract and may result in subaortic obstruction.

Chest X-ray is not diagnostic and ECG shows evidence of left and frequently biventricular hypertrophy with or without ischemic changes. Septal changes are evidenced by abnormal q waves in V5 and V6. The echocardiogram may reveal asymmetric septal hypertrophy. The interventricular septum may be 2–3 cm thick compared with the normal, which is less than or equal to 1 cm. Systolic anterior motion of the mitral valve anterior leaflet is a classic twodimensional echocardiographic finding. It results from the high velocity flow occurring in the LV outflow tract. This creates low pressure, which “pulls” the valve leaflet toward the interventricular septum during systole. Cardiac catheterization and angiography is rarely required.



Patients with HCM usually come to medical attention in one or more of the following ways: • Detection of a murmur • An anginal kind of chest pain • An abnormal ECG • From family screening or a positive family history, or • From evaluation of syncope, palpitations, or out of hospital cardiac arrest. The physical findings can be variable. The peripheral pulse may be of bisferiens character with rapid upstroke, and palpation of the apex may reveal a double impulse. A long systolic ejection murmur is present along the left sternal border and faintly radiates to the base. The murmur varies in intensity with change in position; it is usually loudest with the patient standing in contrast to functional flow murmurs. Third and fourth sounds may be present.

The greatest risk with HCM is sudden death in spite of medical and surgical treatment. For symptomatic patients, beta blockers or verapamil can be tried, and for the control of arrhythmias, disopyramide and amiodarone are the drugs of choice. Digitalis, other inotropic drugs and nitrates, which increase the gradient, are contraindicated. It is necessary that patients with HCM should undergo a 24-hour holter to document for arrhythmias and should be restrained from strenuous games and exercises. Implantable automatic cardioverter/defibrillator (AICD) devices may abort poten tially lethal arrhythmia in some patients. For patients with significant LV outflow tract obstru ction, surgical myomectomy or alcohol ablation can be done. There is increasing evidence that elimination of the obstruction prolongs life and relieves symptoms. ­

Clinical Features

Treatment

­

The disease may be caused by one of many possible mutations of genes coding for various contractile proteins. This condition frequently occurs as an autosomal dominant with a variable penetrance. Multiple generations may be involved. Manifestations can begin at any age. Siblings of the proband may not be affected as children but may show evidence of the disease as they reach adolescence and adulthood. The natural history and prognosis are variable; sudden death is not uncommon even in patients who have no important obstruction or sentinel arrhythmia.



Etiology and Genetics

Prognosis Although ultimately fatal in majority, interval between discovery to death often goes in decades. The risk of sudden 463 death in recent population-based studies has shown to be nearly 1% per year. Following features may be associated with

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Pericardial Disease Pericarditis is the inflammation of the visceral and parietal layer of pericardium. The causes are variable and are listed in Table 7.5.10. Pericardial effusion is the accumulation of excess fluid in pericardial sac. The symptoms that result from pericardial fluid depend upon the status of the myocardium and the volume and the speed at which the fluid accumulates. It may be exudative due to bacterial infections, serous to increased capillary pressures (e.g. CHF) or decreased plasma oncotic pressure (e.g. hypoproteinemia). Cardiac tamponade is a life threatening, slow or rapid compression of the heart due to accumulation of fluid, blood, clots or gas in the pericardial space leading to significant impairment of ventricular filling with reduction in stroke volume and cardiac output. It is most commonly associated with viral infections, neoplasm, uremia and acute hemorrhage. Constrictive pericarditis is due to adherent thick non-compliant pericardium that restricts ventricular filling. In children, tuberculosis is the most common cause in India. The clinical manifestations of pericarditis which may vary from a simple inflammatory response with no cardiovascular compromise to cardiac tamponade and constrictive pericarditis are noted in Table 7.5.11. The differentiation of the constrictive pericarditis and restrictive myocarditis can be challenging. The management of these conditions will depend on the cause and are listed in Table 7.5.11.



A comparison of the three variants of cardiomyopathy has been summarized in Table 7.5.9.



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estrictive Cardiomyopathy This is the rarest form of cardiomyopathy characterized by poor ventricular compliance and limited filling. It may be idiopathic or may be associated with a systemic disease such as scleroderma, amyloidosis, sarcoidosis or inborn error of metabolism (mucopolysaccharidoses). The two common types are endocardial fibroelastosis (EFE) with normal or less than normal left ventricle and endomyocardial fibrosis (EMF). EMF is endemic in Kerela, but rare in North India. Symptoms are nonspecific and similar to those of CHF seen with DCM. In contrast to DCM, the left ventricle is of normal size and may have normal systolic function. This condition alters diastolic ventricular function, so the clinical manifestations are those of elevated left and right atrial pressures. Examination reveals hepatic and splenic enlargement and jugular venous distension. Electrocardiographic abnormalities are usually limited to atrial enlargement. Chest X-ray shows pulmonary vascular congestion with a relatively normal cardiac silhouette. The echocardiogram reveals striking dilatation of the atria and great veins but normal or small ventricles. Physiologically, the condition is similar to constrictive pericarditis and differentiating the two can be difficult. Overall the prognosis is poor in infants and children and cardiac transplantation is advised once the diagnosis is made.

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higher risk for sudden death: diagnosis in childhood, septal thickness exceeding 3 cm, nonsustained VT, failure of normal increase of systolic blood pressure during exercise, family history of premature death associated with HCM, significant LV outflow tract obstruction, and prior cardiac arrest.

 

Table 7.5.9 Overview of myopathies

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Dilated

Hypertrophic

Restrictive

Prevalence

50/100,000

1/500

Unknown

Inheritance

25–50% AD, AR, X-L, Mt

50% AD

Unknown

Ventricular function

Systolic and diastolic dysfunction

Diastolic dysfunction

Severely reduced diastolic function

Arrhythmias

Atrial, ventricular and conduction disturbances

Atrial and ventricular Dynamic systolic outflow obstruction

Atrial fibrillation Normal to reduced systolic function

Echocardiographic findings

Dilated LV cavity with normal to thin wall thickness

Asymmetric, concentric or apical LV hypertrophy

Normal or small ventricular cavity size, marked biatrial enlargement

Medical management

ACE inhibitors Diuretics (furosemide, spironolactone) Digitalis β2-blocking agents

Propranolol Pacemaker Calcium antagonists (digitalis/catechols and nitrates contraindicated and diuretics may worsen symptoms)

Antiarrhythmic agents Careful use of diuretics, milrinone

Surgical/interventional

ICD, resynchronization biventricular pacing Transplantation

ICD, septal myomectomy Transplantation

ICD Transplantation

Sudden death

Yes

Depends on gene 0.7–11% per year, associated with exercise

1.5% per year

Abbreviations: AD, Autosomal dominant; AR, Autosomal recessive; X-L, X-linked; Mt, Mitochondrial; LV, Left ventricular; ACE, Angiotensin converting enzyme; ICD, Implantable cardioverter defibrillator

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Diseases of Car iovas ular ystem

 

Table 7.5.10 Causes of pericardial diseases

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Hematology-Oncology: •  Bleeding diathesis •  Malignancy (primary, metastatic) •  Radiotherapy-induced Post procedural: •  Post cardiac Catheterization •  Cardiac surgery •  Central line placement Drugs: •  Anticoagulants, antithrombolytics •  Hydralazine •  Phenytoin •  INH •  Rifampicin Other: •  Renal failure •  Hypothyroidism •  Chylopericardium

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Congenital: •  Absence of pericardium •  Pericardial cyst Infectious: •  Viral (coxsackievirus A and B, Epstein-Barr virus, hepatitis, HIV, adenovirus) •  Bacterial (Staphylococcus, H influenzae type B, Streptococcus, Pneumococcus) •  Tuberculosis •  Fungal (Histoplasmosis, Actinomycosis) •  Parasitic (Toxoplasmosis, Echinococcosis) Connective Tissue Diseases: •  Rheumatic fever •  Rheumatoid arthritis •  Systemic lupus erythematosus •  Systemic sclerosis •  Kawasaki disease •  Wegener granulomatosis

 

Table 7.5.11 Manifestations and management of pericarditis Non-constrictive pericarditis

Pericardial effusion

Cardiac tamponade

Constrictive pericarditis

Symptoms

Retrosternal chest pain (occasionally radiating to back, aggravated by supine position, relieved by leaning forward, dyspnea

May be asymptomatic, dull ache, and other features of cardiac tamponade

Dyspnea, fatigue, anorexia, cough, cold extremities

Exercise intolerance, syncope with exertion, dyspnea, fatigue, anorexia

Signs

Fever, tachypnea, pericardial rub, distant heart sound

Muffled heart sound, Ewart sign (dullness of posterior left chest wall); tachycardia

Raised JVP, hypotension, tachycardia, pulsus paradoxus (decrease in systolic blood pressure > 10 mm Hg with each inspiration) decreased capillary refill time, silent precordium, distant heart sound, hepatomegaly

Tachycardia, pedal edema, raised JVP, hepatomegaly, ascitis, pericardial knock and signs of low cardiac output

EKG

S-T segment elevation in all leads; PR segment depression

Decreased voltage QRS complex, electrical alternans

Electrical alternans sinus tachycardia, low voltage waves, electrical alternans

Low voltage waves, intraventricular conduction delay

Chest X-ray

Normal

Globular, symmetrical cardiomegaly

Globular, symmetrical cardiomegaly

Normal, pericardial calcification or effusion

Echocardiography

Usually normal

An echo-free space (suggesting fluid) around the heart

Global fluid collection, compressed and collapsing chambers with hyperdynamic cardiac function

Flattening of the left ventricular posterior wall endocardium, abnormal septal motion, dilated SVC, IVC, atria

Treatment

Treat the cause; symptomatic treatment with rest, analgesic and rarely antibiotics

Treat the underlying condition. Pericardiocentesis if sudden accumulation of fluid, NSAIDs or steroids are required occasionally

Needle pericardiocentesis or surgical drainage, pericardial stripping or window in recurrent condition

Analgesic, corticosteroids and antibiotics. Pericardiectomy is definitive treatment but mostly unwarranted as many cases including TB resolve spontaneously

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4. Towbin JA, Lowe LM, Colan SD, et al. Incidence, causes, and outcomes of dilated cardiomyopathy in children. JAMA. 2006;296:1867-76. 5. Wilson W, et al. Prevention of Infective Endocarditis Guidelines From the American Heart Association. A Guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation. 2007;116:1745-54. 6. Working group on management of congenital heart diseases in India. Drug Therapy of Cardiac Diseases in Children. Indian Pediatr. 2009;46:310-38.



1. Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis. Diagnosis, antimicrobial therapy, and management of complications. A statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association. Circulation. 2005;111:e394-433. 2. Kumar RK, Prabhu SS, Ahamed Z. IAP Specialty Textbook of Pediatric Cardiology. New Delhi, India: Jaypee Brothers; 2008. 3. Saxena A. ‘Working Group on Management of Congenital Heart Diseases in India’. Consensus on timing of intervention for common congenital heart disease. Indian Pediatr. 2008;45:117-26.

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ibliography

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inus Bradycardia and inus achycardia

Treatment Drug treatment is not essential as simple vagal maneuvers like carotid sinus massage can effectively terminate SVT in majority of cases. Adenosine with its short half-life is the most preferred drug and verapamil is the next drug of choice. Verapamil is not to be given in children below 1 year of age. Beta blockers, disopyramide and digitalis are less preferred alternatives, and digoxin is not helpful in acute case. Prevention of AV nodal re-entry is achieved by the use of digitalis, beta blockers or calcium channel blockers which act primarily on the antegrade slow pathway. In an emergency, DC cardioversion terminates the attack. Temporary percutaneous venous, atrial or ventricular pacing terminates the attack when drugs fail to do so or in recurrent cases. Catheter radiofrequency ablation of the re-entrant 467 circuit is frequently being resorted to in refractory cases.

achyarrhythmias

Supraventricular Tachyarrhythmia (SVT, Paroxysmal Atrial Tachycardia, AV Nodal Re-entrant Tachycardia). Supraventricular tachyarrhythmia is the most common of the rapid rhythm abnormalities encountered in children, the greatest frequency being recorded in infancy. It is known to occur in fetus as early as in middle fetal life.



T







Sinus bradycardia (heart rate less than 60/min) occurs in older children who are athletic. It also occurs following therapy with drugs, such as beta blockers, digitalis, verapamil; and conditions like hypothyroidism, hypothermia and raised intracranial pressure, etc. Sinus tachycardia (heart rate > 120/min) occurs with sympathetic stimulation after exercise, fever, anxiety, anemia, HF, pregnancy, thyrotoxicosis and administration of drugs which stimulate sympathetics. Sinus arrhythmia is a manifestation of normal automatic nervous activity with increase in sinus heart rate during inspiration and a decrease during expiration. This is seen in young children.



d







The mechanism of supraventricular tachycardia is commonly a re-entry of the electrical impulse back into the conducting system either through an accessory pathway (Wolff-Parkinson-White syndrome) or within the AV node. It may originate in a localized focus of enhanced automaticity in the atria or AV junction. In the absence of antegrade conduction by the bypass accessory pathway, re-entry through the AV node or through a concealed bypass tract is responsible for more than 90% of all SVTs. Atrioventricular nodal re-entrant tachycardia, being the most common of all SVTs, has no specific predisposing factors. It most often occurs in children who are otherwise normal. In infancy, it is more common in children below 6 months of age. The heart rate is regular and often ranges between 200/min and 320/min and all impulses are conducted to the ventricles. These children are often asymptomatic. In infants, if it persists for more than 24 hours, symptoms and signs of CHF occur besides pallor, fatigue and tachypnea. The onset of the paroxysm is as sudden and abrupt as its termination. An older child may sense palpitation with sudden onset. Syncope and hypotension may be the presenting symptoms. Acute pulmonary edema can ensue. In the fetus, when arrhythmia is prolonged, heart failure and nonimmune hydrops fetalis are known to occur. Polyuria may occur due to release of atrial natriuretic peptide during such paroxysms. Electrocardiogram shows marked tachycardia (> 200/ min) with regular narrow QRS complexes and the P waves may be absent, buried in the QRS complex or appear as distortions at the terminal part of the QRS complexes. QRS complexes become wider in presence of associated bundle branch block.

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inus hythms S

S

S









The sinoatrial (SA) node located at the junction of superior vena cava and right atrium acts as an electrical impulse generator or pacemaker with its own intrinsic rate, controlled by the autonomic nervous system. The impulse from SA node passes through AV node and Bundle of His to depolarize the atria and ventricles in sequence determined by the slower conductivity of AV node. If the sinus rate slows down considerably, shift in pacemaker activity occurs and the AV node (nodal rhythm) or the ventricle (idioventricular rhythm) takes over the function of impulse generation and propagation. An arrhythmia is a disturbance in the electrical activity of the heart, which may be episodic or continuous. When heart rate slows down to less than 60/min, it is termed as bradycardia and when the same is more than 120/min, it is called tachycardia. On the standard surface ECG, P wave corresponds to SA node depolarization, the P-R segment to the conduction time in the AV node and the purkinje system, the QRS complex to the ventricular depolarization and the T wave to the ventricular repolarization. The two basic mechanisms that initiate tachycardia are: (1) increased automaticity resulting in ectopic impulse formation and (2) re-entry loop or closed circuit propagation of ectopic impulse generated.

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Cardiac rrhythmias in Children

Diseases of Car iovas ular ystem

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F

trial lutter

In atrial flutter, the characteristic feature is a very rapid atrial activity (250–400 beats/min) with the ventricles responding to every second to fourth atrial beat resulting in a regular or regularly irregular tachycardia.

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Congenital heart diseases resulting in a grossly enlarged atria, e.g. mitral or tricuspid insufficiency, tricuspid atresia, Ebstein’s anomaly, acquired rheumatic mitral valvular heart disease, acute viral myocarditis, pericarditis and intra-atrial surgery.

Pathophysiology An electrically active (irritable), abnormal focus in atria produces abnormal impulse, which gets repeatedly propagated by a circus rhythm resulting in extremely rapid atrial rate. All of these rapid atrial beats cannot get transmitted through AV node. Varying degrees of AV block results in, anywhere from 2:1 to 8:1 atrial ventricular rate ratios.

Symptoms Symptoms depend upon the ventricular rate. No symptoms occur in atrial flutter with reasonable ventricular rate. Prolonged episodes of atrial flutter with very rapid ventri cular rate precipitate CHF. Electrocardiogram is characteristic showing the rapid and regular atrial saw-toothed flutter “F” waves.

Treatment Direct current cardioversion is the most effective method of reverting back to sinus rhythm. If the clinical status is stable, the ventricular rate is first slowed by administration of AV node blocking drugs like beta blockers, calcium channel antagonist (verapamil) or digitalis. Once the ventricular rate is slowed, attempt is made to convert the flutter into normal sinus rhythm by the use of Class 1A drugs (quinidine, procainamide or disopyramide), Class 1C drugs (flecainide) or amiodarone. The same drugs also prevent recurrences of atrial flutter and fibrillation.

E

trial ctopic Beats/ xtrasystoles

F

A

trial lutter and trial ibrillation F

A

Premature atrial beats are recognized by abnormally shaped premature “P” waves followed by near normal P-R interval with normal QRS complex. Rarely, QRS complex may be aberrant. They may occur in normal newborns and disappear with age and do not cause symptoms. Multiple atrial premature beats may sometimes result in transient atrial fibrillation. These two types of atrial arrhythmias are less common in

468 children than in adults.

F

trial ibrillation

Atrial fibrillation is characterized by totally distorted, chaotic, rapid and ineffective atrial contractions with irregular and erratic ventricular response resulting in the diagnostic “irregularly irregular” radial arterial pulse with pulse deficit. It may be paroxysmal or persistent. The same causes, mentioned above in atrial flutter, may also result in atrial fibrillation. It may represent the tachycardiac phase of the sick sinus syndrome.

T

trial achyarrhythmias E

A

A

A





Causes

­

An abnormal band of specialized electrically conductible atrial tissue acts as an accessory pathway bypassing the junctional tissue. This occurs in association with some congenital heart diseases and most commonly with Ebstein’s anomaly. Wolff-Parkinson-White syndrome refers to antegrade conduction by AV bypass tract resulting in a short P-R interval, a slurred upstroke of the QRS complex termed delta wave and a wide QRS complex. Differential conducting speeds of accessory and normal pathways with differing refractory periods cause re-entry phenomenon to occur resulting in paroxysmal SVT. Atrial flutter and atrial fibrillation also occur commonly in this condition. This in turn, may lead to very rapid ventricular rates, even resulting in VT and ventricular fibrillation (VF) because of the lack of decremental conducting properties in the bypass tract as in AV node. Supraventricular tachyarrhythmia is treated as men tioned earlier. Class 1A drug (quinidine, procainamide, disopyramide) or Class 1C (flecainide) may be used to slow conduction and increase refractoriness primarily in the bypass tract. Flecainide is to be limited to be used in otherwise normal heart. Digitalis and verapamil can precipitate VF by shortening the refractory period of the bypass tract. Radiofrequency ablation of an accessory pathway is another treatment option commonly used in patients with re-entrant rhythm or atrial ectopic tachycardia. It is often used electively in children and teenagers, as well as in patients who require multiple agents or find drug side effects intolerable or for whom arrhythmia control is poor. The overall initial success rate ranges approximately from 80%–95%, depending on the location of bypass tract. Surgical ablation of bypass tract may also be successful in related patients. Flecainide is to be limited to be used in otherwise normal heart.



E

A



Wolff-Parkinson-White yndrome (Pre- xcitation yndrome)



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In AV re-entrant tachycardia, retrograde conduction occurs from the ventricles back to the atrium by a concealed bypass tract.

Symptoms Symptoms occur with rapid ventricular rate—fatigue, palpitation, giddiness or syncope, symptoms of heart failure and symptoms of systemic embolization in children with mitral valvular disease.

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F

entricular ibrillation

Ventricular fibrillation is a chaotic ventricular tachyarrhythmia with no effective ventricular contraction. The ECG record shows a wavy line without any discernible QRS complexes; P waves may be discernible. Ventricular fibrillation may be a preterminal event in many illnesses. Hypokalemia, digitalis or quinidine toxicity, myocardial inflammation or damage, catecholamines, aminophylline, anesthetic drugs and plant toxins may precipitate VF. Uncontrolled VT or multifocal ventricular ectopic beats or long Q-T interval syndrome may result in VF. If not terminated instantaneously, death ensues. A thump in the chest may restore sinus rhythm. External cardiac massage with artificial ventilation and DC defibrillation are immediate measures to be undertaken. The precipitating factors are corrected without delay. After defibrillatory conversion, VT is treated with drugs. Refractory cases are treated by implantable automatic cardioverterdefibrillator.

Bradyarrhythmias inus rrest and inoatrial Block

Failure of impulse formation within the sinus node is termed as sinus arrest, and blockade of the generated sinus impulse from reaching the atrium is sinoatrial arrest. Though rare in children, these disturbances may occur secondary to digitalis toxicity and extensive atrial surgery. A





­

­

Myocarditis, ischemic damage, anomalous origin of the coronary artery, cardiomyopathy, mitral valve prolapse, prolonged Q-T interval (congenital or acquired), proarrhy thmogenic drugs, Wolff-Parkinson-White syndrome, drug abuse with cocaine or amphetamine, hypokalemia, hypomag nesemia, hypoxia and severe acidosis are all known predisposing factors. In a significant number of children with SVT, an underlying cause may not be found. Syncope, chest pain and dyspnea are the common presenting symptoms. Ventricular tachycardia must be differentiated from SVT and all broad QRS tachycardias should be considered as VT until proved otherwise. The electrocardiographic features, which are helpful in the diagnosis of VT are the AV dissociation, capture fusion beats, extreme left axis deviation, no response to carotid sinus massage or intravenous administration of adenosine besides the very broad QRS complexes.

S

Cause

A

Ventricular tachycardia is defined as occurrence of at least three or more ectopic ventricular beats in sequence. Sustained VC means a run of ventricular premature contractions (VPCs) in succession for a period of 30 seconds or more. It is less common in children, and it indicates the presence of a serious underlying structural or functional cardiac problem. The prognosis is poor and carries a great risk of mortality unless corrected immediately.

S

Ventricular Tachycardia





T

V



The therapeutic goal is to immediately slow down the ventricular rate by using either beta blockers (propranolol) or calcium channel antagonists (verapamil). Quinidine or other Class 1A drugs as mentioned above or Class 1C drugs like flecainide may then correct the condition to sinus rhythm. If no response occurs within 24 hours, electrical DC conversion is resorted to. The causative factors have to be immediately attended. Anticoagulation 2 weeks prior and 2 weeks after any attempt at cardioversion is indicated to prevent the dreaded thromboembolic complications in situations where atrial fibrillation has been persistent for more than 48–72 hours. In exceptional circumstances of refractory atrial fibrillation, surgical or transvenous catheter radiofrequency ablation may be resorted to deliberately induce complete heart block with simultaneous permanent pacemaker implantation.

Treatment is immediately initiated. DC conversion (1–2 Watt/sec/kg) is the treatment of choice; if it is not available or if VT is relatively well tolerated, bolus dose of lignocaine (1 mg/kg) is intravenously administered with continuing intravenous infusion at a rate of 10–50 mg/kg/min. Bretylium is an alternative drug in lignocaine refractory cases. Mexilitine, flecainide, disopyramide and amiodarone are suitable alternatives. Phenytoin is effective in VT, especially when it occurs following digitalis toxicity. The precipitating factors— hypokalemia, hypomagnesemia and others have to be identified and immediately corrected. Myocardial tumor, anomalous origin of the coronary artery and similar surgical problems are appropriately handled. Failure of drug therapy necessitates alternative treatment strategies—implantation of automatic cardioverter, defibrillator or surgical resection of the diseased myocardial area. V



Treatment

Treatment

Diseases of Car iovas ular ystem

The ECG is characteristic with no organized discernible “P” waves, except for irregular, fibrillatory “f” waves in the baseline with irregular but normal QRS complexes.

trioventricular Block

Atrioventricular block occurs when interference occurs in normal conduction of the electrical impulses from the atria to the ventricles through the AV node.

469

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ext ook of Pe iatri s

 

c

Table 7.6.1 Intravenous antiarrhythmic agents Dosage

Comments

Monitoring

Verapamil

0.1–0.2 mg/kg IV (5–10 mg max)

Contraindicated in children < 12 months of age

For hypotension

Propranolol

0.02 mg/kg IV every 5 minutes to maximum 0.1 mg/kg

Contraindicated in children with asthma, congestive heart failure. Not to be given with verapamil

Pulse, BP

Procainamide

10–15 mg/kg IV over 30 minutes

Continuous monitoring

Dizziness, hypotension

Lidocaine

1–2 mg/kg IV over 15 minutes cont, infusion: 30– 50 µg/kg/min

Causes respiratory depression, hypotension

BP

Adenosine

0.05 mg/kg through a central line; double the dose until effect is seen to a maximum of 0.4 mg/kg

Caution in asthmatics, contraindicated in pre-existing type 2 and 3. Atrioventricular block without pacemaker

T

b

d

Drug

b

econd Degree

AV

S

lock







Some of the atrial impulses are blocked and hence, not conducted to the ventricles. In Mobitz type I (Wenckebach phenomenon), while P-P interval remains constant, progressive increase in P-R interval occurs with successive beats until an atrial impulse seen as P wave is not conducted to the ventricle (absent QRS complex). The P-R interval is again shorter in the cycle following the dropped ventricular complex. It will then progressively increase to result in another blocked ventricular impulse. In Mobitz type II, atrial conduction is blocked at intervals without a change in P-R interval, once every three, four or five beats. It is less often noticed in individuals with normal hearts. The same predisposing factors mentioned in first degree

Congenital/ cquired Complete Heart Block A

P-R interval prolonged beyond what is normal for that age and heart rate without blockage of the conduction of any of the atrial impulses to the ventricles is defined as first degree heart block. No evidence of heart disease is seen in majority of such cases. However, it may be seen in children with CHD like ASD, corrected transposition of great vessels, Ebstein’s anomaly, primary myocardial disease, rheumatic carditis, diphtheria and in children receiving drugs like digitalis and quinidine. Children with first degree block are asymptomatic and need no treatment except for the treatment of primary cause.

AV block also play a role. No treatment is necessary. If Stokes-Adams syndrome occurs, although rare, pacemaker insertion is undertaken. Table 7.6.1 lists intravenous antiarrhythmic agents commonly employed.

AV

lock

Autoimmune injury of the fetal conduction tissue by IgG antibodies transferred from mother with active or inactive systemic lupus erythematosus (SLE) is one of well-known causes of this condition. Other autoimmune diseases such as rheumatoid arthritis are reported to cause congenital heart block. Myocarditis and postsurgical repair involving ventricles are other known causes of acquired complete heart block. In utero, it may result in hydrops fetalis. It may also result in fetal wastage. In some children, it may occur at 3–6 months of age. Older children are asymptomatic. Syncope, fatigue, irritability and night terrors may be some of the symptoms. Slow but bounding pulse less than 60/min not increasing by more than 10–20 beats/min after exercise or atropine administration, cannon a waves, varying intensity of the S1 are diagnostic. The diagnosis is confirmed by ECG. The prognosis of this condition is usually good. In symptomatic children with Stokes-Adams syndrome, insertion of artificial pacemaker is imperative to prevent sudden death. All cardiac depressants should be avoided. Cardiac pacing is recommended in neonates with low ventricular

b

irst Degree

AV

F

Abbreviations: IV, Intravenous; BP, Blood pressure

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d

1. Campbell RM, Dick M, Rosenthal A. Cardiac arrhythmias in children. Annu Rev Med. 1984;35:397-410. 2. Losek JD, Endom E, Dietrich A, et al. Adenosine and pediatric supraventricular tachycardia in the emergency department:





Bibliography

c

5.

S







4.





3.

multicenter study and review. Ann Emerg Med. 1999;33:18591. Sacchetti A, Moyer V, Baricella R, et al. Primary cardiac arrhythmias in children. Pediatr Emerg Care. 1999;15:95-7. Walsh EP, Saul JP, Triedman JK (Eds). Cardiac arrhythmias in the pediatric patient. Philadelphia: Lippincott Williams and Wilkins; 2001. Wolff G, Gelband H, Deal BJ. Arrhythmias in infants and children: Current concepts in diagnosis and management of atrial arrhythmias in infants and children. New Your Futura Publishing Inc; 1998. Ziegler VL, Gillette PC (Eds). Practical Management of Pediatric Cardiac Arrhythmias. New York Futura Publishing Inc; 2001.

Diseases of Car iovas ular ystem

rate (50/min), evidence of heart failure, wide complex rhythms or CHD. Isoproterenol, atropine or epinephrine may be used to increase the heart rate temporarily until pacemaker placement can be arranged. Transthoracic epicardial implants have traditionally been used in infants. Transvenous placement of pacemaker lead is available for young children.

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Section

8 Diseases of Respiratory System



















8.1 8.2 8.3 8.4 8.5 8.6 8.7 8.8 8.9 8.10























Section Editor : TU Sukumaran Examination of the Respiratory System: TU Sukumaran Diagnostic Procedures and Investigations in Respiratory Diseases: D Vijayasekaran Respiratory Distress: Madhumati Otiv Upper Respiratory Tract Infections: Sushil K Kabra Croup: Deepak Ugra Pneumonia: Rohit C Agrawal Bronchiolitis: A Balachandran Empyema: Varinder Singh Suppurative Lung Disease: L Subramanyam Bronchial Asthma: H Paramesh

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Examination of the Respiratory System

iseases





D

8.1

TU Sukumaran

These include abnormal breathing patterns, altered sensorium, convulsions, cyanosis, and inability to drink, sweating, hypotonia, repeated vomiting, dehydration and paralysis. Altered sensorium and convulsions indicate hypoxemia.

Vital Signs Tachypnea (Fast Breathing) This usually occurs in pneumonia, but can also occur in anxiety, asthma, collapsed lung cardiac failure, pulmonary edema, pneumothorax and pleural effusion. The rate of breathing should be assessed by counting it for 1 minute; it should be repeated in case of any doubt. Rapid, shallow breathing denotes respiratory muscle paralysis. Metabolic acidosis of any etiology is characterized by an increased rate and depth of breathing.

Tachycardia Sinus tachycardia may be a manifestation of respiratory tract infection. Anxiety, cardiac failure, respiratory failure, simultaneous intake of sympathomimetic drugs and so on should be considered.

Temperature Temperature of 102°F indicates upper (sinusitis, otitis media, tonsillopharyngitis and mastoiditis) as well as lower respiratory tract bacterial infection. Common causes for high fever in lower respiratory illness are pneumonia, empyema, lung abscess and bronchiectasis. Low grade fever occurs in mycoplasma infections.

Blood Pressure Blood pressure should always be recorded. Hypertension and pulsus paradoxus indicate serious respiratory impairment.

espirator

Apnea which is cessation of breathing for more than 20 seconds is associated with bradycardia or neurologic impairment. A duration of less than 20 seconds which is associated with pallor, limpness, cyanosis or convulsions, should be a cause for alarm • Cheyne-stokes breathing is characterized by rhythmic waxing and waning of the depth of respiration, with regularly recurring periods of apnea. It is seen in congestive heart failure (CCF) and raised intracranial pressure with cerebral cortical impairment • Biot breathing also called ataxic respiration is characterized by irregular periods of apnea, alternating with periods of four or five breaths of identical depth, and indicates severe brainstem damage • Kussmaul breathing is rapid deep breathing of metabolic acidosis • Gasping or jaw breathing is of slow rate with rapid inspiration, prominent jaw movement and slow expiration. It indicates severe hypoxia due to any cause.

ste

Work of Breathing This includes flaring of alae nasi, head nodding (sternomastoids and scalene over-activity) and chest retractions (intercostals, subcostal, suprasternal and infrasternal).

Chest and Abdominal Movements Observe the chest movements from the side in supine and standing positions to confirm that both sides are moving equally and to assess the relative contributions of chest and abdomen. In normal inspirations, the lower chest flares out and the abdomen moves forward by the actions of the lower intercostal muscles and diaphragm, respectively. When the intercostals are paralyzed, as in spinal muscular atrophy, inspiration causes the lower chest to be drawn inward by the diaphragm, and the outward movement of the abdominal wall is prominent. Such movements can occur also in upper airway occlusion and are caused by the violent action of the diaphragm. The reverse movement is seen in diaphragm weakness, in which the abdomen is drawn inward during inspiration (paradoxical breathing). In unilateral phrenic nerve paralysis, the abdomen is drawn in on the paralyzed side during inspiration, but is normal (i.e. moves out) on the non-paralyzed side. Cyanosis in respiratory diseases indicates a serious degree of hypoxia and can be identified by the hyperoxia test. Associated circulatory failure or underlying cardiac lesions should be ruled out.



Look for Danger Signs

•

m

General Assessment

Examination of the Respiratory System

y Sy

Respiratory disorders are as common in children as it is in adults. A systematic history taking coupled with a physical examination, is necessary for arriving at a diagnosis. In this chapter, author has discussed on the examination of the respiratory system. Physical examination consists of general assessment of the patient, vital signs and examination of upper and lower respiratory tract.

Of R

Introduction

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Indicators of Serious Chronic Respiratory Illness These include persistent fever, limitation of physical activity, chronic purulent sputum, cyanosis, clubbing, persistent tachypnea, labored breathing, growth retardation, persistent chest hyperinflation, and a family history of heritable lung diseases.

Examination of the Upper Respiratory Tract Use a bright torch to examine the nose, ears and throat.

symptoms of pharyngeal infection are redness and mottling over the soft palate and uvula. In a retropharyngeal abscess, the neck is hyper extended and respiration becomes noisy with gurgling sounds and pooling of secretions. In lateral pharyngeal abscess, the features are torticollis toward the same side, trismus, and bulging in of the lateral pharyngeal wall. Peritonsillar abscess also is characterized by trismus and torticollis. Adenoidal tissue hypertrophy on the posterior pharyngeal wall may reveal cobble stoning. The integrity of the palate should be investigated by palpation to exclude a submucous cleft. A bifid uvula is a clue to an occult submucous cleft palate.



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T x

Clubbing in respiratory diseases is seen early in cystic fibrosis (CF), bronchiectasis (of at least 1 year duration) lung abscess, empyema and malignancies.

Examination of the Lower Respiratory Tract

Signs of Allergic Problems

Neck

People with allergic rhinitis frequently develop a transverse nasal crease resulting from repeated rubbing of the nose to relieve the itching (Darriers line). Another feature of nasobronchial allergy is dark circles under the eyes (allergic shiners).

The important aspects to be assessed in relation to the respiratory tract are the trachea, neck vein and the presence of surgical emphysema.

Changes in the Anatomical Structures ­

The nasal passages may be narrow, as in midface hypo plasia associated with various syndromes. Congenital abnormalities, such as a deviated nasal septum, should be looked for. Extensive nasal polyps cause widening of the nasal bridge. Signs, such as the presence of ulceration, crusting, purulent or a blood-stained discharge, presence of foreign bodies, trauma and tumors (vascular and nonvascular) should be noted.

Examination of Sinuses Sinus tenderness can be elicited on the affected sinus.



Examination of the Ears The ears should be examined for congenital anomalies, infections, foreign bodies and impacted wax. Gently move the pinna and tragus; tragal pain suggests otitis externa. Examine the mastoids and retroauricular areas for eczema, tenderness and lymph node enlargement. For better visualization of the external ear canal and tympanic membrane, pull the pinna up and posteriorly with the thumb and index finger. Otoscopic evaluation is a must for patients with fever of unknown or known origin, as well as those with ear symptoms. In the latter situation, the healthy side should be evaluated first. The otoscope should have a strong light and the speculum should be of the largest size that can fit comfortably into the ear canal. Gently place the otoscope over the external auditory meatus and inspect the external ear canal. Carefully advance it to observe the tympanic membrane. Absence of the normal light reflex, dull appearance, bulging, retraction, perforation, and so on, should be noted. Examination of the Throat 474 The tonsils should be examined for size (hypoplastic in

X-linked agammaglobulinemia; enlarged in infections and tumors), congestion, follicles or membranes. Other

Trachea This is inspected and palpated for deviation (in the standing or sitting position), with the examiner facing the patient. Tracheal deviation causes the clavicular head of the sternomastoid muscle on that side to appear prominent (Trail sign). In severe respiratory distress, “tracheal tug” (i.e. pulling in of the trachea) occurs because of the vigorous contraction of the diaphragm pulling down the mediastinum. Gently palpate the trachea with the middle finger at the suprasternal notch. Should there be massive pleural effusion, pneumothorax and large intrathoracic cysts and tumors; the finger will slip to the opposite side? It is pulled to the same side in upper lobe collapse, fibrosis and pleural adhesions.

Signs of Superior Mediastinal Obstruction Signs of superior mediastinal obstruction are edema of the head and neck, cyanosis, proptosis, Horner’s syndrome and distended non-pulsatile neck veins. The common cause is mediastinal mass, notably because of a lymphoma.

Examination of the Chest Inspection This should be performed with the chest as maximally exposed as the custom permits, with the eyes at the level of the chest, from head and foot ends and from front and lateral aspects. Evaluate the overall shape and appearance of the chest. Assess the shoulders for drooping (indicates painful conditions of the chest wall on the same side, pleurisy, pneumonia, collapse and fibrosis), position of the cardiac apical impulse, and precordial shape. The anteroposterior (AP) diameter of the chest is increased in hyperinflation. A localized bulge indicates parietal wall inflammatory swellings, hematoma or tumors. In pleural effusion or pneumothorax, intercostal spaces (ICS) appear bulging. Look for chest movements. Localized paucity of movements occurs in trauma and in painful conditions of the chest wall and pleura, pleural effusion, pneumothorax, pneumonia, collapse and tumors of the lung.

vip.persianss.ir

iseases espirator ste

­



Auscultatory Percussion It is helpful to detect mediastinal masses. The patient sits with arms resting on both thighs while the examiner sits facing the patient. With the tip of the terminal phalanx of the middle finger of the dominant side, light percussion is directly applied over the sternum from the center to either side, while the note is auscultated from behind over the corresponding areas. The area of impaired resonance reveals the size of the mediastinal mass.

Auscultation Developing an expertise in interpreting auscultatory findings is an experimental process and, as such, there is no substitute for the experience of having listened to a large number of patients, both with and without lung disease. Follow a consistent pattern for auscultation to avoid missing any area. Start from the infraclavicular area; proceed to mammary, inframammary, axillary and infra-axillary areas, each time comparing with the opposite side. Segmental auscultation is the technique of comparing breath sounds of homologous segments. The examiner should sit facing the patient when auscultating the anterior aspect of the chest. The lateral side of the chest can be auscultated from front as well as from behind the patient. Posteriorly, auscultation is performed in the same way as in the order of percussion, with the examiner sitting behind the child. The parameters to be assessed are the breath sounds, added sounds and vocal resonance. Assess the intensity and quality of the breath sounds. Intensity may be normal (when the lung tissue is inflating normally), reduced or increased. It is reduced in airway obstruction, lung damage, pleural thickness, effusion, and pneumothorax. The normal breath sounds are vesicular. The inspiration is loud and highpitched followed by harsh low-pitched expiration (without 475 a pause in between), which is of short duration, i.e. almost up to half of inspiration. The cycle is followed by a pause.

­





m

The examiner should master the technique of percussion to feel, rather than hear, the normal and abnormal lung resonance. The patient should be in a comfortable position, i.e. sitting or lying down. The left middle finger (the pleximeter) is placed parallel to the long axis over the area to be percussed; back of the middle phalanx of the pleximeter finger is struck, as a tapping movement arising from the wrist. The plexor finger should immediately be raised after the blow. The terminal phalanx of the plexor finger should be at right angles to the metacarpal bone and the pleximeter finger while the blow is delivered. Proceed down the ICS in mammary line, with each blow being compared with that on the other side. The upper border of liver dullness reaches the 5th ICS on the right side in the mammary line and will shift to one space lower down on deep inspiration (tidal percussion). On the left side, the normal resonance is replaced by the tympanitic note of the stomach at the same level. The cardiac dullness should be verified on the left side and will be more resonant in emphysema. To percuss the lateral side of chest, patients’ limbs should be raised above the shoulders with the hands resting over the vertex – one over the other. Each ICS is percussed and compared with the opposite side, with the examiner standing or sitting on the side to be percussed. The normal resonance on the right side is replaced by liver dullness in the 7th space in the mid-axillary line, and on the left side by the tympanitic note of the stomach almost at the same level. Percussion of the back should start from the supra clavicular area, i.e. from the medial to the lateral side, the pleximeter finger being placed across the area with the tip directed forward. A band of lung resonance that normally presents in the central area (Kronig isthmus) will be replaced by a dull note in massive pleural effusion, consolidation, neoplasia, or collapse of the apical part of lung. Subsequently, the upper and lower interscapular and the infrascapular spaces should be percussed. The normal resonance is replaced by the dullness at the 9th and 10th ICS in the infrascapular area on the right (liver) and left side (spleen) respectively. Resonance is the normal feel and sound caused by air being set into vibration. Lung resonance is increased

y Sy

Percussion

Of R

This includes measurement of the expansion of the chest at the level of the nipples after deep inspiration and expiration. Expansion of identical sides of the chest should be assessed. Chest movements are assessed over supraclavicular, upper interscapular and lower interscapular areas from the back, and infraclavicular and inframammary areas from the front. To do this, encircle the chest from both sides with four fingers and palm, with the thumbs meeting in the midline but not touching the chest wall. On inspiration, if one thumb remains closer to the midline it indicates reduced chest movements on that side. Tactile vocal fremitus is compared for spoken words over identical areas on both sides of the chest with the medial margin of the right palm.

in airway obstruction and pneumothorax; in the latter situation it reaches up to a tympanitic note. Localized obstruction occurs in congenital lobar emphysema or in partial obstruction by a foreign body in the bronchus (check valve or ball valve). Overall, hyperinflation occurs in obstructive airway disease, as in asthma pushing down the liver dullness. Percussion note is impaired or dull when the lung becomes more solid (pneumonia, consolidation, collapse, fibrosis, sequestration, abscess, infraction), or the pleura becomes thickened or contains fluid (pleural effusion, empyema, hemothorax) or solid (mesothelioma). A feel of resistance below the pleximeter finger is perceived in pleural effusion, as if percussed against a wall, and is described as a “stony dullness”. In hydropneumothorax, a shifting dullness can be identi fied by percussing the chest (from anterior to posterior) in the supine, lying position of the patient. As the fluid shifts to the posterior part of the chest in the lying position, the dull lower chest (in the sitting position) becomes resonant anteriorly and a definite level below which there is complete dullness can be demonstrated.

D

Palpation

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Parameter

Acute asthma

Consolidation

Collapse

Pleural effusion

Pneumothorax

Respiratory rate

↑

↑↑

↑↑

↑↑↑

↑↑↑

Chest in-drawing

+++ Overall

++ Spares affected region

++ Spares affected region ++ Spares affected region

++ Spares affected region

Chest expansion

Overall reduction

Reduced over affected area

Reduced over affected area

Reduced over affected area

Reduced over affected area

Tracheal and mediastinal shift

Nil

Nil

Toward the affected side

Toward the opposite side

Toward the opposite side

Lung resonance

Hyper-resonant; liver Dull over affected area dullness pushed down

Dull over affected area

Stony dullness over affected area

Tympanitic over affected area

Breath sound intensity

N/↓

↑

↓/ -over affected area

↓ / -over affected area

↓/ -over affected area

Breath sound quality

Bronchovesicular

Bronchial

Vesicular/Bronchial

Vesicular

Vesicular

Normal

↑↑

↓↓

Imperceptible

Imperceptible



476









and expiration; unlike crackles, it does not change after coughing. The intensity increases as the chest piece is pressed firmly; it can be felt also with the palpating hand. Mediastinal crunch (Haman sign) is heard in emphysema and left-sided pneumothorax. A crunching sound will be heard over the left sternal border during a systole. Peristaltic sounds are gurgling sounds occasionally heard over the lower part of the left side. Frequent peristaltic sounds with other clinical evidences indicate diaphragmatic hernia. In addition to peristaltic and diaphragmatic sounds crepitus sounds may occur over the region of a broken rib or surgical emphysema. Additional false sounds arise by the movement of the stethoscope on the patient’s skin, and should be differentiated from the symptomatic sounds. Vocal resonance is the sound perceived by the chest piece as the voice is transmitted through the lungs. The child is auscultated while saying one or his name in the same order of auscultation, and both sides are compared. The intensity of resonance will be decreased in airway obstruction, collapse, pleural effusion or pneumothorax (except when bronchial breathing is present). Intensity is increased over consolidation, cavity, infraction and collapse consolidation. If the patient is asked to whisper the same words, they will be heard clearly in the examiners ears (whispering pectoriloquy) in massive consolidation and bronchopleural fistula (Table 8.1.1).

Bibliography

1. Empey D. The respiratory system. In: Swash M (Ed). Hutchison’s Clinical Methods, 10th edition. London: WB Saunders and Company Ltd. 1995.pp.60-8. 2. Kuruvilla VJ, Thulasi Prasad K. Clinical Evaluation of Newborns, Infants and Children. 2nd edition. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd. 2009.pp.112-20. 3. Silverman M, Callaghan Cl. In: Practical Pediatric Respiratory Medicine, 1st edition. New Delhi: Viva Books Pvt Ltd, 2005.











In bronchovesicular breathing, the expiration is prolonged up to or more than the inspiration, and there is no pause in between. This is typical of asthma. Bronchial breathing is louder in intensity. Expiration is high-pitched, loud and prolonged (equal to or more than the duration of inspiration). There is a pause in between. The normal vesicular breathing is replaced by bronchial breathing when the lung becomes more solid (as in consolidation, collapse consolidation, fibrosis, abscess lung, massive pleural effusion and neoplastic growth) or contains a cavity. In these situations the sounds generated in large airways are transmitted more efficiently and resemble those obtained by listening over the trachea. Adventitious sounds are wheezes, crackles, pleural rub, mediastinal crunch, peristaltic sounds and crepitus. Wheezes arise from narrowed intrathoracic airways. Monophonic wheeze is due to localized narrowing of a single bronchus, as in foreign body aspiration or bronchial adenoma. Widespread polyphonic wheezes (of differing intensity); usually heard in expiration indicate diffuse airway obstruction as in asthma. Crackles or crepitations are short bubbling or crackling noises arising from large airways with secretions (coarse), or from small airways (fine), and from alveoli containing exudates (fine). These sounds are produced by sudden changes in gas pressure from the rapid opening of previously closed small airways or alveoli. Crackles are heard in obstructive airway disease, pneumonia and pulmonary edema. Localized loud and coarse crackles may indicate bronchiectasis. The added sounds should be differentiated from conducted sounds from the throat and pharynx. Conducted sounds disappear after suction and changes in position and are heard with equal intensity over equidistant parts of the chest, and better by auscultation in front of the mouth and neck. Pleural rub has a rubbing, superficial, leathery character, and is heard during an identical phase of inspiration



Vocal resonance



e

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Table 8.1.1 Salient features of common lower respiratory diseases in children

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Complete blood count may give information about the current infection. Leukocytosis [white blood cell (WBC) above 16,000/µL] and leukopenia (WBC below 4,000/µL) may suggest acute infection. Raised ESR suggests chronic infection and inflammatory disorders. The CRP is useful in monitoring the disease.

Optional

Hematological • Complete blood count • Erythrocyte sedimentation rate, C-reactive protein

Pulmonary function tests • Spirometry • Peak expiratory flow rate

Imaging studies • Chest X-ray • Contrast radiography • Fluoroscopy • Computed tomography and magnetic resonance imaging • Ultrasound chest • Radionuclide lung scans

Endoscopy • Fiberoptic bronchoscopy • Bronchoalveolar lavage • Rigid bronchoscopy • Laryngoscopy

Microbiological • Gastric lavage • Induced sputum • Sputum, blood culture

Monitoring • Pulse oximetry • Capnography • Polysomnography

Miscellaneous • Immunoglobulin assay • Radioallergosorbent assay • Mantoux test • Allergic skin tests • Sweat chloride

Procedures • Thoracocentesis • Intercostal drainage • Video assisted thoracoscopy 

M

r

agnetic

The CT provides more information than the plain skiagram and can reconstruct three dimensional views. With the use of intravascular contrast, vascular rings can be studied. In high resolution CT (HRCT), the cuts are taken with the collimator distance at about 1–2 mm. Bronchiectasis (cylindrical) and interstitial lung disease are identified early with HRCT. Since MRI does not involve radiation, it is preferred in young infants for the same indications as CT. F

Common

Computed omography and Resonance maging T

Table 8.2.1 Investigations and procedures in respiratory diseases

Barium swallow gives information about the upper gastrointestinal (GI) tract especially in the evaluation of gastroesophageal reflux, achalasia and hiatus hernia. The demonstration of “pulled up cecum” in barium (meal) follow-through suggests abdominal TB.

I

T

M

One tuberculin unit (TU) purified protein derivative with Tween 80 is injected intradermally and the reaction read between 48–72 hours. Mantoux test is considered positive if the induration is 10 mm or more. Similar to Mantoux, Interferon Gamma Release Assays also detects



The standard chest radiograph is the posteroanterior (PA) but in younger children AP view is taken for convenience. Chest X-ray delineates four densities namely air, fluid, soft tissue and bone density (Figs 8.2.1A to D). Before viewing the skiagram, it is assumed that technical qualities (projection, orientation, rotation, penetration) are fulfilled. Pneumonia, collapse, obstructive emphysema, pneumothorax and pleural effusion can be diagnosed with CXR.

Contrast Radiography

antoux est



S

 

T

Hematological ests

Chest Radiography

y ystem

Respiratory diseases are a major cause of mortality and morbidity in children. Detailed history taking and methodical clinical examination help to arrive to a closer diagnosis but to confirm, investigations are required. Children with chronic lung problems require many investigations (Table 8.2.1).

tuberculosis (TB) infection. Since it uses selective antigens namely early secretion antigen target 6 (ESAT 6) and culture filtrate protein 10 (CFP 10), it is not affected by prior bacille Calmette-Guerin (BCG) and infection due to nontuberculous mycobacterium.



ntroduction

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Diseases Of Respi at

Diagnostic rocedures and nvestigations in Respiratory Diseases

8.2

luoroscopy

The combination of fluoroscopy along with barium swallow forms a useful investigation in the evaluation of children with gastroesophageal reflux disease [GERD (eosinophils for late phase reaction in general)]. To study the diaphragmatic movements and suspected foreign body fluoroscopy plays a significant role.

Ultrasound Chest In the evaluation of eventration of the diaphragm, ultrasound may arrive at diagnosis. It helps to differentiate 477 loculated pleural fluid from lung abscess.

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A

C

D

nduced putum S

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The patient is nebulized with 3% hypertonic saline to induce sputum. Secretions are then collected from the throat or 478 nasopharynx. Recent studies report that induced sputum yield higher results than GL.

eak xpiratory low Rate F

Pediatric TB is a paucibacillary disease. The GL is done in the early morning to isolate the acid fast bacilli. Mycobacterium growth indicator system (MGIT) and battle area clearance and training equipment consultants (BACTEC) detect much faster (< 2 weeks) than Lowenstein Jensen medium. The GL can also be done as an ambulatory procedure after 4–6 hours fasting.

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Gastric Lavage

Spirometry differentiates lung diseases (functionally) into obstructive and restrictive diseases but does not give any information about the etiology. Spirometry measures the forced vital capacity (FVC) and not the individual lung volumes. The other indices like forced expiratory volume in 1 second (FEV1), the ratio of FEV1 with FVC (FEV1/FVC), forced expiratory flow 25–75% of FVC [forced expiratory flow (FEF) 25–75%] are derived from FV C by the machine (Fig. 8.2.2). Achieving a good forced vital capacity curve is the most important aspect of spirometry. For this a child (after appropriate coaching) should take a deep breath to full inhalation followed by a brief hold and then a sustained exhalation (at least 3 seconds) with maximum effort to produce a good curve (flow volume curve or loop). Forced vital capacity is diminished in both obstructive and restrictive diseases. The FEV1 is decreased in obstructive diseases. The FEV1/FVC ratio may be normal or even increased in restrictive diseases.

Microbiological tests in children pose many disadvantages like sputum collection (children < 7 years don’t expectorate), contamination from upper airway flora and difficulty in differentiating infection from colonization.

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Ventilation perfusion studies are indicated in the evaluation of pulmonary embolism or anomalies of lung. Perfusion studies are done with radioactive technetium (99mTc). Radioactive xenon133Xe scan study both perfusion and ventilation in a single sitting.

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Radionuclide Lung cans

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Figures 8.2.1A to D X-ray chest showing four densities namely air, fluid, soft tissue and bone density

Peak flow meter records peak expiratory flow rate, the greatest flow obtained on forced expiration after full inspiration. Peak expiratory flow rate is effort dependent and measures mostly large airway function. It plays a major role in monitoring asthma therapy (correlates with FEV1) and sudden fall may be an indicator of impending asthma attack.

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iberoptic ronchoscopy

Fiberoptic bronchoscopy is an important diagnostic technique, done under local anesthesia. The diagnostic indications and therapeutic utility are increasing (Table 8.2.2).

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Bronchoalveolar lavage (BAL) is a diagnostic procedure, allows the recovery of both cellular and non-cellular components from the epithelial surface of the lower respiratory tract. Bronchoalveolar lavage is rightly called as the “liquid biopsy of the lung”. After wedging the scope into the desired sub-segmental bronchus, BAL is performed by instilling 2 mL/kg of sterile, normal saline. Bronchoalveolar lavage is helpful in diagnosing opportunistic infections like Pneumocystis jiroveci, cytomegalovirus, Aspergillus fumigatus and Mycobacterium tuberculosis. T







Arterial blood gas (ABG) analysis reveals oxygenation status, adequacy of ventilation and acid-base balance. Many serious acid-base disturbances can coexist without significant clinical manifestations. The radial artery at the wrist is the most preferred site of ABG specimen collection as it has adequate collaterals. Heparinized syringe with 22 gauge needle should be held like a pen with 45º angles (with beveled edge of the tip facing downward) and the artery should be punctured just 2 cm above the wrist crease and the sample should be analyzed immediately. The normal pH of our body is 7.4 (range 7.36–7.44), depends upon the levels of PaCO2 and HCO3 and their disturbance results in four simple acid-base disorders namely metabolic acidosis (↓ HCO3), metabolic alkalosis (raised ↑ HCO3), respiratory acidosis (↑ PaCO2) and respiratory alkalosis (↓ PaCO2). Metabolic acidosis results due to loss of HCO3 from the body (diarrhea) or due to addition of acids (lactic acid and keto acids) and the anion gap calculation is useful to differentiate the above two. Metabolic alkalosis results due to loss of acids (H+ ions) from the GI tract (vomiting) or through renal mechanisms (Bartter syndrome). Mild respiratory disorders cause hypoxemia resulting in respiratory alkalosis due to CO2 washout. Advanced respiratory diseases and neuromuscular dysfunction leads to CO2 retention (PaCO2 > 45 mm Hg) resulting in respiratory acidosis.

After lignocaine gel is applied into the nostril, lignocaine solution is instilled through the suction channel of bronchoscope as “spray and precede technique”. Dynamic lesions like vocal cord pathology, laryngomalacia, tracheomalacia and foreign body are better identified with FBS (Figs 8.2.3A to D).

horacocentesis

Thoracocentesis or pleural tap is done to diagnose pleural fluid (preferably after ultrasonographic confirmation). Nature of the fluid and biochemistry may be useful to differentiate transudate versus exudate (Table 8.2.3). Table 8.2.2 Fiberoptic bronchoscopy - indications  

A

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Figure 8.2.2 Spirometry recordings of lung volumes and flow volume loop

Diagnostic

Therapeutic

Persistent pneumonia, atelectasis Prolonged stridor and wheezing Suspected foreign body, endobronchial TB Suspected airway anomaly Evaluation of hemoptysis and hemosiderosis Bronchoalveolar lavage

Removal of mucus plug/ bronchial cast Removal of retained secretions Drug instillation Bronchoscopy guided endotracheal tube intubation Tracheostomy evaluation Endobronchial biopsy

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Figures 8.2.3A to D Bronchoscopic view of laryngomalacia, laryngeal web, tracheomalacia and central foreign body

Feature

Transudate

Exudate

Cause

↑ Hydrostatic and ↓ oncotic pressure

Inflammation Infiltration of pleura

Appearance

Clear

Turbid pus, straw color

Protein

< 3 g/dL

> 3 g/dL

Lactate dehydrogenase

< 200 IU/L

> 200 IU/L

pH

> 7.2

< 7.2

Glucose

> 40 mg/dL

< 40 mg/dL

Pleural fluid/serum protein

< 0.5

> 0.5

Pleural fluid/serum lactate dehydrogenase < 0.6

> 0.6

Possible diagnosis

Complicated parapneumonic effusion, empyema

Congestive heart failure, nephrotic syndrome, cirrhosis, hypoproteinemia

ntercostal Drainage

Intercostal drainage (ICD) is the procedure to remove pus from the pleural cavity by inserting a chest tube. Fifth intercostal space at mid-axillary line is the ideal site.

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Table 8.2.3 Differentiation between transudate and exudate

weat Chloride

Sweat is collected by pilocarpine induced iontophoresis. Electric current (3 mA) is passed for 30 minutes and about 100 mg of sweat is collected. Chloride estimation is done by titration. Sweat chloride more than 60 mEq/L on two occasions confirms CF.

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The main functions of respiratory system are oxygenation and ventilation. This happens appropriately when almost all of the cardiac output (perfusion) returns to the heart only after taking part in gas (ventilation) exchange. Ventilation is poor and perfusion remains relatively normal in cases of pneumonia, non-cardiogenic pulmonary edema and asthma (Low V/Q). On the other hand in cyanotic congenital heart diseases and pulmonary embolism ventilation is normal while perfusion is decreased (High V/Q).

< 2 months

> 60 breaths/min

2–12 months

> 50 breaths/min

1–5 years

> 40 breaths/min

> 5 years

> 20 breaths/min



Disturbance in oxygenation or CO2 removal when sensed by the carotid bodies and the central (medullary) carotid receptors results into increased work of breathing (tachypnea/dyspnea). Also normal respiration requires intact central nervous system (CNS) control and respiratory apparatus therefore loss of central control can also result into abnormal pattern of respiration such as periodic or irregular respiration. Additionally increased metabolic demands such as sepsis can result into respiratory distress. Thus, respiratory distress can be the result of number of diseases which may be respiratory or nonrespiratory. Localization of respiratory distress is usually not so difficult if detailed history and physical examination is carefully performed. Table 8.3.2 shows etiological classification of respiratory distress. There are some conditions such as epiglottitis, anaphylaxis, foreign body, tension pneumothorax, chest trauma (flail chest), cardiac tamponade, which need to be handled very urgently.

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Tachypnea is increased in the respiratory rate beyond the age specific physiological limit (Table 8.3.1) while dyspnea or respiratory distress is characterized by signs of increased work of breathing (characterized by stridor, wheeze, tachypnea or hyperpnea, use of accessory muscles, and/ or retractions). A patient with inadequate respiratory effort may or may not have signs of increased work of breathing such as retractions, but usually has an abnormal pattern of respiration or a respiratory rate that is inappropriately slow for the clinical condition. Respiratory failure is defined as inability of the respiratory system to fulfill the gas exchange needs of the patient. Most of the times physical examination alone is sufficient to realize that the blood gas abnormalities are present or imminent and should never delay the institution of life saving measures. It is characterized by altered sensorium, dusky color, poor tone, weak or absent cry, poor pulses or capillary refill time (N = less than 2 seconds).

Breaths/min

• •

To identify respiratory failure To localize the origin of respiratory distress/respiratory failure. As mentioned earlier in this chapter identification of respiratory failure can be done by simple clinical examination. If child is in respiratory failure, urgent resuscitation as per pediatric advanced life support (PALS) guidelines is the priority. Once respiratory failure is excluded, localization of respiratory distress by physical signs should be done which will help in designing treatment to prevent the child from going into respiratory failure (Table 8.3.3). While examining it is important to provide oxygen in the most comfortable way that the child can tolerate as far as possible in mother’s lap. Respiratory distress worsens in a crying child. A conscious child finds the most comfortable position such as head extension in case of upper airway obstruction. 481 Although this is an emergency, there is no substitute to a detailed history taking after initial stabilization. Availability of pulse oximetry is highly desirable with every

Definitions

Age

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Respiratory distress and respiratory failure together account for nearly 50% of pediatric intensive care unit (PICU) admissions. Infants and young children become fatigued and/or decompensate more quickly than older children and adolescents due to smaller airways, increased metabolic demands, decreased respiratory reserves, transverse placement of ribs with poor mechanical advantage, easy fatigability of intercostal muscles thus inadequate compensatory mechanisms. With supportive care and aggressive treatment of the underlying cause, most children with respiratory distress recover uneventfully. However, outcomes are poor for patients who develop cardiopulmonary arrest as the result of respiratory deterioration. This chapter describes definitions of respiratory distress and failure, diagnosis, pathophysiology, clinical features with emphasis of early diagnosis of respiratory failure and some life-saving maneuvers. Management of individual causes of respiratory distress is discussed elsewhere in this book.



Table 8.3.1 World Health Organization definition of tachypnea in children

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Respiratory Distress

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Respiratory causes of respiratory distress

Nonrespiratory causes of respiratory distress

Respiratory tract Infection • Epiglottitis* • Retropharyngeal abscess • Peritonsillar abscess • Croup • Tracheitis • Bronchiolitis • Pneumonia Asthma Anaphylaxis* Foreign body* • Upper airway • Lower airway • Esophageal Biologic or chemical weapons Chest wall/thoracic • Air leak (e.g. tension pneumothorax*) • Chest wall deformity (e.g. thoracic dystrophy, flail chest*) • Mass lesion (e.g. pulmonary sequestration, malignancy)

Cardiovascular • Heart failure • Cyanotic heart disease • Pericarditis • Cardiac tamponade* • Myocarditis Trauma • Blunt or penetrating (e.g. pneumothorax, lung contusion) • Inhalational injury (e.g. airway burn, smoke inhalation) Nervous system • Depressed ventilation (from ingestion, injury, or infection) • Hypotonia (poor pharyngeal tone, ineffective respiratory effort) • Loss of airway protective reflexes Metabolic/Endocrine • Acidosis (e.g. diabetic ketoacidosis, severe dehydration, sepsis) • Hyperthyroidism/hypothyroidism Hematologic • Decreased oxygen carrying capacity (e.g. severe anemia, methemoglobinemia) Gastrointestinal • Splinting from abdominal pain, abdominal distension, aspiration as a gastroesophageal reflux 

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Table 8.3.2 Etiological classification of acute respiratory distress in children

* Extremely life-threatening, commonly occurring diseases

 

Table 8.3.3 Localization of respiratory distress by physical findings Upper airway obstruction

Lower airway disease

Sniffing position: neck is flexed with head extended to open airway

Retractions: intercostal, subcostal

Nasal flaring: also seen with lower airway disease

Nasal flaring: also seen with upper airway obstruction

Prolonged inspiration

Prolonged expiration: lower airway obstruction

Retractions: supraclavicular, suprasternal

Wheezing: intrathoracic airway obstruction

Abnormal voice: hoarseness, stridor, barking cough

Grunting: expiratory sound heard in young children with severe hypoxia or severe pain from an intra-abdominal process

Transmitted upper airway sounds (stridor)

Crackles (rales) Pleural rub

Cardiac disease

Bronchophony

Gallop or other murmur

Pulsus paradoxus: caused by lower airway obstruction. May also be seen with cardiac tamponade

Jugular venous distention Metabolic disease

Pulsus paradoxus: caused by cardiac tamponade. May also be seen with lower airway obstruction

Kussmaul respirations

Hepatomegaly

or failure suggests CNS cause. Child with trauma requires a very close observation as especially because the chest and abdominal injuries can suddenly decompensate in a subject who could be conscious and apparently stable at the time of admission. I

clinician who treats children. There can be many clues in the history and examination which point toward etiology for example, presence of fever suggests infective cause, tachycardia disproportionate to tachypnea associated with hepatomegaly suggests cardiac cause, a well-child suddenly becoming tachypneic suggests foreign body, 482 a child who is a known wheezer suggests exacerbation of asthma, exposure to some allergen or drug suggests anaphylaxis, altered sensorium or CNS symptoms that started even before there was a marked respiratory distress

nvestigations

After initial clinical evaluation based on the suspected cause further investigation should be done (Table 8.3.4). vip.persianss.ir

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Bedside: pulse oximetry electrocardiogram

All children with respiratory distress Suspected cardiac disease

Arterial blood gas Electrolytes, glucose, and ammonia

Gas exchange evaluation in respiratory failure, a rapidly deteriorating patient

Toxicology screen (e.g. organophosphate poisoning, salicylate, paracetamol) Carbon monoxide/methemoglobin

Only when suspected based on history (Carbon monoxide poisoning patients may be pink, and methemoglobin may be cyanosed)

Lateral neck radiograph

Useful for evaluation of upper airway obstruction

Chest radiograph

Should be performed for all children with persistent asymmetric breath sounds and for most children with significant respiratory distress

Forced expiratory or bilateral decubitus chest radiograph

Indicated for suspected foreign body aspiration

Unilateral decubitus chest radiograph

This study can distinguish a pulmonary infiltrate from an effusion

Abdominal radiographs (supine and upright, or cross-table lateral)

May demonstrate signs of abdominal obstruction or perforation

Computed tomography of the head

May demonstrate mass, injury, or hydrocephalus

Computed tomography pulmonary angiography

May indicate a pulmonary embolism

Abdominal CT

May be useful to evaluate abdominal causes of respiratory distress

Ventilation-perfusion scan (V/Q scan)

Indicated for possible pulmonary embolism

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A child with suspected nasal or airway foreign body if breathing and maintaining saturation above 93%, may best be handed over to a center where anesthesia back-up is

available. This is because there is always a risk of bronchial foreign body getting dislodged and blocking airway at carina. The foreign body removal maneuvers should be used only in children who are unable to phonate. These are summarized in Table 8.3.5.

Diseases Of Respi at

Life- aving aneuvers to Relieve cute Respiratory Distress

Table 8.3.5 Life-saving maneuvers to relieve acute respiratory distress Condition

Maneuver

Comments

Complete upper airway obstruction

Needle cricothyrotomy

Temporary measure, can provide oxygenation, not ventilation

Foreign body

Back blows/chest thrusts (< 1 year of age)

Maneuvers should only be used for patients who are unable to phonate

Abdominal thrusts (≥ 1 year of age) Manual removal with finger sweep

Perform this maneuver only when foreign body is visible in the oropharynx

Laryngoscopy and removal with Magill forceps Laryngospasm

Positive pressure with a ventilation bag and tight fitting mask

Soft tissue upper airway obstruction

Head tilt/chin lift Jaw thrust

Use for patients who may have cervical spine injury

Nasopharyngeal airway

May be tolerated by a conscious patient

Oropharyngeal airway

Use only in an unconscious patient

Bag-mask ventilation

Consider upper airway obstruction if unable to ventilate with proper size equipment and technique

Endotracheal intubation

Use for patient who requires more than a few minutes of assisted ventilation. Consider for patient with complete subglottic upper airway obstruction

Tension pneumothorax

Needle thoracocentesis

Most patients will require chest tube placement following emergent decompression

Cardiac tamponade

Pericardiocentesis

Respiratory failure

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Upper espiratory Tract nfections

ntroduction

Acute respiratory infections are a major cause of morbidity and mortality in children and of particular significance in developing countries like India. Outpatient attendance attributed to acute respiratory infections is as high as 20– 40% of all outpatients and 12–35% of in-patients. The overall incidence of acute respiratory infection in the under-5 may be between 3 and 8 episodes/child/year. Of the majority are upper respiratory tract infections (URTI). Upper respiratory tract infection is a loose term which includes infection of nasal cavity, throat, nasopharynx, ears and sinuses. Upper respiratory tract infections are common causes of morbidity in children.

be given 4–6 hourly. For nasal block normal saline can be instilled in nostrils every 4–6 hourly and specially before giving feeds. Child may be given warm drinks with plenty of liquids. There is no role of antibiotics, antihistaminics, local decongestive drops or steroids. Home remedies for cough and cold such as tulsi, ginger or honey may be beneficial in common cold. However, mother should be told to bring the child to hospital immediately, if there is rapid respiration, lower chest indrawing or poor feeding.

tiology

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Acute nasopharyngitis is caused by viruses. The common viruses include rhinovirus and corona viruses. The other viruses include adenoviruses, influenza, parainfluenza or respiratory syncytial viruses (RSVs). These are spread by droplet infection. Predisposing factors include chilling, sudden exposure to cold air, and overcrowding. Rhinitis could also be due to allergy.

Clinical features of common cold are due to congestion, swelling and increased secretion of nasopharyngeal mucosa. Clinical manifestations are more distressing in infant and young children. The common manifestation includes nasal discharge, initially watery than thick white to yellowish, nasal block, cough and conjunctival congestion. Nasal block causes difficulty in feeding, irritability, excessive crying and breathing from mouth. Occasionally may be complicated by secondary bacterial sinusitis and otitis media. Otitis media should be suspected in a child with no relief in crying, even after treatment for nasal block. If a course of common cold is prolonged beyond 7–10 days, then sinusitis should be considered in a school going child.

Treatment

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Acute nasopharyngitis is caused by virus and self-limiting requires no specific treatment. For fever paracetamol can

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tiology

Commonly caused by viruses such as rhino, corona, influenza, parainfluenza and adenoviruses. The 10–20% of sore throats caused by bacteria. The important bacterial pathogen is group A beta hemolytic Streptococcus. Rarely Corynebacterium diphtheria may present with acute pharyngitis. C

E

Infection of nasopharynx is also called common cold. It is probably the most common infection in children. In young children 3–8 episodes of common cold may occur in 1 year.

Acute pharyngitis includes infection of pharynx and tonsils. This is also called acute tonsillopharyngitis. Most of the times, it is associated with rhinitis, sinusitis and occasionally laryngitis.

linical eatures

Children with acute pharyngitis may have fever, sore throat, pain during deglutition, nasal discharge, conjunctival congestion and discomfort in throat. There may be enlargement of tonsils and soreness in throat. Sore throat may lead to dysphagia and drooling of saliva cervical lymph nodes may be enlarged and tender. Examination may reveal grayish-white pseudomembrane specifically in infection with C. diphtheria and Epstein-barr virus. Infection due to group A streptococcus may show pus points over tonsillar surface, palate or pharyngeal wall. Viral pharyngitis is self-limiting and recovers in 5–7 days. Pharyngitis caused by group A beta hemolytic streptococcus, may lead to suppurative complication such as retropharyngeal and peritonsillar abscess. Presence of these complications may be indicated by high-grade fever severe dysphagia and bulge in the posterior wall of pharynx or around tonsils. The non-suppurative complications due to streptococcal pharyngitis include acute rheumatic fever and acute glomerulonephritis. These complications can be prevented by administration of antibiotics. It is very difficult to differentiate viral from bacterial pharyngitis. Presence of exudates/pus points on pharynx with enlarged tender cervical nodes and absence of nasal discharge suggests bacterial pharyngitis and may be used to start antibiotics.

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Acute suppurative otitis media in children is commonly caused by Streptococcus pneumoniae, Hemophilus influenzae and Moraxella catarrhalis. Very rarely, it may be caused due to Staphylococcus and Gram-negative organisms. The latter is more common in immunocompromised hosts.

Acute suppurative otitis media presents with fever, ear pain, ear discharge and restlessness. In young children, this is common cause of excessive crying. Once the tympanic membrane perforates, the child may get relief in pain but could develop pus discharge from ear. Acute suppurative otitis media may cause infection of mastoids in older children. The intracranial extension may be in form of pyogenic brain abscess. Sometimes, ASOM may cause lower motor neuron facial palsy. Children may develop middle ear effusion even after treatment with antibiotics, it is self-limiting and resolve in majority in 12 weeks’ time. If it

D

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cute inusitis

In children, ethmoid and maxillary sinuses are present in infancy. Sphenoid sinuses are well-developed by 3–5 years and frontal sinus develop between 6 and 11 years of age. Infection of sinuses is common and associated with nasopharyngitis and pharyngitis.

tiology

Commonly, the viruses causing pharyngitis and naso pharyngitis are responsible for sinusitis. Sometimes, they may be invaded by bacterial pathogens. The common bacterial pathogens include Streptococcus pneumoniae, Hemophilus influenzae and Moraxella catarrhalis. Gram- 485 negative bacteria and fungi may invade paranasal sinuses in immunocompromised patients. ­

tiology

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Acute suppurative otitis media (ASOM) is a common cause of morbidity in children. It is defined as inflammation of mucoperiosteal lining of the middle ear. If the duration of illness is more than 2 weeks, it is termed as chronic suppurative otitis media. Children are more prone for ASOM because, the eustachian tubes communicating throat with ears are straight and short. Acute suppurative otitis media may be one of the complications of other respiratory infections.

Acute suppurative otitis media is a bacterial infection and should be treated with antibiotics. The antibacterial useful in ASOM includes ampicillin, amoxicillin, oral cephalosporins or macrolide. Children below 2 years of age may be treated with antibiotics from the time of diagnosis. However, in children above 2 years of age with mild disease one can wait for 2–3 days for improvement in clinical symptoms without antibiotics. In severe disease as indicated by presence of high fever (explosive onset, severe otalgia and toxic appearance and high-grade fever more than 102°F) and children with mild disease in beginning but deterioration in 48–72 hours one should consider starting antibiotics. The antibiotic of choice is amoxicillin. The antibiotic is continued for 10 days to prevent recurrence and development of chronicity. If the child is not improving by 3–4 days, an alternative antibiotic like injectable third generation cephalosporin or amoxicillin clavulanic acid combination may be started. In severe cases injectable third generation cephalosporin (cefotaxime or ceftriaxone) may be started. For relief of pain, paracetamol or one of the nonsteroidal anti-inflammatory, i.e. ibuprofen may be given, round the clock. Occasionally, tympanocentesis may be required to relieve pain. There is no role of local antibiotic drugs in ASOM. For treatment of chronic otitis media (COM), it is recommended to keep the ears dry by cotton wick. One course of oral antibiotics sometimes may be useful.

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The major consideration in treatment of acute pharyngitis is to prevent acute rheumatic fever. If a clinical diagnosis of streptococcal pharyngitis is made, a throat swab should be taken or rapid diagnostic test performed to demonstrate streptococci and penicillin should be administered. Penicillin can be given orally or by intramuscular route. The duration of oral penicillin is for 10–14 days. If compliance is a problem, single injection of Benzathine penicillin can be given. The other alternative antibiotics are ampicillin, amoxicillin or oral cephalosporins. If an individual is sensitive to penicillin, he or she may be treated with erythromycin. The newer macrolide antibiotics such as roxithromycin, clarithromycin and azithromycin are alternative to erythromycin.

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Treatment

iagnosis

In a setting of URTI if a child is crying excessively, his ears should be examined by otoscope. The eardrum may be inflamed, and bulging with loss of normal anatomy with fluid in middle ear. Otoscopic examination should be part of routine examination in young children, presenting with fever without localization.

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Acute pharyngitis is a clinical diagnosis. At times, it is very difficult to differentiate nasopharyngitis from pharyngitis. Diagnosis of streptococcal pharyngitis can be made with presence of exudates, enlarged tonsils and absence of nasal discharge. The diagnosis can be confirmed by throat swab culture. Now, a rapid diagnostic test based on latex agglutination is also available for diagnosis of streptococcal pharyngitis and can be carried out in office practice.

persists, these children should be sent to otolaryngologists for consideration of grommet insertion. Chronic middle ear effusion may lead to hearing impairment.

iseases f es ira ory ys em

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The clinical significance of sinusitis is due to bacterial invasion. A course of amoxicillin, ampicillin or oral cephalosporin should

B









Treatment

1. Aroll B. Antibiotics for upper respiratory tract infections: an overview of Cochrane reviews. Respir Med. 2005;99(3):255-61. 2. Casey JR, Pichichero ME. Meta-analysis of short course antibiotic treatment for group a streptococcal tonsillopharyngitis. Pediatr Infect Dis J. 2005;24(10):909-17. 3. Kabra SK, Lodha R. Acute respiratory mortality. In Child Survival and Development: Recommendations of National Consultation Meeting on Child Survival and Development 20-21 Nov 2004, Held at All India Institute of Medical Sciences. New Delhi: Indian Academy of Pediatrics. 2004.pp.19-29. 4. Mirza A, Wludyka P, Chiu TT, et al. Throat culture is necessary after negative rapid antigen detection tests. Clin Pediatr (Phila). 2007;46(3):241-6. 5. Simasek M, Blandino DA. Treatment of the common cold. Am Fam Physician. 2007;75(4):515-20. 6. Tiewsoh K, Kaur J, Lodha R, et al. Management of Upper respiratory tract infection. Indian J Pediatr. 2008;75:S28-S32.



Usually prolonged course of nasopharyngitis in form of persistence of fever and nasal discharge could be due to sinusitis. If tenderness over sinuses can be demonstrated or periorbital puffiness is present in young children, a clinical diagnosis of sinusitis can be made. It can be confirmed by demonstrating opacity or mucosal thickening or fluid level in paranasal sinuses on X-ray films. Other imaging such as CT or MRI scan of sinuses may be done in immunocompromised host or complicated cases.



iagnosis

ibliography



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Common presentation of sinusitis includes non-resolving rhinitis or common cold even after 7 days, thick purulent nasal discharge, fever and tenderness over sinuses. In young infants there may be swelling around eyes. There may be headache-unilateral, bilateral, temporal or occipital depending on sinus involvement.

be given to the child. The supportive care includes normal saline in nostrils and paracetamol for fever and pain relief. There is no role of routine administration of antihistamines.



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Croup is a clinical diagnosis and does not require any investigation. Radiographs are used only if diagnosis is uncertain. The X-ray of the neck may show the typical subglottic narrowing or steeple sign on the PA view (Fig. 8.5.1). However, the steeple sign may be absent in patients with croup. Radiograph does not reflect the severity of airway obstruction.

Differential Diagnosis The differential diagnosis includes conditions that cause obstruction in the region of larynx: • piglottitis: It is very rare in India • Laryngeal foreign body: Sudden onset of choking and coughing without prodromal signs of infection • cute angioedema: Usually presents with swelling of the face and neck and other manifestations of allergic reactions • Retropharyngeal and peritonsillar abscess: A peri tonsillar abscess is often a clinical diagnosis whereas radiograph or CT scan of upper airway helps in diagnosis of retropharyngeal abscess • Bacterial tracheitis: Although, it is very rare, it is impor tant differential diagnosis as it may have fulminant course and needs antibiotic • Laryngeal diphtheria: Early symptoms of diphtheria include malaise, sore throat, anorexia, and low-grade fever. Within 2–3 days a typical gray-white membrane ­

­



The parainfluenza viruses (types 1, 2 and 3) account for 75% of cases; other viruses associated with croup include influenza A and B, adenovirus, rhinovirus, RSV and measles. Influenza A has been associated with severe laryngotracheobronchitis. Rarely, Mycoplasma pneumoniae has been isolated from children with croup. Viral infection of the upper airway causes inflammation of pharynx, larynx, trachea and bronchi. The subglottic inflammation compromises the airway in croup.

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tiology and athogenesis

nvestigations

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Croup is the most common infectious cause of upper respiratory obstruction amongst children, with peak incidence ranging from 6 months to 6 years of age with the peak incidence at around 2 years of age. It is an acute and infectious process and is also termed as acute laryngotracheitis or laryngotracheobronchitis. It affects boys more often than girls. Traditionally, spasmodic croup and recurrent croup are considered as separate diagnoses, but, many believe that they are a part of the spectrum of a single disease. Croup occurs most commonly in winter but can occur throughout the year. Recurrences are frequent from 3–6 years of age and decrease with age. Approximately 15% of patients have a strong family history of croup. Most children with croup have uncomplicated course, managed with symptomatic treatment and have complete recovery. Only a small number of patients require hospitalization. E

In severe cases the child appears tired and exhausted due to labored breathing, has significant tachypnea and tachycardia and is restless and agitated. Some of the children may have altered sensorium, hypotonia, cyanosis and marked pallor due to severe airway obstruction and resultant hypoxia.

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Clinical eatures





The diagnosis of croup is usually clinical. It presents with barking cough, hoarse voice and high-pitched inspiratory stridor and respiratory distress. These symptoms usually follow a prodrome of mild fever, rhinorrhea and sore throat for 2–3 days. The symptoms are characteristically worse at night. The breath sounds are normal with no other adventitious sounds in chest. Occasionally, there may be wheezing. Immunity to viral infection is transient and repeat infections are common; however, in older children, symptoms are less severe. The disease can be of varying severity from mild to severe. In most children the illness is mild. The child appears happy, playful and feeds well. The stridor appears on coughing and crying. There may be mild respiratory distress. In moderate illness the stridor is audible at rest and gets worse on crying. Tachypnea, respiratory distress and sometimes tachycardia are present. The child may be irritable but is alert and comforted by parents.

487  

Figure 8.5.1 Radiograph of an airway of a child with croup, showing typical subglottic narrowing (steeple sign)

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T

ext T

Children with mild croup do not need any specific treatment. Steam inhalation at home or saline nebulization in a clinic is often effective in humidifying the airway and providing symptomatic relief. Children with moderate to severe croup need definitive therapy (Table 8.5.1). The components of definitive therapy are: • Oxygen • Corticosteroids • Nebulized adrenaline • Intubation.

Oxygen Oxygen is the most important component of the definitive therapy of moderate to severe croup. Humidified oxygen is given to children with significant upper airway obstruction and SpO2 less than 92%.

Corticosteroids Steroids are useful in moderate to severe croup. Nebulized Budesonide 2 mg 12 hourly for up to 48 hours shows improvement in croup symptoms. The onset of action is seen within 30 minutes. Oral prednisolone (1–2 mg/kg),

Nebulized drenaline A

M

reatment

oral or IM dexamethasone (0.15–0.3 mg/kg) are equally efficacious. Steroid therapy causes significant decrease in the need for nebulized adrenaline, need and duration of intubation and also average stay in hospital.

It should be given immediately to children with severe croup. The doses are 0.5 mL/kg of body weight of 1:1,000 dilutions to a maximum of 5 mL. The onset of action is seen within 30 minutes and the effect lasts for about 2 hours. In case of persistent stridor the dose can be repeated every 2–4 hours. I

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boo

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•

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•

on tonsils and/or soft palate is seen on pharyngeal examination. The membrane is adherent to the tissue, and forcible attempts to remove it cause bleeding easles croup: It almost always has full manifestations of systemic disease and the course may be fulminant Bronchial asthma: A croupy cough may be an early sign of asthma ubglottic stenosis: It presents from early infancy and is not associated with prodromal symptoms.

ntubation

Children with signs of impending respiratory failure should be intubated for a better control on airway. An endotracheal tube (ET) of 0.5 mm smaller than expected for the child’s size is selected. Intubation is maintained till an air leak develops to a maximum of 5 days.

Outcome Croup is a common infectious condition amongst small children. Most children have mild symptoms and are treated at home and the illness resolves in 3–4 days. It is observed that if the child’s symptoms are minimal at discharge, return within 24 hours is unlikely. Only about 5% of children discharged from the emergency department after corticosteroid therapy need to return because of worsening of symptoms. Intubation is rarely required. In Canada, of all children with croup, about 4% have been estimated to require hospitalization, and intubation was required for only 1 of the 170 hospitalized children or 1 in 4,500 of all children with croup.

Table 8.5.1 Evaluation and management of children with croup  

Croup severity (Westley score) Mild (≤2)

Moderate (3–7)

Severe (≥8)

Barking cough, hoarseness; no stridor, no or minimal chest wall retractions at rest

Stridor and chest wall retractions at rest; no agitation

Stridor, sternal contractions at rest, accompanied by agitation or fatigue

Decongestants, cough Not recommended suppressants, antibiotics

Not recommended

Not recommended

Humidification

Not proven beneficial

Not effective

Not effective

Corticosteroids

Dexamethasone (0.6 mg/kg, 1 dose PO)

Dexamethasone (0.6 mg/kg, 1 dose PO or IM)

Dexamethasone (0.6 mg/kg, 1 dose PO or IM)

Nebulized epinephrine

Not recommended

Not recommended

Nebulized racemic epinephrine (2.25%, 0.5 mL in 2.5 mL of saline or l-epinephrine (1:1,000 dilution in 5 mL of saline)

Discharge home

Discharge to home if no stridor, no retractions at rest. If no improvement in 4 hours, consider hospitalization

Observe 2 hours Good response: no recurrence, no stridor and no retractions at rest. Discharge to home possible Poor response: stridor, retractions at rest after 2 epinephrine doses. Hospitalize

  Therapy

Disposition

488

Source: Mandell, Douglas and Bennett’s Principles and Practice of Infectious Disease. 5th edition.

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neumonia

P



Diseases Of Respi at

8.6

E

pidemiology

r or S

tiology

Definition Pneumonia is defined as an inflammatory process involving lung parenchyma usually due to microorganisms. It is





It depends on various factors like age, immune status, underlying comorbidity and various risk factors as shown in Flow chart 8.6.1. The causative agents may be viral, bacterial or atypical pathogens. They are usually age specific as shown in Table 8.6.1. Most common bacterial pathogens are Streptococcus pneumoniae and Hemophilus influenzae which together are responsible for 60–70% of total pneumonia cases, followed by viruses which account for 30–35% of pneumonia cases. Mycoplasma pneumoniae and chlamydia are most common causes of “atypical pneumonia” in school-going





­

Approximately 150 million episodes of childhood pneu monia are reported every year from the world out of which 95% are from developing countries. Fifteen countries account for nearly 75% and 6 countries including India account for 50%. India alone bears the brunt of 25% disease burden. Out of the 7.6 million under-5 childhood mortality world over 16%, i.e. 12 million deaths are due to pneumonia. More than 90% of deaths due to pneumonia among young children occur in 68 poor nations, mostly from Africa and Asia. In India the disease burden is huge. 45 million episodes are estimated annually with 6.6 million hospitalizations, which contribute to 24% national disease burden and 0.37 million deaths annually.

y ystem

Pneumonia probably is one of the oldest diseases, as old as antiquity known to human kind and has always remained a subject of challenge to medical science, despite extensive research. Pneumonia is number one cause of under-5 childhood mortality across the globe particularly in developing countries. Unfortunately, over the years the mortality remained almost the same and hence it is also been called as “forgotten killer” or “silent killer”.

referred as “Pneumonitis” when the cause is non-infective. Pneumonia’s are mainly classified as: • Community acquired—pneumonia acquired outside the hospital environment in a previously healthy immune competent subject. The patient should not have been hospitalized within 14 days prior to the onset of symptoms. • Nosocomial pneumonia—pneumonia acquired within hospital setting more than 48 hours after hospitalization [hospital-acquired pneumonia (HAP)] or more than 48 to 72 hours after endotracheal intubation [ventilatorassociated pneumonia (VAP)]. This classification does not include “Recurrent Pneumonia” which is defined as two episodes of pneumonia in 1 year or 3 episodes in any time frame, and “Aspiration Pneumonia” which occurs due to aspiration of foreign materials in the lower airways.

ntroduction

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Rohit C Agrawal

 

Flow chart 8.6.1 Predisposing factors for community acquired pneumonia (CAP)

(Source: Study by Burman et al. Epidemiology of ARI in children of developing countries. Rev Inf Dis. 1991)

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Streptococcus pneumoniae Viruses (35%) Hemophilus influenzae Staphylococcus Mycoplasma pneumoniae

>5 years

Streptococcus pneumoniae Mycoplasma pneumoniae (24–30%) Viruses Staphylococcus Staphylococcus pyogenes

T

3 months to 5 years

P

children older than 5 years of age accounting for 11–30% cases. Legionella is another rare and frequent cause of atypical pneumonia. Significant proportion of pneumonia is due to mixed infection (8–40%) and in 20–60% of cases pathogens are not identified.

athogenesis

linical eatures F

C

Pneumonia is usually preceded by respiratory viral infection which disturbs the defense mechanism of the lungs and also disrupts the normal epithelial layer of respiratory tract and as a result there is dysfunction of ciliary brush border clearing mechanism. There is inhibition of phagocytosis by alveolar macrophages. Thus, bacteria and other organisms invade the lung parenchyma and produce a pneumonic lesion. The invasion could be either direct spread from nasopharyngeal tract by respiratory droplet infection or could be by invasion through hematogenous dissemination within the lung parenchyma. When the spread is hematogenous it is called “invasive or bacteremic pneumonia” and when the spread is direct it is called “non-bacteremic pneumonia”. However, the pathogenesis is still ill understood till date.

Diagnosis of pneumonia is essentially clinical and seldom requires lab support. Absence of past history of recurrent cough and presence of fever with fast breathing is a hallmark presentation in clinical diagnosis of pneumonia. It should always be remembered that there are no definite differentiating markers between viral, bacterial and atypical pneumonia. However, there are certain clinical clues which can help to nail down on etiological diagnosis (Table 8.6.3).

Characteristics of Viral Pneumonia • • • • •

Acute – sudden onset Younger age Preceding upper respiratory catarrh Wheeze with crackles Clinical evidence of hyperinflation with scattered exudates on radiology due to segmental atelectasis. For optimum antimicrobial management of pneumonia it is prudent to differentiate between bacterial, viral and atypical pneumonia clinically, as it is often very difficult to isolate the offending pathogen (Table 8.6.4).

Laboratory Diagnosis Acute phase reactants, like CBC, CRP, ESR, have poor sensitivity and specificity. They do not distinguish between viral and bacterial etiology, nor they help in making decision of antibiotic choice; however, they may be useful tools for monitoring the course of the disease. Radiology is not routinely required in non-severe pneumonia to confirm the diagnosis. At times it may not correlate with the clinical signs; there is also wide variation in the interpretation by radiologists. Moreover, reliability in predicting the etiology is poor. However, CXR may be indicated in very severe disease, ambiguous picture, no Table 8.6.2 The WHO grading of pneumonia Pneumonia

Fever less than 38.5°C, no feeding difficulties, no dehydration, cough and tachypnea

Severe pneumonia

High-grade fever more than 39°C, difficulty in feeding, tachypnea, respiratory distress with intercostal retraction (ICR) or subcostal retraction (SCR), dehydration, grunt, bronchial breath sounds on auscultation with or without crackles, SpO2 > 92 at room air, radiological opacity on CXR +/–

Very severe pneumonia

Inability to feed, altered sensorium, intermittent apneic spells, cyanosis, excessive diaphoresis, narrow pulse pressure, acidemia, SpO2 < 92 at room air



Constellation of symptoms triad of fever, cough, rapid breathing and or difficult breathing is classical clinical manifestations of pneumonia. Diagnosis of pneumonia is essentially clinical. Tachypnea is single most sensitive and specific sign to diagnose pneumonia, as sensitive as 66–88% of auscultation (Table 8.3.1 for grading of tachypnea.) Clinical features may differ from neonate to older child. In the neonate there could be absence of cough and fever, and common presenting features are excessive irritability or lethargy, difficulty in feeding, intermittent apneic 490 spells, cyanosis +/–, progressive air hunger, rapid clinical deterioration with or without evidence of sepsis. In severely

Diagnosis

 

Gram-negative Enterobacteriaceae Enterococci Chlamydia trachomatis Group B streptococci Hemophilus influenzae Streptococcus pneumoniae Listeria monocytogenes



0–3 months



 

r

Etiology

d

Age group

malnourished children, the breathing efforts will be poor. The WHO has graded pneumonia as given in Table 8.6.2 based on symptoms. Assessment and grading of severity is most important for optimum and successful management.



k f e iat ics

Table 8.6.1 Etiology of pneumonia – relation to age

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Diseases Of Respi at

 

Table 8.6.3 Clinical clues which help in diagnosis of etiological diagnosis of pneumonia Organisms (apart from usual ones)

Pyoderma, measles, pneumatoceles

Staphylococcus

Human immunodeficiency virus (HIV)

Pneumocystis

Neutropenia

Gram-negative, Aspergillus

CF

Pseudomonas, Staphylococcus

Severe protein-energy malnutrition (PEM)

Gram-negative, Staphylococcus

Preceding coryza, wheeze

Viral

Young afebrile infant with neonatal conjunctivitis

Chlamydia

Multisystem involvement (rash, anemia, hepatitis, encephalitis)

Mycoplasma

Marked leukocytosis

Bacterial

Acute otitis media

Streptococcus pneumoniae/Hemophilus influenzae

S

y ystem

or

r

Predisposing factors

 

Table 8.6.4 Differential diagnosis between typical and atypical pneumonia Features

Typical pneumonia

Atypical pneumonia

Age

More common in young infants, children and also in older children

School going children, adolescents and adults

Onset

Acute/sudden

Gradual/insidious

Facies

Toxic

Well

Rigors

Shaking chills

Chilliness

Wheeze

Rare or nil

Common

Cough

Productive

Non-productive/paroxysmal

Sputum

Purulent/bloody

Mucoid

Temperature

High 102–104°F

Mild-Moderate <102°F

Pleurisy

Frequent

Rare

Consolidation

Frequent

Rare

Extra-pulmonary manifestations

Uncommon

Common

Gram staining (Sputum)

Neutrophils

Mononuclear cells

Sputum culture

Occasional growth of microbe

Rarely any growth

WBC count

>15,000 /cu mm; shift to left

>15,000 /cu mm; no shift

Chest radiography

Defined density

Non-defined infiltrates

Differential Diagnosis Though symptom complex of fever, cough and rapid/difficult breathing is classical presentation of pneumonia; it is prudent to differentiate pneumonia from other masqueraders which may mimic with same symptomatology.



M

anagement

The mainstays of management are antibiotics and supportive treatment. It is imperative to understand that all pneumonias deserve antibiotics as differentiation between viral and bacterial is difficult—“Empirical antibiotics are prudent and rational in pneumonia”. Non-severe pneumonia above the age of 3 months can be managed at domiciliary level with oral antibiotics.







improvement/worsening more than 48–72 hours of therapy, suspected complications and known immunocompromised child (Figs 8.6.1A to C). Microbiology—sputum culture or blood culture though may be more specific, but the yield is very poor (10–15%). There is also a risk of growing normal nasopharyngeal flora. Serology—serology, urinary antigens, rapid antigen detection test (RADT) and cold agglutinins for mycoplasma are not easily available, expensive with time lagging and have poor sensitivity. Invasive procedures, like bronchoscopy, BAL and lung aspiration, have high sensitivity and specificity; however, they are too invasive to be advised in office practice. Pulse oximetry is a mandatory tool for monitoring the course of the disease in all the hospitalized children.

491

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B

X-Rays – Bacterial lobar consolidation

C

Bronchopneumonia

Interstitial pneumonia



extb T

a

 

Figures 8.6.1A to C Radiologic findings in bacterial lobar consolidation, bronchopneumonia and interstitial pneumonia

 

Table 8.6.5 Choice of antibiotics Age

anagement

All non-severe pneumonias more than 3 months of age, when the child is not toxic, accepting oral feeds, not dehydrated, maintaining normal saturation and fever less than 38.5ºC can be managed at domiciliary level with supportive care like maintenance of hydration, nutrition and antipyretics and adjuvants if needed. The choice of oral antibiotic is as shown in Table 8.6.5. First line oral antibiotics should be given minimum for 5 days and second line for 7 days. Child should be followed-up after 48 hours and if there is clinical improvement the child should be continued with the same management. If the condition clinically deteriorates after 48 hours, one should revise the diagnosis, look for associated complication and co-morbidities, changing the antibiotic to second line and if need be, the child should be hospitalized (Table 8.6.6).



Macrolideb/Co-amoxiclav/ Cefuroxime

Amoxicillina

Standard doses: 40–45 mg/kg/day in two or three divided doses Erythromycin: 30–40 mg/kg/day in three divided doses; Clarithromycin: 15 mg/kg/day in two divided doses; Azithromycin: 10 mg/kg/day in OD dose

 

Table 8.6.6 Indications for hospitalization •  •  •  •  •  •  •  •  •  • 

Infants less than 3 months Severe malnutrition More than two risk factors Comorbidities Associated complications Respiratory rate more than 70/min in infants and more than 50/min in older children Respiratory distress – grunting, alae nasi flare, ICR or SCR Cyanosis or SpO2 less than 92% in room air Poor oral intake/dehydration Inappropriate observation or supervision at home

divided doses) and should never be cefixime as it has no activity against Pneumococcus and poor activity against community pathogens responsible for pneumonia. Despite rational choice of antibiotics in right dose and for optimal duration, if there is failure in clinical improvement, one needs to:

M

> 5 years

b

anagement

Management comprises of specific antimicrobial along with supportive care of nutrition, hydration, oxygen if needed, antipyretics (paracetamol) and bronchodilators along with chest physiotherapy if needed (Table 8.6.7). In case of methicillin-sensitive Staphylococcus aureus (MSSA), the duration should be for 2 weeks and in case of Methicillin-resistant Staphylococcus aureus (MRSA), it should be 4–6 weeks. The duration for IV antibiotics should be for 5–7 days in uncomplicated cases, however, switch over to oral antibiotics may be considered if accepted orally. The switch over therapy for injections of third generation cephalosporins should be either cefpodoxime (10 mg/kg/ day in two divided doses) or cefdinir (15 mg/kg/day in two

Second line Co-amoxiclav/Cefuroxime/ Chloramphenicol

a

I

npatient

First line

3 months to 5 years Amoxicillina



Outpatient

M

However, any pneumonia below the age of 3 months should be hospitalized and treated with parenteral antibiotics. The choice of antibiotics though empirical should be determined by age, severity, pre-disposing conditions if any and local epidemiology and drug resistance pattern.

• •

•

Check the diagnosis and rule out foreign body, aspiration pneumonia and interstitial lung disease Look for underlying comorbidity like lung abscess, empyema, bronchiectasis, left to right shunts, GERD asthma, CF and ciliary dyskinesia Evaluate immunosuppression in the host like HIV and hypogammaglobulinemia

492

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Table 8.6.7 Specific antimicrobial therapy in pneumonia Age

First line

Second line

<3 months

Cefotaxime /Ceftriaxone ± Aminoglycosides

3 months to 5 years

Co-amoxiclava or Ampicillin + Chloramphenicol

Ceftriaxoneb/Cefotaximec

>5 years

Ampicillin/Penicillin G Co-amoxiclav/Macrolide (if mycoplasma suspected)

Ceftriaxoneb/Cefotaximec and Macrolides

Suspected staph

Cefuroximed or Co-amoxiclav or IV 3rd generation Cephalosporins + Cloxacillin

Ceftriaxoneb/Cefotaximec and Vancomycin/ Teicoplanin/Linezolid

e

r

b

y ystem

or

c

Co-amoxiclav: 30–40 mg/kg/day Ceftriaxone: 50–100 mg/kg/day c Cefotaxime: 100–200 mg/kg/day d Cefuroxime: 20–30 mg/kg/day e Aminoglycosides: 15 mg/kg/day in single or two divided doses

S

a

b

20% cases of pneumonia receive proper and adequate antibiotics, which is the main reason for high infant mortality due to pneumonias particularly in developing countries.

P

Test phagocytic dysfunctions for chronic granulomatous disease (CGD) • Look for drug resistance, particularly if child is from day care center, has received multiple courses of betalactams and corticosteroids • Search for the possibility of polymicrobial etiology. There is no need to chase for follow-up X-rays since total radiological resolution may take 4–12 weeks’ time depending on offending organisms.

revention

C



•

omplicationsv

P

These include empyema, pneumothorax, bronchogenic dissemination, septicemia, osteomyelitis, multiple systemic abscesses, septic arthritis and meningitis.

rognosis

Prognosis is fairly good provided there is appropriate recognition and proper referral by the health care provider and early initiation of antibiotics. Unfortunately only 15–

A multifaceted approach is needed to prevent and control childhood pneumonia. These include: • • • • •

Exclusive breast feeding for first 6 months of life Weaning to solid foods after 6 months of age, preferably with home-made foods Avoidance of risk factors like overcrowded environment, exposure to pollution and bottle feeding Protection from malnutrition and supplementation of vitamin A and D Optimum immunization with DPT, measles, Hemophilus influenzae b (Hib), pneumococcal vaccines at appropriate ages.

493

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B



ronchiolitis

implicated occasionally in children with lower respiratory tract infection (LRTI) and wheezing.

isk actors F

R

Bronchiolitis is a clinical syndrome characterized by the acute onset of respiratory symptoms in a child younger than 2 years of age. Typically, the initial symptoms of upper respiratory tract viral infection, such as fever and coryza, progress within 4–6 days to include evidence of lower respiratory tract involvement with the onset of cough and wheezing.

E

­

­



In bronchiolitis, an increased risk for hospitalization has been seen among infants attending day care, in those exposed to passive smoking and overcrowding in the household. Environmental and genetic factors may also contribute to the severity of disease. High-risk group includes age less than 3 months of age, premature delivery, low birth weight, congenital heart disease, chronic lung disease (CF, recurrent aspiration pneumonitis, bronchopulmonary dysplasia (BPD), congenital lung malformations, trachea-esophageal fistula, and neurogenic disorders interfering with pulmonary toilet), immunodeficiency and malnourished infants. The high-risk groups are vulnerable for rapid deterio ration and more severe disease. Pulmonary patch (consoli dation or atelectasis) on radiograph, hypoxia, repeat episodes of apnea, extreme tachypnea at admission are at higher risk of admission to the intensive care unit (ICU) and may need mechanical ventilation.

tiology

Bronchiolitis is usually a result of a viral respiratory tract infection. Respiratory syncytial virus is the most common underlying viral infection. Other viral pathogens such as 494 influenza, parainfluenza, adenovirus, coronaviruses and rhinoviruses can also cause bronchiolitis. Mycoplasma is also

Respiratory syncytial virus infection, results in loss of epithelial cilia and sloughing of epithelial cells in the airways. This leads to collection of desquamated airway epithelial cells, polymorphonuclear cells and lymphocytes within the airway. There may also be cellular infiltration and airway mucosal edema with very little or no alveolar infiltration. In acute bronchiolitis, sloughed epithelial cells, neutrophils, and lymphocytes appear to be the major contributors to airway obstruction. The complete plugging of some airways and partial plugging of others may lead to localized atelectasis of some units of lung parenchyma and over distention of other units. These results in ventilationperfusion mismatch causing hypoxemia, which is generally relieved by the administration of oxygen.

linical eatures F

efinition

Pathology

Clinical features are quite variable. Initially, they present like any other viral URTI with cough or cold with or without fever. Later disturbing cough, tachypnea, respiratory distress and poor feeding may develop depending on the severity of illness. Fever is present in almost 50% of infants. In patients with adenovirus or influenza associated bronchiolitis, fever is often higher than 39°C. On examination, infants typically may have tachypnea, respiratory distress, audible wheezing, rales or rhonchi, crackles, poor air movement and the expiratory phase is usually prolonged. Other concomitant findings like conjunctivitis, rhinitis and otitis media may be present. Once hypoxia sets in, there can be lethargy, seizure and death.

Grading of ronchiolitis B

Bronchiolitis is a common viral respiratory illness in children. It accounts for a substantial portion of the pediatric burden of illness all over the world; it is the most common and serious lower respiratory tract syndrome that results in hospital admission among infants with associated considerable morbidity. It is generally a selflimiting condition and is most commonly associated with RSV infection. Babies with chronic lung disease are at risk for more severe RSV-associated illness. Bronchiolitis occurs most frequently among children younger than 12 months of age. Most cases occur between late autumn and early spring, with sporadic cases any time.

C

ntroduction

Based on the ability to feed, the respiratory effort and oxygen saturation observed at admission each infant’s condition can be clinically graded as mild, moderate, and severe bronchiolitis (Table 8.7.1). I

I

A Balachandran

D

t

t

Tex book of Pedia rics

8.7

nvestigations

Bronchiolitis is a clinical diagnosis. The specific and supportive investigations which can be done in bronchiolitis include: • Nasopharyngeal aspirate for RSV and viral culture • Full blood count • Electrolytes, to look for evidence of syndrome of inappropriate antidiuretic hormone secretion (SIADH), especially when intravenous (IV) fluids are needed

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D

Ability to feed normally

Appear short of breath during feeds

May be reluctant or unable to feed

Respiratory effort

Little or no respiratory distress

Moderate distress with some chest wall retractions and nasal flaring

Severe distress with marked chest wall retractions, nasal flaring and grunting May have frequent or prolonged apneic episodes

Oxygen saturation

Saturations SaO2 more than 92%

Saturations less than 92%, correctable with oxygen

Saturations less than 92%, may or may not be correctable with oxygen

O

Ability to feed

R

Severe

t

Moderate

p

 

Mild

iseases f es ira ory ys em

Table 8.7.1 Grading of bronchiolitis

D

ifferential iagnosis

anagement

Supportive care is the mainstay of therapy for infants with bronchiolitis. Children with mild bronchiolitis can be managed on outpatient basis. They need to be followed and reviewed earlier if there is clinical worsening. Infants in high-risk group are better hospitalized and managed even if they are graded as mild in view of their propensity to deteriorate rapidly. Whereas moderate and severe cases have to be definitely admitted and monitored. Considerable, unexplained variation exists in inpatient management of bronchiolitis (Flow chart 8.7.1).

Noncontroversial ssues I

•

Blood culture if temperature more than 38.5°C Arterial blood gas analysis to look for CO2 retention when there is evidence of respiratory failure The CXR need not be done routinely and is indicated only in children with severe respiratory distress or when there is diagnostic dilemma. The radiographic findings of bronchiolitis include hyperinflation, patchy infiltrates that are typically migratory and attributable to postobstructive atelectasis, and peribronchial cuffing. Because bronchiolitis is not a disease of the alveolar spaces, a secondary bacterial pneumonitis should be suspected if a true alveolar infiltrate is seen on chest radiograph. D

• •

(* Source: Respiratory Tract Infection – Group Education Module, IAP Action Plan, 2006.)

M

 

t

S

 

Flow chart 8.7.1 Management algorithm*

Congenital anomalies, such as vascular ring, congenital heart disease, gastroesophageal reflux, aspiration pneumonia or foreign body aspiration can mimic the symptoms of bronchiolitis.

Oxygen The drug of choice in bronchiolitis is oxygen. Oxygen is used when the SaO2 is less than 94% or in a combination 495 of clinically significant respiratory distress, a respiratory

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If infant tolerates well, oral feeds are continued as is the case with mild to moderate severity. Intravenous fluids are needed to maintain hydration in moderate-to-severe or severe respiratory distress (marked retractions, nasal flaring), marked tachypnea (> 60/min), coughing and choking with feeds, vomiting, decreased intake, apneic episodes and tiring during feeds. Normal general maintenance fluids with normal maintenance volumes are used with N/2 or N/4 dextrose saline.

Nasogastric Feeding Nasogastric (NG) feeding is avoided during acute phase and is reserved for recovery phase. During acute phase the NG tube blocks one nostril and increases upper airway resistance which in turn further increases the work of breathing.

Symptomatic Management

ontroversial ssues I

C

Symptomatic management like antipyretics is needed to relieve fever.

Bronchodilators

Sedation should be avoided in an irritable child as this may be a sign of hypoxia and sedation further compromises the respiratory drive of the child.

Antibiotics There is no role for routine or prophylactic antibiotics in bronchiolitis. Since secondary bacterial infection of the lower respiratory tract are unusual in children with bronchiolitis.

Aerosolized Ribavirin Respiratory syncytial virus is the most common cause of bronchiolitis but specific antiviral therapy for symptomatic infants has been of limited value. Aerosolized ribavirin, used to treat mild to moderately ill infants with laboratory confirmed RSV bronchiolitis neither prevents the need for mechanical ventilation nor reduces the length of hospital stay.

Noninvasive Ventilation Continuous positive airway pressure (CPAP) may potentially benefit infants with bronchiolitis, by stenting open the smaller airways during all phases of respiration, preventing air trapping and obstructive disease and by serving as a constant or ipratropium stimulus in infants with a propensity to experience apnea.

Role of Steroids There is no role for systemic (parenteral/oral) or inhaled steroids or ipratropium bromide in the management of bronchiolitis.

Intensive Care Unit Management It will be needed in the following category if there is: • Progression to severe respiratory distress, especially in high-risk group • Any significant apneic episodes (more than 15 seconds or associated with desaturation) or frequent recurrent brief episodes • Persistent desaturation despite oxygen where ABG shows evidence of respiratory failure, i.e. PO2 less than 80 mm Hg; PCO2 more than 50 mm Hg; pH less than 7.25.

ther Nonstandard Therapies

Anti-Respiratory Syncytial Virus preparation The use of intravenous immunoglobulin with a neutra lizing activity against RSV [RSV-immune globulin intra venous (IGIV)] or RSV-specific humanized monoclonal antibody (palivizumab) has failed to improve outcomes in infants with or without risk factors, hospitalized with RSV infection. ­



The role of bronchodilators (salbutamol and epinephrine) in acute bronchiolitis is controversial. Though there is no absolute contraindication, bronchodilators neither treats hypoxemia nor affects the duration or progress of bronchiolitis. Inhaled beta agonist therapy when used should be on a case-by-case basis, by critically evaluating its effectiveness in the individual patient. They might be of benefit in intermediate conditions like early wheezers or children with atopy. Since mucosal edema is an important component of airway obstruction in infants with bronchiolitis, a logical approach to therapy might be to use a combined (alpha-adrenergic and beta-adrenergic agonist, such as epinephrine (0.3 mL/kg of 1:1,000 solution). Till date there is no definitive evidence to support the use of nebulized epinephrine in all children with moderate or severe bronchiolitis. When the effect of epinephrine was compared with placebo, the improvement in respiratory symptoms across studies has been inconsistent and potentially shortlived. It may therefore be appropriate, for clinicians to use nebulized epinephrine as a potential rescue medication for patients who are to be admitted.

Sedation

­

Fluid Therapy

bronchiolitis. Several trials have indicated the potential benefit of hypertonic saline (3% NaCl) in acute bronchiolitis with conflicting results.

O

t

t

Tex book of Pedia rics

rate above 60/min, and difficulty in feeding. The aim of humidified oxygen supplementation is to maintain oxygen saturation above 95% using suitable device, preferably in a non-threatening fashion. During recovery, SaO2 of 90–92% in room air is acceptable if baby is feeding well and not distressed except in children with chronic lung disease infants.

Hypertonic Saline

496 Hypertonic saline has the potential to reduce airway edema and mucus plugging the predominant feature of acute

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Prognosis The need for supplemental oxygen (based on SaO2 in room air) at admission is highly predictive of the length of the hospital stay. The case fatality rate for bronchiolitis is highest among infants less than 3 months age.

Prevention Respiratory syncytial virus is highly contagious and spreads via inhalation of small particle aerosols or direct transfer via hand-to-hand contact. Respiratory syncytial virus crossinfection is common, but is largely preventable by: • Simple hand washing by nursing, medical, other staff and parents • Isolation of RSV infected cases will minimize this problem.

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1. Balachandran A, Gowrishankar NC. Bronchiolitis. In: Subramanyam L, Shivbalan So, Gowrishankar NC, Vijayasekaran D, Balachandran A (Eds). Essentials of Pediatric Pulmonology, 3rd edition. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd. 2008.pp.91-5. 2. Christakis DA, Cowan CA, Garrison MM, et al. Variation in inpatient diagnostic testing and management of bronchiolitis. Pediatrics. 2005;115(4):878-84. 3. Coffin SE. Bronchiolitis: in-patient focus. Pediatr Clin North Am. 2005;52(4):1047-57. 4. Dayan SP, Roskind GC, Levine AD, et al. Controversies in the management of children with bronchiolitis. Clin Pediatr Emerg Med. 2004;5:41-53. 5. Grimaldi M, Gouyon B, Michaut F, et al. Severe respiratory syncytial virus bronchiolitis: epidemiologic variations associated with the initiation of palivizumab in severely premature infants with bronchopulmonary dysplasia. Pediatr Infect Dis J. 2004;23(12):1081-5. 6. King VJ, Viswanathan M, Bordley WC, et al. Pharmacologic treatment of bronchiolitis in infants and children: a systematic review. Arch Pediatr Adolesc Med. 2004;158(2):127-37. 7. Respiratory Tract Infection – Group Education Module. IAP Consensus Protocol for the Management of Respiratory Tract Infection for Children. IAP Action Plan, 2006. 8. Wainwright C, Altamirano L, Cheney M, et al. A Multicenter Randomized Double-blind controlled trial of nebulized epinephrine in infants with acute bronchiolitis. N Engl J Med. 2003;349(1):27-35.

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Complication rates are higher in former premature infants, infants with congenital heart disease and infants with other congenital abnormalities compared to infants without risk factors. Serious respiratory complications, includes respiratory failure, apnea and pneumothorax. Others include secondary infection, cardiovascular involvement and electrolyte imbalance.

ibliography



omplications



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Infant is considered ready for discharge if the child had not received supplemental oxygen for 10 hours, had minimal or no chest recession, and is feeding adequately, without the need for intravenous fluids.

Generally a self-limiting condition Commonly of viral etiology Diagnosis is clinical Oxygen (humidified) is the drug of choice Little support for use of beta-2 agonist and steroids

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It is a mixture of helium and oxygen (80:20%). It can flow through airways with less turbulence and resistance than oxygen. Only very small benefit is observed in a limited group of children who were administered heliox, hence not recommended for routine use. D

Palivizumab (RSV Ig) prophylaxis in BPD may be beneficial and has to be decided on case by case basis.

Heliox

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mpyema

tiopathogenesis

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linical eatures F

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Staphylococcus aureus, Streptococcus pneumoniae and Streptococcus pyogenes are the organisms most commonly implicated in empyema thoracis. While S. pneumoniae is the most common organism implicated in most western and developed countries, the prevalence of Hemophilus influenzae pneumonia with empyema has decreased following Hib vaccination. In India, S. aureus continues to be the commonest organism. S. pneumoniae, H. influenzae and gram-negative bacilli form rest of the burden. Frank tuberculous empyema is very uncommon.

Clinical signs vary depending on the age of the patient, stage of the effusion and type of prior antibiotic therapy.



iagnosis F

hest kiagram - rontal Views

Chest skiagram - frontal views form the most important and primary investigation for patients with pleural disease. There is no role for a routine lateral or decubitus views. The earliest sign to be seen is the obliteration of the costophrenic angle. White opacity of the lateral part or whole of hemithorax is usually seen. Skiagrams, however, cannot differentiate empyema from a parapneumonic effusion. Scoliosis may also be seen.

onography of hest C

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The reported global incidence of parapneumonic effusion and empyema is 3.3 per 10,000 children but this varies with different populace and economic level. Some of the developed nations are showing an increased prevalence lately. It is more common in infants and young children under 5 years of age.

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isease urden

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Involvement of the pleural space with pulmonary infections has been recognized since ancient times. Bacterial pneumonia with associated pleural empyema is the most common cause of pleural effusion found in the pediatric population. They need to be understood differently from parapneumonic effusions which are exudative thin effusions which can be seen in a significant proportion of those admitted with a severe and complicated pneumonia. Parapneumonic effusion and empyema lie on a continuum: the stage of the effusion is best assessed using chest ultrasound. While simple effusions have free flowing pleural fluid; more complex effusions have fibrin strands and loculations, whereas an empyema has multiple loculations and often a thick pleural rind. Importantly, a clinician must know that while most parapneumonic effusions resolve with adequate and appropriate antimicrobial therapy but antibiotics alone are almost never sufficient to treat empyema (frank pus in the pleural cavity).

A high index of suspicion and appreciation of factors that predispose to development of empyema facilitates its recognition. Children usually present with a severe pneumonia, or a pneumonia that does not respond well to initial therapy. Lack of response to antibiotics after 48 hours of treatment should raise the suspicion of an effusion. However, some may also present with a fever without clear focus, or with chest or abdominal pain. Usual features of pneumonia like fever, tachypnea, hypoxia, respiratory distress are present. The patient often has rapid and shallow breathing due to pleural pain and the child may prefer to lie on the affected side. Few children may also be septicemic, dehydrated and/or in respiratory failure. Fever can be absent in immunocompromised or debilitated patients. On physical examination, chest-asymmetry with swelling/splinting of the chest on the affected side, decreased chest expansion, decreased or bronchial breath sounds, dullness to percussion and contralateral mediastinal shift are common signs. Few children can have pleural friction rub, bronchophony or egophony above pleural effusion. Oxygen saturation levels below 92% may indicate severe disease. Some children may have other stigmata of staphylococcal infection like skin pustules or boils, infected scabies, pyomyositis, septic arthritis, pyopericardium, etc.

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It is a very useful tool for diagnosis, guidance of thoracocentesis, or pleural catheter placement. It is especially helpful when the radiograph shows a white out. Sonography can distinguish solid from liquid pleural abnormalities with much higher accuracy compared to skiagrams. Sonography gives valuable information regarding size of effusion, presence of adhesions or loculations and the echogenicity of the pleural fluid. Sonographic appearance of pleural fluid varies according to the stage of effusion; ranging from an anechoic completely echo-free or sonolucent parapneumonic effu-

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Pus/ spirate

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Most important investigation is the aspiration of the pleural fluid to confirm that it is pus. Fluid/pus aspirated should be sent for gram stain and culture to guide therapy. In case non-pus fluid is aspirated, it should also be subjected to cytological and biochemical examination to differentiate between transudative and exudative effusions.

anagement

upportive

Oxygen (in cases with SaO2 < 92%) and fluid therapy, if child is dehydrated or unable to drink should be provided. Adequate analgesia should be given especially if the child has a chest tube. It helps prevent scoliosis and aids mobilization.

Chest tube can be placed following marking done by ultrasound. If the initial aspiration fails, the drainage may be done under ultrasound. Conscious sedation can be used for the chest tube insertion with all the personnel and equipment necessary for resuscitation.

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Antipyretics

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Antipyretics should be judiciously used as fever is one of the parameters used to assess response.

ntimicrobial Therapy

The choice of empirical antibiotics is based on the likeliest causative organisms. Anti-staphylococcal penicillin (cloxacillin 100–200 mg/kg/day) along with 3rd generation cephalosporin like ceftriaxone may be used as first line drug. Aminoglycoside may be used instead of ceftriaxone. Coamoxiclav is another good alternative drug. The preferred route of therapy is intravenous. R

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rainage

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Oxygen

All children with empyema should be admitted to hospital and given intravenous antibiotics and tubethoracotomy should be done. Small collections (< 10 mm in a child below 2 years and < 20 mm in a child above 2 years) with no significant symptoms or distress may respond to antibiotic therapy alone, otherwise all symptomatic cases need drainage. Repeated thoracocentesis is not recommended except in a few with very thin pus. If the aspirate is in the form of thick pus, chest tube must be inserted at the outset.

t

anagement

The treatment options for management of empyema thoracis are antibiotics, with any of the following: Insertion of chest drain alone Intercostal drainage with addition of fibrinolytics Open decortication Video assisted thoracic surgery Rib resection/thoracoplasty/lobectomy.

D



Empyema appears well-defined, smooth, round or elliptical on CT scan. The parietal and visceral layers are separated by interposed empyema fluid, giving rise to “split pleura sign” of empyema. CT scans should not be performed routinely as it exposes the child to a very high radiation dose while most information for diagnosis and for guiding treatment decisions can be received from a good sonogram. It may have a limited role in the cases which do not respond to the initial medical management or before surgery to delineate the anatomy and to rule out a lung abscess.



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T can

The chest tube is connected to an underwater seal bottle which must always be kept below the level of the patient’s chest. The drain should be clamped for 1 hour once around 10 mL/kg of initial removal of pleural pus. In larger children and adolescents no more than 1.5 L should be drained at one time. A chest radiograph is repeated after chest drain insertion to check the placement of tube and lung expansion. The chest tube can be removed when the drainage decreases to less than 30–50 mL/day and there is no air leak from any accompanying bronchopleural fistula and the lung has expanded. A non-functional drain (no air column movement) should also be removed and the need for replacement has to be assessed by repeat imaging. Loculation should be ruled out. The chest tube should be removed during expiration or a Valsalva manoeuver. Chest X-ray is repeated after 24 hours to check for any recollection. The agents such as urokinase, streptokinase and alteplase have been used to facilitate drainage. Their use is recommended for complicated parapneumonic effusion (thick fluid with loculations) or empyema (frank pus) as it increases the drainage and obviates the need for more invasive procedures, shortens hospital stay. The treatment however is expensive and has side effects which can be serious.

iseases f es ira ory ys em

sion to very echogenic fluid with septa as seen in frank empyema. Ultrasonography shows limiting membranes suggesting the presence of loculated collections even when they are not so well seen on CT scan.

esponse to Therapy

Children may continue to be febrile for 5–7 days after starting antibiotic therapy in the case of S. pneumoniae and

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H. influenzae and a little longer in the case of Staphylococcus aureus infection. The clinical response to therapy should be assessed with parameters such as decrease in fever, normalization of lab parameters such as WBC count, CRP, decrease in drain volume, clearing in CXR, improvement in the overall condition of the patient. In case of total non-response after 96 hours of treatment, as evidenced by high spiking fever and persistent drainage, second line treatment may be instituted. A combination of vancomycin with ceftazidime is suggested. Parenteral therapy is continued till the child becomes afebrile or at least till the chest tube is removed and subsequently can be started on oral antibiotics to finish 4–6 weeks of therapy. Failure of medical therapy, persisting sepsis and large pleural collection beyond 10 days should prompt surgical referral. Cases of chronic empyema with a symptomatic child should be referred for open thoracotomy and decortication. Cases with persistent bronchopleural fistula will also benefit from surgical intervention. A persistent radiological abnormality in a symptom free child is not an indication for surgery.

ey Points

• There is no “one size fits all” treatment for parapneumonic effusions and empyema • The pathogenicity of empyema is a dynamic process: it is not feasible to manage all stages of with a single therapeutic strategy • Management, therefore, needs to be tailor made using the broad principals described above on a case-by-case basis and requires clinical experience • The outcome is usually good • Key steps in treatment are diagnostic thoracocentesis and preference for percutaneous drain • The use of fibrinolysis in the early empyema stage may be guided by the user’s experience, affordability and cost vs. benefit expected • Non-resolving cases may benefit from surgical intervention. However, efforts to achieve complete radiological clearance are largely non-productive and inconsequential • In the long term, most children will eventually show a complete expansion of the lung, if appropriately treated in the early phase.

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athophysiology



The continued cycle of infection, inflammation, and airway injury with impaired mucociliary clearance results in loss of the airway muscular and elastic components with dilation and distortion of the airways and increased mucus production. The airways become collapsible, limiting airflow, especially with forced expiration. The lung parenchyma is often involved, developing areas of atelectasis, emphysema and fibrosis. In addition, there is marked hypertrophy of the bronchial vasculature, which is prone to rupture. Morphologically bronchiectasis is classified as cylindrical (fusiform), varicose and saccular (cystic). Cylindrical is mildly enlarged bronchi that fails to taper distally, this is an early feature after an infection and can be reversed on appropriate management. Varicose type has a beaded appearance due to areas of constriction and dilation. Saccular is the most severe form, i.e. irreversible ballooning of airways.

M

Etiological factors in bronchiectasis are traditionally classified as congenital and acquired. Congenital causes of bronchiectasis are unusual either due to abnormal tracheobronchial development or inherited disorders. Acquired bronchiectasis is always due to two mechanisms, obstruction and infection. It is usually the net result of the classic triad of bronchial obstruction, infection and inflammation causing progressive irreversible airway damage resulting in bronchiectasis.

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anifestations

The most common symptom in children with bronchiectasis is persistent cough, which is present in 80–90% of children with bronchiectasis, and is typically “wet” or productive. About 50–70% of children also produce purulent sputum. The absence of sputum production does not exclude bronchiectasis, because children younger than 6 or 7 years old may not be able to expectorate sputum. Some patients present with episodic exacerbations of infection, characterized by increased cough and sputum production that may be associated with fever, pleuritic chest pain and dyspnea. These exacerbations typically respond to antibiotic therapy. Hemoptysis is caused by erosion of inflamed airway tissue adjacent to pulmonary vessels. The amount of bleeding can range from mild, with blood streaked sputum, to profuse amounts of fresh bleeding if larger pulmonary vessels rupture. Dyspnea and exercise intolerance are uncommon at presentation but may develop as the disease progresses, or may occur during an acute exacerbation of the disease due to intercurrent infection. Children with severe bronchiectatic lung disease may have cyanosis, indicating severe hypoxemia due to mismatched pulmonary ventilation and perfusion. If the hypoxemia is prolonged and profound, it may lead to pulmonary hypertension and cor pulmonale. The underlying disorder responsible for the bron­ chiectasis may also cause other symptoms at presentation, and provide clues to the diagnosis. As example, failure to thrive is frequently seen in diseases such as CF and immunodeficiency disorders. Chronic sinusitis is common among children with CF, ciliary dysfunction disorders, and immunodeficiencies. The presence of congenital anomalies should alert the clinician to the possibility of associated anomalies that predispose to bronchiectasis (e.g. congenital heart disease and anomalies of the tracheobronchial tree). 501

Causes

Clinical



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Bronchiectasis is a structural abnormality characterized by abnormal dilation and distortion of the bronchial tree, resulting in chronic obstructive lung disease. This condition is typically the end result of a variety of pathophysiologic processes that render the bronchial walls weakened, easily collapsible, chronically inflamed, and plugged with mucus secretions. The prevalence of bronchiectasis in developed nations has gradually declined in recent years, probably because of improvements in sanitation and housing, immunizations against respiratory illnesses (e.g. measles and pertussis) and antibiotic use.



Bronchiectasis

y ystem



Suppurative disease of the lung includes bronchiectasis, lung abscess and empyema. Bronchiectasis and lung abscess have been discussed here. Empyema is discussed separately in Chapter “Empyema”.

The types of disorders that cause bronchiectasis vary among populations and age groups. As examples, infections and acquired causes of bronchiectasis predominate in developing nations, whereas congenital anomalies of the airways or immune system are more prominent in children of developed nations. The conditions that predispose to bronchiectasis can be classified into the following categories (Table 8.9.1): • Congenital anatomic defects • Immunodeficiency states • Altered pulmonary host defences • Acquired bronchial obstruction • Infection • Miscellaneous disorders.

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uppurative Lung Disease

Diseases Of Respi at

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Infections – Childhood infections - Pertussis - Measles – Persistent bacterial bronchitis - Staphylococcus aureus - Klebsiella pneumoniae - Pseudomonas aeruginosa – Post-viral – adenovirus – Other infections - Mycobacterium tuberculosis - Fungal – Mycoplasma pneumoniae

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Acquired bronchial obstruction – Intraluminal obstruction - Airway foreign-body - Granulation tissue – Extraluminal compression - Lymphadenopathy (TB) - Vascular compression – Right middle lobe syndrome - Chronic or recurrent atelectasis usually seen in asthmatics









Altered pulmonary host defences – Cystic fibrosis (mucoviscidosis) – Primary ciliary dyskinesia - Kartagener syndrome – Impaired cough (e.g. neuromuscular weakness condition)













Miscellaneous disorders – Allergic bronchopulmonary aspergillosis – Recurrent aspiration - Tracheoesophageal fistula - Neurological disorders - GERD – Bronchiolitis obliterans

valuation

The aims of evaluating children with suspected bronchiec­ tasis are: • To confirm the diagnosis • To define the distribution and severity of airway involve­ ment • To characterize extrapulmonary organ involvement associated with bronchiectasis (e.g. cor pulmonale) 502

Figure 8.9.1 Bronchiectasis of left lower lobe  

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• Immunodeficiency states – Primary abnormality - Congenital (Bruton’s type) agammaglobulinemia - Selective immunoglobulin A, immunoglobulin G sub-class deficiency - Severe Combined T and B cell immunodeficiency (SCID) – Secondary abnormality - HIV infection - Immunosuppressive agents

To identify familial and treatable underlying causes of bronchiectasis. The evaluation includes a complete medical history and physical examination, as well as laboratory testing, radiographic imaging and pulmonary function test. A complete medical history, including past medical, family, travel and environmental history, is a crucial part of the evaluation and can be helpful in identifying the underlying cause for bronchiectasis. Certain features of the history should raise concern for specific underlying disorders (e.g. history of choking suggests foreign body aspiration; chronic aspiration should be considered in patients with recurrent pneumonia particularly those with neurologic dysfunction). The general physical examination of the patient with suspected bronchiectasis may also identify the features described above that point to an underlying etiology, including failure to thrive, sinus and ear infections, neurologic dysfunction, and the presence of congenital anomalies. In addition, the pulmonary examination may reveal the following features: crackles and rhonchi, which are often heard over the area of bronchiectasis; wheezing, which is less common; clubbing of the nail bed, which is a basic clinical sign of bronchiectasis; and chest wall deformity, which can be seen in obstructive lung diseases (e.g. CF), in which hyperinflation of the lungs results in increased anterior to posterior chest diameter. On evaluation chest radiograph, findings that are suspicious for bronchiectasis include recurrent/persistent infiltrates or atelectasis in the same lobe or segment (Fig. 8.9.1). The HRCT is the most sensitive imaging method to detect bronchiectasis (Fig. 8.9.2). For patients with diffusely distributed bronchiectasis, the minimum evaluation includes testing for CF [sweat chloride or deoxyribonucleic acid (DNA) testing] and immunodeficiency (including CBC with differential, immunoglobulin’s and IgG sub classes). Ciliary dyskinesia should be considered in patients with recurrent sinus and ear infections, and evaluated with a nasal mucosal biopsy. Potential mechanisms of aspiration

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• Congenital anatomic defects – Tracheobronchomalacia – Pulmonary sequestration – Cartilage deficiency (Williams-Campbell syndrome) – Tracheobronchomegaly (Mounier-Kuhn syndrome)

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k f e iat i s

Table 8.9.1 Bronchiectasis in children - predisposing conditions

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revention

Appropriate management of aspiration [gastroesophageal reflux (GER), foreign body] aggressive management of lower respiratory infections to prevent postinfectious bron­ chiectasis and routine immunization against respiratory pathogens (measles, pertussis, H. influenzae, viral influenzae, pneumococcal) are helpful in preventing bronchiectasis.

rognosis

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Overall, the prognosis for patients with bronchiectasis has improved considerably in the past few decades. Earlier recognition or prevention of predisposing conditions, more powerful and wide spectrum antibiotics, and improved surgical outcomes are likely reasons.

or S

Both anaerobic and aerobic organisms can cause lung ab­ scesses. Common anaerobic bacteria that can cause a pul­ monary abscess include Bacteroides species, Fusobacterium species, and Peptostreptococcus species. Abscesses can be caused by aerobic organisms such as Streptococcus species; Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa. Staphylococcus aureus is the organism most frequently involved. F

Clinical eatures Clinical manifestations of lung abscess are nonspecific and similar to those of pneumonia. They include fever, cough, dyspnea, chest pain, anorexia, hemoptysis and putrid breath. The course may be indolent. Physical examination typically reveals tachypnea, dyspnea, and retractions with accessory muscle use, decreased breath sounds and dullness to percussion in the affected area. Crackles may be heard on examination.

Diagnosis -

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The diagnosis is suggested by a chest radiograph demonstrating a thick walled cavity with an air fluid level (Fig. 8.9.3) and confirmed by contrast enhanced computed tomography. Lung abscess is often accompanied by parapneumonic effusion. Lung abscess should be suspected when consolidation is unusually persistent, when pneumonia remains persistently round or mass like, and when the volume of the involved lobe is increased (as suggested by a bulging fissure). Interventional radiology may be helpful in obtaining a specimen from the abscess cavity for diagnostic studies. -

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The initial therapy for patients with bronchiectasis is medical and aims at decreasing airway obstruction and controlling infection. Chest physiotherapy (postural drainage), anti­ biotics and bronchodilators are essential. Two to four weeks of parenteral antibiotics are often necessary to manage acute exacerbations adequately. Antibiotic choice is dictated by the identification and sensitivity of organisms found on sputum (induced or spontaneous), or BAL fluid cultures. Low dose long term macrolide therapy is found to be beneficial in idiopathic bronchiectasis. Nutritional support is important in children. They should be routinely advised on adequate calories and good protein diet. Any underlying disorder (immunodeficiency, aspiration) that may be contributing must be addressed. When localized bronchiectasis becomes more severe or resistant to medical management, segmental or lobar resection may be warranted.

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should be assessed using video fluoroscopy, esophageal pH monitoring, and/or nuclear scintigraphy. For patients with focal bronchiectasis, imaging and/or bronchoscopy should be performed to assess for airway obstruction (e.g. airway foreign body or congenital pulmonary anomalies). Pulmonary function tests can be helpful to evaluate the severity of lung disease and should be performed in older children. Most patients with bronchiectasis have features of obstructive lung disease, indicated by low FEV1 and FEV1/ FVC ratio.

A lung abscess is an accumulation of inflammatory cells, accompanied by tissue destruction or necrosis that produces one or more cavities in the lung. A primary lung abscess occurs in a previously healthy patient with no underlying disorders. A secondary lung abscess occurs in a patient with underlying or predisposing condition. Aspiration is the most important predisposing factor for lung abscess, which may develop 1–2 weeks after the aspiration event; other predisposing factors include airway obstruction and congenitally abnormal lung.

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Figure 8.9.2 Bilateral bronchiectasis of lower lobes

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increased risk of complications that occurs in children with necrotizing pneumonia. Percutaneous drainage should be considered in children with lung abscess whose condition fails to improve or worsens after 72 hours of antibiotic therapy. At least 3 weeks of IV antibiotic therapy should be delivered before lobectomy is considered for treatment failure.

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Complications

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The most common complication of lung abscess is intracavitary hemorrhage. This can cause hemoptysis or spillage of the abscess contents with spread of infection to other areas of the lung. Other complications of lung abscess include empyema, bronchopleural fistula, septicemia and cerebral abscess.

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Figure 8.9.3 Lung abscess right lower lobe with air fluid level

anagement

Overall, prognosis for children with primary pulmonary abscesses is excellent. Most children become asymptomatic within 7–10 days. Radiologic abnormalities usually resolve in 1–3 months.

Bibliography 1. Chang AB, Redding GJ. Bronchiectasis. Kendig’s Disorders of the Respiratory Tract in Children. Philadelphia, PA: Saunders. 2006.pp.463 77. 2. Fakhoury K, Kanu A. Clinical manifestations and evaluation of bronchiectasis in children. UpToDate; www.uptodate.com Apr 18, 2012. 3. Lakser O. Bronchiectasis, Lung abscess. Nelson Textbook of Pediatrics, 18th edition. 2008.pp.1800 3. 4. Redding GJ. Bronchiectasis in children. Pediatr Clin North Am. 2009;56(1):157 71. 5. Sethi GR, Batra V. Bronchiectasis: causes and management. Indian J Pediatr. 2000;67(2):133 9. 6. Vijayasekaran D, Shivbalan So. Bronchiectasis. Essentials of Pediatric Pulmonology, 3rd edition. 2008. pp.196 200.





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Treatment of lung abscess requires a prolonged course of antibiotic therapy usually initiated parenterally. Antibiotic choice should be guided by gram stain and culture but initially should include aerobic and anaerobic coverage. Treatment regimens should include a penicillinase resistant agent active against S. aureus and anaerobic coverage, typically with clindamycin or ticarcillin/clavulanic acid. If Gram negative bacteria are suspected or isolated, an aminoglycoside should be added. The duration is determined by the clinical response, but is usually a total of 4 weeks or 2 weeks after the patient is afebrile and has clinical improvement. The average duration of fever is 4–8 days. Eighty to ninety percent of lung abscesses in children resolve with antibiotic therapy alone, provided that bronchial obstruction is removed. In cases that fail to resolve with antibiotics alone, needle aspiration or percutaneous catheter drainage may provide diagnostic information and therapeutic benefit without the

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The incidence of asthma has steadily increased in both developed and developing countries from 1970 to 2000. There is a marginal decrease in the incidence in Australia, Hong Kong, UK, Italy and México after 2000 most probably due to saturation of the genetically predisposed population. However, prevalence of persistent asthma needing constant medications is increasing. A hospital based study in Bengaluru showed that the prevalence of asthma steadily increased from 9% in 1979 to 29.5% in 1999. It decreased by 3% in 2004 and further by 1% in 2009. However, persistent asthma increased by 20–72% and persistent severe asthma by 4–11% from 1999 to 2009. The increased prevalence of asthma is noticed in the following situations: • Urban children • Rapid urbanization increasing prevalence in the semirural areas compared to rural • Children attending schools in heavy traffic areas especially from lower socioeconomic population • Children living in poorly ventilated homes and single room dwelling huts • Children living in houses with tobacco smoking persons • Children living in houses where cow dung cakes, agricultural waste and firewood are used as cooking fuel • During Diwali and similar festivals (by 100%) due to increase in SO2 • Children in the age group of less than 5 years (≈75%); above 5 years of age ≈25% • Male predominance—the male to female ratio is 2:1 owing to the relatively small airways with which they are born and inherited as an autosomal dominant trait • Positive family history of asthma either in parents, siblings or grandparents.

tiopathogenesis

The etiological factors can be classified as biologicals and irritants (Table 8.10.1).

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Children develop sensitivity to indoor allergens as they grow older in the atmosphere they are reared. The predominant indoor allergen is the house dust mite. It takes 100 mites/g of dust to get sensitization and 500 dust mites/g of dust to produce wheezing. Fifty percent of perennial asthma is due to dust mites. The pollen and mould sensitivity is observed less frequently whereas cockroach sensitivity is fairly common.

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Viral nfections I

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erobiologicals

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Asthma is a non-communicable chronic lung disease, characterized by the following: • Airway inflammation • Airway obstruction mainly due to muscle spasm, associated with mucosal edema and stagnation of the mucus • Airway hyper-reactivity to aerobiologicals and irritants • Airway remodeling in uncontrolled asthma.

The precipitating factor for an asthma attack in 40% of the children is viral URTI. Most children develop rhinitis with or without fever followed by cough. In these children chest congestion persists over 10 days and often along with wheeze. The incidence varies from 29% to 54% in both atopic and non-atopic individuals. Respiratory syncytial virus and rhinoviruses are the predominant viruses triggering asthma. S

ntroduction

eason

Seasonal variation of asthma attacks is experienced by 35% of children. Of these the incidence during monsoon, followed by winter and less common in summer. Recently there is an increase of asthma attacks in summer from 3% to 20%. This is attributed to increase in automobile emission and the bright sun converting the oxides of nitrogen to O3, which aggravates the asthma sensitivity. F

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The role of food allergy in asthma is difficult to prove in children. Parents do observe that the children do relatively well when a suspected food allergen is avoided. The most blamed offenders include grapes, banana, guavas, citrus fruits, ice creams, fried foods, and tomatoes with other items less common. Table 8.10.1 Etiological factors in asthma Biologicals

Irritants

Dust mites

Tobacco smoke

Cockroaches

Cooking fuel smoke

Pollens

Mosquito coil smoke

Fungi

Sprays

Pets - saliva, urine

Perfumes

Viral infections Food

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Air pollution is both outdoor and indoor. The important outdoor pollutants are black smoke, respirable suspended particulates, SO2, NO, CO, O3 and lead produced by combustion of fossil fuels, factories, mines, paper pulp mills and automobile exhaust. Nitrogen oxide triggers asthma in 65% of patients and also sensitizes to dust mites allergy. Ozone triggers asthma in 43% of patients and SO2 sensitizes the asthmatics by tenfold.

• • • •

athophysiology

Asthma is a complex condition where interaction of genetics and environment occurs involving many inflammatory cells which release a wide range of variety of mediators. These mediators act on the cells of the airway leading to smooth muscle contraction, mucus hypersecretion, plasma leakage, edema, activation of cholinergic reflexes and activation of sensory nerves, which lead to amplification of the continuing inflammatory response. The chronic inflammation leads to structural changes, including sub-epithelial fibrosis and smooth muscle hypertrophy and hyperplasia. This late process is less easily reversed than the acute changes and might end up with airway remodeling. To mount an allergic response one has to be sensitized to an allergen. When an allergen enters the epithelial cell the dendritic cells below the epithelia cell act like custom officer, catch the allergen by their long arms and break the allergen into small pieces called epitomes. These are handed over to the T lymphocytes, the orchestrator of the immune system, which give the instruction to various cells for proper action. The B lymphocytes are instructed to handle pollens which produce interleukins, IL4 and IL13 to make immunoglobulin E (IgE) antibodies. The IgE arms the mast cell, the muscle man of immune system. The mast cell binds very large number of IgE molecules of various allergens. The activation of mast cell (mast cell degranulation) releases histamine. The continued exposure to allergen brings eosinophils (dreaded cell for parasites) into action. The eosinophilic granules release toxic chemicals such as eosinophil cation protein, eosinophil derived neurotoxin and major basic protein, which damage the epithelium and sensory nerves causing hyper-responsiveness to nonallergic stimuli. The mast cells are responsible for early phase reaction and eosinophils for late phase reaction in general.

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All that wheezes is not asthma but most asthmatics don’t wheeze. The common clinical features include the following: • Recurrent cough: The majority of children present with recurrent cough 90% of the time. The cough is more 506

at night, or early morning time; induced by physical or emotional stress (crying, laughing and shouting) Recurrent wheeze is a prominent feature of lower airway obstruction. Many people mistake rattling in the chest as wheeze. Wheezing is not felt on palpation of the chest Retractions are a common feature for airway obstruction, depending on the severity of asthma they may be present over subcostal, intercostal, or suprasternal area, with flaring of nostrils Post-tussive vomiting (vomiting after a bout of coughing) occurs in 5% of cases Abdominal pain rarely occurs due to over-working of expiratory abdominal muscles Chest pain is present rarely Other comorbid conditions like allergic rhinitis, sinusitis, serous otitis media, eczema and conjunctivitis may be present.

Diagnosis Diagnosis of asthma is mainly by history and physical examination. The diagnosis of asthma in infants and preschoolers is difficult due to poor cooperation in diagnostic procedures, hesitation by pediatricians, time consuming and practicality, and ethical issues. However, the need for diagnosis is essential for early treatment, to improve the quality of life, physical and psychological development, to avoid chronic pulmonary disease “airway remodeling” and to educate on the preventive measures, to cut the health care cost and to prognosticate.

reschoolers

The diagnosis of asthma is made based on national guidelines in an infant who has more than 3 episodes of wheeze in 1 year with family history of asthma, has atopic features, afebrile episodes and cough persisting more than 2 weeks with good response to bronchodilators. In some children a therapeutic trial of treatment with quick relievers and inhaled steroids for 8–12 weeks with good improvement and relapse after stopping treatment is diagnostic of asthma.

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chool-Going hildren C

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ir ollution and sthma

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Pets are not the major factors for the asthma in India. Cats are more allergic than dogs. The saliva, urine and dander are the causes for allergy sensitization.

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ets

Peak expiratory flow (PEF) measurement before and after salbutamol nebulization with improvement (12–15%) is highly suggestive of reversible airway obstruction in asthma. This simple and less expensive procedure can be used to monitor the therapeutic response. Early asthma attack can be recognized by measuring diurnal variation PEF. It measures the air coming out of larger and medium size airways Spirometry is the central tool for defining the obstructive airway disease. In asthma there is decreased FEV1, FEV1/ FVC ratio and FEF 25–75 Eosinophil count: The increased eosinophil count in the blood is suggestive of an allergic phenomenon

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The drugs used in the management of asthma include quick relievers, preventers and long-term symptoms relievers as listed in Table 8.10.2. The choice of the drugs depends on the age and severity of the wheezing episodes (Table 8.10.3). It should be ideally follow carried out in a stepwise manner. Always use quick reliever as a rescue treatment in acute exacerbation of persistent asthmatics that are on preventers. Inhalation method is the best way to administer medication to avoid adverse reactions and for quick actions.

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ducation

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harmacotherapy

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ollow-up

Regular follow-up is needed to assess the control of asthma by using the parameters as listed in Table 8.10.4. Always give hope, confidence and encourage sports activities.

The management of asthma includes: • Education • Environment control • Pharmacotherapy • Regular follow-up.

The pediatrician must spend time to clear the misconceptions about the disease, sexual bias, non-communicability of the disease, fear of inhalers, steroids, etc. In India, doctors should always include the grandparents in counseling. Individual counseling is preferred in adolescents. C

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ungus: Attend to damp walls, have good ventilation, and clean the shower curtains weekly ets: Keep them away from sleeping area, if possible outside the house Avoid strong odors, smoke, mosquito coil burning, and especially tobacco smoke Have indoor plants to absorb formaldehyde and volatile organic compounds from modern furniture, etc. and expose to sunlight once a week and remove the water from trays once a week. P

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anagement

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y ystem

Total IgE level: It is beneficial only to recognize the atopic background of asthma. One can predict the possibility of development of persistent asthma, prognosis, strongly advocate environment control and good response to steroids • Specific IgE level: It is needed for specific immunotherapy and before the use of anti-IgE antibody treatment • Chest X-ray is not needed to diagnose asthma. It is needed only when the diagnosis is not clear or any complications are suspected. Please note that in children under-5 years who are devoid of lung collaterals, one can see sub-segmental, segmental or lobar atelectasis quite often, which might be treated as recurrent pneumonia • Breath nitric oxide is used in some pulmonary centers for monitoring the eosinophilic airway inflammation. It is not used much in children for various reasons • Skin testing with allergens is the gold standard to identify the specific allergens and used before immunotherapy for aeroallergens • Bronchial challenge tests and other physiological tests do not have a major role in the diagnosis of asthma in children.

Diseases Of Respi at

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It is the most important factor in the control of asthma. The aim should be to avoid allergens and irritants: • Dust mites: Avoid carpets, upholstered furniture, use plastic covers to pillows and mattresses; and expose to sunlight once a week; wash soft toys periodically; and wet mop the floorings • ockroach: Cover garbage and unused food containers

omorbidities

The most common comorbid conditions are: • Allergic rhinitis: Nearly three-fourths of asthmatic children develop allergic rhinitis which complicates and worsens asthma. Nasal breathing is protective to asthma. Always evaluate as a unified airway disease and successful treatment of allergic rhinitis can control asthma • Sinusitis: Nearly 9% of asthmatics have sinusitis and the incidence in uncontrolled asthma is nearly 35%. The sinusitis is a result of blockage of osteomeatuses of sinuses due to edematous nasal mucosa and compromise in the mucociliary function of sinus • Otitis media: Nearly 25% of children have serous otitis media due to blockage of eustachian tube from edema of nasal mucosa

Table 8.10.2 Classification of drugs used for the management of asthma











Used to relieve bronchospasm for longer hours. • Long acting beta-2-agonists – Salmeterol – Formoterol – Bambuterol • Always use with inhaled Steroids



Long-term symptoms relievers

Used for long-term to control the inflammation and to prevent further attacks. • Leukotriene receptor antagonists • Steroids – Oral – Inhaled (ICS) • Theophylline



Preventers

Used for acute attacks to relieve bronchospasm as and when needed. • Short acting beta-2- agonists – Salbutamol – Terbutaline • Adrenaline • Aminophylline

Quick relievers

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Step 1 (Intermittent) • The SABA as needed • If needed more than 2 times/week add preventers

Step 2 (Persistent mild) • LTRA or • ICS low dose

Step 2 (Persistent mild) • Low dose ICS or • LTRA

Step 3 (Persistent moderate) • Low dose ICS + LTRA or • Double the dose of ICS

Step 3 (Persistent moderate) • Low dose ICS + LTRA or • Low dose ICS + LABA or • Low dose ICS + Theophylline sustained release or • Double the dose of ICS

Step 4 (Persistent severe) • Medium dose of ICS + LTRA or • High dose ICS Use oral steroids during acute severe exacerbation

Step 4 (Persistent severe) • Medium dose ICS +LABA or • Medium dose ICS + LTRA or • Medium dose ICS + Theophylline SR or • High dose ICS











More than 5 years

Step 1 (Intermittent) • The SABA as and when needed • If SABA is needed more than 2 times/week, add preventers 

Less than 5 years















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Table 8.10.3 Selection of drugs

Step 5 • Add oral steroids • Anti-IgE antibody treatment • Immunotherapy Abbreviations: SABA: Short acting beta-2-agonists; LABA: Long acting beta-2-agonists; LTRA: Leukotriene receptor antagonist; ICS: Inhaled corticosteroids; SR: Sustained release Key: Low dose of ICS: 200 µg Medium dose of ICS: 400 µg High dose of ICS: 400 to 500 µg

 

Table 8.10.4 Level of control of asthma Parameters

Controlled

Partly controlled

Poorly controlled

Daytime symptoms

Less than 2 times/week

More than 2 times/week

Limitations of activities

None

Any

Nocturnal symptoms of disturbed sleep

None

Any

Three or more features of partly controlled asthma in any week

Need for relievers or rescue treatment

Less than 2 times/week

More than 2 times/week

Lung functions (PEF or FEV1)

Normal

Less than 80% of predicted or personal best

Exacerbation

None

One or more per year

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hospitalization for intensive treatment. This occurs when the early signs of severity are missed or ignored by the patients, parents and physicians. A

S

A

anagement of cute evere sthma in the Hospitalized atient P

Gastroesophageal reflux disease: GERD is quite common in infants, but GERD as a cause for worsening of asthma is seen in few cases of refractory asthma. It should be suspected in children with prominent asthma symptoms while eating or sleeping or who prop up in beds themselves to relieve nocturnal symptoms. The gold standard for diagnosis is esophageal pH monitoring Acute severe asthma: Asthma attacks can be very severe in untreated or improperly treated cases needing

M

•

One in any week

To cover all aspects in acute severe attack of asthma and to prioritize the treatment, please remember six ‘M’s in aiming therapy (Table 8.10.5).

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Recognition of unified airway disease Recognition of chronic inflammatory disease concept Appreciating the asthma phenotypes based on infla mmatory cells involved and mediators release by eosinophils, neutrophils, T-lymphocytes and vascular endothelial cells The importance of environment control The use of breathing exercise or yoga to avoid chest and spinal deformity which have increase morbidity and mortality Use of Anti-IgE antibody treatment in difficult case The use of immunotherapy preferably by sublingual route.

• •

• •

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y ystem

The primary prevention is to prevent sensitization to allergens. The deprivation of protective germs in early life might drive early immune development with T-helper cells (TH2) stimulation and from allergic sensitization, persistent airway inflammation and remodeling. The farming environment has protective effect from exposures to lipopolysaccharide endotoxin from microorganism. Avoid unnecessary use of high spectrum antibiotics. Use of probiotics has doubtful effect in the prevention of development of asthma. The secondary prevention is to prevent occurrence of symptoms in sensitized child is to avoid triggering factors like environmental factors predominantly the tobacco smoke and indoor pollutants like dust mites, cockroach, fungi, pollens and other smokes. Prolonged breast feeding

• • •

­

revention

Recent dvances

P

P P

Long term follow-up of published studies are not available in India. Viral infection triggered asthmas tend to outgrow by 5 years of age when the immune system reaches adult levels. Some more outgrow by 8 years when the airway caliber reaches adult levels, more so in boys. During adolescent period majority tend to outgrow the attacks. However, those with atopic asthma (high IgE level) and children with low lung capacities and girls have the tendency for indefinite period.

up to 6 months, which is Indian tradition, can help to prevent infection triggered asthma. The tertiary prevention is to control the symptoms by environment control and long-term use of antiinflammatory drugs and quick relievers as rescue medicines in any exacerbations.

Diseases Of Respi at

rognosis

ractice Guidelines

Use quick reliever as and when necessary and use preventers in step 2–5 as described in Table 8.10.6.

 

Table 8.10.5 Six ‘M’s in the management of acute severe asthma in children Principle of management

Pathogenetic mechanism

Management

Metabolic correction

Hypoxemia, metabolic acidosis

Humidified oxygen by mask, nasal prongs

Muscle spasm to be relieved

Airway obstruction

Beta-2-agonists + ipratropium bromide in O2 driven nebulizers

Mucosal edema

Inflammation, airway obstruction

Systemic or oral prednisolone or methylprednisolone (IV) or inhaled fluticasone 1,500 µg

Mucus secretions

Excess mucus secretion and airway obstruction

Appropriate hydration, staccato type of coughing

Monitor for infection

Pneumonia, otitis media, sinusitis

Antibiotics

Mechanical ventilation

Respiratory acidosis, apnea ventilation failure

Ventilatory care as last resort

Table 8.10.6 Stepwise management of bronchial asthma Step 1

Step 2

Step 3

Step 4

Step 5

Asthma education - include grand parents Environment Control Beta-2-agonists SOS Controller options

Beta-2-agonists in rescue treatment SOS Select one

Select one

To step 3. add any one in the list

To step 4. add any one

ICS low dose or LTRA

ICS low dose + LABA or LTRA or Theophylline SR or ICS med dose

Medium or high dose ICS + LABA or LTRA or Theophylline SR

Oral steroid (short course) or Anti-IgE (Omalizumab) or Immunotherapy

509

Abbreviations: LABA: Long acting beta-2-agonists; LTRA: Leukotriene receptor antagonist; ICS: Inhaled corticosteroids; SR: Sustained release

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Aim at good control of asthma with good education and bonding with patient, parents, and grandparents for better compliance Avoid prolonged use of systemic steroids or high dose of inhaled steroids Always use spacer preferably clear, valved one for better delivery. For metered dose inhaler (MDI) slow inhalation and for powder inhaler faster inhalation is needed Always assess the compliance and technique of inhalation during follow-up while infusing trust, hope and confidence Counsel the adolescent separately and stress on ill effect of TOBACCO smoke. Stress on good environment control and to have indoor plants which needs to be exposed to sunlight and to remove water from the tray once a week.

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Depending on the response either step-up or stepdown the dose of preventers, some studies recommend starting with high dose and then reducing the dose earlier.

essages

• Please keep it in mind that while dealing with a biological system based on expert opinion there should be enough room for individualization • Always look for availability, accessibility and affordability in managing our children with asthma • Do realize that different forms of asthma respond differently to drugs

• Phenotype based treatments are likely to be more effective and safer than standard uniform treatment that we currently offer to all asthma phenotypes • Be optimistic; newer research needs a link between clinicians, researchers and pharmacological companies for better, costeffective individual treatment of patients

Bibliography 1. Bisgaard H, Bonnelykke K. Long-term studies of the natural history of asthma in childhood. J Allergy Clinical Immunol. 2010;126(2):187-97. 2. IAP and Allergy and applied immunology chapter – Allergic Rhinitis and comorbidities training module (ARCTM), 2011. 3. IAP and Respiratory chapter: asthma training module (ATM). 2011. 4. Pan SJ, Kuo CH, Lam KP, et al. Probiotics and allergy in children – an update review. Pediatr Allergy Immunol. 2010;21(4 Pt 2): e659-66. 5. Paramesh H. Epidemiology of asthma in India. Indian J Pediatr. 2002;69:309-12. 6. Paramesh H. Asthma and environment, Indian J Pediatr. 2006;73(Suppl):S51-5. 7. Paramesh H. Asthma in children: seasonal variations. International J Environ Health. 2008;2:410-6. 8. Paramesh H. Textbook of Practical Pediatric Pulmonology. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd, 2009. 9. Petsky HL, Cates CJ, Lasserson TJ, et al. A systemic review and meta-analysis: tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils). Throax. 2012;67(3):199-208. 10. Zhang WX, Li CC. Airway remodeling: a potential therapeutic target in asthma. World J Pediatr. 2011;7(2):124-8.

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Section

9

Diseases of Gastrointestinal System and Liver







































9.1 9.2 9.3 9.4 9.5 9.6 9.7 9.8 9.9 9.10 9.11 9.12 9.13 9.14 9.15 9.16 9.17 9.18 9.19 9.20











































Section Editor : VS Sankaranarayanan Acute Diarrhea: Ashok K Patwari Persistent and Chronic Diarrhea in Children: Gadadhar Sarangi Malabsorption Syndrome in Children: Ujjal Poddar Vomiting in Children and Gastroesophageal Reflux Disease: Shashidhararao Nagabhushana Parasitic Bowel Disease: BD Gupta Gastrointestinal Bleeding in Children: Neelam Mohan Constipation in Children: VR Ravikumar Hirschsprung Disease: Kanishka Das Abdominal Pain in Children: Srinivas Sankaranarayanan Hepatomegaly: A Practical Diagnostic Approach: Sheila Bhave Clinical Relevance of Liver Function Tests and Imaging Modalities in Hepatobiliary Disorders: Geetha M Viral Hepatitis: Malathi Sathiyasekaran Chronic Liver Disease and Cirrhosis of Liver in Children: VS Sankaranarayanan Neonatal Cholestasis Syndromes: A Riyaz Cholestatic Disorders in Older Children: B Bhaskar Raju Fulminant Hepatic Failure: Rajiv Chandra Mathur Ascites: Balvir S Tomar Common Metabolic Liver Disorders in Children: Ashish Bavdekar Acute Pancreatitis in Children: D Nirmala Chronic Pancreatitis in Children: Seema Alam

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Acute Diarrhea Ashok K Patwari

Diarrhea is usually defined as passage of three or more loose or watery stools in a 24-hour period a loose stool being one that would take the shape of a container. However, for practical purposes, it is the recent change in consistency and character of stool and its water content rather than the number of stools that is important. Infants who are exclusively breastfed normally pass several soft or semi-liquid stools each day; for them, it is practical to define diarrhea as an increase in stool frequency or liquidity that is considered abnormal by mother.

Acute Watery Diarrhea It refers to diarrhea that begins acutely, lasts for less than 14 days, with passage of frequent loose or watery stools without visible blood. Vomiting may occur and fever may be present. Loss of large volume of water and electrolytes can result in dehydration and dyselectrolytemia.

Dysentery It is the term used for diarrhea with visible blood and mucus. It is often associated with fever and tenesmus. Common clinical features of dysentery include anorexia, rapid weight loss and complications like renal failure and encephalopathy.

Persistent Diarrhea It represents diarrhea, presumed to be caused by infectious agents that begins acutely, but is of usually long duration (more than 14 days). The episode may begin either as acute watery diarrhea (AWD) or as dysentery. Marked weight loss is common. Diarrheal stool volume may also be great, with a risk of dehydration. Persistent diarrhea should not 512 be confused with “chronic diarrhea” which is recurrent or

E

Acute diarrhea constitutes a leading cause of morbidity and mortality among children below 5 years of age in developing countries. On an average, 3.3 episodes of diarrhea are experienced per child per year, but in some areas the average exceeds 9 episodes per year. More than 2 million deaths are estimated to result each year as a consequence of diarrheal disease in under-fives. Eighty percent of these deaths occur in the first 2 years of life, main causes being dehydration, complications associated with dysentery, malnutrition and serious infection such as pneumonia. Most of the diarrheal episodes occur during the first 2 years of life (highest incidence 6–11 months), low socioeconomic status, in non-breastfed infants, and in association with measles, severe malnutrition and immunodeficiency. ­

Definition

pidemiology



Worldwide, particularly in developing countries, diarrheal diseases still constitute significant causes of mortality and morbidity. There is considerable reduction in the mortality in infants suffering from acute diarrhea which is attributed to the proven efficacy of treatment with reduced osmolar oral rehydration solutions (ORS), oral zinc and proper diet monitoring and continuation of breastfeeds in young infants, avoiding unnecessary medications and commercial milk-free foods. It is essential to understand various types of diarrhea based on duration and etiology as the approach and management differs.

long lasting diarrhea due to non-infectious causes such as sensitivity to gluten or inherited metabolic disorder.

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Introduction

tiopathogenesis

In developing countries, the organisms most frequently associated with AWD include enterotoxigenic Escherichia coli (ETEC), enteropathogenic Escherichia coli (EPEC), Shigella dysenteriae and Campylobacter jejuni. Rotavirus is a common cause of severe diarrhea, vomiting and fever leading to rapid dehydration. Vibrio cholerae is an important organism in endemic areas and during epidemics. Nontyphoidal Salmonella is a common organism in areas where commercially processed foods are widely used and in hospital outbreaks. Most of these organisms produce watery diarrhea. The main cause of acute dysentery is S. dysenteriae, C. jejuni and infrequently enteroinvasive Escherichia coli (EIEC) or Salmonella. Epidemics of dysentery are usually caused by S. dysenteriae type 1. Entamoeba histolytica can cause dysentery in adults but is a less common cause in young children. Diarrhea may also be caused by a number of antibacterial agents like ampicillin, cotrimoxazole, chloramphenicol, amoxicillin, clindamycin, etc. Pseudomembranous colitis is the most severe form of antibiotic associated diarrhea.

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Clinical Features Most enteropathogens can cause diarrhea by more than one mechanism. Hence the clinical presentation depends upon the underlying pathophysiological changes taking place in the gastrointestinal tract. Three clinical types of diarrhea have been defined, each reflecting a different pathogenesis and requiring different approach to treatment.

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Management

iv

Injury to enterocytes may result in brush border damage and epithelial destruction leading to decreased mucosal disaccharidase activity. Clinical presentation is characterized by passage of large, frothy, explosive and acidic stools. High osmolar solutions given orally (e.g. carbonated soft drinks and ORS with high sugar content) can also result in osmotic diarrhea. Besides worsening in the hydration status of the child, there is a serious danger of developing hypernatremia.

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Osmotic Diarrhea

e

Intestinal mucosal cells are actually invaded by the microorganisms which set up an inflammatory reaction clinically presenting with blood and mucus in the stools. This group is prone to develop other complications like intestinal perforation, toxic megacolon, rectal prolapse, convulsions, septicemia and hemolytic uremic syndrome (HUS).

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Invasive Diarrhea (Dysentery)

e

It is characterized by AWD with profound losses of water and electrolytes due to sodium pump failure as a result of the action of identified toxins. This group is at risk for rapid development of dehydration and electrolyte imbalance. Common causes are ETEC and V. cholerae.

of dehydration. The first symptom of dehydration appears after fluid loss of 5% of body weight. When fluid loss reaches 10%, shock often sets in, and the cascade of events that follows can culminate in death unless there is immediate intervention to rehydrate. Routine stool examination is not recommended except in situations such as young infants with fever, suspected protozoan Giardia or Entamoeba histolytica as a cause, extra gut infections or persistent colitis or disaccharide intolerance and prolonged/persistent diarrhea with malnutrition. Stool culture is invariably non-contributory. Diarrhea when prolonged or recurrent, is a major cause of malnutrition in children, owing to use of bottle feeds, stoppage of breastfeeds and lack of energy dense feeds and hygiene like hand washing, low food intake during the illness (poor appetite, vomiting, oral thrush or stomatitis, diluting/withholding of food, etc.), reduced nutrient absorption in the intestines, and increased requirements as a result of infection. Repeated and prolonged episodes of diarrhea have even more deleterious effects and may eventually result in growth failure, intercurrent infections and problems associated with severe malnutrition and even death.

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Secretory Diarrhea



• • • •

General assessment of the child. Assessment of hydration status. A number of clinical signs and symptoms can help in detecting dehydration. However, a simple assessment chart can be referred for quick assessment of dehydration (Table 9.1.1) and administration of appropriate fluids for prevention and treatment of dehydration. Correction of electrolyte and acid-base imbalance. Proper feeding to provide normal nutritional require ments. Zinc supplementation. Treatment of associated problems like dysentery and persistent diarrhea. ­

Diagnosis of acute diarrhea is based on clinical history of passing frequent, loose or watery stools, with or without vomiting, fever, pain in abdomen or blood in the stools. Many children may have symptoms and signs of other associated illnesses like cough, skin rashes/measles or urinary symptoms. The clinical triad of rotaviral diarrhea is fever, vomiting and profuse watery stools with tendency for dehydration. Dehydration is the commonest and life-threatening consequence of diarrhea. Loss of water and electrolytes in the diarrheal stool results in depletion of the ECF volume, electrolyte imbalance and clinical manifestation

• •

r

Principles of Treatment

Diagnosis

 

Table 9.1.1 Assessment of hydration status in a patient with diarrhea Clinical signs Well, alert

Restless, irritable

Lethargic or unconscious

Normal

Sunken

Sunken

Thirst*

Drinks normally, not thirsty

Drinks eagerly, thirsty

Drinks poorly, not able to drink

Skin pinch

Goes back quickly

Goes back “slowly”

Goes back “very slowly”

Decide hydration status

The patient has “no signs of dehydration”

If the patient has two or more signs, there is “some dehydration”

If the patient has two or more signs, there is “severe dehydration”

Treatment plan

Plan A

Plan B

Plan C



General condition Eyes

* In a young infant less than 2 months of age, thirst is not assessed and decision regarding “some” or “severe dehydration” is made if “two” of the three signs are present.

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Nutritional rehabilitation. Health education for prevention of diarrhea.

Table 9.1.3 Guidelines for replacement of fluid and electrolytes in children with “no dehydration” (Plan A)  

Oral Rehydration Therapy

Age

After each loose stool, offer*

Concept of oral rehydration therapy (ORT) has revolutionized the management of diarrhea with the discovery of coupled active transport of glucose and sodium in the small bowel, resulting in the passive absorption of water and other electrolytes even during copious diarrhea. Oral rehydration therapy includes: • ORS solution of recommended composition • Solution made from sugar and salt (if prepared correctly) • Food based solutions with appropriate concentration of salt, like lentil soup, rice, kanji, butter milk, etc. • Plain water given along with continued feeding.

< 6 months

Quarter glass or cup (50 mL)

7 months to 2 years

Quarter to half glass or cup (50–100 mL)

2–5 years

Half to one glass or cup (100–200 mL)

Older children

As much as the child can take

* Fluids which can be offered include ORS, lemon water, butter milk, rice kanji, lentil soup, light tea, etc.

Correction of Dehydration For correction of fluid and electrolyte deficit on account of dehydration, 50–100 m /kg body weight (75 m /kg) of ORS must be administered, over a period of 4 hours. If the child wants more, more ORS should be given. Breastfeeding should be continued. Older children should have free access to plain water. Acceptance of ORS, purge rate and vomiting should be closely monitored. l

•

Low Osmolarity Oral Rehydration Salts (ORS) Solution The standard WHO-ORS, used for over three decades, has saved millions of lives but did not decrease diarrheal duration or stool output. More effective low osmolarity ORS (Table 9.1.2) is now recommended as the universal solution for treatment and prevention of dehydration for all causes of diarrhea and at all ages.

Management of “No Dehydration”

•

The objective of treatment is prevention of dehydration and malnutrition (Plan A). The management can be successfully carried out at home, by the mother/caretaker who is advised to: • Give more fluids than normal (Table 9.1.3) • Continue feeding • Bring the child back after 2 days, or earlier if he has any of the danger signs (thirsty, irritable/restless, fever, high purge rate, repeated vomiting, and blood in the stool, eating or drinking poorly, and lethargic).

Management of “Some Dehydration” The objective of treatment is to treat dehydration and electrolyte imbalance, and to continue feeding. These children should be rehydrated with ORS under supervision in a health facility (Plan B).

 

Table 9.1.2 Low osmolarity ORS formulation recommended by WHO/UNICEF

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Reassess After 4 Hours •

Prevention and Treatment of Dehydration

Reduced osmolarity ORS

g/L

Reduced osmolarity ORS

mmol/L

Sodium chloride

2.6

Sodium

75

Glucose, anhydrous

13.5

Chloride

65

Potassium chloride

1.5

Glucose, anhydrous

75

Potassium

20

Citrate

10

Total osmolarity

245

Trisodium citrate, dihydrate 2.9

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If still dehydrated, deficit therapy should be repeated (Plan B) and milk/food should also be offered. If rehydrated, it is treated as “no dehydration” with maintenance therapy with ORS as in plan A. If ORT is not successful, it is treated as “severe dehydration” with intravenous (IV) fluids as in plan C.

Management of “Severe Dehydration” The primary objective is to quickly rehydrate the child in a hospital with facilities for IV fluid therapy. Ringer’s lactate is the preferred solution for rehydration and is given as 100 mL/kg over 6 hours in infants less than 1 year and over 3 hours in older children (Table 9.1.4). If Ringer’s lactate is not available, other alternatives like normal saline may be used.

Rehydration of Severely Malnourished Children Rehydration of severely malnourished children deserves special attention owing to certain pathophysiological changes in water and electrolyte balance peculiar to protein energy malnutrition (PEM). Dehydration may be over or underestimated in the presence of marasmus or edema, respectively. These children are at risk to develop hypoglycemia and electrolyte imbalance. Rehydration with ORS solution should be preferred because IV fluids can easily cause overhydration and heart failure. Therefore, it is recommended that severely malnourished children are slowly rehydrated, carefully monitored and feeding is started early.

Feeding During Acute Diarrhea and Dysentery Nutritional management of acute diarrhea and dysentery takes optimal advantage of intestinal absorption capacity, which is affected to some extent during diarrhea, by

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Table 9.1.4 Deficit fluid therapy for “severe dehydration” (Plan C)

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l

Assess for improvement every 1–2 hours: •  If not improving, give IV infusion more rapidly •  Encourage oral feeding by giving ORS 5 mL/kg/hour, along with IV fluids, as soon as the child is able to drink Reassess hydration status: •  After 6 hours (infants) and 3 hours (older children) assess hydration status and choose appropriate plan for hydration (Plan A, B or C)

e

Monitoring

as

Older child (> 1 year)

30 mL/kg body weight within first 1 hour, followed by 70 30 mL/kg body weight within half an hour, followed by 70 m /kg body weight over next 5 hours m /kg body weight over next 2½ hours

s

Infants (< 1 year) Volume of Ringer’s lactate



astroint



G stinal

e

 

Table 9.1.5 Feeding during diarrhea Stage of hydration During rehydration phase •  Breastfed infants •  Non-breastfed infants

Recommended schedule of feeding

st

   

 

m and

 

•  Breastfeed more frequently •  Offer undiluted milk as before •  Give easily digestible energy rich complementary foods in addition to breast/animal milk •  Give thick preparation of staple food with extra vegetable oil or animal fats, rich in potassium (legumes, banana), carotene (dark green leafy vegetables, red palm oil, carrot, pumpkin) •  Encourage to eat at least six times a day 

r

iv



L e

Zinc Supplementation for Treatment of Diarrhea Zinc deficiency is common in children from developing countries because of intake of predominant vegetarian diets and the high content of dietary phytates. Increased fecal losses during many episodes of diarrhea aggravate pre-existing zinc deficiency. WHO and Indian Academy of Pediatrics (IAP) recommends zinc supplementation as an adjunct to ORS in the treatment of diarrhea. The National IAP Task Force recommends that all children older than 6 months suffering from diarrhea should receive a uniform dose of 20 mg of elemental zinc as soon as diarrhea starts and continue for a total period of 14 days. Children aged 2–6 months should be advised 10 mg per day of elemental zinc for a total period of 14 days.

Use of Antimicrobial Agents Antibiotic therapy should be reserved only for cases of dysentery and suspected cholera (Table 9.1.6). Every case of diarrhea needs to be carefully evaluated for the

presence of blood in the stools which indicates dysentery and to identify cases of suspected cholera (high purge rate with severe dehydration in a child above 2 years in an area where cholera is known to be present). In view of widespread resistance to trimethoprim-sulfamethoxazole (TMP-SMX) and reported resistance to nalidixic acid, IAP Task Force recommends ciprofloxacin as first-line drug in areas where resistance rates to TMP-SMX exceeds 30%. No chemoprophylaxis is needed for contacts. Associated non-gastrointestinal infections like pneu monia, meningitis, urinary tract infection, etc. should also be carefully looked for and appropriately treated. In severe malnutrition, the usual signs of infection such as fever are often absent, yet multiple infections are common in these children. Therefore, it is assumed that all severely malnourished children may have an underlying infection which should be treated with broad-spectrum parenteral antibiotics. ­

feeding small, frequent, energy dense food taking into consideration the age, pre-illness feeding pattern and state of hydration of the child (Table 9.1.5). Feeding is continued in children with no dehydration, and resumed as early as possible in some dehydration.



•  For older children

e

After rehydration phase •  Breastfed infants •  Non-breastfed infants •  Infants 6–12 months

Sy

•  Breastfed infants – Should be preferable given only ORS till they are rehydrated – Animal milk/food should be offered, if rehydration takes longer than 4 hours •  Severely malnourished children •  Offer some food as soon as possible

Nutritional Rehabilitation Nutritional support to a child following an episode of acute or persistent diarrhea is of immense importance in view of the known adverse impact of diarrheal diseases on the nutrition of a young child. The need for proper feeding after an episode of diarrhea has even greater importance 515

vip.persianss.ir

diatrics

 

Table 9.1.6 Antimicrobials used to treat specific causes of diarrhea in children Drug of choice First line Doxycycline Second line Ciprofloxacin *

of

Pe

Cause Cholera

Tex

tboo

k

Dysentery

First line Ciprofloxacin ** Second line Pivmecillinam Ceftriaxone

Dose Single dose of 6 mg/kg PO Single dose 15 mg/kg 15 mg/kg two times a day orally x 3 days 20 mg/kg four times a day PO x 5 days 50–100 mg/kg once a day IM x 2–5 days

Amebic dysentery

Metronidazole

30 mg/kg/day in three divided doses PO x 5–10 days

Acute giardiasis

Metronidazole OR Tinidazole

15 mg/kg/day in three divided doses PO x 5 days 15 mg/kg/day in three divided doses PO x 5 days

* Can be used if there is resistance to doxycycline or no clinical response ** In view of widespread resistance to trimethoprim-sulfamethoxazole (TMP-SMX) and reported resistance to nalidixic acid, Indian Academy of Pediatrics Task Force recommends ciprofloxacin as first-line drug in areas where resistance rates to TMP-SMX exceeds 30%.

E

Complications lectrolyte Imbalance

With appropriate use of oral rehydration therapy, access to plain water and continued feeding, the risk of electrolyte disturbances is minimized. However, following electrolyte disturbances may be encountered in some cases.

Hypernatremia Some children with diarrhea, especially young infants, develop hypernatremic dehydration which usually follows use of hypertonic drinks (canned fruit juices, carbonated cold drink, and incorrectly prepared salt and sugar solutions, ORS with high glucose content). Children with hypernatremic dehydration (serum sodium > 150 mEq/L osmolality > 295 mOsm/kg) are extremely thirsty, out of proportion to their other signs of dehydration and sometimes have convulsions. These children can be successfully treated with low osmolarity ORS. However, if the child is unable to drink orally, Ringer’s lactate can be initially given to treat shock and later switch over to ORT with low osmolarity ORS.

Hyponatremia Patients who ingest only large amount of water or watery drinks that contain very little salt, may present with hyponatremia (serum sodium < 130 mEq/L, osmolality < 516 275 mOsm/kg), which may be clinically associated with

lethargy and seizures. ORS is safe and effective therapy for hyponatremia as well. For children who are unable to drink orally, IV infusion of Ringer’s lactate can effectively treat hyponatremia.

Hypokalemia Inadequate replacement of potassium losses during diarrhea can lead to potassium depletion and hypokalemia (serum potassium < 3 mEq/L), which may result in muscle weakness, paralytic ileus, renal impairment and cardiac arrhythmias. Severe potassium depletion particularly in malnourished children may lead to acute onset flaccid paralysis ranging from neck flop to quadriparesis and even respiratory paralysis. The potassium deficit can be corrected by using ORS solution for rehydration therapy and by feeding potassium rich foods (e.g. banana, fresh fruit juices) during and after diarrhea. Oral potassium supplementation (2 mEq/kg/day) is indicated in malnourished children. In transient flaccid paralysis due to hypokalemia, potassium can be administered parenterally by using 15% solution of potassium chloride (1 mL = 2 mEq of potassium), but not exceeding 40 mEq/L of IV fluids after ensuring adequate renal functions.

Hypoglycemia Continued feeding during an episode of diarrhea minimizes the risk of getting hypoglycemia. However some children, particularly those severely malnourished, are at a risk of getting hypoglycemia. Early feeding can prevent hypoglycemia in these cases. Sick young infants (less than 2 months) who are not able to breastfed or have low weight for age and a child with symptoms of hypoglycemia should be given 20–50 mL (10 mL/kg) expressed breast milk or locally appropriate animal milk (with added sugar). If neither of these is available, give 20–50 m (10 mL/kg) sugar water. l

particularly because the efforts made by the mother/ caretaker to feed during convalescence are more rewarding when these children tend to have better appetite. Therefore, one extra meal, at least for 2 weeks after an episode of acute diarrhea and for at least 1 month after persistent diarrhea, stressing the need for “catch up growth”, is likely to help in nutritional rehabilitation of these children.

vip.persianss.ir

is as

Diarrheal diseases can be prevented to a great extent by improving infant feeding practices and personal and domestic hygiene. Some of the interventions which are feasible and cost effective include: • Promotion of exclusive breastfeeding up to 6 months of age • Improved complementary feeding practices • Use of clean drinking water and sufficient water for personal hygiene • Hand washing • Use of sanitary toilets • Safe disposal of the stool of young children • Measles vaccination.

s of stinal

e

astroint

G

Rotavirus Vaccines

Sy

K

m and r

iv

L e

Severe dehydration and shock lead to decrease in renal blood flow resulting in prerenal type of acute renal failure. Immediate replacement of fluids is generally helpful to revive kidney functions unless renal failure is irreversible. In case fluid challenge, after rehydration fails to reverse the process, the child needs to be hospitalized and managed as per acute renal failure protocol.

st

Recent studies have demonstrated safety and efficacy of two new live, oral, attenuated rotavirus vaccines in middle and high income countries, thereby suggesting a combined preventive and treatment strategy (vaccine, low osmolarity ORS and zinc supplementation) to significantly reduce child mortality. However, the diversity of rotavirus strains and high prevalence of mixed infections are unique features of rotavirus epidemiology in India. Two new vaccines against Indian rotavirus strains are under review.

e

Acute Renal Failure

Prevention

e

During acute diarrhea, large amounts of bicarbonate may be lost in the stool. If the kidneys continue to function normally, most of the lost bicarbonate is replaced and a serious base deficit does not develop. Metabolic acidosis tends to correct spontaneously in most of the cases as the child is properly rehydrated. ORS solution contains adequate bicarbonate/citrate to counter acidosis in less severe cases. However, in severe dehydration, compromised renal function leads to rapid development of base deficit and metabolic acidosis. Hypovolemic shock occurs as a consequence of rapid loss of water and electrolytes in severe diarrhea. This results in excessive production of lactic acid, which may further contribute to metabolic acidosis. Rapid IV infusion of Ringer’s lactate, containing 28 mEq/L of lactate (metabolized to bicarbonate), is recommended in severe dehydration. However, in the presence of circulatory failure, bicarbonate precursors (e.g. citrate, lactate) may not be readily metabolized in the body. If the patient presents with severe metabolic acidosis, (pH < 7.20, serum HCO3− < 8 mEq/L) sodium bicarbonate in a bolus dose of 2–3 mEq/kg can be given to correct acidosis. Attention should be paid to serum potassium concentration as correction of acidosis in a patient with low potassium can lead to life-threatening severe hypokalemia.

D e

Metabolic Acidosis

ey Messages

• Diarrhea is a self-limiting disorder and does not need any antibiotics for treatment. • Oral rehydration with low osmolarity ORS, continued feeding and zinc supplementation is the key to treatment of diarrhea in children. • Intravenous fluids are indicated in a few cases who have severe dehydration or unable to drink orally. Ringer’s lactate is the most suitable solution for IV therapy. • A child with diarrhea should be thoroughly examined for associated illnesses. • Exclusive breastfeeding up to 6 months of age and hand washing significantly reduce incidence of diarrhea.

Hemolytic Uremic Syndrome Some children with invasive diarrhea due to S. dysenteriae or enteroinvasive E. coli may have HUS due to nephrotoxin liberated by these organisms. These children develop intravascular hemolysis with acute renal failure. This is a serious condition and needs to be managed in a hospital setting.



1. Consensus Statement of IAP National Task Force: Status Report on Management of Acute Diarrhea. Indian Pediatr. 2004;41:335-48. 2. Integrated Management of Neonatal and Childhood Illness. Physician Chart Booklet. Ministry of Health and Family Welfare, Govt. of India; 2009.



­

Acute diarrhea is a self-limiting disorder. Early administration of ORS or home available fluids prevents onset of dehy dration. Appropriate use of low osmolarity ORS in some dehydration and Ringer’s lactate in severe dehydration can prevent all diarrheal deaths.



Bibliography

Prognosis

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D

C





Persistent and hronic iarrhea in hildren

efinition

E

The World Health Organization (WHO) has defined persistent diarrhea (PD) as a diarrheal illness with passage of three or more loose stools of presumed infectious etiology, starting acutely and lasting for more than 14 days. Intractable diarrhea of infancy often begins before the age of 3 months with more than three liquid stools lasting for more than 2 weeks under 1 year of age with either weight loss or no weight gain during this period.



Three clinical types of persistent diarrhea are recognized: 1. Mild form is characterized by several motions/day without significant weight loss and dehydration and can be managed successfully as outpatients with good follow-up. 2. Moderate form is characterized by several motions/ day with marginal weight loss, without dehydration and non-tolerance to milk and milk products and need frequent admissions due to acute exacerbations with complications, improper treatment and no follow-up. 3. Severe form of persistent diarrhea is often lifethreatening and is heralded by dehydration, weight loss and nontolerance to milk and cereals. Secondary infection often coexists with this category (Figs 9.2.1A and B) and these infants need to stay in the tertiary care hospitals for

Less than 10% of infants are likely to suffer from persistent diarrhea and the risk factors broadly include host factors, disease characteristics, contributed by caregiver or attending physician. The severity may vary from mild to severe type and whatever the type of presentation, the basic defect is small intestinal mucosal damage, infection including small intestinal bacterial overgrowth (SIBO) and malnutrition and growth failure with significant morbidity and mortality depending on the severity.

linical Presentation



D

Persistent iarrhea

C

Gadadhar Sarangi

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Tex book of Pedia rics

9.2

tiology

Common causes of persistent diarrhea include persistent infection with one or more enteric pathogens, secondary malabsorption of carbohydrates and fat, intestinal parasitosis and infrequently dietary protein allergy/ intolerance.

a

Pathology

518

B Figures 9.2.1A and B Persistent diarrhea with marasmic kwashiorkor as a result of infection and malnutrition  

Prolonged cell-mediated immune (CMI) form of damage to the small intestinal mucosa is probably the final common pathway by which a variety of noxious influences like nutritional, infective and possibly allergic perpetuate the syndrome of persistent diarrhea in children in developing countries. There is impairment and considerable delay in the repair of damaged epithelium of the gut. Carbohydrate, fat and protein malabsorption ensues as a result of the damage to the upper small intestinal mucosal absorptive surface. The loss of brush border enzymes and direct absorption of macromolecular foreign proteins result in food intolerance and allergy (Cow’s milk or wheat protein allergy). Overgrowth of bacteria in small bowel and altered intestinal flora are also marked as a consequence. Infection is injury to the small intestinal absorptive mucosa and malabsorption of both macro and micronutrients are the untoward events in these unfortunate victims.

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Criteria for changing over from Plan A to B to C Purge volume and rate more than 7 stools/day at the end of 7 days Tendency for dehydration No weight gain/weight loss despite oral intake of 100 cal/kg/day x 3 days

 

Table 9.2.2 Diets for persistent diarrhea Plan C (chicken based diet for persistent diarrhea)

Ingredient Amount (g) Puffed rice 12.5 Milk 40.0 Sugar 2.25 Oil 2.0 Water to make 100.0 The above will yield following: Energy density 96 Kcal/100 g Protein 10.0% Carbohydrate 55.87% Lactose 1.73% Fat 33.9% Amino acid score 1.0% Note: Puffed rice is ground and appropriate quantities are mixed with sugar and oil. Boiled water is then added to make a thick gruel. This feed has a shelf life of around 3 hours.

Ingredient Amount (g) Puffed rice 13.5 Egg 11.0 Sugar/Glucose 3.5 Oil 3.5 Water to make 100.0 The above will yield following: Energy density: 92.2 Kcal/100 g Protein: 9.5% Carbohydrate: 56.9% Fat: 33.29% Amino acid score: 1.0%

Ingredient













l





l





Chicken 100 g Glucose 20–40 g Coconut oil 40–50 g KCL (15%) 7.5 mL NaHCO3 (7.5%) 20–30 m Total 1000 m The above will yield energy 720 Kcal and protein 26 g









Note: •  It is prepared by grinding the precooked boneless chicken stuff in a mixer. Glucose, oil and some water are added to it and the feed is brought to a boil. Additional Note: water is added to make a final volume of 1 liter. Finally Egg white is added to the mixture of KCl and NaHCO3 are added to safeguard against weighed rice, sugar and oil. Boiled water spoilage it is stored in a refrigerator. is added to make a thick gruel weighing •  Glucose is initially added in 2% concentration and then 100 g. built up to 4% by increasing 1% every alternate day. To reduce osmolar load a mixture of glucose and sugar may be employed. •  Any vegetable oil may be employed in place of coconut oil.











Amount/L















Plan B (egg based milk free diet for persistent diarrhea)



Plan A (milk rice diet for persistent diarrhea)



A

ntimicrobials in Persistent iarrhea

t

5 days onwards (nutritional rehabilitation) Monitor weight Hypo-osmolar, hypoallergenic, home available caloridense non-offending (lactose free) feeds (plan B) in gradual increments depending upon tolerance. If it fails, diet of plan C (chicken/egg white, glucose and oil) along with PPN to be given. If no response, total parenteral nutrition (TPN) will be lifesaving.

t

Phase - III

S

Partial control of diarrhea, sustained maintenance of vital signs Electrolyte, metabolic and hemodynamic balance by partial parenteral nutrition (PPN), intravenous fluids, colloids, parenteral antimicrobials (1–4 days)

t

Resuscitation < 24 hours

Phase - II

The management of persistent diarrhea is given in Tables 9.2.1 and 9.2.2.

These are useful in the presence of gross blood in the stool or >10 pus cells/HPF (quinolones/oral third generation cephalosporins), systemic sepsis (parenteral ampicillin and aminoglycosides), severe malnutrition (ampicillin and aminoglycosides), very young infants (< 3 months of age) associated extra-gut infections (e.g. UTI, LRTI) and HIV.

D

 

Phase - I

L

anagement

Severe persistent diarrhea



M

The emergency risk factors arising out of dehydration, malnutrition and infection should be assessed. Stool examination for culture and reducing sugar with pH will help in management. The effect of previous treatment modalities and diet regimen should be evaluated. The attitude and cooperation of the parents remains the cornerstone in therapy.

Mild persistent diarrhea Try low milk formula feeds (rice, milk, sugar and oil—diet of plan A) Moderate persistent diarrhea Do not try milk. Permit cereal based feeds (Rice/wheat/bengal gram/ragi, sugar, oil—diet of plan B)



D

iagnosis

Table 9.2.1 Management guidelines for persistent diarrhea

iseases of Gas roin es inal ys em and iver

indefinite period till they recover, needing intestinal biopsy, total care including total/partial parenteral and enteral nutrition support with elemental diets. The mortality is still high in most of the centers in developing countries.

519

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D

actobacilli and Saccharomyces Boulardii

These are only adjuncts with little benefit. N

D

I

ndications for Total Parenteral utrition in Persistent iarrhea

upplemental itamins and

M

Protracted diarrhea with recurrent dehydration Intolerance to plan C treatment Weight loss or no weight gain even after plan C treatment. V

inerals

alnourished nfants I

Magnesium sulfate IM and oral potassium in recommended doses should be given for at least 2 weeks.

Prevention Promotion of breastfeeding, active and prompt management of acute diarrhea, and appropriate dietetic management during diarrhea with judicious administration of drugs will prevent PD of infancy. Rotavirus and other enteric vaccines do help in reducing PD. Role of zinc and probiotics in prevention is controversial.

The common causes of chronic diarrhea are given in Table 9.2.3.

valuation

The evaluation should be done in a stepwise manner in order to avoid confusion in diagnosis (Table 9.2.4).

Table 9.2.3 Common causes of chronic diarrhea

F

Predisposing actors

auses

 

everely

M

S

­

About twice recommended daily allowance of supple mental multivitamins and minerals are to be given for at least 2–4 weeks (special attention to be given for vitamin A (200,000 units for children > 12 months or 1,00,000 IU for infants elemental zinc 10 mg/day from 2 months and 20 mg/day above 6 months of age for 14 days. Folic acid (1 mg/day), elemental copper (0.3 mg/kg/day) and vitamin D (200–400 U/day) are recommended.

C

• • •

responsible for digestion as well as secretion. The mechanisms of diarrhea with the involved intestinal sites are as follows: • Osmotic diarrhea in which the undigested nutrients get fragmented to short chain fatty acids and increase the intraluminal osmotic load in colon. It shows good response to fasting. • Secretory diarrhea is one in which due to noxious agents or exotoxins there is increase of intracellular adenosine monophosphate or guanosine monophosphate (GMP) which results in sodium and fluid secretion. • Mutation in apical membrane transport protein like chloride bicarbonate exchange transporter which results in chronic diarrhea from neonatal period with failure to thrive. • Reduction in anatomic surface area of the gut due to extensive resection in necrotizing enterocolitis, midgut volvulus or intestinal atresia results in loss of fluid, electrolyte and nutrients from the gut. • Alteration in intestinal motility as in malnutrition and diabetes mellitus causes secretory diarrhea. • Inflammatory processes like regional enteritis and ulcerative colitis involving a significant portion of the gut causes chronic diarrhea.

E

A L

For Giardia or Entamoeba histolytica trophozoites in the stool (metronidazole).

S

t

t

Tex book of Pedia rics

ntiprotozoal rugs

D

hronic iarrhea D

C

efinition

Chronic diarrhea is defined as diarrhea greater than 2 weeks duration, with an insidious onset and usually due to noninfectious cause. Almost all patients need a complete workup for underlying malabsorptive state.

520

Pathophysiology Chronic diarrhea results from breakdown of intraluminal factors responsible for digestion and mucosal factors

Infancy •  •  •  •  • 

Post-gastroenteritis malabsorption syndrome Protein energy malnutrition Cow’s milk/soy protein intolerance Secondary/primary disaccharidase deficiencies Cystic fibrosis

Childhood •  Excessive consumption of carbonated fluids (Chronic nonspecific diarrhea) •  Secondary disaccharide deficiency •  Intestinal parasites: Giardia, E. histolytica, Cryptosporidium. •  Post-gastroenteritis malabsorption syndrome •  Celiac disease •  Cystic fibrosis •  Intestinal infection: Enteropathogens, Mycobacterium tuberculosis •  Tropical sprue 

Prevention factors during the management of AWD such as bottle feeding and stopping breast milk, inadvertent and empiric use of banned drugs, malnutrition, extragut infections especially non-breastfed infant of less than 4 months of age, immune deficiency, infections like adenovirus, enteroaggregative E. coli (EAggEC), EPEC, Salmonella, Clostridium difficile, Candida, HIV, etc. small bowel overgrowth with significant mucosal atrophy should be focused.

Adolescence •  •  •  • 

Irritable bowel syndrome Inflammatory bowel disease: Crohn’s disease, ulcerative colitis Giardiasis Lactose intolerance

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n U

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Treatment depends upon the cause. • Restriction of carbonated drinks or excess fruit juice will reduce stool frequency in chronic nonspecific diarrhea. In diarrhea, due to secondary carbohydrate intolerance, reduction of lactose or sucrose in the diet will help. Lactase can be used to aid in digestion of lactose. If diarrhea persists, elimination of lactose/sucrose depending upon the situation is indicated. • If stool examination reveals more fat, malabsorption syndrome (MAS) remains a distinct possibility. Postgastroenteritis MAS needs predigested formula to which a great proportion responds favorably.

G R

V d

Treatment



Hormonal studies: vasoactive intestinal polypeptide 5-hydroxyindoleacetic acid, gastrin, secretin assays



Phase- IV



Endoscopic studies Small bowel biopsy Sigmoidoscopy or colonoscopy with biopsies Barium studies

1. Bhutta ZA, Ghishan F, Lindley K, et al. Persistent and chronic diarrhea and malabsorption: working group report of the second world congress of pediatric gastroenterology, hepatology, and nutrition. J Pediatr Gastroenterol Nutr. 2004;39 Suppl 2:S711-6. 2. Bhutta ZA, Hendricks KM. Nutritional management of persistent diarrhea in childhood: a perspective from the developing world. J Pediatr Gastroenterol Nutr. 1996;22:1737. 3. Cohen SA. Use of nitazoxanide as a new therapeutic option for persistent diarrhea: a pediatric perspective. Curr Med Res Opin. 2005;21(7):999-1004. 4. Donowitz M, Kokke FT, Saidi R. Evaluation of patients with chronic diarrhea. N Engl J Med. 1995;332:725. 5. Fayez K. Ghisshan diarrhea. In: Behrman RE, Kliegman RM, Jenson HB (Eds). Nelson’s Textbook of Pediatrics, 18th edition; 1621-6. 6. Grimwood K, Forbes DA. Acute and persistent diarrhea. Pediatr Clin North Am. 2009;56(6):1343-61. 7. Gupte S, Anderson RA. Persistent diarrhea and chronic diarrhea. In: Gupte S (Ed). The Short Text Book of Pediatrics, 10th edition; 2004. pp. 382-7. 8. IAP Guidelines for management of diarrhea in children; 1994. 9. IAP Specialty series on Pediatric Gastroenterology, Vol. 5 and 6; 2008. pp. 42-76. 10. Lima AA, Guerrant RL. Persistent diarrhea in children: epidemiology, risk factors, pathophysiology, nutritional impact, and management. Epidemiol Rev. 1992;14:222-42.

Phase- III

ibliography



Sweat chloride 72-hour stool collection for fat determination Stool electrolytes, osmolality Stool for phenolphthalein, magnesium sulfate, phosphate, breath H2 test



Phase- II



B

•



Clinical history including specific amounts of fluids ingested per day Physical examination including nutritional assessment Stool exam (pH, reducing substances, smear for white blood cell count, fat, ova, and parasites) Stool culture Stool for Clostridium difficile toxin Blood studies (complete blood cell count, erythrocyte sedimentation rate, electrolytes, blood urea nitrogen, and creatinine)

t

 

Phase- I

Infants presenting with secretory diarrhea in the first month of life need nutritional support as the likely cause is congenital defect in transport proteins. In instances, where chronic diarrhea is a manifestation of a disease, the etiology should be established and specific treatment instituted. Nitazoxanide therapy can be instituted where Giardia lamblia or Cryptosporidium parvum are suspected or found.

iseases of Gas roin es inal ys em and iver

•

Table 9.2.4 Evaluation of patients with chronic diarrhea

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S





Malabsorption yndrome in hildren

Malabsorption

ntroduction

Malabsorption syndrome (MAS) is defined as the failure of absorption of one or more nutrients. Over the years, the spectrum of MAS in India has changed. Initial studies of 1960s and 1970s were mainly on young (< 5 years) malnourished children and the main focus was on stool examination to isolate infections and infestations. Almost half of those cases were due to gastrointestinal infestations like Giardia. Nevertheless, with improvement of nutritional status, personal hygiene and frequent use of antimicrobials, the prevalence of gastrointestinal infestations (especially Giardia) as a primary cause of MAS has decreased tremendously. Due to increasing awareness, easy availability of diagnostic tests including serology and endoscopic biopsy, the focus has now been shifted from infestation to celiac disease. As a result of which, recent studies have shown that celiac deisease is the commonest cause of MAS in the West as well as in India (especially in North India) both in children as well as in adults.



Maldigestion

n U

The luminal phase of digestion requires pancreatic enzymes, bile salts and the absence of either of them give rises to failure of digestion of carbohydrate (lack of pancreatic amylase), fat (pancreatic lipase and bile salts) and proteins (pancreatic trypsin and chymotrypsin). Similarly, small intestinal bacterial overgrowth (SIBO) due to surgical causes (stricture, fistulae, blind loop, diverticula, etc.) or due to reduced motility of gut (pseudo-obstruction) can cause maldigestion by breaking down bile salts (deconjugation of conjugated bile salts) in the proximal small intestine by bacteria and thereby rendering them (conjugated bile salts) unavailable for mixed micelle formation for fat digestion. Even carbohydrate and protein malabsorption can happen in SIBO, primarily due to bacterial degradation of carbohydrate and mucosal injury by bacterial overgrowth, leading to brush-border enzyme deficiency. 522 Other prominent feature of SIBO is vitamin B12 deficiency, as bacteria utilize vitamin B12.





Malabsorption syndrome is grossly divided into two categories: 1. Impaired breakdown of nutrients (maldigestion). 2. Defective mucosal uptake and transport of adequately digested nutrients (true malabsorption). The latter one may be specific malabsorption of a particular nutrient or a group of nutrients or generalized malabsorption or pan-malabsorption (malabsorption of broad range of nutrients).

G R

V d

ti e

Pathogenesis

Diseases that causes small intestinal mucosal damage like celiac disease, tropical sprue, food protein allergy [like cow’s milk protein allergy (CMPA)], etc. give rise to panmalabsorption of carbohydrate, proteins and fat due to deficiency of brush-border enzymes and lack of transport system located on the apical surface of enterocytes. The important brush-border enzymes for carbohydrate digestion are lactase (lactose malabsorption), maltase (maltose: up to nine residue oligosaccharides) and sucrase (sucrose malabsorption). For proteins, these are oligopeptidases (cleave amino acids from 3–8 residue peptides), dipeptidases and tripeptidases. In malabsorption, the unabsorbed carbohydrate (oligosaccharides, disaccharides like lactose, sucrose) and proteins (oligopeptides, dipeptides and tripeptides) reache colon, where colonic bacteria ferment carbohydrate and produce short chain fatty acids (propionic acid, acetoacetic acid and butyric acid), and gas (hydrogen, methane and carbon dioxide). Short chain fatty acids (2–4 carbon length) in colon produce osmotic effect and draw water into the lumen and the net result is diarrhea and bloating. Bacterial degradation of proteins (especially sulfur containing amino acids) produces odor in flatus (hydrogen sulfide, mercaptan, etc.). Similarly, unabsorbed fat and bile salts produce cathartic effect in colon and cause diarrhea. Congenital absence of selective brush-border enzymes like congenital alactasia and sucrase-isomaltase deficiency gives rise to selective malabsorption of lactose and sucrose, respectively. Post-mucosal phase of digestion is basically transport of fat from mucosa through lymphatics. Lymphatic blockage (congenital: primary intestinal lymphangiectasia or acquired due to lymphoma, tuberculosis, retroperitoneal fibrosis or surgery) gives rise to dilated lacteals in the intestinal mucosa which rupture due to overdistension leading to fat malabsorption (selective malabsorption).

I

Ujjal Poddar

E

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9.3

tiology

The etiology of malabsorption depends on the age and geographic location of the patient. In the West, celiac disease, cystic fibrosis, immune deficiency and Crohn’s disease are the main causes of MAS in children. In India, etiology is different in North from South and also between younger (less than 2 years) and older children. In North India, celiac disease is the commonest cause but in South India, celiac disease is a rare entity. We do not have much information in the literature about the etiology of MAS from south India. In a recent report from Delhi, it has been shown that the majority of children (74%) with MAS were due to celiac disease and gastrointestinal infestations with

vip.persianss.ir

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nvestigations

Approach to MAS can be divided into three stages: 1. Firstly, clinical suspicion of MAS on the basis of history and physical examination 2. Secondly, confirmation of its presence by laboratory tests 3. Lastly, demonstrating its cause by structural tests like endoscopy, mucosal biopsy, imaging, etc.

Yachha et al. (1993) PGI, Chandigarh

Poddar et al. (2010) SGPGI, Lucknow

Behera et al. (2008) AIIMS, New Delhi

N = 62 (< 2 years) %

N = 75 (> 2 years) %

N = 135 (< 5 years) %

N = 50 (up to 12 years) %

73

0

—

—

13

0

29.6

—

Celiac disease

5

43

55.5

74

Parasites

3

15

4 (Giardia)

26 (Giardia, cryptosporidia, isospora)

IBD

—

—

6

—

2

—

Tuberculosis

0

9

0.7

—

Miscellaneous*

6

9

1.5

—

Unknown

0

24

0

—





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The commonest presentation of MAS in children is chronic diarrhea. However, almost one-fifth of them present without diarrhea with nutritional deficiency signs and symptoms like short stature, anemia, rickets and even constipation. The diarrhea of MAS is usually of small bowel type, i.e. large volume stools with features of carbohydrate (explosive diarrhea, abdominal distension and flatulence), proteins (offensive stools, edema) and fat (steatorrhea) malabsorption. Presence of chronic malnutrition with features of water-soluble vitamins deficiencies (anemia, glossitis, angular stomatitis, etc.) substantiates the clinical suspicion of MAS. In severe cases, features of fat-soluble vitamins deficiency may present. In selective malabsorption, like in lymphangiectasia, the predominant manifestations are of fat malabsorption and loss of plasma proteins and lymphocytes due to rupture of intestinal lymphatic channels (diarrhea with disproportionate edema, lymphopenia, hypokalemia and hypocalcemia).

iseases of Gas roin es inal ys e

linical eatures

F

linical eatures of eliac isease In the West, the age of onset of the disease is 6–12 months and the age of diagnosis is around 18 months. The latent period between introduction of gluten and the onset of symptoms is variable (months to years). In India, it has been reported that the age of onset of symptoms is 2.4–3 years and the age of diagnosis is 6.3–8.3 years. This delay (3–6 years) in diagnosis is mainly due to lack of awareness among parents and pediatricians and the delay in the onset of symptoms may be due to prolonged breastfeeding and delayed weaning. Almost 80–90% cases of celiac disease in India present with typical features of chronic diarrhea (small bowel type with features of malabsorption), with failure to thrive and anemia (Table 9.3.2). However, a proportion of celiac disease cases present with nutritional deficiency features without diarrhea (atypical celiac disease) and attend various specialties (Table 9.3.3). In the West, almost half of the cases of celiac disease do not present with diarrhea (Table 9.3.2). With the increasing awareness and easy availability of diagnostic tests especially celiac serology, the ratio of typical to atypical cases of celiac disease is fast changing. In a recent study from Lucknow, we have shown that 44% of all celiac disease cases are atypical.

pathogenic parasites (like Giardia) are often associated with some underlying causes of MAS like celiac disease. However, a proportion of children (10%) with MAS were due to giardiasis and the other common infestation was Cryptosporidium (14%) which was seen in malnourished young children of less than 2 years of age (71%). Cow’s milk protein allergy is an important cause in less than 3 years of age but tuberculosis is a rare cause of MAS even in a developing country like India. The recent data suggests that inflammatory bowel disease (IBD) and AIDS are becoming common in India too. The etiology of MAS in India is given in Table 9.3.1.

 

Table 9.3.1 Etiology of malabsorption syndrome in children in India Etiology

Protracted diarrhea CMPA

AIDS

Abbreviations: CMPA, Cow’s milk protein allergy; IBD, Inflammatory bowel disease; AIDS, Acquired immune deficiency syndrome. *Miscellaneous: Short bowel syndrome 2, acrodermatitis enteropathica 2, cystic fibrosis 2, tropical sprue 2, trichobezoar 1, nodular lymphoid hyperplasia 1, isolated lactase deficiency 1.

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Presentation

George et al. (n= 185)

Mohindra et al. (n = 42)

Poddar et al. (n=300)

Mean age at diagnosis (years)

3.1 ± 3

8.3 (3–14)

6.7 ± 3

Diarrhea

63%

88%

84%

Abdominal distension

55%

—

48%

Growth failure

50%

90%

91%

Undernutrition

60%

90%

92%

Short stature

5.4%

100%

80%

Anemia

5%

90%

84%

Short stature

Endocrinology

Refractory anemia

Hematology

Constipation with abdominal distension

Pediatric surgery

Rickets with fracture and deformity

Orthopedic

Neuropathy, ataxia

Neurology

Infertility, impotence, amenorrhea

Gynecology

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linical uspicion of Malabsorption yndrome

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Clinical features of MAS have already been elucidated.

onfirmation of Malabsorption yndrome

Simple laboratory tests help in finding out the presence or absence of malabsorption. The presence and type of anemia is assessed by complete hemogram. Besides anemia some specific features of MAS like lymphocytopenia (in lymphangiectasia), thrombocytosis (in celiac disease), and acanthocytes in peripheral blood film (in abetalipoproteinemia) can be picked up in hemogram. Stool pH (< 5.5) and presence of reducing substances confirm carbohydrate malabsorption. Similarly fat malabsorption is diagnosed by fecal fat estimation (fat globules or fatty acid crystals on microscopy and quantitative fecal fat estimation). Though it is not easily available, fecal alpha-1-antitrypsin estimation is the test for intestinal protein loss. Other tests which are commonly used in MAS are D-xylose excretion test, lactose tolerance and lactose hydrogen breathe test, Schilling test (for vitamin B12 malabsorption).

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emonstrating the ause of Malabsorption yndrome C

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The third stage of approach to MAS is to find out the cause. Structural tests like endoscopy, small intestinal biopsy, barium meal follow through CT scan, etc. play an important role in finding out the cause of MAS. In addition to structural tests, some other specific tests, like celiac serology, sweat chloride test and mutation analysis help in finding a specific cause. Upper gastrointestinal (UGI) endoscopy and duodenal biopsy are the mainstay of all 524 investigations for MAS. Mere presence of villous atrophy does not give a diagnosis of MAS. Mucosal biopsy is

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iagnosis of eliac isease D

Primary specialty

diagnostic (means always positive) in abetalipoproteinemia (fat globule within enterocytes), Whipple’s disease (finding a specific acid fast organism), and agammaglobulinemia (absence of plasma cells in the lamina propria). There are conditions where biopsy changes are diagnostic but patchy (diagnostic if found) like lymphangiectasia (dilated lacteals in lamina propria), giardiasis, strongyloidosis, lymphoma, eosinophilic gastroenteritis, Crohn’s disease, etc. However, in the majority of cases of MAS, the mucosal biopsies are abnormal (show villous atrophy) but not diagnostic of a particular condition like celiac disease, tropical sprue, cow’s milk protein allergy, severe protein energy malnutrition (PEM), prolonged iron and folate deficiencies, etc. Approach to MAS is given in Flow chart 9.3.1. In a suspected case of CMPA, rectal biopsy plays a pivotal role (eosinophilic proctitis: > 6 eosinophils per high power field). In this era of sophisticated investigations, a simple stool examination (consecutive three days) cannot be ignored especially in young malnourished children to document parasitic infestations. C

Presentation

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Table 9.3.3 Atypical presentations of malabsorption syndrome

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Table 9.3.2 Clinical presentation of celiac disease: East versus West

Celiac disease is diagnosed by modified European Society of Pediatric Gastroenterology and Nutrition (ESPGAN) criteria. According to this criteria, small intestinal biopsy should be suggestive of celiac disease; means there should be villous atrophy and the patient should show unequivocal clinical response to gluten-free diet (GFD) in weeks. However, there are many conditions other than celiac disease, which can give rise to villous atrophy, especially in India. Hence, if these criteria are applied in our population then celiac disease will be overdiagnosed. To overcome this problem, additional criteria, over and above ESPGAN criteria are needed. The best option to confirm the diagnosis is gluten challenge but it is cumbersome and requires repeated endoscopic biopsies, and needs parents and child’s co-operation. On the other hand, celiac serology is simple, effective, and if positive at the time of diagnosis and becomes negative on followup on “GFD”, it confirms the diagnosis. The best antibody test is anti-endomysial antibody (EMA) with a sensitivity and specificity of 97%, but it is a technically demanding test (done by indirect immunofluorescent technique). On the other hand anti-tissue transglutaminase (tTG) is almost as good as EMA and it is done by enzyme linked

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Flow chart 9.3.1 Approach to malabsorption syndrome

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Management



Besides managing the underlying cause of MAS, these patients need supplements with iron, folic acid, multivitamins and calcium. Severely malnourished children should be supplemented with extra calorie and proteins. Caution should be maintained to not to be too aggressive in restarting feeding in a severely malnourished MAS patient as they are at risk of developing “refeeding or nutritional recovery syndrome”. All such patients should be supplemented with thiamine, calcium, phosphate, magnesium, potassium and feeding should be started with half of the daily requirements and to be increased gradually over a week. Parasitic infestations are quite common in MAS patients but many of them are associated with another cause for MAS. Hence, just treatment of isolated parasites (like metronidazole for Giardia, nitazoxanide

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Small intestinal biopsy should show villous atrophy. Celiac serology (EMA or tTG) should be positive. There should be unequivocal clinical response to GFDs in weeks.

for Cryptosporidium) may not cure the condition. All such children should be followed up and if their symptoms persist despite anti-parasitic treatment they should be investigated for underlying diseases like celiac disease or CMPA. In CMPA, besides stopping cow’s milk the attention should be paid to milk products like biscuits, dairy products, butter, ghee, etc. as even a minute quantity of milk proteins can cause persistence or flare of the disease. All such children should be supplemented with calcium as milk is the richest source of calcium. Fortunately CMPA is a transient condition and the majority of children (> 90%) grow out of this condition by 3 years of age. On the contrary, celiac disease is a lifelong condition and the patient (and parents) should be given a clear understanding that the gluten cannot be introduced at any stage.

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Proposed Criteria to Diagnose Celiac Disease in India

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immunosorbent assay (ELISA) technique. The sensitivity and specificity of tTG is around 95%. In a prospective study in 180 children with celiac disease, we have shown that the tTG has got 95% concordance with EMA and its sensitivity and specificity were 94% and 97%, respectively. Hence, in Indian setting tTG is the best antibody to diagnose celiac disease.

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ey Messages

• The etiology of MAS depends on age and geographic location. • Protracted diarrhea due to CMPA and parasitic infestations are common causes in first 2 years of life. • Celiac disease is the commonest cause of MAS in more than 2 years of age in North India. • Consecutive 3 days stool examinations needs to be done in all cases before embarking on sophisticated investigations. • Endoscopy and mucosal biopsy play important role in the diagnosis.

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1. Behera B, Mirdha BR, Makharia GK, et al. Parasites in patients with malabsorption syndrome: a clinical study in children and adults. Dig Dis Sci. 2008;53:672-9. 2. George EK, Mearin ML, Franken HCM, et al. Twenty years of childhood celiac disease in the Netherlands: a rapidly increasing incidence? Gut. 1997;40:61-6. 3. Mohindra S, Yachha SK, Srivastava A, et al. Celiac disease in Indian children: assessment of clinical, nutritional and pathologic characteristics. J Health Popul Nutr. 2001; 19:204-8.



t t

ibliography

4. Poddar U, Thapa BR, Nain CK, et al. Celiac disease in India: are they true cases of celiac disease? J Pediatr Gastroenterol Nutr. 2002;35:508-12. 5. Poddar U, Thapa BR, Nain CK, et al. Is tissue transglutaminase autoantibody is the best for diagnosing celiac disease in children of developing countries? J Clin Gastroenterol. 2008;42:147-51. 6. Poddar U, Thapa BR, Singh K. Clinical features of celiac disease in Indian children: are they different from the West? J Pediatr Gastroenterol Nutr. 2006;43:313-7. 7. Poddar U, Yachha SK, Krishanani N, et al. Cow’s milk protein allergy (CMPA): an entity for recognition in developing countries. J Gastroenterol Hepatol. 2010;25:178-82. 8. Rastogi A, Malhotra V, Uppal B, et al. Aetiology of chronic diarrhea in tropical children. Tropical Gastroenterol. 1999;20:45-9. 9. Sharma A, Poddar U, Yachha SK. Time to recognize atypical celiac disease in India. Indian J Gastroenterol. 2007;26:269-73. 10. Walker-Smith JA, Guandalini S, Schmitz J, et al. Revised criteria for diagnosis of celiac disease. Arch Dis Child. 1990;65:909-11. 11. Yachha SK, Misra S, Malik AK, et al. Spectrum of malabsorption syndrome in north Indian children. Indian J Gastroenterol. 1993;12:120-5. 12. Yadav P, Das P, Mirdha BR, et al. Current spectrum of malabsorption syndrome in adults in India. Indian J Gastroenterol. 2011;30(1):22-8.

Tex book of Pedia rics

• Non-diarrheal manifestations of celiac disease are not so uncommon in India and a high index of suspicion is required to diagnose atypical celiac disease. • Parasitic infestations are common in MAS and many a times they are not the primary cause of malabsorption. • Adequate supplements with minerals and vitamins, and gradual introduction of feed is the key to prevent nutritional recovery syndrome in severely malnourished MAS patients.

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Diseases of Gastrointestinal ystem an

omiting in Children and Gastroesophageal eflux Disease

9.4

I

Shashidhararao Nagabhushana Flow chart 9.4.1 Mechanism of vomiting in children  

ntroduction

Vomiting is a common symptom in pediatric practice associated with not only gastrointestinal but also other system involvement like CNS, renal, psychological, etc. Red flags like persistent/severe vomiting, copious bilious vomiting with colic/visible peristalsis, presence of other signs of raised intracranial pressure and failure to thrive warrant specific evaluation for their cause.

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The causative mechanisms can be depicted as shown in Flow chart 9.4.1. The common causes of vomiting in children and at different age groups are provided in Tables 9.4.1 and 9.4.2, respectively.

anagement

•

• • •

• • •

An accurate history and thorough physical examination helps in proper diagnosis. The child’s age and the clinical profile dictate the most probable etiology (Table 9.4.2).

•

d

Enquire about the duration, frequency, presence of blood or bile in the vomitus. Ask about associated abdominal pain, recent changes in feeding pattern, changes in urine color, drug consumption and presence of associated fever or altered sensorium. Look out for symptoms and signs attributable to the respiratory, gastrointestinal, urinary and central nervous system in that order. Assess the child for signs of dehydration. In neonates and infants with acute vomiting, the possibility of serious infections like sepsis, meningitis or urinary tract infection needs to be considered and ruled out, i.e. the cause of vomiting may be outside the gastrointestinal tract. In a neonate, vomiting may be the first sign of intestinal obstruction. Vomiting due to benign non-organic causes does not lead to significant dehydration or weight loss. If a behavioral element is present, non-organic causes can be considered. Remember that parental perception of how sick their child is in between episodes of vomiting helps us

L



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Vomiting is forceful expulsion of the stomach contents. It occurs in three phases, i.e. (a) nausea, (b) retching and (c) emesis. In very young children and in those with raised intracranial pressure, vomiting is induced without nausea. Regurgitation (posseting) is effortless expulsion of gastric contents through the mouth. It is common in neonates and infants, is often a developmental process and does not need therapy; symptoms resolve with age and the child thrives well. In contrast, gastroesophageal reflux disease (GERD) is abnormal as in addition to vomiting it is usually associated with complications like aspiration, pneumonia and esophagitis and the child may not thrive well. It therefore needs early recognition and prompt therapy.

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Definition

 

Table 9.4.1 Etiology of vomiting Common

Less common

Rare

Gastroenteritis/gastritis Motion sickness Acute hepatitis

Surgical abdomen Gastroesophageal reflux Pyelonephritis Cholecystitis Raised intracranial pressure Tumor, intracranial infection Pseudo-tumor Vestibular dysfunction

Inborn errors of metabolism Migraine variant Cyclic vomiting syndrome Chronic renal failure Endocrine causes Diabetic ketoacidosis Addison’s disease Psychogenic

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Table 9.4.2 Common causes of vomiting by age of presentation Newborn

Infant and child

Infections

Sepsis Meningitis

Gastroenteritis Meningitis Respiratory tract infections

Anatomic

Atresia and webs Duplications Malrotation/volvulus

Pyloric stenosis Intussusception

Gastrointestinal

Overfeeding/posseting Gastroesophageal reflux Gastritis-swallowed meconium

Gastroesophageal reflux Gastritis Hepatitis Appendicitis

Renal

Urinary tract infection

Urinary tract infection

Neurologic

Birth trauma

Subdural hematoma Increased intracranial tension Migraine Uremia

Endocrine

Congenital adrenal hyperplasia Diabetes mellitus Acute intermittent porphyria

Others

Cyclical vomiting Toxin ingestion

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I



to determine the seriousness of the illness and the measures to be adopted. The clinical features that indicate common organic causes of vomiting are given in Table 9.4.3.

nvestigations

The history, age of the child and the clinical features on presentation most often guide the appropriate investigations to be done. These include: • Urine for evidence of infection (pus cells, granular casts, bacteria, Gram stain, culture and sensitivity), proteinuria and abnormal metabolites. • Blood for evidence of systemic infection [leukocytosis, toxic granules, band forms, C-reactive protein (CRP), appropriate cultures, etc.]. • Liver function tests. • Renal function tests, electrolyte studies and metabolic screening tests (e.g. lactate, organic acids, ammonia, etc.). • Stool for blood, pus cells, evidence of parasitic infestations. 528

•

anagement

The steps of management include recognition and treatment of the primary causes of vomiting in addition to symptomatic therapy and correction of dehydration (Flow chart 9.4.2). Symptomatic treatment includes stomach wash in neonates and infants, withholding oral fluids for a few hours and gradually restarting in sips. If a child is persistently vomiting, dehydrated or has electrolyte imbalances, IV fluids are indicated. The preferred fluid is Normal saline. Vomiting due to simple gastroenteritis is relieved by a single dose of antiemetic. It is always prudent to remember that organic causes of vomiting do not satisfactorily respond despite adequate doses of antiemetics. In clinical practice, hasty use of an antiemetic without definite diagnosis of the cause has to be avoided. Antiemetics like Metaclopromide or Domperidone hasten stomach emptying and are useful if used judiciously. Ondansetron, a serotonin antagonist, is effective in the treatment of chemotherapy-induced as well as in managing refractory causes of vomiting.

Cyclic omiting yndrome S

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Radiological studies: Plain and contrast X-rays of abdomen, ultrasound or endoscopy. Lumbar puncture and CSF analysis in children with clinically suspected intracranial infection. CT or MRI scan of skull and/or sinuses or abdomen as and when indicated.

V

Persistent forceful vomiting Abdominal distension Palpable mass/abdomen or visible peristalsis Failure to gain weight/loss of weight Altered sensorium/failure to accept/demand feeds Bulging fontanels/persistent headache Sudden onset in a well-child/vomiting in an ill child with fever Persistent irritability in an infant with vomiting Persistent copious bilious vomiting

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Table 9.4.3 Features indicating organic causes •  •  •  •  •  •  •  •  • 

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Metabolic



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Etiology

Typically cyclic vomiting syndrome (CVS) is seen in schoolgoing children (4–18 years of age) presenting with severe,

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Diseases of Gastrointestinal ystem an

Flow chart 9.4.2 Management of vomiting in children

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ecurrent omiting

Common causes of recurrent vomiting in children include gastroesophageal reflux (GER) or GERD and functional vomiting due to CVS. Other causes include following chemotherapy, intracranial space occupying lesions (SOL), anatomic obstruction, metabolic causes, psychogenic and organic causes especially of Pancreatic and Renal etiology. In adolescence GERD, functional causes especially migraine, CVS, intracranial SOL and psychogenic vomiting are the leading causes. Management depends upon the cause. It is important first to assess the hydration status and attend to life

Table 9.4.4 Differential diagnosis of cyclic vomiting and chronic vomiting Cyclic vomiting syndrome Chronic vomiting High intensity Low intensity Low frequency High frequency Very high need for IVF and rehydration Not often required Family h/o migraine +ve (5 fold) Low Migraine symptoms +ve with triggers Nil Evaluation of lesions outside gut Gut - peptic esophagitis  

It is mainly clinical with high degree of suspicion especially when there are no positive findings in physical examination and by exclusion. CVS needs to be differentiated from chronic vomiting (Table 9.4.4), gastroparesis and intestinal pseudo-obstruction.

iver

Diagnosis

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periodic, discrete, stereotypical, short term, early morning or nocturnal, self-limiting episodes with abdominal pain with high intense retch and apprehension. In 70–80%, a uniform symptom-free interval of 4 weeks in children and 3 months in adults is noted. Associated headache, sometimes with family history of migraine gives a clue for diagnosis. Alarming features are absent except dehydration needing IV fluids.

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Management Cyclic vomiting syndrome was previously thought to be a migraine variant (because of positive family history and response to anti-migraine treatment), but the current view is that both are separate clinical entities. Treatment of CVS consists of rest, IV rehydration with dextrose saline administration and Ondansetron and preventers such as Amitriptyline and Cyproheptadine.

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1. Anderson CM, Burke V, Gracey M. Pediatric Gastroenterology, 2nd edition. Oxford: Blackwell Scientific Publication; 1987. p. 86. 2. Flake ZA, Scalley RD, Bailey AG. Practical selection of antiemetics. Am Family Physician. 2004;69:1169-74, 1176. 3. Graef JW. Manual of Pediatric Therapeutics, 4th edition. Boston: Little Brown Company; 1988. pp. 33-34. 4. Illingworth RS (Ed). Common Symptoms of Disease in Children, 9th edition. Oxford: Blackwell Scientific Publication; 1998. pp. 69-82. 5. Indian Academy of Pediatrics. Vomiting: In: Rapid Approach to common symptoms- Standardization of pediatric office practice; 2005. pp. 51-53. 6. Kliegman RM, Behrman RE, Jenson HB, Stanton BF (Eds). Nelson’s Textbook of Pediatrics, 19th edition. Philadelphia: Saunders Elsevier; 2004. pp. 1199-200. 7. McIntosh N, Helms P, Symth R, Logan S (Eds.). Forfar and Arneil’s Textbook of Pediatrics, 7th edition. Edinburgh: Churchill Livingstone; 2008. pp. 658-63. 8. Rudolph AM, Hoffmann JIE, Rudolph CD (Eds). Approach to a child with acute, chronic or cyclic vomiting. In: Rudolph”s Pediatrics, 20th edition. USA: Prentice Hall International Inc, 1991;(2):1523-24.

Physiological GER in infants, being a benign condition, needs often lifestyle modifications (LSM) like positioning (head up prone position at 45° angle), small, frequent, thick feeds; and in severe cases nasogastric drip feeds, addition of rice cereal and prokinetics (e.g. domperidone). Acid inhibitors like Ranitidine 3–5 mg/kg/dose twice or thrice daily along with LSM for non-erosive reflux.



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Proton pump inhibitors (PPI) 1 mg/kg/day 1 hour before breakfast along with LSM for relief of symptoms of erosive esophagitis and healing are recommended. Barrier agents like Sucralfate and Alginates may give symptomatic relief. Antacids are outdated in view of better and effective drugs being available. Prokinetic drugs like levosulpiride, cinitapride are useful in adolescents and adults only. Extraesophageal manifestations of GERD need specific tests to confirm the etiology and more aggressive treatment with twice daily long-term PPI (for at least 3 months) and follow-up. Indications for surgery include refractoriness to adequate medical treatment, life-threatening complications like aspiration pneumonia, failure to thrive, dysphagia, odynophagia, hematemesis, anemia, and rarely Barrett’s ulcer especially in adolescents. In impaired neurodevelopmental children, Nissen fundoplication laparoscopic or endoscopic techniques are popular modalities of treatment.



Gastroesophageal reflux is one of the common causes of chronic abdominal pain in children with increasing incidence (1–8%). Children often suffer from involuntary passage of gastric contents into esophagus. Pathological GER is GERD characterized by symptoms like irritability, abdominal colic, epigastric or retrosternal burning pain, failure to thrive, GI bleed, dysphagia or odynophagia, belching, apnea, satiation, extraesophageal manifestations such as globus, throat clearing, recurrent aspirations, nocturnal cough or wheeze, dental erosions and caries of teeth. Regurgitation with abnormal posturing in neonates and very young infants is termed Sandifer’s syndrome. The high-risk group includes children with neurological abnormalities, obesity, transient LES relaxations (TLESR), asthma and those with nocturnal refluxing. Clinically regurgitation of milk lasts up to 3–4 months of life and many get over it by 12–24 months. Chronic untreated esophagitis is rare and can result in strictures, Barret’s esophagus and adenocarcinoma in adults. Diagnostic modalities include barium swallow which has low sensitivity and specificity, 24-hour ambulatory esophageal pH monitoring (which however cannot detect non-acid reflux) and nuclear scintigraphy (99mTc milk scan). These are especially useful in children with GERD-associated asthma or pneumonia. Upper GI endoscopy grading and biopsy are useful for Barret’s esophagus. Other special tests such as esophageal manometry and impedance for bolus nonacid reflux are done depending on specific situations.

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threatening complications before going in for specific investigations for etiology. Always ascertain whether the vomitus is bilious, especially copious as in GI obstruction, bloody or contaminated with blood.

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9.5

Parasitic Bowel Disease BD Gupta

Definition



pidemiology

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Parasitic bowel diseases are group of infectious diseases due to protozoa and helminths, and are a major cause of morbidity in infants and children in many parts of the world. Parasitic bowel diseases may be classified according to their etiological agents as under: • Protozoan diseases: Due to Entamoeba histolytica, G. lamblia, Balantidium coli, Cryptosporidium parvum, Blastocystis, Isospora belli, Cyclospora cayetanensis and Microsporidia. • Helminthic diseases: Due to – Nematodes: Ascaris lumbricoides, Enterobius vermicu­ laris, hookworms, i.e. Ankylostoma duodenale and Necator americanus, Trichinella spiralis, and Trichuris trichiura. – Trematodes: Fasciolopsis buski, Nanophyetus salmincola, and Heterophyes heterophyes. – Cestodes: Taenia solium, Taenia saginata, Diphyllo­ bothrium latum, Hymenolepis nana, and Echinococcus granulosus. E

tiopathogenesis

Parasitic bowel diseases are endemic in areas of world with poor levels of sanitation and low socioeconomic standards.

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Intestinal parasitic infestation is more common in developing countries, though worldwide the vulnerable groups are children of both urban poor and rural population. Parasitic infestation is seen in both asymptomatic and symptomatic in a hospital-based study. A study on rural and urban school children showed an infection parasitic infestation rate of 91% and 33%, respectively. Most often the larva or ova of intestinal parasites are passed intermittently in stools and hence repeated fresh stool examination of stools are recommended for better yield rate especially in immune deficient children when we screen them for parasites causing diarrhea such as Giardia lamblia, Cryptosporidium, and S. stercoralis and so on.



E

A parasite is an organism that grows, feeds and is sheltered by or within a different organism while contributing nothing to survival of its host. Unlike protozoa, most helminths do not multiply within the human body, except Strongyloides stercoralis.

Two distinct modes of transmission are known, namely feco-oral route and cutaneous route. 1. Protozoa like E. histolytica, G. lamblia and B. coli infect humans by ingestion of cysts while nematodes like A. lumbricoides, T. trichiura, E. vermicularis and cestodes like T. saginata, T. solium and D. latum spread by ingestion of contaminated food and water with eggs of respective parasites. 2. Hookworms like A. duodenale and N. americanus enter the human body through skin penetration by their larvae. These larvae undergo extraintestinal migration through the venous circulation and lungs before they are swallowed to reach intestines. Various parasites localize themselves at various sites in small as well as large intestine as per their suitable environment, e.g. E. histolytica dwell in colon, G. lamblia colonize in the lumen of duodenum and proximal jejunum, B. coli infests the large intestine, A. lumbricoides in small intestine, T. trichiura in cecum and ascending colon, E. vermicularis typically inhabits cecum, appendix and adjacent areas of ileum and ascending colon. Various parasites cause symptoms due to invasion (E. histolytica), obstruction (A. lumbricoides), reduced absor ptive surface (G. lamblia) and blood sucking (Hookworms). It has been observed that parasitic bowel disease have a role in prevention of IBDs like Crohn’s disease, which are most prevalent in highly industrialized countries with temperate climate and occur rarely in tropical third world countries with poor environmental sanitation. Many helminths live within and migrate through human gut and interact with the mucosal immune system. The host mounts a mucosal response including Th2 cytokine production limiting helminthic colonization, as helminthes and their eggs are probably most potent stimulus of mucosal Th2 response. This may modulate immune reaction to parasitic bacterial and viral infections. Perhaps, failure to acquire these parasites and experience mucosal Th2 conditioning predisposes to Crohn’s disease, which is an overtly active Th1 inflammation.

Parasitic bowel disease is associated with wide variety of clinical manifestations ranging from asymptomatic carrier stage to various intestinal and extraintestinal manifestations. The clinical features depend largely on the parasite, site of involvement, mechanical factors and interference with host’s nutrition.

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Most of parasites present with pain abdomen and diarrhea which can be acute, chronic or recurrent; bloody or nonbloody; associated or not associated with tenesmus, abdominal cramps, bloating, flatulence, etc. Other symptoms include nausea, vomiting, anorexia, weight loss, fever, abdominal distension, malaise, myalgia, headache, etc. Various other clinical features caused by different parasites are summarized in Table 9.5.1. L

aboratory Diagnosis

Parasitic bowel diseases can be diagnosed by examination of stool samples under direct microscopy. Repeated

fresh samples may be required to reach diagnosis of clinically suspected organisms. The stool examination may be supported by blood examination for evidence of eosinophilia and various serological tests specifically designed for the organism under consideration. Stool examination along with endoscopically obtained smears and tissue biopsy helps a lot in diagnosis of specific parasitic infestation. Ideally fresh stools should be examined within 30 minutes of passage for evidence of trophozoites/cysts in case of E. histolytica or G. lamblia. Stool samples preserved in polyvinyl alcohol helps in diagnosis of these organisms. Serological tests like indirect hemagglutination are available for E. histolytica. Enterotest on duodenal fluid for giardiasis is another alternative. Stool examination and demonstration of oocysts helps in diagnosis of spore forming intestinal protozoa like Cryptosporidium, isospora, cyclospora, etc. Other tests for these parasites are enzyme immunoassay, indirect immunofluorescence and polymerase chain reaction (PCR). Demonstration of eggs of helminthes in stool is the mainstay of diagnosis of most of parasites. For ascariasis, Kato’s thick smear examination of stool is easy and sensitive method. Fertilized eggs signify infection with both male and female worms while unfertilized eggs show infection with female worm only. Enterobiasis can be diagnosed by examining cellophane tape imprint from perianal area. For trichinosis serologic tests like Bentonite flocculation test, muscle biopsy, levels of muscle enzymes like creatine kinase and lactic dehydrogenase (LDH) help in diagnosis.

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Table 9.5.1 Clinical manifestations Clinical manifestation Parasitic bowel disease(s) Ascariasis, giardiasis, and infection by Nutritional deficiency intestinal flukes (Vitamin A deficiency) Anemia Hookworm disease Iron deficiency Diphyllobothrium latum B12 or folic acid deficiency (Diphyllobothriasis), trichuriasis Giardiasis, ascariasis, hookworm disease Malabsorption syndrome and infestation by intestinal flukes Giardiasis, hookworm disease, Weight loss diphyllobothriasis and spore forming protozoa like cryptosporidiasis, isosporiasis and cyclosporiasis Ascariasis, taeniasis Intestinal obstruction Giardiasis, trichuriasis Rectal prolapse Extraintestinal involvement Amebiasis, intestinal flukes Liver Trichinosis, flukes, spore forming protozoa, Muscles e.g. microsporidia Cutaneous larva migrans—hookworm, Skin Strongyloides stercoralis Amebiasis, trichinosis, microsporidiasis, Brain taeniasis—neurocysticercosis Amebiasis, ascariasis, hookworm disease Lungs Strongyloides stercoralis Associated parasites: Cryptosporidium Immunodeficiency states parvum, Isospora belli, Cyclospora cayetanensis, microsporidium (AIDS), giardiasis, amebiasis





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anagement

Treatment of various parasitic infestations is summarized in Table 9.5.2.

Prevention and Control Parasitic bowel diseases essentially are much more prevalent in areas of poor sanitation and environmental conditions. Hence, these diseases can be prevented by following measures, viz. safe disposal of human excreta, safe water supply, proper food hygiene, personal and community hygiene, health education, and early diagnosis and treatment of symptomatic and asymptomatic cases.

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Table 9.5.2 Common parasitic infections and their treatment Etiological agent Major clinical features Treatment Entamoeba histolytica

Diarrhea Dysentery Liver abscess

Giardia lamblia

Diarrhea Malabsorption

Isospora belli

Cyclospora Microsporidium

Strongyloides stercoralis

Enterobius vermicularis

Trichuris trichiura

Hookworm infection (Ankylostoma duodenale, Necator americanus) Hymenolepis nana

Trichinella spiralis Diphyllobothrium latum

S

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Ascaris lumbricoides

Quinacrine 2 mg/kg tid orally for 5 days Albendazole 400 mg OD for 5 days Tinidazole 50 mg/kg once Diarrhea Tetracycline 40 mg/kg q 6 hours for 10 days (>8 Dysentery years) Painful abdomen Iodoquinol 40 mg/kg/day q 8 hours PO (10 days) Severe diarrhea with Nitazoxanide 100 mg bid orally for 3 days Paromomycin 1 g bid orally + malabsorption in AIDS Azithromycin 600 mg/day orally for 4 weeks patients followed by Paromomycin 1 g bid orally for 8 weeks As above Trimethoprim 5 mg/kg/dose + Sulfamethoxazole Ciprofloxacin or pyrimethamine +/− folinic acid 25 mg/kg/dose 8 hourly for 10 days; then bid for in sulpha-intolerant patients 3 weeks As above Trimethoprim 5 mg/kg/dose + Sulfamethoxazole Ciprofloxacin 25 mg/kg/dose bid orally for 7 days As above Albendazole 400 mg bid for 3 weeks Nitazoxanide 7.5 mg/kg bid for 3 days Atovaquone Piperazine citrate 15 initially followed by 65 mg/ Abdominal pain Albendazole 400 mg orally once Cough Mebendazole 100 mg bid orally for 3 days or 500 kg/dose 12 hourly for six doses Ivermectin 200 mcg/kg/day od orally for 1–2 Nausea mg once days Pyrantel pamoate 11 mg/kg once Loeffler like syndrome Ivermectin 200 mcg/kg/day once orally for 1–2 Thiabendazole 50 mg/kg bid orally for 2 days days Albendazole 400 mg once for 2 days Abdominal pain Diarrhea Malabsorption Ivermectin 200 mcg/kg/day orally for 1–2 days Pruritus ani Pyrantel pamoate 11 mg/kg once Sleeplessness Mebendazole 100 mg bid PO for 3 days Albendazole 400 mg once (Therapy to be repeated after 2 weeks Chronic dysentery Mebendazole 100 mg bid orally for 3 days or 500 Albendazole 400 mg once Rectal prolapse mg once Anemia Chronic dysentery Albendazole 400 mg/day orally once Pyrantel pamoate 11 mg/kg/day once for 3 days Rectal prolapse Mebendazole 100 mg bid for 3 days Anemia Praziquantel 25 mg/kg orally once (if available) Albendazole 400 mg/day for 3 days Abdominal pain Nitazoxanide 7.5 mg/kg bid orally for 3 days Loss of appetite Diarrhea Anemia Hypoalbuminemia Abdominal pain Mebendazole 200–400 mg tid orally for 3 days Albendazole 400 mg bid orally for 8–14 days Discomfort then 400–500 mg tid for 10 days Praziquantel 5–10 mg/kg orally once Niclosamide 50 mg/kg once Diarrhea Fever Periorbital edema Myalgia Megaloblastic anemia Leukopenia Thrombocytopenia

d

Cryptosporidium

Ornidazole 30–50 mg/kg/day orally in two doses Nitazoxanide 7.5 mg/kg twice daily for 3 days

L

Balantidium coli

Metronidazole 30–50 mg/kg/day orally in 3 doses for 10 days Diloxanide furoate 20 mg/kg/day orally in 3 doses for 10 days Dehydroemetine 1 mg/kg/day SC or IM daily for 7–10 days Metronidazole 5–10 mg/kg tid orally for 5 days Furazolidone 6 mg/kg/day q 6 hours for 10 days Nitazoxanide 7.5 mg/kg twice daily for 3 days Metronidazole 45 mg/kg/day q 8 hours orally for 5 days

Alternative Drug(s)

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1. Chen X-M, Keithly JS, Paya CV, et al. Cryptosporidiasis. N Engl J Med. 2002;346:1723-31. 2. Conteas CN, Berlin OG, Ash LR, et al. Therapy for human gastrointestinal microsporidiasis. Am J Trop Med Hyg. 2000;63:121-27. 3. Elliott DE, Urban JF, Arco CK, et al. Does the failure to acquire helminthic parasites predispose to Crohn’s disease. The FASEB Journal. 2000;14:1848-55. 4. Kliegman RM, Behrman RE, Jenson HB, Stanton BF (Eds). Infectious diseases. Nelson’s Textbook of Pediatrics, 18th

edition. New Delhi: Saunders Elsevier Indian Edition; 2008. pp. 1448-519. 5. Pankaj V. Intestinal parasites in children. IAP Specialty Series on Pediatric Gastroenterology, Vol. 9. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2008. pp. 107-24. 6. Park K. Intestinal infections. In: Park K (Ed). Park’s Textbook of Preventive and Social Medicine, 21st edition. Jabalpur: Banarsidas Bhanot; 2011. pp. 167-205. 7. Tripathi KD. Antiamoebic and other antiprotozoal drugs and anthelmintic drugs. In: Tripathi KD (Ed). Essentials of Medical Pharmacology, 6th edition. New Delhi: Jaypee Brothers Medical Publishers; 2010. pp. 797-816.

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Gastrointestinal Bleeding in Children





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Tables 9.6.1 to 9.6.3 list the common causes of gastro intestinal bleeding in children.

allory-Weiss ears

It occurs at the gastroesophageal (GE) junction primary on the gastric side, resulting, retching or coughing is classically reported prior to hematemesis. It is more common in adults and is less frequently seen with children.

Hemorrhagic and rosive Gastropathy It refers to subepithelial hemorrhage and erosions. These are restricted to the mucosa, where no large blood vessels are present and therefore do not cause major bleeding. Erosions are reported in around 2–10% of patients with upper gastrointestinal bleeding (UGIB). The most common causes are nonsteroidal anti-inflammatory drug (NSAID) use and stress. Prevalence in neonatal intensive care unit (NICU) is around 44% but out of these only 5% are clinically significant.

Table 9.6.1 Causes of upper gastrointestinal bleed  

•

tiology

iver

•

Upper GI bleeding is defined as overt or occult bleeding from a source in the esophagus, stomach or duodenum proximal to the duodenojejunal junction (ligament of Treitz) and lower GI bleeding occurs distal to the duodenojejunal junction. Obscure GI bleeding is overt GI bleeding from remote sites where both upper GI endoscopy and ileocolonoscopy do not reveal the cause for GI bleeding. Spurious hematemesis can present as swallowed blood in a neonate or the source can be from oral cavity or as part of malingering/attention seeking ill health behavior. Major GI bleeding is alarming with overt clots of blood, tarry stools (melena) with over 100 ml of bleeding, postural hypotension/shock needing at least two units of blood transfusion. The site of GI bleeding is categorized as: Upper GI bleeding: Bleeding above the ampulla of Vater. Mid GI bleeding: GI bleeding occurs between ampulla of Vater and terminal ileum ower GI bleeding refers to colonic GI bleeds. L

•

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Definition

Upper GI bleeding is an indication for UGI endoscopy in 5% of children and 5% of total GI bleeding may present as obscure GI bleeding. ower GI bleeding needing hospitalization, is only one-third of upper GI bleeding patients. Etiological spectrum varies in neonates, infants and older children (Table 9.6.1). A meticulous history, physical examination and step by step evaluation is necessary in a tertiary care center preferably by trained pediatric gastroenterologist in association with team of imaging, nuclear medicine and intervention specialists and sometimes surgeons.

E

Gastrointestinal (GI) bleeding—upper or lower—refers to the pathology either proximal or distal to the ligament of Treitz and if obscure, massive and recurrent, it will be frightening and poses a challenge to both pediatrician and gastroenterologist. A systematic diagnostic and definite therapeutic approach is essential not to delay diagnosis, to do relevant and specific investigations for appropriate treatment in tertiary medical care center.

pidemiology

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Neelam Mohan

Newborn

Infant

Children

•  •  •  •  •  •  • 

•  •  •  •  •  •  •  • 

•  •  •  •  •  •  •  •  •  •  •  • 

Swallowed maternal blood Hemorrhagic disease of newborn Stress gastritis Cow’s milk protein allergy Acid peptic disease Vascular anomaly Coagulopathy

Stress ulcer/gastritis Acid-peptic disease Mallory-Weiss tear Vascular anomaly Duplication cyst Varices Webs Intestinal obstruction

Abbreviation: GERD, Gastroesophageal reflux disease

Mallory-Weiss tear GERD/Acid-peptic disease Varices Stress ulcer/erosive gastritis Caustic injury Foreign body Vasculitis Crohn’s disease Intestinal obstruction Dieulafoy lesion Hemobilia Pancreatic pseudoaneurysm

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Older child •  Inflammatory bowel disease •  Ischemic/collagenous colitis •  Vascular malformations •  Intestinal duplication •  Bleeding diathesis •  Henoch-Schonlein purpura •  Hemolytic uremic syndrome •  Hemorrhoids, rectal varices •  Perianal cellulitis •  Rectal prolapse •  Solitary rectal ulcer •  Hereditary polyposis syndrome •  Sexual abuse and anorectal trauma

Peptic Ulcer

V

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–

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–

–

–

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Incidence of bleeding due to NSAID induced erosive gastritis is common but bleeding ulcers appears to be rare compared to adults. Approximately one-third of patients found to have an ulcer with active bleeding or a nonbleeding visible vessel will have further bleeding requiring surgery if treated expectantly. These patients should receive endoscopic therapy and IV infusion of PPI. In less than 10 years of age, around 77% of the peptic ulcer disease (PUD) is in duodenum. Hematemesis and perforation are more in secondary PUD. Factors associated with PUD include: • Primary: Related to Helicobacter pylori, bile reflux • econdary: Related to – NSAID intake – Stress: Shock, ischemia – Drugs – Corrosives – Ménétrier’s disease – Zollinger-Ellison syndrome.

ariceal Bleeding

In country like India, portal hypertension is caused by extrahepatic portal vein obstruction [(EHPVO (68–76%)], cirrhosis (24–28%); and infrequently due to congenital hepatic fibrosis (3%), non-cirrhotic portal fibrosis and Budd Chiari syndrome. Extrahepatic portal vein obstruction is also the most common cause of GI bleeding in children (70%). Predictors of variceal bleed include large varices and presence of red color signs (red wale marking, diffuse 536 redness, and hematocystic malformation).



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Infant •  Vascular lesions •  Bleeding diathesis •  Hirschsprung enterocolitis •  Meckel diverticulum •  Malrotation with volvulus •  Intestinal duplication •  Intussusception

The mean age of presentation is 5–6 years. In India, 83% of patients with EHPVO present with UGIB before the age of 20 years. Hematemesis with or without melena is the commonest presentation; only 8–10% patients may not bleed. UGI bleeding is massive and recurrent but risk of rebleeding after major episode is less than cirrhosis but is fairly uniform and occurs once in every 2 years. The average number of bleed is 2.5–5 episodes per patient. Firm splenomegaly is almost universal in patient with EHPVO. It can be present as early as 1 month of age and is usually seen before 3 years of age. Splenomegaly is mild (< 6 cm) in 42%, moderate (6–10 cm) in 40% and massive (> 10 cm) in 18%. Children with EHPVO do not grow as do their healthy siblings. Variceal bleeding in EHPVO is well tolerated with reference to the liver function, viz. following the GI variceal bleeding, they usually do not develop encephalopathy even with massive GI bleed and they have normal liver functions. They may develop transient ascites following major bleeding episode. Persistent or massive ascites in children with EHPVO should doubt about the diagnosis or suggest the possibility of presence of coexistent cirrhosis. Recurrent GI bleeding in EHPVO decreases with age. Abdominal ultrasonography and Doppler study are diagnostic. Children with EHPVO when compared to chronic liver disease (C D) have more chances of UGI bleed (61.6% versus 14.7%), more previous bleeding episodes (2.7 versus 1.2), long duration of symptoms (26 versus 12 months), and absence of jaundice, preservation of liver function and less Hb value.

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Table 9.6.3 Less common causes of rectal bleeding in children

xtrahepatic Portal ein bstruction and Portal Hypertension

E

Older child •  Anal fissure •  Intussusception •  Infectious enterocolitis, Amebiasis •  Meckel diverticulum •  Juvenile polyp

valuation of a Gi Bleeder

Vital signs include the pulse rate and the blood pressure in lying, sitting and if possible, in standing position for postural hypotension. It is essential to monitor urine output and fluid intake and respiratory rate throughout fluid resuscitation of patients in shock and altered sensorium/ coma. Hyperventilation is an early sign of a developing acidosis. Physical examination to evaluate capillary perfusion, skin color for the presence of cyanosis, pulse, blood pressure, respiratory pattern, and level of consciousness should continue on an ongoing basis during active bleeding. Nasogastric aspirations that are grossly bleeding confirm upper GI sources but a negative aspiration does not rule out. Some clinical clues to etiology in a GI bleed patient are given in Table 9.6.4. Presence of melena followed by any bright colored blood in stool indicates rebleed and these patients of GI bleeding with melena should be monitored and managed in the pediatric intensive care unit.

 

c d

Infant •  Anal fissure •  Milk protein intolerance •  Necrotizing enterocolitis •  Swallowed maternal blood •  Vitamin K deficiency

Gastric varices are found most commonly with splenic vein thrombosis or after endoscopic sclerotherapy (EST) of esophageal varices.



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Table 9.6.2 Common causes of rectal bleeding in children

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Clinical clues

Mallory-Weiss tear

Emesis before hematemesis, pain +

Esophageal ulcer

Odynophagia, GERD, H/O pill ingestion

Stress gastritis/PUD

Sick patient in ICU, respiratory failure/NSAID ingestion/pain

Angiodysplasia

Renal failure, hereditary hemorrhagic telangiectasia

Aortoenteric fistula

H/O aortic aneurysm or surgery

Variceal bleed

Significant, painless, splenomegaly, jaundice, stigmata of CLD, ascites

erlipressin: This is a synthetic analog of vasopressin and acts by immediate vasoconstriction. Its use in children requires further evaluation though found to be more effective in controlling bleeding (up to 79%) than vasopressin without any adverse side effects. It can be given as IV injections (2 mg) every 4 hours till bleeding free interval of 24–48 hours is achieved. • omatostatin: It acts by inhibiting release of several vasodilatory hormones such as glucagon. It induces selective splanchnic vasoconstriction. The recommended dosage is one to three bolus injections (250 µg/bolus) during first hour of therapy followed by infusion of 250 µg/hour of continuous infusion for 2–5 days. There is lower failure rate and complications in comparison to vasopressin but the disadvantage is its short half-life. • ctreotide: It is a synthetic analog of somatostatin with half-life of 90 minutes. In children the dose is 1–2 µg/kg over 2–5 min, then 1–2 µg/kg per hour for 5 days. Sideeffects are uncommon.

anagement esuscitation

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Balloon Tamponade

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Control of cute ariceal Bleeding It can be by the following modalities:

Pharmacotherapy

V

The most widely used agents to stop variceal bleeds are: • asopressin: It is a potent non-selective vasoconstrictor. It lowers the portal pressure by causing splanchnic arterial vasoconstriction and reducing the splanchnic blood flow to the varices. It is given in a bolus of 1 unit per 3 kg of body weight diluted with 2 ml/kg of 5% dextrose given over a period of 15–20 minutes. Nitroglycerine, a vasodilator, may reduce the cardiac side effects of vasopressin by increasing local concentration of NO and reducing cardiac output.

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Sengstaken-Blackmore tube (three lumen and two balloons for esophageal and gastric variceal bleed), inton-Nachlas tube (three lumen and single balloon more effective for gastric variceal than esophageal bleed) and the Minnesota tube (four lumen and two balloons) are handled by only by experienced specialists as a lifesaver in active variceal bleeding if emergency sclerotherapy or banding is unavailable or not technically possible because visibility is obscured. In patients with active bleeding, an endotracheal tube should be inserted to protect the airway before attempting to place the esophageal balloon tube. Continued bleeding during balloon tamponade indicates an incorrectly positioned tube and bleeding from another source. After resuscitation, and within 12 hours, the tube is removed and endoscopic treatment repeated.

iver

This includes achieving hemodynamic stability and treatment of hypovolemic shock. Adequate IV access should be established and carefully monitor pulse, blood pressure and central venous pressure. Oxygen is given to counter hypoxia due to acute blood loss. Nasogastric aspiration is done to know the magnitude of bleeding, to clear the stomach for endoscopy and to prevent hepatic encephalopathy.

Endotherapy (Endoscopic Variceal Ligation or Sclerotherapy) •

ndoscopic variceal ligation: Using multiband ligator banding has less complications and is more effective than sclerotherapy. However it is not possible in small children between 2 and 3 years of age (Table 9.6.5). E

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Abrreviations: GERD, Gastroesophageal reflux disease; PUD, Peptic ulcer disease; NSAID, Nonsteroidal anti-inflammatory drug; CLD, Chronic liver disease

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Table 9.6.4 Clinical clues to etiology in a gastrointestinal bleed patient

 

Table 9.6.5 Comparison of endoscopic variceal ligation (EVL) and endoscopic sclerotherapy (EST) EVL

EST

Indications

Large varices, difficult in small children

Any size

Complications

Less (4%)

More (25%)

Rebleeding rate

Low (4%)

More (25%)

Sessions needed

More (17%)

Less (10%)

Recurrence of varices

Increase

IGV and GOV

Gastric varices

Increase

Increase

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pecific anagement of Common Conditions Presenting as G Bleeding •

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nal fissure: Treatment of constipation, laxatives, Sitz bath, topical 0.2% glyceryl nitrate twice daily • olitary rectal ulcer syndrome: Sucralfate enema, twice daily, for 3–6 weeks with training on “not to strain during defecation” and yttrium-aluminum garnet (YAG) laser treatment for severe bleeds. • Hemorrhagic infective colitis: Antimicrobials. • Polyps: Colonoscopic snare polypectomy. • nflammatory bowel disease and ulcerative colitis: 5 amino-salicylic acid, steroids, cyclosporine, total colectomy. • Crohn’s disease: Steroids, azathioprine, infliximab, metronidazole and ciprofloxacin. • ascular lesions: Therapeutic endoscopy. • Portal colopathy and variceal bleed: Octreotide, transjugular intrahepatic portosystemic stent shunt and shunt surgery. bscure G Bleed It may occur as overt or occult bleed often in small bowel such as Crohn’s, anastomotic, cytomegalovirus (CMV)/viral, or other infections like vascular (angiodysplasia, Dieulafoy’s lesion, varices, or lymphangioma) or tumors (polyps, carcinoid, or lymphoma) and others like Meckel’s diverticulum, diverticulosis, etc. Various diagnostic modalities include small bowel follow through, enteroclysis, push enteroscopy and capsule endoscopy. Rarely, surgery with intraoperative endoscopy may be required (Flow chart 9.6.1).

Indications for Surgery Failure of medical treatment, hypersplenism, isolated splenic vein thrombosis, patients from remote and underprivileged places and of rare blood group. Emergency devascularization and esophageal transection (modified Tanner’s) or elective Warren distal splenorenal shunt or rarely Rex shunt (superior mesenteric vein to left portal vein branch with venous graft) or liver transplantation are useful.

Identifying the Other Sources of GI Hemorrhage The other sources can be identified by esophago-gastroduodenoscopy, colonoscopy, Meckel’s scans (99mTcpertechatate scan), bleeding isotope scan, angiography, capsule endoscopy, double balloon enteroscopy, imaging, upper GI radiography and barium enema and preoperative endoscopy. ­

ndoscopy: Esophago-gastro-duodenoscopy or colono scopy is very useful to detect esophagitis, Mallory-Weiss E

•

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Treatment depends on the cause of the bleeding. Various treatment modalities are H2 receptor antagonists/PPIs, vasoactive agents, endotherapy including electrothermal agents such as endoclips and argon plasma coagulation.

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Control of Non-Variceal Bleeding

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Transjugular intrahepatic portosystemic shunt (TIPS) is ideal for patients whose bleeding is not controlled by endoscopy. It is effective only in portal hypertension of hepatic origin and contraindicated in portal vein thrombosis, biliary block, septicemia and severe hepatic encephalopathy. Complications include thrombosis of stent and encephalopathy.

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Transjugular Intrahepatic Portosystemic Shunt

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Beta-blockers (propranolol) in a dose of 1–2 mg/kg lowers venous flow and the portal pressure by decreasing the heart rate by 25% and the blood pressure by 15 mm Hg and causing splanchnic vasoconstriction and decreasing portal venous flow.

A

For Secondary Prophylaxis

tears, varices, gastritis, ulcer, vascular malformations, etc. Bleeding from an ulcer is controlled using injection with adrenaline and recently hemoclips are also available for clipping at the site of vessel bleed at the base of the ulcer. Similarly, colonoscopy helps diagnosis and therapy of common causes like polyps and the less common vascular malformations and diagnosis of colitis, IBD, solitary rectal ulcer, vascular malformations, etc. • ngiography: It is indicated in active GI bleeding and the rate of bleeding must be at least 0.5 ml/minute. The diagnostic yield of emergency arteriography is low. • UG radiology: Radiographic studies are particularly useful in the diagnosis of esophageal strictures, malrotation of the bowel, or deep ulcerations. • Barium enema: Barium enema is useful in neonates and infants presenting with malrotation with secondary intestinal volvulus, intussusception which can be diagnosed and in many cases treated by barium enema. The barium enema is also effective in identifying the presence of polyps.

E

ndoscopic sclerotherapy: Injection into (intravariceal) or around (perivariceal) of sclerosant. Various sclerosants used in esophageal varices are polydocanol, sodium tetradecylsulfate, absolute alcohol, sodium morrhuate and in bleeding gastric varices, injection of glue (N-butyl2-cyanoacrylate) is done. • Complications of endotherapy: Fever, chest pain, dysphagia, superficial mucosal ulcerations (6–70%), esophageal perforation, pulmonary complications and esophageal stricture.

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Intraoperative enteroscopy using pediatric colonoscpe or enteroscope is very specific for small bowel imaging. • Surgery of Meckel’s diverticulum, duplication of small bowel, Hirschsprung disease (HD). • Portosystemic shunt, esophageal transection, TIPS. • iver transplantation may be necessary in the upper GI hemorrhage refractory to medical, endoscopic and radiologic interventions. • In lower GI hemorrhage, hemicolectomy or subtotal colectomy is occasionally required. • Complications due to endotherapy such as perforation.



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1. D’Amico G, Pagliaro , Bosch J, et al. Pharmacological treatment of portal hypertension. An evidence based approach. Semin iver Dis. 1999;19:475. 2. Garcia-Tsao G, Sanyal AJ, Grace ND, et al. and the Practice Guidelines Committee of the American Association for the Study of iver Diseases, the Practice Parameters Committee of the American College of Gastroenterology. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. AAS D Practice guidelines. Hepatol. 2007;646(3):923-38. 3. Gottumukkala SR, auren G, Das A, et al. American Gastroenterological Association (AGA) Institute Medical Position Statement on Obscure Gastrointestinal Bleeding. Gastroenterol. 2007;133(5):1694-6. 4. Poddar U, Borkar V. Management of extrahepatic portal venous obstruction (EHPO): Current strategies. Trop Gastroenterol. 2011;32(2):94-102.



Bibliography



Flow chart 9.6.1 Management of obscure bleeding

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onstipation in hildren

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efinitions onstipation

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Constipation is the passage of firm or hard pellet like stools at infrequent (< 3 stools/week) and long intervals with difficulty to expel. Normally the stool frequency reduces progressively in childhood from an average of 4/day in the first month to 1.7/day at 2 years and 1.2/day at 4 years of age.

ncopresis

Encopresis is involuntary passage of stools soiling the underwear in the presence of functional or habitual constipation and the term fecal incontinence replaces the term encopresis.

C

Obstipation refers to the absence of passage of both feces and flatus and denote often an underlying organic obstruction or pseudo-obstruction.

auses



The common causes of constipation are listed in Table 9.7.1. The list is not exhaustive and a condition may manifest in both the age groups. Other rare causes of constipation are neuronal intestinal dysplasia, Chagas disease, small left colon syndrome, neurofibromatosis, and intrinsic hollow visceral myopathy leading on to pseudo-obstruction. Red flags on examination to be noted are failure to thrive, abdominal distension, pilonidal sinus, midline pigmentary abnormalities, patulous/anteriorly placed anus, empty rectum and gush of air and wind from rectum on withdrawal of finger on per rectal examination, absent anal wink or cremastric reflex and lower limb weakness. F

Constipation is a symptom of an underlying disorder commonly presenting with chronic abdominal pain. Approximately 10–25% of all patients attending the pediatric gastroenterology clinics present with various defecation disorders and 1.3–5% of them have encopresis. Almost all of them (Table 9.7.1) pose a real challenge to understand and to treat effectively. Nearly 90% of them are functional and often does not need extensive tests. A good history, physical examination including per rectal and checking for red flags is needed to differentiate functional from an organic cause (5%). Significant number of children has associated urinary bladder voiding dysfunction. Most protocols of treatment are based on experience and recommend prolonged therapy and follow-up over months and sometimes years.

bstipation

unctional onstipation (Habitual onstipation) C

ntroduction

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9.7

It is the most common cause of constipation in children between 4 years and 18 years due to improper toilet training or fissure in anus; mostly voluntary retention of stools avoiding normal calls of nature. However, it can manifest earlier during weaning, during toilet training or at the time of joining a school. The causes include a combination of poor diet including formula weaning, improper bowel training/habituation to move bowels and impact of varying other stressful childhood, e.g. joining the school.

 

Table 9.7.1 Common causes of constipation

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Newborn

Infants and children

Prematurity Underfeeding, formula feeds Hypothyroidism Hirschsprung disease Low anorectal anomalies, e.g. anterior perineal/ectopic anus, anal stenosis Spinal abnormalities Meconium plug syndrome Pre-sacral/pelvic masses

Poor dietary habits, lack of fiber Weaning formulas Hypothyroidism Hirschsprung disease Functional or psychogenic Irritable Bowel syndrome—constipating type Hypoxic ischemic encephalopathy Cerebral palsy Mental retardation Drugs: Antispasmodics, antimotility drugs, phenothiazines, codeine, containing cough mixtures, vincristine and vinblastine

vip.persianss.ir

Treatment

isimpaction

Oral

Diet Diet in constipation includes fiber containing items like sprouted whole grains, pulses, beans, sorbitol rich fruits (apple with peel, guava, pomegranate, pear, and prune juice), green leafy vegetables and water. Fiber intake is recommended over 2 years of age and the dose is calculated as age in years plus 5 g/day. Involvement of dietician is beneficial.

D t S

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Maintenance therapy is aimed to avoid reimpaction and to ensure regular passage of stools by diet, laxatives and behavioral therapy. We train the caregivers a simplified use of stool diary and recording of daily stool and defecation details.

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aintenance

Behavioral Therapy Behavioral therapy includes proper toilet training, after feeds, three times daily for 5–10 minutes. One word, one person, one year, one stool/day, one sitting posture policy is ideal. School teachers are informed about the child’s problem.

Laxatives axatives such as lubricants, osmotic and stimulants for maintenance are required for a longer period even over years to regulate the bowel habits and hence the need for explaining to this parents at the onset. Guidelines for maintenance dose of commonly used drugs are given in Table 9.7.3.

Hirschsprung disease

More common

Less common

Meconium history—normal

Delayed passage

Onset beyond infancy

From birth

Fecal soiling

Spurious diarrhea

Abdominal distension—rare

Common

Loaded rectum

Empty rectum Grips finger Gush of air and fluid on release

FTT/enterocolitis—not common

FTT and enterocolitis—common

•

ollow-up chedule S

Functional constipation

onthly follow up till regular bowel movement is achieved: Check diary, physical and rectal examination. axative dose is to be adjusted. • ollow-up of 3 months for next 2 years: Continue same dose of laxative for at least 3 months (distended bowel to regain its function) and then slow tapering (early withdrawal of laxative is the most common cause 541 of recurrence). M

 

Table 9.7.2 Differences between Hirschsprung disease and functional constipation

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Polyethylene glycol (PEG) orally or through Ryle’s tube in the hospital in a dose of 25 ml/kg/hour till the fluid per rectum is watery with no fecal matter or 1 to 1.5 g/kg/day

Twice daily anal applications of petroleum jelly or zinc oxide cream or Diltiazem or nitroglycerine or with 2% xylocaine jelly using ear bud are effective in anal cracks.

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The main steps in the management of constipation are: • Disimpaction • Maintenance therapy with diet, laxative and behavioral training • Regular follow-up • Evaluation of refractory constipation.

Topical

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In addition to constipation, many present with chronic recurrent abdominal pain and occasionally poor feeding. Enuresis and other voiding disturbances, some culminating in urinary infections, may be the presenting feature. Unlike HD, the abdomen is only mildly distended with hard palpable fecalomas in the left lower quadrant of the abdomen. Rectal examination reveals a dilated rectum filled with hard fecal masses. Children adopt peculiar postures during defecation with many crossing their legs (Vincent’s curtsy) or attempting to defecate in the standing position. With a vicious cycle leading to fecal retention and impaction, there is soiling of the undergarments (Table 9.7.2). Presence of a firm fecal mass in the lower abdomen, full of hard and dry stools on per rectal (PR) examination and fecal soiling suggest fecal impaction. Diagnosis is invariably clinical.

This route by digital is quick, invasive and but may increase the fear of defecation though effective. Rectal suppositories are useful in infants and include glycerine suppository 1 g for pediatric size and 2–3 g for adolescents. Rectal enema includes glycerine, sodium biphosphate, saline or dioctyl sodium sulphosuccinate enema.

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linical Presentation

Rectal

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The vicious cycle of events in the genesis of chronic functional constipation is as follows: fecal retention → rectal distension → decreased sensory perception → hard stool → fissure in ano → pain/bleeding during defecation, partial evacuation → impaction → fecaloma formation.

over 4 hours at home for 3 days or magracol can be used. Mineral oil 15–30 ml/year of age up to 240 ml OD or BD doses for 2–3 days may be tried in older children but not recommended in infants.

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Dose

Side effects

Lubricant: Mineral oil

1–3 mL/kg/day once daily or in divided doses for a short period only

Do not give to infants. Anal leakage, lipoid pneumonia

Osmotic: Lactulose Or Lactitol Or Sorbitol

1–3 mL/kg/day in two doses

Bloating, cramps and diarrhea

Polyethylene glycol

5–10 mL/kg/day

Nausea, vomiting, cramps, diarrhea

Magnesium hydroxide

1–3 mL/kg/day in two doses

Hypermagnesemia, hypophosphatemia, hypocalcemia

Stimulant: Bisacodyl

>2 years: 5–10 mg daily oral 5 mg per rectally

Cramps, diarrhea, anal irritation

Sodium pecosulphate

5–10 mg daily

Cramps, diarrhea

Senna

>6 years 5–15 ml/day (8.8 mg/5 ml) 2–6 years 2.5–7.5 mL/day

Melanosis coli, hepatitis

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early follow-up: Points to be remembered while treating infants with constipation are to exclude organic causes such as HD, cystic fibrosis, cretinism, etc. to avoid mineral oil, stimulant laxatives and glycerine enemas for fecal impaction. Stool softeners like sorbitol containing juices, lactulose or lactitol and polyethylene glycol (PEG) and magracol are recommended in infants.

essages



1. Clinical Practice Guidelines: Evaluation and Treatment of Constipation in Children. Summary of updated recommendations of North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2006;43:405-7. 2. Srivatsava A. Management of functional constipation. Indian J Pediatr. 2008;75Supp: 519-25. 3. Thapa BR. Constipation in children. IAP Specialty series on Pediatric Gastroenterology. 2008;10:125-44.

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efractory onstipation

Children with refractory constipation with recurrent impaction, not responding to routine use of laxatives, diet and behavioral therapy needs evaluation of organic diseases and timely referral for specific investigations such as rectal biopsy or to rule out anatomic defects by referral to pediatric surgeons or pediatric gastroenterologists for anorectal manometry, metabolic screen (hypothyroidism, cystic fibrosis, hypercalcemia, celiac disease, lead poisoning, mental retardation, etc.), colonic transit study, colonic manometry or ileo-colonoscopy, planning work for spinal dysraphism by MRI of lumbosacral spine and brain. These patients, especially school-going children, may need to be diagnosed whether they are functional or organic, or irritable bowel syndrome (IBS)-constipating type or if functional whether they are of slow transit or normal transit type or pelvic floor dysfunction (rectoanal dyskinesia) which needs biofeedback training.

ey

• Constipation is a common problem in children and often presents as chronic periumbilical pain with difficulty and delay in passing dry stools. • Nearly 95% is of functional and often does not need any investigation; diagnosis is invariably clinical including per rectal examination and long-term follow up is essential. • Management includes drugs, diet modification, toilet training and regular follow up and behavioral therapy. • Refractory cases need referral to the pediatric gastro­ enterologist to further workup to know the cause and for management guidance.

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Table 9.7.3 Laxatives: dose and side effects

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Hirschsprung Disease





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Clinical eatures F

ntroduction

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The ganglion cells originate in the neural crest and migrate aborally along the bowel till the proximal anal canal; further they migrate centripetally into the myenteric plexus and then the submucous plexus. These parasympathetic ganglion cells of the intrinsic enteric nervous system employ nitric oxide as the neurotransmitter and modulate smooth muscle excitatory/inhibitory interactions in the bowel to effect a relaxation during rest and a coordinated antegrade peristalsis with a luminal bolus. HD results from a failure of such migration or destruction of the ganglion cells in a hostile local environment. Additionally there is a deficiency of pacemaker cells of intestine—interstitial cells of Cajal (ICC). The resultant loss of receptive relaxation of the distal aganglionic bowel in response to the antegrade propulsive peristalsis of the proximal ganglionic bowel leads to a functional bowel obstruction. The extrinsic nerves supplying the bowel respond by proliferation and elaboration of both cholinergic (excitatory) and adrenergic (inhibitory, excitatory) neurotransmitters; the excitatory effects of both predominate to render the aganglionic colon and internal anal sphincter spastic.



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mbryology, tiopathogenesis and Pathophysiology

A clinical presentation of large bowel obstruction presenting at any time from the postnatal period to adulthood but dating back to infancy/early childhood is characteristic. Currently, nearly 90% is diagnosed in the neonatal period or early infancy. Failure to pass meconium within 48 hours of birth is a cardinal clinical feature seen in 80–90% infants with HD but also with 30–40 % children with non-HD and 30–35% healthy preemies. Symptoms of abdominal distension, poor feeding, non-bilious vomiting and progressive constipation are characteristic. Infantile constipation often manifests at weaning, and the recurrent symptom complex of constipation—spurious diarrhea—abdominal distension— failure to thrive during childhood. Hirschsprung enterocolitis is an immune-mediated toxic fulminant sepsis occurring at any age, even after definitive management is completed. It presents with fever, foul smelling diarrhea, abdominal distension and lethargy; some progressing to perforation of the cecum or appendix, particularly in the neonate. Common associated anomalies include trisomy 21 (5– 15%), bowel atresias and anorectal malformations. HD may be associated with neoplastic or non-neoplastic manifestations of aberrant migration of neural crest cells into the skin, retina, thyroid, adrenal, etc., the “neurocristopathies”, e.g. multiple endocrine neoplasia (MEN) syndromes, neuroblastoma, and skin pigmentation. The physical findings vary with the presentation. Typical features in non-acute states are gaseous abdominal distension, visible/palpable bowel loops, and a spastic tight

Hirschsprung disease (HD), named after Harald Hirschsprung, a pediatrician, is a disorder of bowel motility characterized by uncoordinated peristalsis and functional bowel obstruction. It has an incidence of 1/4,000–7,000 live births and an overall 4:1 male preponderance. Approximately 80–90% of HD occurs sporadically in full-term births, the rest accounts for the rare genetic/familial/syndromic forms.



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Classification ­

In the classic rectosigmoid form (85%) of HD, the agan glionosis commonly involves the anal canal and the rectum with a transition to normal ganglionic bowel at the sigmoid; rarely the aganglionosis extends proximally into the rest of the colon, terminal ileum [total colonic aganglionosis (TCA)] or more proximally till the esophagus [total intestinal aganglionosis (TIA)]. Such long segment disease is characterized by relative female preponderance and association with familial, syndromic and genetic forms (Fig. 9.8.1). Ultrashort segment HD (USSHD) refers to a localized spasm/achalasia of the internal anal sphincter identifiable at manometry; it does not show the typical histology of HD.

 

Figure 9.8.1 Total colonic aganglionosis in twin female neonates, the pigmented skin lesions suggest a neurocristopathy

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Differential Diagnosis and nvestigations

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Hirschsprung disease is more common than many other conditions that may mimic it in the neonatal period. The differential diagnosis include meconium plug syndrome, small left colon syndrome (diabetic mother), distal small bowel/colonic atresia, meconium ileus—cystic fibrosis complex and other medical conditions like hypothyroidism and sepsis. Historical clues and clinical features help to resolve the issue and direct the confirmatory investigations. Habitual constipation in the older child can be differentiated from HD by several factors that predominate in the former: a normal meconium history, secondary/recent onset of constipation, lack of significant abdominal distension, fecal loading of rectum and perianal soiling, poor dietary fiber, evidence of associated voiding disturbances and psychological overlay. The diagnosis of HD is based on an amalgamation of information from the following investigative modalities.

norectal

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anus at per rectal examination and a rectal blast of stool and gas at withdrawal of the finger.

mark microcolon” of TCA is typical (Fig. 9.8.3). Despite precautionary measures and guarded interpretation, a significant false positive/negative rate is recognized in diagnosis of long segment disease; also there is much speculation regarding the site and extent of the transition zone. In conclusion, the contrast enema is a good screening investigation prior to rectal biopsy in the diagnosis of HD.

Histopathology Histopathological evaluation is the gold standard for diagnosis with a 93–98% sensitivity and specificity. A rectal biopsy is essential to confirm the diagnosis of all forms of HD and further colonic, appendicular or ileal biopsies determine the proximal extent of aganglionosis (leveling). The rectal biopsy may be full or partial (mucosubmucosal) thickness and is taken at least 2 cm above the dentate line to avoid the physiological hypoganglionic anal zone. A suction

anometry

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The principle of anorectal manometry (ARM) is an absence of the normal rectoanal inhibitory reflex (RAIR)—inhibition of the resting rhythmic activity of the internal anal sphincter with rectal distension in HD (including USSHD). This is preserved in the normal and the habitually constipated child. Though it is least invasive and attractive and has 75–95% accuracy, it is not widely available and difficult in the young uncooperative child. It may be performed under sedation/anesthesia. Since the RAIR is noted by 26 weeks of gestation, it is also useful in premature neonates. It can exclude a diagnosis of HD but histopathological confirmation of the diagnosis of HD is invariably required prior to surgical intervention.



Plain abdominopelvic X-ray and contrast enema remain the basic diagnostic investigations that are easily performed and interpreted. An erect plain X-ray showing generalized dilatation of bowel, especially the peripherally placed colonic loop and an absence of the normal rectal gas pattern in the pelvis is suggestive of the common rectosigmoid form of HD. The contrast enema is diagnostic in the majority of rectosigmoid disease. A dilated sigmoid and a narrow rectum, a reversed rectosigmoid ratio and a typical conical transition zone between the two is characteristic in rectosigmoid HD (Fig. 9.8.2). The mixed barium-stool picture in the delayed contrast enema film at 24 hours is also reliable. In associated colitis, double contrast enemas show a saw tooth mucosal contour and irregular uncoordinated contractions of the aganglionic segment. In distal small bowel obstruction, it delineates the “microcolon” which 544 clarifies the wide differential diagnosis. The “question

Figure 9.8.2 Contrast enema (lateral view) showing a narrow rectum and a dilated sigmoid diagnostic of rectosigmoid Hirschsprung disease  

adiography

 

Figure 9.8.3 Contrast enema (anteroposterior view) of the twins in Figure 9.8.1. Note the question mark microcolon of total colonic aganglionosis in both

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1. Amiel J, Sproat-Emison E, Garcia-Barcelo M, et al. Hirschsprung disease, associated syndromes and genetics: a review. Hirschsprung Disease Consortium. J Med Genet. 2008;45:1-14. 2. de Lorijn F, Boeckxstaens GE, Benninga MA. Symptomatology, pathophysiology, diagnostic work-up, and treatment of Hirschsprung disease in infancy and childhood. Curr Gastroenterol Rep. 2007;9(3):245-53. 3. Haricharan RN, Georgeson KE. Hirschsprung disease. Semin Pediatr Surg. 2008; 17(4):266-75. 4. Swenson O. Hirschsprung’s Disease: A Review. Pediatrics. 2002;109:914-8. 5. Teitelbaum DH, Coran AG, Martucciello G, et al. Hirschsprung’s disease and related neuromuscular disorders of the intestine. In: Grosfeld JL, O’Neill JA, Fonkalsrud EW, Coran AG (Eds). Pediatric Surgery, 6th edition, Vol. 2. Philadelphia: Mosby Elsevier; 2006. pp. 1514-59.



ibliography



 

Figure 9.8.4 Acetylcholinesterase staining of rectal biopsy in Hirschsprung disease showing absence of ganglion cells and hypertrophic arborizing nerve bundles in a typical pattern

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The majority of HD being sporadic rectosigmoid disease, early management with standard protocols outlined above yields an excellent outcome. Longterm complications or sequel like frequency of bowel movement, incontinence—perianal soiling, anastomotic strictures, recurrent constipation, residual/secondary aganglionosis and variable somatic retardation occur in less than 10%, especially in long segment disease and TCA and those managed without accurate histological leveling. Associated anomalies and neurocristopathies also influence the outcome.



The treatment of HD is based on the surgical principle of near total or total resection of the aganglionic bowel and

Prognosis and utcome



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Hirschsprung disease is multifactorial state with a sex modified heterogeneous inheritance involving dominant or recessive and polygenic forms in multiple pathways and more than 10 genes. The two major gene loci for diagnostic purposes are the long arm of chromosome 10 and the 13q22EDNRB gene. However variable expressivity, incomplete sex dependent penetrance have limited attempts at prenatal diagnosis, pedigree analysis and genetic counseling.



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apposition of the distal most ganglionic bowel within a centimeter of the dentate line, thus partially dividing the spastic internal anal sphincter. This may be achieved in a single stage pull-through or a staged procedure with initial leveling stoma (colostomy or ileostomy) and a sub sequent pull through (Duhamel, Soave, Swenson or their modifications) by an abdominal, transanal, combined or laparoscopic assisted procedure at any age depending on the modalities of diagnosis, leveling and surgical expertise available at a center. Generally, an initial stoma is preferred in poor risk malnourished patients, massively dilated proximal bowel, emergency surgery, (enterocolitis, bowel perforation or peritonitis) or non-availability of intraoperative histo logical leveling. In TCA, all pull-through procedures are technically modified to patch a longitudinal strip of aganglionic colon along the ganglionic ileum to facilitate optimal fluid reabsorption and avert troublesome diarrhea. USSHD is usually amenable to a transanal longitudinal myotomy/myectomy of the internal anal sphincter. In toxic acute states without bowel perforation, IV fluids, triple antibiotics (beta-lactam, aminoglycosides and metronidazole), gentle rectal washes with warm saline and other supportive critical care is vital prior to further surgical management.

Diseases of Gastrointestinal ystem an

rectal biopsy is also available. At laparotomy/laparoscopy, the gross transition zone, where evident, guides the siting of more proximal leveling biopsies. Various histological methods are in use including: • Simple paraffin H and E staining on formalin fixed tissues • Intraoperative evaluation with fresh frozen tissue—H and E/additional histochemical staining—acetyl cholinesterase (AChE), NADPH—diaphorase • Immunohistochemistry— ICC-c Kit, calretinin, etc. The histological features seen in the aganglionic (absence of ganglion cells and hypertrophic nerve bundles in described locations), ganglionic (regularly distributed normal morphology ganglion cells along the entire circumference, normal nerve fibers in the different plexii) and intervening transition segment (a variable mixture of both features) are well known; these are clearly visualized with AChE staining of the proliferating extrinsic cholinergic nerve fibers in characteristic patterns (Fig. 9.8.4). The routine rectal biopsy is normal in USSHD.

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bdominal Pain in hildren

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ntroduction

The evaluation of tummy ache can challenge both parents and the physician. A number of disorders can cause abdominal pain; the most medical cause being constipation, and the most common surgical cause being appendicitis. This topic will cover chronic abdominal pain in children.

efinition

The prevalence of chronic abdominal pain in communitybased US studies is estimated to be up to 19%. Yet only in a small number of children is the pain caused by organic disease and in the majority the pain is functional, i.e. without demonstrable evidence of a pathologic condition. Functional abdominal pain is uncommon under 5 years of age. The differential diagnosis of abdominal pain in children varies with age, sex, genetic and environmental factors. Besides organic and functional components are not mutually exclusive, since psychological complications of organic disease are common in children. Hence the diagnostic approach to abdominal pain in children relies heavily on the history provided by the parent and child to direct a stepwise approach to investigation rather than multiple “exclusionary” investigations. E



The traditional definition of recurrent abdominal pain used over the last 40 years are based on Apley and Naish’s criteria of at least three pain episodes over a three-month period interfering with daily function. This has been replaced by the term chronic abdominal pain which refers to pain present continuously or occurring on a weekly basis for a minimum period of 2 months. It is a description, not a diagnosis, and can be due to organic disease or functional causes. A child with chronic abdominal pain poses a formidable challenge as the parents may be terribly worried; child may be distressed and the practitioner may be concerned about ordering multiple tests to avoid missing occult disease.

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tiology

Table 9.9.1 lists the common causes of chronic abdominal pain in children.

 

Table 9.9.1 Causes of chronic abdominal pain in children Functional disorders (as classified by Rome III Criteria) •  Functional dyspepsia •  Irritable bowel syndrome •  Abdominal migraine •  Childhood functional abdominal pain •  Childhood functional abdominal syndrome Gastrointestinal causes •  Constipation •  Reflux esophagitis •  H. pylori gastritis •  Peptic ulcer •  Lactose intolerance •  Giardiasis •  Mesenteric adenitis syndrome •  Inflammatory bowel disease

Liver, spleen, and biliary tract disorders •  Hepatitis •  Liver abscess •  Cholelithiasis •  Recurrent or chronic pancreatitis

Genitourinary causes •  Urinary tract infection •  Urinary calculi •  Hydronephrosis •  Dysmenorrhea •  Pelvic inflammatory disease

Surgical causes •  Malrotation with intermittent volvulus •  Chronic appendicitis

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Miscellaneous •  Infantile colic •  Lead poisoning •  Familial Mediterranean fever •  Vasculitis like Henoch-Schönlein purpura •  Angioneurotic edema •  Acute intermittent porphyria

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The routine screening laboratory evaluation of abdominal pain in children includes the complete blood cell count with differential and erythrocyte sedimentation rate. Anemia, leukocytosis, thrombocytosis and elevated C-reactive protein (C P) are frequently seen in inflammatory diseases. Urinalysis and routine urine culture are indicated. A sample to check the stool for blood is obtained during the rectal examination and the result is often confirmed with three additional outpatient samples. Additional laboratory investigations are chosen on the basis of the history and physical examination. These investigations include stool testing for parasites or Giardia antigen, a chemistry profile to evaluate liver enzymes, serum amylase, lipase and serology testing for celiac disease and H. pylori. Carbohydrate breath testing for lactose intolerance is indicated if empiric dietary interventions are inconclusive. I

maging nvestigations

Sonography of the Abdomen and Pelvis

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This is usually performed first to exclude non-intestinal origins of the pain, which include gall stones and renal stones. With the use of high-resolution ultrasonogram (US ) probes, there is increasing detection of mesenteric lymph nodes. Mesenteric lymph nodes should be considered as significant only when they are more than 10 mm in size. The syndrome of mesenteric adenitis causes colicky pain in the right lower quadrant and can closely mimic appendicitis.

Pelvic Sonography This is indicated because of its sensitivity for free fluid, the frequency of retroperitoneal disease and the visualization of the ileum for Crohn’s disease, lymphadenopathy and chronic features of abscess from fistula or Meckel’s diverticulum. It also provides information about possible pelvic or ovarian disease in adolescent girls.

Barium Studies Barium swallow is not a sensitive test for gastroesophageal reflux disease ( D). A barium contrast of the U I tract may be useful to rule out malrotation especially if episodes of colicky abdominal pain are associated with vomiting. Barium enema is indicated primarily in the context of 547 obstruction or chronic intussusception. G

Anthropometric data of weight, height and growth velocity are documented. Blood pressure is recorded and the weight-for-height is plotted to assess malnutrition or obesity. The physician should percuss the liver span, document the spleen and kidney size and determine the influence of leg motion (psoas sign). xamination for pain should be performed with gentle and deep pressure as well as with rebound. Abdominal and rectal examinations will identify constipation, perianal inflammatory lesions of Crohn’s disease,

aboratory Testing

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iagnosis



The location of the pain is important and the child may indicate the location of the pain by pointing with one finger or with the whole hand. Apley’s observation that “the further the pain from the umbilicus, the greater the likelihood of organic disease” has held up reasonably well and most children with functional abdominal pain present with pain around the region of the umbilicus. • Children often deny heartburn, but other features of peptic disease include early satiety, nausea and the complications of gastroesophageal reflux (ger). • A diary that lists diet, symptoms and associated features for 3–7 days is invaluable since it will indicate potential causes of the symptoms, such as exposure to lactose or the failure to have a normal bowel movement. • A history of abdominal distension, involuntary weight loss, deceleration of linear growth, prolonged fever, bile stained or persistent vomiting, chronic diarrhea, dysphagia, nocturnal symptoms, family history of inflammatory bowel disease (IBD) and pain persistently located away from the central abdominal area are the “red flag” symptoms and should trigger a search for organic disease. • History of recent medications is important as anti biotics may predispose the patient to intestinal bacterial overgrowth, acne medications may induce esophagitis and tricyclic antidepressants may cause constipation. • Family history of peptic disease, irritable or IBD, pancreatitis, biliary disease or migraine should be determined. • A history of arthralgia or skin rashes should make us suspect the possibility of Henoch-Schönlein purpura (HSP). Sometimes abdominal pain can precede the skin manifestations. • The influence of pain on the child’s daily activity is assessed through questions about school attendance, athletic endeavors and peer relationships. • Whenever possible, a few minutes should be taken alone with adolescents to address concerns in the absence of parents and to elicit honest answers about sexual issues, psychological fears and the disruptions to lifestyle caused by the parents’ interventions. ­

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History

abdominal tumors such as neuroblastoma or Wilms tumor and the presence of umbilical or abdominal wall hernias. The pelvic examination may suggest gynecologic problems, such as endometriosis, ectopic pregnancy or ovarian cysts or torsion. The red flag signs of organic disease include localized tenderness in right upper or lower quadrants, localized fullness or palpable mass, hepatomegaly, splenomegaly, costovertebral angle tenderness or perianal abnormalities.

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Pathophysiology The pathophysiology of functional abdominal pain is thought to involve abnormalities in the enteric nervous system leading to dysregulation of brain gut communications.



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rug Therapy Drug therapy for pain-related functional gastrointestinal disorders (F IDs) has generally been directed at symptoms alleviation rather than at precise pathophysiological abnormalities. However with increased understanding on the etiology of visceral hypersensitivity and dysmotility, newer strategies are being developed which include 5HT3 antagonists. Since pain-related F IDs tend to be chronic, waxing and waning, a quick cure is unlikely. As they have a high rate of spontaneous remission, a stepwise approach is necessary with the initial step being education, alleviation of stress factors and diet modifications. Children with chronic pain are a diagnostic and therapeutic challenge as they often have two or more different pain diagnoses (like tension type headache, migraine and musculoskeletal pain) and they are prone to misuse of analgesics and are severely impaired. They are at increased risk for developmental stagnation. Adequate treatment and referral are essential to interrupt progression of the chronic pain process into adulthood. G

E

Functional abdominal pain is uncommon under 5 years of age. The typical presentation is a child aged 5–10 years of age with vague, peri-umbilical pain which can be quite severe, interrupt normal activities and be associated with nausea, pallor and headache. pigastric pain is also described. The pain occurs during daytime and is unrelated to food intake, activity levels or stool pattern. The episodes resolve spontaneously and the child functions normally in between bouts of pain. The physical examination is striking for its normality, and the screening laboratory investigations are by definition normal. The family history is often positive for functional bowel disease such as irritable bowel syndrome. Although there is a high rate of spontaneous remission (30–70%) of chronic abdominal pain in children; there is also evidence that some children with chronic abdominal pain can progress to have irritable bowel syndrome as adults.

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unctional bdominal Pain A

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Once a clear cut diagnosis is established specific treatment of the organic condition is indicated (further elaboration is out of scope of this chapter). Functional abdominal pain is discussed in detail below.



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anagement

The management of functional abdominal pain begins with the acknowledgment that the pain is real, that extensive investigations are not warranted. ducation of the family in simple understandable language is an important part of treating a child with functional abdominal pain such as likening the abdominal pain to a headache and giving examples of hyperalgesia like a healing scar. The primary goal of therapy is not eradication of pain but resumption of a normal lifestyle with regular school attendance, extracurricular activities and a normal sleep pattern. Parents must be discouraged from reinforcing the symptoms by allowing the child to miss school and paying too much positive attention to the pain. It is important to identify, clarify and reverse possible physical and psychological stress factors that may exacerbate or maintain pain. Dietary interventions that have been tried with variable benefit include increasing dietary fiber intake. Psychological approaches including cognitive behavioral therapy and gut-directed hypnotherapy are increasingly being used with success in children with functional abdominal pain.

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mpiric ntervention The child’s response to empiric intervention is also part of the diagnostic evaluation. This may include: • Addition of a fiber supplement to rule out constipation D or peptic ulcer • A trial of H2 blocker in children with disease prior to confirmatory investigations • A trial of lactose elimination. mpiric trials of antispasmodic, anxiolytic or antidepres sant medications are not indicated.

anagement of unctional bdominal Pain

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Upper endoscopy is rarely indicated as a first-line investigation. The yield is maximal in patients with epigastric pain, symptoms of or positive celiac screen. Biopsies of the esophagus, gastric antrum and duodenum may be indicated even in the absence of macroscopic disease to identify microscopic diagnostic features of reflux esophagitis, H. pylori infection, eosinophilic gastritis, granuloma of Crohn’s disease and villous injury with enteropathy. Colonoscopy has replaced barium enema in the evaluation of pain with chronic diarrhea or bleeding.





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Abdominal computed tomographic (CT) scan with contrast allows evaluation of the pancreas, extraintestinal mass lesions, abscess and retroperitoneal disease.

Two factors are of primary importance in the perception of functional abdominal pain: 1. Visceral hypersensitivity 2. Altered intestinal motility. There is increasing evidence that visceral hyperalgesia (decreased threshold of pain to changes in intraluminal pressure) has been triggered by mucosal inflammation secondary to infection, allergies or IBDs. The pathophysiology of adult functional disorders such as irritable bowel syndrome has been extensively studied. Immune, neuronal and genetic factors have been studied. Serotonin has been found to be decreased in the enterocromaffin cells of the rectal mucosa. Alterations in bowel flora can cause dysregulation and result in IBS.



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• The two most common causes of chronic abdominal pain in children are constipation and functional abdominal pain. • Detailed history taking and physical examination will give us a clue to the cause of abdominal pain and helps us to rationalize investigations. • Understanding and counseling about the patho­ physiology of functional abdominal pain plays a pivotal role in the management.

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1. Di Lorenzo C, Colletti B, Lehmann HP, et al. American Academy of Pediatrics Subcommittee on Chronic Abdominal Pain; NASP HAN Committee on Abdominal Pain. Chronic abdominal pain in children: a clinical report of the American Academy of Pediatrics and the North American Society for Pediatric astroenterology, Hepatology and Nutrition. J Pediatr astroenterol Nutr. 2005;40:245-8. 2. anesh , Arvind Kumar , Suresh N, et al. veryday practice: chronic abdominal pain in children. Natl Med J India. 2010;23(2):94-9. 3. Lake A. Chronic abdominal pain in childhood: diagnosis and management. Am Fam Physician. 1999;59:1823-30. 4. asquin A, Di Lorenzo C, Forbes D, et al. Childhood functional gastrointestinal disorders: child/ adolescent. astroenterology. 2006;130:1527-37. 5. Zernikow B, Wager J, Hechler T, et al. Characteristics of highly impaired children with severe chronic pain: a 5-year retrospective study on 2249 pediatric pain patients. BMC Pediatr. 2012;16:12-54.



Fifty percent children continue to have pain in adulthood, the risk factors being: • Male gender • Onset less than 6 years of age • Strong family history of abdominal pain • Pain more than 6 months.

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Hepatomegaly:

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Hepatomegaly, often associated with enlargement of the spleen, is a common clinical problem in infants and children. Many disease processes, which may or may not be primarily hepatic, cause liver enlargement. The pathophysiological mechanisms causing hepato­ megaly are: • Infection, inflammation (hepatitis, fibrosis) • Kupffer cell hyperplasia • Venous congestion • Storage (glycogen, fat and other metabolites) • Infiltrations • Tumors and neoplasia.

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Figure 9.10.1 Assessment of hepatosplenomegaly

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The liver occupies most of the right upper quadrant of the abdomen attached to the lower surface of the diaphragm. The liver accounts for 1/20th of body weight in neonates and 1/50th of that of the adult. In infancy and early childhood, the liver and spleen may be felt normally up to 3 cm below the costal margin. In chest diseases, such as pneumothorax, bronchiolitis and emphysema and in chest deformities such as in rickets, the liver may be pushed down giving an “apparent” hepatomegaly. Hence, percussion for the upper border of the liver is important in the assessment of hepatomegaly especially to recognize “pushed down liver” which should be differentiated from true hepatomegaly.

Size, Margin, Contour and Consistency of Liver



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The liver is to be palpated like any routine palpation of abdomen from left iliac fossa in an anti clockwise manner. Sometimes right subcostal palpation by cupping method from above especially for shrunken firm to hard liver will be useful. Size of the liver is better assessed by “liver span”, i.e. the height of the liver in right mid clavicular line (superior border by percussion and inferior border by palpation as shown in Figure 9.10.1). Normal liver span at various ages is: • Less than 1 year: 4–5 cm • 1–5 year: 5–7 cm • 5–12 years: 7–9 cm • More than 12 years: 9–12 cm. Besides the size of the liver, the consistency and character of the surface and margin should be evaluated. 550 Liver should be examined for tenderness and auscultated

for any murmurs. The abdomen should also be palpated for other masses and for enlargement of the spleen. Epigastrium should always be palpated for the left lobe. Enlarged liver with firm to hard consistency and sharp margin usually implies cirrhosis or fibrosis. Soft, enlarged and tender liver occurs in inflammatory and congestive processes such as viral hepatitis and congestive heart failure. An isolated mass felt in an otherwise normal liver or an asymmetric enlargement may suggest tumor or cyst. The spleen is to be measured in its long axis, i.e. left upper quadrant to right iliac fossa. Although tip of the spleen is palpable in up to 5–10% of normal infants and children, it has to enlarge at least two to three times to be appreciably felt on physical examination.

Is the Liver Really Enlarged?

Is Hepatomegaly due to a Primary Liver Disorder or a Part of a Generalized Disease? Common pediatric conditions such as protein energy malnutrition, anemia and tuberculosis can cause significant hepatomegaly. History and general clinical examination can give important clues to these diseases. Primary liver disorders usually present with signs of liver cell failure (e.g. jaundice and ascites) and abnormal liver function tests.

Age of the Child The age of onset is an important clue to the etiology of pediatric liver disease (Table 9.10.1). Neonatal cholestasis syndrome presents in early infancy; Indian childhood cirrhosis occurs typically in preschool children whereas Wilson disease (WD) affects older children and adolescents.

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• Jaundice: Obstructive, hemolytic and hepatocellular types; each type is associated with different group of diseases.

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Important aspects of the approach to diagnosis of hepatosplenomegaly are: • Accurate clinical history and thorough clinical exami­ nation. • Multidisciplinary approach. • Neonatal/infantile liver disease: Usually presents with persistent jaundice (Jaundice beyond 15–21 days must

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Important Associated Features in Differential Diagnosis of Hepatomegaly

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Splenomegaly is commonly associated with hepatomegaly because of common pathogenetic mechanisms. Causes of predominant and massive splenomegaly are seen in Table 9.10.3. Ascites, edema and bleeding tendencies are signs of liver damage. Drowsiness (precoma, coma) and gastrointestinal hemorrhage (hematemesis, melena) are ominous signs of impending hepatic failure (Table 9.10.4).

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Helpful clues are: • nset: Acute (viral hepatitis) or chronic (as in cirrhosis and chronic hepatitis). • ever: Typhoid, dengue, malaria, tuberculosis. • amily history and consanguinity: Wilson disease, thalassemia. • Hepatotoxic drugs: Antitubercular, antiepileptic, anti­ cancer drugs. • nemia: Hemolytic anemia, leukemia. • ymphadenopathy: Disseminated tuberculosis, malig­ nancy. Some other clinical clues to diagnosis are given in Table 9.10.2.

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Table 9.10.1 Common causes of hepatosplenomegaly according to age Children and adolescents

Intrauterine infections

Infections: Acute viral hepatitis A-E, Dengue, typhoid, leptospirosis

Neonatal cholestasis syndrome Biliary atresia Neonatal hepatitis

Infection: Chronic Tuberculosis, malaria, kala azar

Erythroblastosis (Rh, ABO incompatibility) Congestive heart failure Sepsis, systemic viral infections

Liver cirrhosis Indian childhood cirrhosis Budd Chiari, Veno-occlusive disease Chronic active hepatitis

Metabolic liver disease Galactosemia Tyrosinemia, Alpha1AT deficiency Hemochromatosis

Metabolic liver disease Wilson disease Glycogen storage disease Gaucher, Niemann-Pick disease Mucopolysaccharidosis Nonalcoholic fatty liver disease

Secondaries Wilms tumor Neuroblastoma

Extrahepatic portal hypertension Hepatic fibrosis Cystic fibrosis

           

 

 

 

 

 

 

 

 

 

 

 

 

 

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Hematological disorders Hemolytic anemias Leukemia, lymphoma Cysts (congenital, hydatid) Abscesses (amebic, pyogenic)

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Galactosemia, Wilson disease

KF rings

Wilson disease

Tremors, dysarthria

Wilson disease

Mental retardation

Galactosemia, lipid storage disorder

Engorged neck veins

Congestive heart failure, constrictive pericarditis

Rickets

Wilson disease, tyrosinemia

Cystic kidneys

Congenital hepatic fibrosis

Skin rashes

Histiocytosis

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Intrauterine infections (e.g. Rubella, toxoplasmosis, CMV)

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always be investigated, even in the breastfed baby) (Flow chart 9.10.1). • Hepatomegaly (with or without splenomegaly) in preschool or older children (Flow chart 9.10.2). • ssess severity: Clinical signs of liver cell failure and laboratory tests (Table 9.10.4). Most useful lab tests are: – Plasma albumin (Low levels suggestive of chronicity) – Increased coagulation time (severity of hepatic dysfunction) – Low fasting blood sugar levels indicating poor hepatic function. The scheme of investigations should be directed judiciously at detecting the etiology and the mechanism of hepatomegaly as also the extent and severity of the disease. Base line and special additional tests are given in Table 9.10.5.

 

Clinical features

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Table 9.10.2 Associated clinical manifestations which aid in the diagnosis of hepatomegaly

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•  Hepatomegaly (especially enlarged left lobe) – Alternately a “small” liver or a “hard” liver •  Firm splenomegaly •  Jaundice (usually prolonged/recurrent) •  Pruritus •  Ascites •  Bleeding – Varices (Hematemesis, melena) – Epistaxis   –  Bruising/petechiae •  Encephalopathy •  Cutaneous features – Spider angiomata – Xanthomata – Papular acrodermatitis – Clubbing – Palmar erythema •  Rickets •  Hypotonia •  Growth failure/malnutrition •  Malabsorption of fats and fat soluble vitamins •  Hepatorenal failure

 

 

Table 9.10.4 Clinical signs of liver cell failure and chronic liver disease

 

Chronic malaria, kala azar Hypersplenism, tropical splenomegaly

Hemogram: Band cells, ESR, rectic count, CRP. Urine routine, culture Liver function tests –  Serum bilirubin (Conjugated/unconjugated) – Serum glutamic pyruvic transaminase (SGPT), Serum glutamic oxaloacetic transaminase (SGOT), alkaline phosphatase, gamma GT – Serum albumin, globulin Coagulation profile: Prothrombin time (PT), Partial thromboplastin time with kaolin (PTTK) Blood sugar levels Serum ammonia Liver biopsy Imaging studies – USG abdomen –  CT/MRI scan – Radionuclide scanning Additional special tests – Viral markers: Hepatic A-E, dengue – Autoimmune markers: Autoimmune hepatitis – TORCH titers: Intrauterine infections – Metabolic studies – Metabolic screen (urine) and confirmatory tests: Metabolic liver disease – Enzyme estimations: Galactosemia, Gaucher disease, NiemannPick disease – Urine succinylacetone: Tyrosinemia – Copper studies: Ceruloplasmin, urinary Cu, Cu stains on liver biopsy, hepatic Cu: ICC, Wilson disease – Alpha-fetoprotein: Hepatoblastoma, tyrosinemia –  Sweat chlorides: Cystic fibrosis  

Tumors, primary or secondary, Acute Budd-Chiari syndrome

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Myelofibrosis

 

Chronic extrahepatic cholestasis

Table 9.10.5 Lab tests in diagnosis of hepatosplenomegaly

 

Chronic myeloid leukemia (juvenile)

 

Cyst (hydatid, abscess)

 

Extrahepatic portal hypertension

 

Hemolytic anemias

Extrahepatic biliary atresia

 

Congenital hepatic fibrosis

 

Gaucher disease



Glycogen storage disease (type 1)



Spleen



Liver



Predominant enlargement of

Important conclusions can be based on careful follow up of hepatomegaly. Benign hepatomegaly associated with common febrile illnesses of children usually recedes completely within a few weeks. Cases of acute viral hepatitis also usually resolve within 6 weeks. On the other hand,



 

Table 9.10.3 Causes of massive hepatosplenomegaly

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1. Bhave SA. Chronic liver disorders in children. In: Bavdekar A, Mathai J, Sathyasekaran M, Yachha SK (Eds). Pediatric Gastroenterology (IAP Specialty Series). New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2008. pp. 188 96. 2. Bhave SA. Indian childhood cirrhosis (Update). In: Gupte S (Ed). Recent Advances in Pediatrics. Gastroenterology, Hepatology and Nutrition. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2000. pp. 322 31.





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3. Boamah L, Ballistreri W. Manifestations of Liver disease. In: Kliegman RM, Behrman RE, Jenson HB, Stanton BE (Eds). Nelson’s Textbook of Pediatrics. New Delhi: Elsevier (India); 2008. pp. 1661 66. 4. Consensus Report on Neonatal Cholestasis Syndrome (NCS). Pediatric gastroenterology subspecialty chapter of Indian Academy of Pediatrics document. Indian Pediatr. 2000;37:845 51. 5. Kelly DA. The approach to the child with liver disease: differential diagnosis and useful investigations. In: Kelly DA (Ed). Diseases of the Liver and the Biliary System in Children, 3rd edition. UK: Wiley Blackwell Publishing; 2008. pp. 21 35.

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continued hepatomegaly with signs of progressive liver failure must be evaluated for chronic liver diseases and cirrhosis.



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Flow chart 9.10.2 Approach to diagnosis of hepatosplenomegaly in the older child

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They consist of ALT and AST, earlier called serum glutamic pyruvic transaminase (SGPT) and serum glutamic oxaloacetic transaminase (SGOT), respectively. These enzymes are located in the cytoplasm of the hepatocytes

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Usually this is the most common liver function test which is done. By itself, it gives a very little information. The normal value is less than 1 mg/dL of which 20% is conjugated. The type of jaundice can be categorized as direct, indirect or mixed hyperbilirubinemia. • Hemolytic conditions have raised indirect serum bilirubin with normal enzymes and PT. • Benign conditions like Gilbert syndrome have mildly raised indirect bilirubin level. • Bilirubin levels more than 30 mg/dL would suggest: – Concomitant hemolysis + significant liver injury as in hepatitis A (HAV), hepatitis E (HEV), HAV+ HEV, drugs or superadded sepsis. – Acute viral hepatitis (AVH-HAV)/HEV/HAV+HEV on herbals. – Sepsis and renal impairment can also increase bilirubin levels.

In children, the alkaline phosphatase (ALP) levels are higher than in adults and this is contributed by the growing bones. The normal values in adults are up to 100 IU/L while in children it can rise up to 400–500 IU/L. Hence, it is not unusual to find an isolated raised ALP. Also, in conditions like rickets and intestinal obstruction, the levels may be markedly raised. To differentiate bone ALP from liver ALP, a GGT test can be done. If this is normal, the raised ALP is extrahepatic in origin. A raised GGT or 5’nucleotidase along with raised ALP indicates a hepatic cause. The value may be raised four to tenfold or greater in obstructive jaundice. Elevated ALP with 555



Bilirubin

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Liver function tests (LFT) are a set of basic investigations done in all suspected hepatobiliary diseases. They should be interpreted with the background of the clinical history and physical findings to yield meaningful conclusions. The frequently requested LFT include serum bilirubin (total, direct and indirect), alanine aminotransferases (ALT) and aspartate aminotransferases (AST), serum alkaline phosphatase (SAP), gamma-glutamyl transferase (GGT), proteins (total, albumin and globulin) and prothrombin time (PT). In addition to the initial and basic urine tests, urine tests for bilirubin pigment, bile salt and urobilinogen are also done. Blood glucose and serum ammonia are also relevant with useful clinical implications. The other blood tests requested sometimes in a clinical context are lactate dehydrogenase (LDH), bile acids and 5’ nucleotidase. No single test alone is sufficient to provide complete estimate of the function of liver. LFT reflects liver cell injury (AST, ALT and LDH) indicates the synthetic function of liver (albumin, prothrombin time and blood glucose), cholestasis (SAP, GGTP and LDH), and organic ion transport or drug metabolism status (serum bilirubin, bile acids and urine bilirubin and urobilinogen).

and are released when there is hepatocellular damage resulting in raised serum levels. The normal adult values are less than 45 IU/L. The same values are extrapolated for children. The value may range from 2 times the upper limit of normal (ULN) to 10 times ULN. • In acute viral hepatitis (AVH), the level can rise up 10,000 IU/L or more. • In fact, the three most common causes of very high ALT and AST (>2000 IU/L) are AVH, toxic hepatitis (e.g. paracetamol poisoning and drug induced) and ischemic hepatitis. • If in this scenario, the PT is also prolonged, the prognosis is poor. Conversely, if the PT is normal, irrespective of the bilirubin level, the child has a good prognosis. • Conditions where transaminases are raised 5–50 times ULN are viral hepatitis, toxic hepatitis, autoimmune hepatitis, Wilson disease, storage diseases (e.g. glycogen storage disorders) and infections such as leptospirosis, dengue and malaria. • Conditions where transaminases are raised up to 200– 300 IU/L are same as above; and include sepsis like urinary tract infection (UTI) with bacteremia especially in younger children, non-alcoholic steatohepatitis (NASH), cholestasis, and extrahepatic causes like cholecystitis with choledocholithiasis. • In cirrhosis and obstructive jaundice the levels are usually below 400 IU/L. • In patients with choledocholithiasis with cholangitis the value can sometimes rise above 400 IU/L but rapidly declines within 2–3 days. • Among the two transaminases, ALT is more liver specific. AST can be raised in extrahepatic conditions like myopathies, myositis, cardiac diseases, etc. since it is also found in muscle tissue.



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This is the simplest and cheapest modality for imaging the liver and usually suffices in most cases. It provides information regarding organomegaly, any lesions, masses, portal flow, collaterals, presence of ascites, obstructive causes, etc. The presence of dilated intrahepatic radicals indicates that the source of obstruction is extrahepatic. The only notable exception to this is extrahepatic biliary atresia (EHBA). In case of doubtful masses in the liver, CT abdomen may be required for accurate delineation.

bdomen ­

CT scan helps delineate masses of liver, causes of obstructive jaundice like cholecystitis and choledocholithiasis, chole dochal cyst, and ductal disease much more accurately. However for diffuse, infiltrative lesions, like storage disorders it is not very useful. The arterial and portal phases can help differentiate hemangiomas from other tumors. R

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Among all the LFT, it is the PT which carries the greatest importance, especially in acute liver disease. This test is done along with a control since the value can differ slightly from lab to lab. The normal value is 14 sec. A prolongation of PT more than 2 seconds ULN which is not corrected by vitamin K injection is generally considered a poor prognostic factor; if PT is > 4 sec, liver biopsy is not advisable and if persistently high, one should get liver transplant team’s opinion. International normalization ratio (INR) standardizes PT to different reagents. Normal INR value is 0.08–1.2. • If INR value is more than 1.5 seconds, liver biopsy is not advisable. • If INR is more than 3 seconds in fulminant hepatic failure, it indicates poor prognosis and an important factor taken into consideration for liver transplantation. In case of acute viral hepatitis, if the enzymes are very high but the PT continues to remain normal, the prognosis and outcome is good. Abnormal LFT need not always mean liver disease such as: • Elevated bilirubin seen in Gilbert and Dubin Johnson syndromes. • Isolated elevation in serum ALP seen in growing children and rickets. • Mild AST/ALT elevation in myopathies. • Hypoalbuminemia can occur in other extrahepatic causes. • Prolonged PT in vitamin K deficiency. • Elevated ammonia in urea cycle disorders. • Hypoglycemia in sepsis. Normal LFT need not mean absence of liver disease: • Serum transaminases and other synthetic liver functions could be transiently normal in chronic hepatitis, well compensated cirrhosis, noncirrhotic portal fibrosis 556 (NCPF), methotrexate hepatotoxicity, etc.

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Various imaging modalities are available for the hepatobiliary system, each with its unique indications and limitations. The common tests which have performed include USG of abdomen, CT scan of abdomen, MRI of abdomen, hepatobiliary scintigraphy, endoscopic retrograde cholangio pancreatography (ERCP) and endoscopic ultrasonography.

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Serum albumin is also low in varieties of diseases other than liver diseases such as protein energy malnutrition (PEM) and nephrosis. In PEM, its value is indicative of the synthetic function of liver. It is not very helpful in acute conditions but in cases of jaundice it helps to identify if there is an underlying chronic liver disease. In acute conditions, albumin and total proteins may be transiently reduced but subsequently it normalizes. Reversal of albumin: globulin ratio (A:G ratio) <1 (normal >1.1) associated with low serum albumin (<3 g/dL), PT > 3 sec and AST:ALT of >1 are biochemical laboratory clues for chronic liver disease.

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The terminology LFT is a misnomer: A conventional LFT tests the degree of liver injury or severity of cholestasis but not of liver synthetic function and most tests are not specific to the liver; hence liver function test is only a colloquial term.

This is a very useful test especially in early infancy to help diagnose cases of EHBA. Children with severe cholestatic jaundice are primed with phenobarbitone and imaging is done. Mebrofenin is the preferred agent used. The hepatocytes actively take up the dye and promptly secrete it into the biliary tree. In cases of EHBA, the uptake is prompt but excretion is not seen even after 24 hours. In cases of neonatal hepatitis, the uptake itself is slow but excretion can be detected. However, in severe cases of neonatal hepatitis, it may not be possible to differentiate it from EHBA with this test and hence it is useful in only about 80% of the cases. Tc–99m labeled hepato-imino-diacetic acid derivative (HIDA) scanning is also useful in conditions of suspected bile leak, e.g. trauma, postsurgical and even spontaneous perforation of bile duct.

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low GGT is suggestive of progressive familial intrahepatic cholestasis (PFIC 1 and 2); but elevated ALP with normal or above normal GGT is seen in progressive familial intrahepatic cholestasis (PFIC) 3, blood group B or O and bone disease associated with chronic renal failure.

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• Interpret LFTs in the clinical context. • Careful history including drugs/sibling history of chronic liver disease (CLD) is a must for interpretation. • Physical examination especially BMI (fatty liver), and stigmata of CLD should be done in all cases. • Prothrombin time (PT) and serum albumin should be included in routine LFT. • Include blood sugar and arterial ammonia in sick children. • Ultrasonogram abdomen is a very useful investigation. • Investigate for treatable cause and get hepatologist’s opinion early when in doubt.

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1. Boyer TD, Manns MP, Sanyal AJ. Zakim and Boyer’s hepatology. A Textbook of Liver Disease, Vol. 4, 6th edition. Philadelphia: Saunders Elsevier; 2009(14):235-50. 2. Feldman M, Friedman LS, Brandt LJ. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, 9th edition. Philadelphia: Saunders-Elsevier; 2010. pp. 1227-37. 3. Suchy FJ, Sokol RJ, Balistreri WF. Liver Disease in Children, Vol. 8, 3rd edition. New York: Cambridge University Press; 2007. pp. 163-78. 4. Yamada T, Alpers DH, Kalloo AN, et al. Principles of Clinical Gastroenterology, Vol 21, 5th edition. Chichester: Wiley Blackwell Publication; 2009. pp. 400-22.



Bibliography

iver

This is a relatively newer modality of investigation. The test involves the use of a specialized endoscope which has an ultrasonic transducer at the tip and helps in imaging the organs from inside the bowel. Hence certain areas which are not clearly delineated in CT scan—for egg, the lower CBD can be better imaged. In addition, it helps image the left lobe of liver, pancreas and any submucous bulges. It also offers the advantage of being able to biopsy any suspicious lesion as well as drainage of pseudocyst of pancreas up to 6 cm distance. Though there are many tests available for investigating and imaging the hepatobiliary tree, a judicious combination of these tests in a logical manner will help clinch the diagnosis in most cases, rather than doing all the tests at once.

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This is an invasive test by which the biliary system and the pancreatic duct can be imaged by injecting dye through the ampulla of Vater. The image obtained is similar to percutaneous cholangiography (PTC). However, it has the advantage of offering therapeutic potential. Common bile duct (CBD) stones can be imaged and removed, strictures dilated and obstructions stented. Biopsy can also be obtained by brush method. Earlier on, it was the diagnostic test for choledochal cyst but with the advent of magnetic resonance cholangio pancreatography (MRCP), it is no longer used for this indication.

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Viral Hepatitis

period of 15–40 days similar to HAV. The mechanism of hepatocyte injury due to HEV is still unknown but most likely due to an immune-mediated reaction. Hepatitis B virus (HBV) is a 42 nm hepa DNA virus which causes an immune-mediated injury and the severity of the illness depends on the degree of immune response by the host. HBV is a very contagious virus with an incubation period of 60–180 days and is transmitted by blood, blood products and body fluids. The three antigens hepatitis B surface antigen (HBsAg), envelope antigen (HBeAg) and core antigen (HBcAg) and the corresponding antibodies have a distinct pattern of appearance and disappearance from the blood which helps in distinguishing acute from chronic hepatitis (Table 9.12.1). Perinatal transmission of HBV is a special problem seen in children and is more common in areas of high endemicity. Hepatitis C virus (HCV) is a 30–80 nm RNA virus similar to a flavivirus and results in a complex immune response. Recently non-immunologic genes have also been recognized to influence its clearance. HCV is less infective but more dangerous than HBV and is spread by blood and blood products. Perinatal transmission occurs from mothers who are anti-HCV positive with a high viral load. Hepatitis D virus (HDV) is a defective virus with a small RNA molecule and an envelope constituted by HBsAg. This virus can infect only those who are HBsAg positive.

ntroduction

Hepatitis or inflammation of the hepatocytes may be acute or chronic in its presentation. Acute hepatitis is a self-limiting illness characterized by an abrupt onset of symptoms with the inflammation or necrosis usually resolving completely within 4 weeks. When there is a continuing inflammation beyond 6 months (in children 3 months) it is termed as chronic hepatitis. Viruses are the most important causative agents of hepatitis and the term viral hepatitis is preferred when the illness is due to the major hepatotropic viruses: hepatitis A, B, C, D, E and G (HAV, HBV, HCV, HDV, HEV, and HGV, respectively), though several other viruses such as coxsackie, Ebstein-Barr, and cytomegalovirus can cause hepatitis. This article will be highlighting the features of acute viral hepatitis (AVH).

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tiopathogenesis Hepatitis A virus (HAV) is a 27 nm picoRNA virus spread by the oro-fecal route. The necroinflammatory inflammation is believed to be an immune response of the host to the hepatitis A virus. Hepatitis E virus (HEV) is a 30 nm RNA virus which has recently been assigned as a herpes virus and is transmitted by the orofecal route with an incubation

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In India sporadic AVH is caused mainly by the two enterally transmitted viruses namely hepatitis A (60–70%) and hepatitis E (10–20%). The two parenterally transmitted viruses namely hepatitis B virus or HBV (10–15 %) and hepatitis C virus or HCV (<1%) are less common causes of acute sporadic hepatitis. Improvement in socioeconomic status has resulted in a shift in epidemiology of HAV with older children being susceptible to the infection. The prevalence of hepatitis B surface antigen (HBsAg) positivity in India is approximately 2–7% whereas HCV is 1–2.5%. HEV has been isolated in all the major epidemics in India and is more common in North India especially in regions around the river Ganges. Infections due to HAV and HEV are selflimiting and do not progress to chronicity whereas HBV and HCV infections may resolve but also progress to chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC).

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In the majority of young children acute viral hepatitis may be subclinical or anicteric whereas in older children the three stages of AVH, namely the prodrome, icteric stage and convalescence may be more distinct. The clinical presentation is common to all the types of viral hepatitis with a prodrome which usually lasts for 2–7 days characterized by nausea, vomiting, high colored urine, fever and right hypochondrial pain followed by jaundice, pale stools and tender hepatomegaly. The icteric stage usually lasts for 7–14 days but may persist longer, as long as 12 weeks in older children. The recovery is heralded by the disappearance of the constitutional symptoms, improvement in appetite and decrease in size of the liver.

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Older children with HAV infection may present with atypical manifestations such as ascites, pleural effusion, firm hepatomegaly and disturbing pruritus. Extrahepatic manifestations due to circulating immune complexes are uncommon and include evanescent skin rash, transient arthralgia, pancreatitis, vasculitis, thrombocytopenia,

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SEN and TTV (transfusion-transmitted virus or Torque teno virus) derive their identity from the patients from whom they were isolated. SEN-V is a single stranded, circular, nonenveloped DNA circovirus with eight subtypes of which SEN-V-D and SEN-V-H are associated with post-transfusion hepatitis. Its definite role in acute or chronic hepatitis is still debated. Transfusion-transmitted virus (TTV) is also a single stranded DNA circovirus transmitted parenterally. It has also been associated with transfusion associated hepatitis. The prevalence rates of this virus in hemodialysis patients and blood donors are reported as high as 50%.

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Transfusion Transmitted Virus and elated Viral Hepatitis



The majority of children with acute HBV infection are anicteric. Those with icteric hepatitis may be symptomatic for 1–2 months. Immune-mediated extrahepatic manifestations such as maculopapular or urticarial rash, migratory arthritis, nephritis and papular acrodermatitis of childhood (Gianotti-Crosti syndrome) may be present. Since the risk of chronicity is inversely proportional to the age of acquisition of the illness, a neonate born to a mother who is HBsAg and HBeAg positive has about 90% chance of acquiring the infection. This decreases to 30% if the age of acquisition is 1–5 years and 5–10% if acquired after the age of 5 years. The five stages in the natural history of HBV infection, namely immune tolerance, immune active HBeAg positive or negative, inactive HBsAg carrier and viral clearance are categorized according to the transaminase level and viral replication status (Table 9.12.1). The phase of immune tolerance where there is active viral replication but minimal hepatic inflammation lasts for many years and is associated with a low annual HBeAg clearance in children infected perinatally. Acute HCV hepatitis takes a milder course in children and acute liver failure occurs in <1%. The symptoms of malaise, fatigue and jaundice are mild but the transaminases are elevated for a longer period. Approximately 40–50% may progress to chronicity and later to cirrhosis and hepatocellular carcinoma (HCC). Sporadic hepatitis in children due to type C hepatitis is rare and is reported in children receiving multiple blood transfusions.

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B

H V Hepatitis and H V Hepatitis

The search for additional hepatitis viruses that could explain the occurrence of non A-E hepatitis led to the discovery of hepatitis G (HGV) a flavivirus and to a number of viruses belonging to the circoviridae family. Hepatitis G (HGV) virus is a single stranded RNA flavivirus which shares limited identity with HCV. It is distributed widely (18–80%) among the high risk multitransfused people, drug addicts, hemodialysis patients and spreads by parenteral route. HGV has been linked to post-transfusion hepatitis, chronic hepatitis and cirrhosis but it is unlikely that HGV by itself can cause disease. Some workers feel that the virus is still searching for a disease and is an innocent bystander.

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triggering of autoimmune hepatitis, red cell aplasia, myocarditis, nephritis, cryoglobulinemia and Guillain-Barré syndrome. Acute liver failure occurs in less than 1% of children. Infection due to HEV is similar to HAV. During HEV epidemics children usually have a milder or subclinical infection and the brunt of the attack is on the pregnant women with an associated high mortality.

O



HGV Hepatitis and ther Hepatitis Viruses

Basic investigations such as urine for bile salts, bile pigments, total bilirubin with fractionation, alanine transaminase (ALT) and aspartate transaminase (AST) will suffice in the majority of children with AVH. Prothrombin time is a useful test for assessing prognosis. Complete blood counts, glucose, urea, creatinine, total protein, albumin are checked if the child is hospitalized. Hepatitis is diagnosed only if the transaminases are more than twice the upper limit of normal. In viral hepatitis, ALT is markedly increased more than 20 times the upper limit of normal and is higher than AST indicating cytoplasmic rather than mitochondrial injury.

The candidate F virus is no longer accepted as hepatotropic; however it has been associated with sporadic and fulminant hepatitis.

 

Table 9.12.1 Interpretation of serologic markers in hepatitis B infection HBsAg

HBeAg

Anti-HBe

Anti-HBc

Anti-HBs

HBV DNA

ALT

Significance

+

+

–

IgM

–

>2,00,000 IU/L

>1,000 IU/L

Acute hepatitis

+

+

–

IgG

–

>2,00,000 IU/L

normal

Immune tolerance. No treatment

+

+

–

IgG

–

>20,000 IU/L

>2 UL/ N

Immune active HBeAg +ve. TREAT

+

–

+

IgG

–

>2,000 IU/L

>2UL/ N

Immune active HBeAg –ve. TREAT

+

–

+

IgG

–

<2,000 IU/L

normal

Inactive carrier. No treatment

–

–

+/–

IgG

+

Not detected

normal

Viral clearance

559

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anagement

Prognosis The majority of children with acute HAV and HEV hepatitis recover without any complications. Hepatotoxic drugs, indigenous medications and underlying metabolic liver disease may trigger acute liver failure in these children. The case fatality rate among pregnant women is between 15% and 25% during HEV epidemics. The response to IFN in chronic hepatitis B is around 40–50%. Lamivudine which has been studied extensively has been associated with very high drug resistance. The response to therapy in chronic hepatitis C with IFN and ribavirin is best for non I genotypes.

General

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omplications

560 Acute viral hepatitis is a self-limiting illness and the majority recover without any sequel. Fever, hyperbilirubinemia,

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Prevention easures

Hepatitis A virus and Hepatitis E virus infection can be prevented by improving the environmental hygiene. Drinking clean water, washing hands and hygienic preparation of food are important steps in preventing the spread of Hepatitis A and E viruses. Since HBV and HCV are spread parenterally proper screening of blood and blood products is necessary prior to transfusion. Disposable needles should be used and unnecessary needle pricks including tattooing should be avoided. I



The majority of children with AVH will recover spontaneously and require only supportive treatment. A nutritious diet should be provided and undue physical exertion, hepatotoxic drugs and constipation should be avoided. Children with persistent vomiting, fever, fluid retention, altered sensorium or gastrointestinal bleed require hospitalization. Cholestasis can be managed with ursodeoxycholic acid (UDCA) 20 mg/kg/day. There is no role for antivirals in acute HAV and HEV hepatitis. Recently there are few reports of antivirals lamivudine and entecavir in children with acute HBV hepatitis. Patients with acute hepatitis C who have persistent viremia (i.e. HCV RNA positive for 12 weeks) following infection require treatment. The current recommendation is to initiate treatment with interferon (IFN) alpha or pegylated interferon (PEG-IFN) as early as possible in asymptomatic patients infected with HCV genotype 1, while treatment may be delayed in icteric individuals with significant symptoms and those with genotype 2 and 3. Children with chronic hepatitis B with elevated transaminases who are HBeAg positive with HBV DNA >20,000 IU/L or HBeAg negative with HBV DNA >2,000 IU/L should be treated. The aim of treatment is to suppress viral replication, induce remission in liver disease and prevent the development of HCC. The options available for children are IF and antivirals. The treatment for chronic hepatitis C has been well standardized and includes IFN with ribavirin.

prolonged cholestasis, ascites and coagulopathy may be a presentation in older children. The most important complication is acute liver failure. Chronic hepatitis, cirrhosis and hepatocellular carcinoma are the complications seen in HBV and HCV infections.

mmunization

R

Hepatitis A virus can be prevented by active immunization with two doses of hepatitis A vaccine given 6 months apart after the age of 18 months. Active immunization with three doses of hepatitis B vaccine given at 0, 1 and 6 months is recommended with the first dose preferably given soon after birth and may be combined with the primary immunization.

ecent dvances A

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Investigations for etiology are not necessary unless there are atypical manifestations or the child is hospitalized. All children should be screened for HBsAg. The presence of anti-HAV IgM or anti-HEV IgM confirms the diagnosis of acute HAV and HEV hepatitis respectively. HBsAg positivity along with anti-HBc IgM indicates acute HBV hepatitis; whereas anti-HCV IgM positivity indicates acute HCV hepatitis. Infection due to non-hepatotropic viruses such as measles, parvovirus B19, herpes simplex 1 and 2, dengue virus, cytomegalovirus (CMV), Epstein-Barr virus (EBV) and human immunodeficiency virus (HIV) may present with jaundice, moderate elevation of transaminases and associated clinical features of the underlying illness. Other causes of hepatitis such as leptospirosis, typhoid, Wilson disease (WD) and autoimmune hepatitis need to be excluded if there are atypical manifestations or features suggestive of nonviral hepatitis. Ultrasound examination is done to exclude liver abscess or gallstones. Liver biopsy is not recommended in children with acute hepatitis but is essential in those with suspected acute on chronic liver disease or chronic hepatitis.

Hepatitis B vaccines have played a major role in decreasing the prevalence of HBV and thereby its complications, namely chronic hepatitis, cirrhosis and HCC. However in 5–10% of children vaccine failure has been well documented. Researchers are developing more potent vaccines such as DNA vaccine and cell-based vaccines to increase the efficacy. At present there is no recommendation for treatment of children in the immune tolerance stage in spite of the active viral replication. More potent drugs to suppress the virus at this stage and also drugs which will act on the covalently closed circular DNA (cccDNA) are in the pipeline. Liver transplant is an excellent option in children with acute liver failure who fulfill the criteria for liver transplantation.

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1. Kamath SR, Sathiyasekaran M, Raja TE, Sudha L. Profile of viral hepatitis A in Chennai. Indian Pediatr. 2009;46:642-3. 2. Lok ASF. Hepatitis B. In: Dooley JS, Lok ASF, Burroughs AK, Heathcoate JE (Eds). Sherlock’s Diseases of the Liver and Biliary System, 12th edition. UK: Blackwell Publishing Ltd; 2011. pp. 367-92. 3. Malathi S, Mohanavalli B, Menon T, et al. Clinical and viral markers pattern of acute sporadic hepatitis in children in Madras, South India. J Trop Pediatr 1998;44:275-8. 4. Poddar U, Agarwal J, Yachha SK. Atypical manifestations of hepatitis A in children. Indian J Gastroenterol. 2010;29:20910. 5. Schiff ER. Viral hepatitis. In: Schiff ER, Sorrell MF, Maddrey WS (Eds). Schiff’s Diseases of the Liver, 10th edition. USA: Lippincott Williams and Wilkins; 2007. pp. 709-836.



ibliography



• HAV, HEV and HBV are the most important causes of viral hepatitis. • HAV and HEV hepatitis are self-limiting illnesses. • HBV and HCV hepatitis may progress to chronic hepatitis, hepatocellular carcinoma and cirrhosis. • The incidence of acute liver failure in acute viral hepatitis (AVH) is less than 1%. • HAV and HBV hepatitis can be prevented by vaccination. • HBV and HCV hepatitis can be prevented by screening blood donors. • HAV and HEV hepatitis can be prevented by improving water supply and the hygiene of the surrounding areas. • Viral hepatitis is therefore a communicable yet preventable disease.



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ey

561

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hronic iver isease and irrhosis of iver in hildren

• •

Chronic liver disease (CLD) in children encompasses a wide spectrum of disorders with infectious, metabolic, genetic, drug-induced, vascular, autoimmune and idiopathic etiologies. The ultimate result of ongoing liver injury and dysfunction appears to be chronic hepatitis or if left untreated, cirrhosis and its complications. The duration criterion for diagnosis of CLD in children is after a period of at least 3–6 months or more (unlike 6 months in adults) in view of the irreversible liver damage that is likely to occur even before the onset of symptoms. A detailed history, clinical findings, laboratory tests, imaging studies, upper gastrointestinal (UGI) endoscopy for varices, work-up for specific etiology and prognosis, and the gold standard liver biopsy are essential initially for diagnosis and for long-term follow-up. S

E

tiologic pectrum

Acute on CLD Asymptomatic presentation The common presentation is with an insidious onset, characterized by abdominal distension, hematemesis, prolonged or repeated episodes of jaundice, portal hyper tension, shrunken or enlarged firm left lobe of liver, firm splenomegaly, ascites (Fig. 9.13.1), cutaneous portosystemic shunts, failure to thrive, muscle wasting, bleeding manifestations (epistaxis, hematemesis and melena) and peripheral edema (Fig. 9.13.2). Other features include skin manifestations such as palmar erythema, leukonychia, (Fig. 9.13.3), clubbing, spider angiomata, xanthomata, papular acrodermatitis; endocrine changes such as irregular menstruation, delayed standard mortality ratio (SMR), gynecomastia and infertility; liver flap; fetor hepaticus; and encephalopathy (poor attention span, loss of memory, dull activity, poor scholastic performance and altered sleep rhythm). ­

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9.13

 

Figure 9.13.1 Decompensated, active, advanced macronodular cirrhosis

linical Presentation of cld and irrhosis C

Chronic liver disease may present with: 562 • Chronic insidious type of onset (common) • Acute viral hepatitis like onset

Figure 9.13. 2 Pitting edema—decompensated cirrhosis  

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C

C

­

­

C

The etiologic spectrum of CLD includes the following: • Prolonged cholestasis of infancy: Biliary atresia, neonatal hepatitis, ductal paucity, choledochal cyst, progressive familial intrahepatic cholestasis (PFIC), inspissated bile syndrome, and spontaneous perforation of bile duct. • hronic hepatitis: Chronic viral hepatitis, e.g. B, C and D, others; autoimmune hepatitis; and drug induced hepatitis, e.g. anti-cancer drugs, anticonvulsants and anti-TB drugs. • Metabolic or genetic liver diseases: Tyrosinemia, glycogen storage disease (GSD type IV and type III— cirrhosis prone), Gaucher’s disease, Niemann-Pick disease, Wolman disease, galactosemia, fructosemia, alpha 1-antitrypsin deficiency (rarely), and mucopoly saccharidosis (Hurler disease). • opper and iron associated disorders: Wilson disease and Indian childhood cirrhosis. • hronic venous congestion or vascular: Budd-Chiari syndrome, veno-occlusive disease, non-cirrhotic portal fibrosis (NCPF), congestive heart failure and constrictive pericarditis. • Miscellaneous: Fibropolycystic disease (polycystic dis ease of liver and kidney), histiocytosis-X, cystic fibrosis, fatty liver, and idiopathic or nutritional cirrhosis.

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The laboratory tests should be chosen to arrive at an early diagnosis of the disease, assess the status of liver function, detect complications, and determine the etiology and prognosis of end stage CLD. • Clinical evidence of decompensation with liver cell failure as mentioned above with supportive evidence of defective synthetic function of liver such as hypoalbuminemia, reversal of albumin: globulin ratio and abnormally raised nternational normalized ratio (INR) (>3) are diagnostic of cirrhosis. • Elevated liver transaminases with conjugated hyper bilirubinemia suggest active liver injury. • Presence of pruritus and deep icterus with elevated cholestatic enzymes such as serum alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase (GGTP) suggest the evidence of cholestasis, both due to intra hepatic and extrahepatic causes. • Raised ALP and low or normal GGTP indicate PFIC type 1 and 2, but raised ALP and high GGTP are diagnostic of PFIC-3.

Additional Laboratory Tests •

•

Ultrasound (USG) of abdomen may reveal splenomegaly, tortuous and dilated splenic vein, portal vein collaterals, and hyperechoic liver with dilated intrahepatic portal vein radicals, minimal ascites, right-sided pleural effusion, and lenorenal collaterals in cirrhotic patients. Choledochal cyst, extrahepatic biliary atresia, and Budd-Chiari syndrome can also be recognized by USG abdomen. Ultrasonogram color Doppler of spleno-porto-venous axis is useful in diagnosing the portal venous flow pattern and collateral circulation.

D t t t S t

Liver Biopsy Liver biopsy is the gold standard and confirmatory for chronic hepatitis and cirrhosis liver. Presence of periportal fibrosis and necrosis, nodular regeneration with loss of hepatic lobular architecture are the confirmatory findings for cirrhosis. Biopsy helps in diagnosis, assessing disease activity, classification, follow up and identifying etiology such as extrahepatic biliary atresia (EHBA), Alagille syndrome with ductal paucity, HBV (ground glass hepatocytes), PFIC, alpha 1-antitrypsin deficiency, hemochromatosis, Wilson disease, Caroli disease, and fibropolycystic disease.

Differential Diagnosis • •

C

iagnosis

Extrahepatic portal hypertension (absent liver cell failure and abdominal wall veins). Chronic hepatitis (absence of nodular liver, abdominal wall veins and portal hypertension).

ourse and Prognosis

It is variable, depending on Child-Pugh grading (Table 9.13.1).

Interpretation Child-Pugh A: Patient with good liver dysfunction (score 5–6). 563 Child-Pugh B: Intermediate (score 7–9).

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Advanced and decompensated cirrhosis is characterized by ascites, coagulopathy, encephalopathy, GI bleeds, hepatorenal syndrome (HRS), hepatopulmonary syndrome (cyanosis), spontaneous bacterial peritonitis (SBP) and hepatocellular carcinoma (especially following HBV, HCV and HDV cirrhosis), growth failure, malabsorption and malnutrition.

m

Complications of Advanced and Decompensated Cirrhosis

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Figure 9.13.3 White nail of decompensated liver disease

and iver

Upper GI endoscopy can detect the presence of esophageal and gastric fundic varices, portal hypertensive congestive gastropathy commonly and also helps with endotherapy. • Complete hemogram may show pancytopenia indicating hypersplenism, and persistent thrombocytopenia sugg esting end-stage liver disease which is poor prognostic marker. Leukocytosis occurs in intercurrent infections. • Recurrent hypoglycemia and coagulopathy (high prothrombin time despite vitamin K and INR) are poor prognostic markers. • Psychometry tests and serum ammonia are needed in minimal hepatic encephalopathy and overt hepatic encephalopathy. Additional etiologic work-up will depend on the clinical context and will include tests for infective causes (hepatitis B and C, Toxoplasmosis, other infections, Rubella, cytomegalovirus and Herpes simplex virus-2 (TORCH) and HIV), drugs, and specific metabolic work-up for storage disorders (bone marrow and liver biopsy), WD and copper related disorders [Kayser-Fleischer (KF ring, serum and hepatic copper)], and lipid storage disorders (cataract or cherry-red spots). Prognostic evaluation requires estimation of ChildPugh score (see below) or model for end stage liver disease (MELD) score. In addition, chronic liver cell failure patients may need periodically repeated prognostic laboratory tests especially pre, per and post-liver transplantation stage apart from donor screening tests. Fibroscan of liver helps to assess degree of liver fibrosis.

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•

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Prognosis

Compensated (A)

Guarded (B)

Decompensated (C)

Jaundice (bilirubin)

Mild or nil <2 mg/dL

Moderate 2–3 mg/dL

Intense >3 mg/dL

Ascites

--

Mild and treatable

Severe or refractory

Albumin

>3.5 g/dL

3–3.5 g/dL

<3 g/dL

Encephalopathy

----

Past history

++

Prothrombin time

N or × 1 ↑

×2↑

× many ↑

Child-Pugh C: Patient with poor liver function and surgical or invasive procedures will carry increased mortality in 90% in non-bleeding cirrhotics (score 10–15).

major surgical procedures, and electrolyte imbalance (diuretics).

Management

Goal of therapy is to identify the complications of hepatic encephalopathy and decompensated cirrhosis, and prevent them by avoiding predisposing factors mentioned above.

• • • • • •

•

Early detection and management of complications due to decompensated cirrhosis. There is no specific treatment for cirrhosis per se that will arrest or reverse the cirrhotic changes. Treatment of portal hypertension, ascites and hepatic encephalopathy are discussed separately. Treatment of specific cause if any, like Wilson disease (WD), drug induced hepatitis, and hepatitis B and C. Patients with compensated cirrhosis can lead a normal life and no specific diet is helpful. Hepatic herbal supportives, antioxidants, liver cell membrane protectives, maintenance of adequate calories, fluid and electrolytes, vitamin especially fat soluble vitamins are routinely recommended with variable outcome. Liver transplantation is the future hope in EHBA, tyrosinemia, GSD, acetyl transferase deficiency and severe bile acid metabolic defects (PFIC).

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Hepatic ncephalopathy

­

­



Hepatic encephalopathy is characterized by: • Irritability, incoherent speech, mental confusion and violence (Grade I). • Drowsiness and somnolence, flapping tremor, and fetor hepaticus (Grade II). • Exaggerated reflexes with up-going plantar reflexes, and stupor (Grade III). • Coma (Grade IV). Metabolic complications like hypoglycemia, dyselec trolytemia, renal failure, coagulopathy with bleeding, hyper ammonemia, and convulsions may supervene in Grade III and IV encephalopathy. Early detection of hepatic encephalopathy is possible by demonstrating constructional apraxia (inability to draw or copy a star).

Predisposing Causes These include GI bleeds with excess protein in the bowel, rapid abdominal paracentesis, intercurrent infection (Gram564 negative septicemia), use of hepatotoxic drugs (morphine),

Management Guidelines

Specific Treatment These include: • Identification of any site of bleeding by fibroscopy and appropriate treatment of variceal bleed, gastric or duodenal erosions, etc. • Variceal bleeds to be treated by somatostatin, octreotide, vasopressin or glypressin or endoscopic band ligation or sclero/glue therapy and Sengstaken tube. • Maintenance of fluid and electrolyte balance. Sodium restriction may be required despite hyponatremia which may be dilutional. • Potassium preparations for hypokalemia. • Diuretics (spironolactone/loop diuretics). • Parenteral IV glucose for hyponatremia. • Infection: Culture studies especially of ascitic fluid and if positive to treat infection as indicated. Please remember that liver disease may influence drug choice and dose. The role of rifampicin in hepatic encephalopathy in pediatric age group needs more study. • Lactulose produces two liquid stools (15–30 m twice or thrice daily.) It produces osmotic diarrhea, prevents absorption of ammonia from colon and prevents proliferation of ammonia producing organisms. Lactilol and sodium benzoate like ammonia reducing drugs are more beneficial. • Selective intestinal decontamination by administration of non-absorbable antibiotics (norfloxacin or neomycin). • Sedation (short-acting benzodiazepines, oxazepam, and midazolam) is preferred. • Coagulation defects to be corrected with fresh frozen plasma, clotting factors and vitamin K (single dose). • Parenteral vitamins (fat soluble and water soluble especially B vitamins). • Management of treatable causes like WD, autoimmune hepatitis, and drug induced hepatitis, hepatitis B and C. • Liver transplantation is lifesaving for end stage cirrhosis liver though cost prohibitive. l



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Table: 9.13.1 Child-Pugh score for grading of portal hypertension

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LCF

iagnostic aboratory nvestigations If ascites is present, serum sodium, potassium, bicar bonate, chloride, urea and creatinine levels may help. Serology for hepatitis B virus (HBsAg, HBeAg, anti HBeAb, and HBV DNA), and hepatitis C virus (Anti HCV enzyme linked immunosorbent assay (ELISA) and HCV RNA). Serology for other viruses: CMV, EB virus, HIV and TORCH 565 group. ­

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NCS

•

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•

Management of Portal Hypertension Management should include emergency resuscitation of upper GI bleeding patients, control of bleeding with somatostatin and analogs or vasopressin and glypressin, emergency endoscopy therapy, and long-term prevention of variceal bleeds with propranalol (1 mg/kg/day) and isosorbide mononitrate. Proper counseling of close relatives for long-term follow-up and the natural course of the illness is mandatory.

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•



This will be the gold standard for confirmation of cirrhosis. Diagnosis of portal hypertension should also include screening for hypersplenism, post-transfusion complications and work-up for minimal chronic hepatic encephalopathy like psychometry analysis.

•

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Liver Biopsy

• • •

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Abdominal ultrasound, esophago-gastro-duodenoscopy, liver function text (LFT), and complete hemogram, as mentioned earlier, are relevant for diagnosis and management. Identification of the cause of portal hypertension requires almost the laboratory etiologic work of cirrhosis liver and chronic hepatitis. Evaluation of hypercoagulable state causing thrombosis of SPV axis includes complete coagulation profile, protein S and C, antiphospholipid antibody, antithrombin and fibrinogen estimation in selected patients, as specific therapy is possible.

• •

S

Diagnosis

•

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•

amily or sibling history of liver disease: Metabolic liver disease (WD, GSD, tyrosinemia, galactosemia, NiemannPick disease, Gaucher’s disease, hemochromatosis, alpha-1 antitrypsin deficiency, and urea cycle defects). Peripheral neuropathy, parotidomegaly and Dupuytren’s contracture (PPD) and hepatomegaly in alcohol induced liver disease. ayser- leischer ring, sun flower cataract: Wilson disease. Hyperpigmentation: Hemochromatosis. History of blood transfusion or tattooing: Hepatitis B or C. cratch marks and xanthomas: Chronic cholestasis. Drug history in CLD and drug abuse in hepatitis B infection. ysmorphic facies: Ductal paucity syndrome, e.g. Alagille syndrome. arly onset liver cell failure ( ), decompensation and neonatal cholestasis syndromes ( ): Tyrosi nemia, galactosemia, hemochromatosis and alpha-1 antitrypsin deficiency. evere itching or chronic diarrhea or malabsorption: Byler disease (PFIC 1). ataract: Congenital rubella syndrome, galactosemia, and WD. eborrheic dermatitis, otitis media, lumpy-bony swellings, hepatosplenomegaly and cholestasis: Histiocytosis. Restricted growth, frequent eating habits, large liver, cherubic face, and tendency to be drowsy on fasting or acidosis: Glycogen storage disease 1. D

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ome lues for tiology (Table 9.13.2)

Hepatic Venous Pressure Gradient If it is more than 12 mm, it is a useful predictor of impending variceal bleed.

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ther hronic iver isorders

Pressure Criteria Portal venous pressure should be more than 10 mm Hg (normal less than 10 mm Hg).

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Refer to Chapter 9.17 for details.

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scites

C

It is suspected with a history and clinical features of underlying chronic liver disease. Nodular and shrunken liver, abdominal veins and features of decompensation with extrahepatic manifestations of chronic liver disease will differentiate patients of extrahepatic portal hypertension where the above features are absent until late stage. However laboratory work up including USG and Doppler abdomen will help to identify the pathology in the splenoportovenous (SPV) axis.

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Cirrhotic Portal Hypertension

These include: • Recurrent rebleeds even after four to six endotherapy sessions. • Hypersplenism. • Outstation patients (from remote places) where medical treatment is not available. • If patient is not fit for surgery or not willing for surgery or transjugular intrahepatic portosystemic shunt (TIPS).

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Clinical criteria for portal hypertension include variceal upper GI bleed, splenomegaly, tortuous veins on anterior abdominal wall away from umbilicus especially in intra hepatic type and ascites getting localized in end stage of cirrhosis.

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Indications for Surgical Management

Portal Hypertension

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Cataracts

Galactosemia, Wilson disease, Rubella syndrome

KF rings, tremors, dysarthria, extrapyramidal signs

Wilson disease

Progressive liver cell failure, renal tubular function, hypophosphatemic rickets

Tyrosinemia type I

Mental retardation

Galactosemia, lipid storage disorders

Rickets

Wilson disease, tyrosinemia

Cystic kidneys

Congenital hepatic fibrosis

Skin rashes

Histiocytosis

Blue berry muffin

CMV infection

Pruritus

Extrahepatic biliary obstruction, PFIC 1, Chronic hepatitis B/C with cholestasis, Alagille syndrome

•

Biochemical Clues for CLD and Cirrhosis Liver 1. Persistently low serum albumin (< 3 g/dL). 2. Persistently raised serum gammaglobulin; low albumin with reversal of albumin: globulin ratio (<1). 3. Prolonged PT (> 3 times above normal limits). 4. Aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio >1. 5. Persistently elevated transaminases and serum alkaline phosphatase (ALP) in chronic biliary disorders.

Alagille syndrome



Broad forehead, small chin, saddle nose, low set ears, posterior embryotoxon, cardiac and renal anomalies Developmental delay

omplications of

CLD





Suggestive of

Autoantibodies (ANA, anti-SMA, anti-LKM, p-ANCA). Serum ceruloplasmin, 24-hour urinary copper and slit lamp examination for KF ring for WD. Urine reducing sugars and screening tests for inherited metabolic liver disease, galactose-1-phosphate uridyl transferase (GALT) assay (galactosemia).



 

Clinical Features

• •

C

These include portal hypertension with ascites, hyper splenism, variceal bleeding, and synthetic dysfunction of liver such as hypoalbuminemia, coagulopathy (Table 9.13.3), hypoglycemia, growth failure, reduced standardized mortality ratio (SMR) and the end stage complications like hepatic encephalopathy, minimal hepatic encephalopathy, ­

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Table 9.13.2 CLD: extrahepatic manifestations

 

Table 9.13.3 Summary of various chronic liver disorders Disease

Defect

Clinical features

Diagnosis

Treatment and prevention

Extrahepatic Biliary Atresia (EHBA)

Post-inflammatory obstruction of biliary tract, chronic cholestasis, progressive fibrosis and secondary biliary cirrhosis

Full term Normal birth weight and growth velocity No dysmorphic facies Early dark urine with diaper stain and persistent pale stools Firm and moderately large liver

Rectal swab: Persistent pale stools Serum ALP and GGTP elevated. USG abdomen: Absent gall bladder Hepatobiliary radioisotope study: Uptake normal but no excretion into intestine even after 24 hours Liver biopsy: Ductular proliferation with widened portal tract, bile plugs and dense fibrosis and cirrhosis Per-operative cholangiogram: Gold standard - confirmation

Medical conservative: EBF MCT, Vitamins UDCA (empiric)

LFT: Raised transaminases and cholestatic enzymes USG abdomen: Normal Liver biopsy: Lobular disarray, ballooning and focal necrosis of hepatocytes and giant cell formation and extramedullary erythropoiesis

Supportive-conservative

Idiopathic (Giant cell) Hepatitis

566

No cause detectable Sporadic/familial forms: of late , less common

Normal birth weight No dysmorphism Onset: neonatal, self-limiting Neonatal conjunctivitis in a normal infant Hyperbilirubinemia with no other clinical clue for cause Recovery usually complete

Early Kasai porto-enterostomy (<4–6 weeks ideal) Liver transplant

Contd...

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Disease

Defect

Clinical features

Diagnosis

Treatment and prevention

Alagille syndrome

Autosomal dominant; JAG-1 gene mutation on chromosome 20p12

Chronic cholestasis Dysmorphism: Triangular facies -broad forehead, pointed chin, saddle nose with bulbous tip, hypertelorism, low set ears, and posterior embryotoxon Renal anomalies Cardiac abnormalities

Radiology - butterfly vertebra, curved phalanges, short ulna Liver biopsy: Ductal paucity reduced ratio of interlobar bile ducts to portal tracts (Normal = 0.9-1.8’ in ductal paucity = <0.5).

Supportive UDCA

Tyrosinemia Type I Fumaryl acetoacetate hydrolase deficiency, enzyme for oxidative degradation pathway of phenyl alanine and tyrosine Gene mutation Accumulation of succinyl acetone in liver and kidneys causing damage

Progressive liver failure. Renal tubular dysfunction Hypophosphatemic rickets Excretion of tyrosine metabolites Large liver with fibrosis; cirrhosis liver and after 2 years of age hepatocellular carcinoma Acute form: early liver cell failure features and death by 8 months

LFT: Abnormal Alpha-fetoprotein: Very high (1–100 times) Urine succinyl acetone present Urine aminoaciduria

Restrict phenyl alanine and tyrosine in diet Drug therapy: Nitisinone (Orfadin) -prevents accumulation of succinyl acetone Dose: 1 mg/kg/day PO, bid, 1 hour bf initially step-up dose to 2 mg/kg/day

Galactosemia

Autosomal recessive Deficiency of galactose-1phosphate uridyl transferase (GALT; EC2.7.712) Accumulation of galactose and toxic metabolites and damage to liver and CNS

Clinical spectrum varies according to type and number of GALT gene mutations Onset in neonatal period, soon after breast milk and top milk with jaundice Hepato-splenomegaly Liver dysfunction Hypoglycemia Renal tubular dysfunction Hypotonia Cataract. E. coli sepsis. Untreated cases develop cirrhosis and die.

Urine Benedict’s test for reducing substance + ve

Galactose –restricted diet (milk and milk products including breast milk) lifelong

Autosomal recessive Gene mutation Bile transport defects Type 1 (Byler disease): PFIC1 gene encoding on P-type ATPase protein aminophospholipid transport- chromosome 18q21-22

All types have pruritus, jaundice, fat soluble vitamin deficiencies Type 1: Systemic involvement includes liver, pancreas, diarrhea Cirrhosis in 1st decade of life. Liver involved Overlap with type 1 Bad prognosis Onset delayed until adulthood H/o cholestasis of pregnancy in the mother

Type 2: SPGP (Sister of P-Glycoprotein) gene encoding on BSEP (Bile salt export pump)-located on chromosome 2q 24 PFIC3: MDR3 gene mutations (multidrug resistance-3) encoding on biliary phospholipid Transporter located on chromosome 7q21

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Measurement of GALT activity in red blood cells

UDCA liver transplant in 2nd decade

Raised serum ALP and Normal/ low GGTP Liver biopsy: Paucity of intralobular bile ducts and granular bile in electron microscopy SAP raised and normal/low GGPT Liver biopsy: Giant cell hepatitis, canalicular/ hepatocellular cholestasis, amorphous bile Both SAP and GGTP are raised Liver biopsy similar to EHBA

Supportive Liver transplant in 1st decade Supportive, UDCA

Liver transplant

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Defect

Clinical features

Diagnosis

Treatment and prevention

Indian Childhood Cirrhosis (ICC)

Copper contaminated milk feeds

Age 6 months to 5 years Boy’s predominance 20% sib history + ve Not a disease of poverty Clinically early stage: Nonspecific findings (irregular fever, altered appetite, mild abdominal distension, prolonged AVH like presentation) Onset may be insidious or acute Jaundice may be present Liver initially leafy edge and firm, later hard micronodular cirrhosis Decompensation in end stage

LFT- abnormal but not diagnostic Liver biopsy: ntralobular pericellular creeping fibrosis; Mallory hyaline; Orcein + for liver copper, no fatty change; no other histological clue

D-penicillamine Zinc Steroids?

Rare Early liver cell failure with congenital cirrhosis Shrunken liver If not treated— early death History of oligohydramnio, placental edema, IUGR/still birth

High degree of suspicion Complete saturation of iron binding capacity, iron staining buccal mucosa Minor salivary gland biopsy tissue Decreased intensity on T2weighted MRI (pancreas, heart) characteristic of iron Serum ferritin is elevated

N-acetyl cysteine Selenium Desferrioxamine Vitamin E Prostaglandin E1 alpha Sepsis management Liver transplant

Neonatal Congenital? Hemochromatosis Maternal factor Iron deposition in liver and almost all organs except reticuloendothelial system

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Prevention: Remove copper from diet

 

Table 9.13.4 Acute liver failure: Indicators of poor prognosis and immediate referral for liver transplantation Biochemical

Increasing depth of jaundice

*Serum bilirubin >300 mmol/L (>17.6 mg/dL)

Rapidly decreasing liver size

Decreasing transaminase levels



Clinical

Recurrent or persistent hypoglycemia

<4 mmol/L needing often dextrose infusions

Coagulopathy: bleeds

*Prothrombin time >60 sec (INR >3.5 and in paracetamol poisoning >6.5)

Clinical acidosis

*Acid-base pH <7.3 (acetaminophen poison)

Hepatic encephalopathy grade 2/3

Raised S. ammonia levels

*Age <10 years with jaundice More than 7 days before encephalopathy Note: *King’s college criteria

•

Maintenance of adequate calories, fluid and electrolytes, vitamin especially fat soluble vitamins. • Liver transplantation. Liver transplantation and indicators of poor prognosis and immediate referral for liver transplantation in acute liver failure are well defined (Table 9.13.4).

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and hepatorenal and hepatopulmonary syndromes and in late stages hepatocellular carcinoma. Table 9.13.3 summarizes the brief clinical details about various disorders.

Management • •

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Early detection and management of complications due to decompensated cirrhosis. Treatment of specific cause if any, like WD, drug induced hepatitis, and hepatitis B and C. Patients with compensated cirrhosis can lead a normal life and no specific diet is helpful.

Liver Transplantation: Common Indications (Table 9.13.4) These include extrahepatic biliary atresia, fulminant hepatic failure (AVH, paracetamol toxicity), PFIC, tyrosinemia type 1, WD, Alagille syndrome, non-syndromic intrahepatic ductal paucity, cryptogenic, polycystic liver disease (Caroli), hepatitis

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• Chronic hepatitis, metabolic liver disorders (MLDs) and neonatal cholestasis are the leading causes of CLD. • Minimal hepatic encephalopathy, a new entity, needs focus in the CLD work-up. • Children with decompensated cirrhosis require both prevention and appropriate management of lifethreatening complications and periodic counseling regarding orthotopic liver transplantation (OLT).

1. Arora NK, Bhatia V. Chronic Liver Disease in India. Indian J Pediatr. 2008;75 Suppl:S69-73. 2. Hardy S, Kleinman ER. Cirrhosis and chronic liver failure. In: Suchy FJ, Sokol RJ. Balistreri WF (Eds). Textbook of Liver Disease in Children, 2nd edition. Philadelphia: Lippincott Williams and Wilkins; 2001. pp. 89-127. 3. IAP Speciality Series on Pediatric Gastroenterology. 2008;(14):188-96. 4. IAP Speciality Series on Pediatric Gastroenterology. 2008;(16):217-27. 5. Malathi S. Approach to a child with CLD. Indian J Pract Pediatr Hepatology. 2002;4(4):362-9.

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B and C cirrhosis, GSD type IV, autoimmune end stage liver disease, Budd-Chiari syndrome and hepatoblastoma.

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Neonatal holestasis yndromes

Idiopathic Neonatal Hepatitis

ntroduction

Neonatal cholestasis syndromes (NCS) are characterized by prolonged conjugated jaundice beyond 2 weeks of life and high colored urine with or without pale stools. The presence of high level of conjugated bilirubin (>20% of total bilirubin if serum bilirubin >5 mg/dL or >1 mg/dL if total serum bilirubin <5 mg/dL) is suggestive of NCS.

These infants tend to be small for gestational age (SGA) or premature. More than one child in a family may be affected. Liver biopsy shows extensive giant cell transformation, but bile ducts are relatively normal. It may be very difficult to differentiate idiopathic NH from BA. The prognosis is much better than that of BA.

Biliary Atresia This is a fatal progressive fibro-inflammatory cholangiopathy resulting in complete obliteration of the entire or portions of the extrahepatic and intrahepatic biliary tree within weeks of birth. The exact etiology of BA is not known. Reovirus 3, EpsteinBarr virus, rotavirus, cytomegalovirus and maternal diabetes have been implicated in etiology. It is more common in term female babies with normal birth weight. Stools are initially pale and then become completely acholic. Firm hepatomegaly is common. Splenomegaly is late and is a sign of hepatic fibrosis. Bleeding may occur due to uncorrected vitamin K deficiency, especially in breastfed babies. Biliary atresia should be ruled out in any neonate with conjugated jaundice persisting beyond 14 days of life.









Based on the primary site of pathology, NCS may be classified as intrahepatic (medical) or extrahepatic (surgical). 1. Intrahepatic cholestasis is seen in Toxoplasmosis, Other infections, Rubella, Cytomegalovirus and Herpes simplex virus-2 (TORCH) infections, septicemia, total parenteral nutrition (TPN), and various inborn errors of metabolism (such as galactosemia, neonatal hemochromatosis), and progressive familial intrahepatic cholestasis (PFIC). 2. In the extrahepatic group, biliary atresia (BA) is the most important. The spectrum of diseases causing NCS in India and the West is quite different as shown in Table 9.14.1. It is also useful to classify NCS as babies who are sick and non-sick, as the sick babies require urgent work-up for prompt therapy (Flow chart 9.14.1).



lassification



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TORCH Infections ­

TORCH infections are characterized by hepatosplenomegaly, failure to thrive (FTT), purpura, microcephaly, and chorio retinitis, and congenital heart disease in congenital rubella.

Choledochal Cysts Choledochal cysts are a rare but important treatable cause of NCS. Ultrasonography, endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography (PTC) are very useful in diagnosis. Treatment is by complete surgical excision with drainage of the biliary tract into the jejunum.

 

Table 9.14.1 The spectrum of neonatal cholestasis syndromes: West versus India Disease

West*

India** (Multicentric)

Biliary atresia/Choledochal cyst

25%

38%

Neonatal hepatitis (NH)

15%

37%

Metabolic diseases

20%

4%

PFIC/Alagille syndrome/Bile acid synthesis disorders

25%

3%

Alpha 1-antitrypsin deficiency

10%

—

Viral infections

5%

10%

Others

—

2%

Unknown

—

6%

* Balistreri WF, Bezerra JA. Whatever happened to “Neonatal hepatitis”? Clin Liver Dis. 2006;10:27-54. ** Yachha SK. Indian Pediatr. 2000;37:845-51.

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Flow chart 9.14.1 Classification of NCS

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The workup should be done in a stepwise manner to establish the specific cause of cholestasis. Potentially lifethreatening conditions like sepsis, galactosemia, tyrosinemia and endocrinopathies that need immediate intervention should be ruled out first and the next step is to rule out BA.

ataract: Galactosemia, HFI, congenital rubella syndrome, CMV and Zellweger syndrome. In galactosemia and HFI, cataract is not present at birth. icrophthalmia: Rubella, CMV. rushfield spots: Down syndrome. horioretinitis: NH due to CMV, toxoplasmosis, rubella. Posterior embryotoxon: Alagille syndrome (Fig. 9.14.1). C

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ntrauterine growth restriction: TORCH infections. ex: BA and choledochal cyst are more common in girls. onsanguinity and similar illness in siblings: Inborn error of metabolism (IEM) and PFIC. E. coli sepsis: Galactosemia. ecurrent abortions: Neonatal hemochromatosis. nset immediately after breastfeeds: Galactosemia; after ingestion of fruits: hereditary fructose intolerance (HFI). eizures, vomiting: Galactosemia, HFI, hypopituitarism, intracranial hemorrhage. ysmorphism: Down syndrome, Alagille syndrome, Zellweger syndrome. arly hepatosplenomegaly: NH. E

• • •

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Figure 9.14.1 Child with Alagille syndrome  

picanthic folds: Down syndrome and Zellweger syn drome. E

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Metabolic Work-up

Endoscopic Retrograde Cholangiopancreatography Though useful, the need for high technical expertise and general anesthesia limits its usefulness.

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Percutaneous Transhepatic Cholangiography Here, dye is injected into the liver through a very thin Chiba needle and X-rays taken. Visualization of a patent biliary tract with antegrade flow of the contrast medium into the duodenum excludes BA. Near infrared reflectance spectroscopy of homogenized stool specimens for bilirubin and bile acids is both highly sensitive and specific for BA.

Liver Biopsy If there is no excretion in the hepatobiliary scintigraphy scan, liver biopsy is the single most valuable test to distinguish BA from NH. • The features of include: – Marked bile ductular proliferation and fibrosis. – Minimal giant cell formation. – Presence of bile lakes. • eatures of NH include: – Very little bile ductular proliferation. – Striking giant cell formation. – Focal hepatocellular necrosis. • The characteristic findings of alpha 1-antitrypsin deficiency: – Diastase-resistant, periodic acid schiff (PAS) positive, magenta-colored, globular inclusions in periportal hepatocytes.

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anagement of Ncs

Radionuclide Hepatobiliary Scintigraphy

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Technetium-99m-labeled derivatives of iminodiacetic acid are used to assess the continuity of the biliary tract with the small intestine. • In medical cholestasis, the uptake is decreased, but the excretion into the gut is normal. • In BA, the uptake is normal but excretion into gut is decreased, so that there is no radioactivity in the gut, even 24 hours later. • The presence of radioactivity in the gut is a strong point against the diagnosis of BA. • In the advanced stage of NH, the hepatocytes are so 572 much damaged that they are not able to excrete the isotope and hence it may be mistaken for BA.

•

Malnutrition is very common and breastfeeding should be encouraged. 200 calories/kg and 1–2 g/kg protein should be given. itamin : 5 mg of vitamin K should be given daily for the first 3 days after diagnosis and then 5 mg weekly. Dose may be adjusted depending on prothrombin time done monthly. itamin : 2,500 to 5,000 IU/day orally. Monitor serum level. If less than 30 mg/dL, increase oral dose by ten fold or give 50,000 IU IM. Vitamin D 40,000 IU IM monthly. Vitamin E 50–200 mg daily. Water-soluble vitamins: Excess doses of B complex vitamins should be given. Minerals: – Oral elemental calcium: 25–100 mg/kg/day. – Phosphorus: 25–50 mg/kg/day. – Zinc: 1 mg/kg/day. K

•

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Non-imaged or small gallbladder in fasting state: Suggestive of BA, but not diagnostic. If normal gallbladder (GB) and bile ducts can be visualized: BA is unlikely. Triangular cord sign: A cone-shaped fibrotic mass cranial to the bifurcation of the portal vein—highly suggestive of BA. In NH, GB is of normal size and contracts well after feeding. Dilated intrahepatic biliary radicles are not seen BA.

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Ultrasonography

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• iffuse cerebral calcification: Congenital toxoplasmosis. • Periventricular calcification: Congenital CMV infection. • Wimberger’s sign (erosion of the upper medial surface of tibia): Congenital syphilis. • elery stalk appearance of metaphysis: Congenital rubella syndrome.

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Radiological Work-up

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erum alpha 1-antitrypsin level: Low in alpha 1-antitrypsin deficiency. Hypoglycemia: Galactosemia, HFI, and hypopituitarism. High sweat chloride: Cystic fibrosis. ow galactose1-phosphate uridyl transferase: Galactosemia. lpha-fetoprotein levels: Elevated in NH and normal in BA; extremely high in type I tyrosinemia. L

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Non-visualization of the CBD and presence of small GB suggest BA.

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Urine sugar: Galactosemia, HFI. Urine microscopy: Owl-eye bodies in CMV hepatitis. High urinary succinyl acetone: Type 1 tyrosinemia. ow/ normal GGT: PFIC I and II. TORCH screen Venereal Disease Research Laboratory (VDRL) test HBV serology Culture of blood, urine and CSF.

Magnetic Resonance Cholangiography











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1. Balistreri WF, Bezerra JA. Whatever happened to “Neonatal hepatitis”? Clin Liver Dis. 2006;10:27-54. 2. Poddar U, Thapa BR, Das A. Neonatal cholestasis: differentiation of biliary atresia from neonatal hepatitis in a developing country. Acta Paediatr. 2009.pp.1260-4. 3. Riyaz A. Cholestatic liver disorders. In: Riyaz A (Ed). Pediatric Gastroenterology and Hepatology. Hyderabad: Paras Publishers; 2008. pp. 389-418. 4. Roberts EA. Neonatal hepatitis syndrome. Seminars Neonatol. 2003;8:357-74. 5. Yachha SK. Consensus report on neonatal cholestatic syndrome. Indian Pediatr. 2000;37:845-51.



If Kasai operation is done before 2 months of age, 80% may improve (Fig. 9.14.2). Results are very bad after 2 months. In the best of centers, the overall 5-year survival following Kasai ranges from 40% to 50%. Of these, 45% progress to cirrhosis and 55% have cholestasis on follow-up. Finally, for the non-correctable BA or failed Kasai, liver transplantation is the best modality of treatment.

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A combination of ampicillin and aminoglycosides like gentamicin or amikacin is the best, if septicemia is suspected. It is better to avoid ceftriaxone, as it tends to cause biliary sludge and gallstones. Cefotaxime and ceftazidime are better choices. S

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• In all neonates with conjugated jaundice, serious underlying diseases should be ruled out. • Yellowish staining of the diaper which is an important marker of NCS should never be ignored. • Sick infants who require urgent treatment should be picked up at the earliest. • Simple dietary measures like lactose elimination in galactosemia are rewarding. • Kasai operation for BA should be done before 2 months.

In general, all routine vaccines including HB vaccine should be given to children with NCS. HA vaccine should be given to children of more than 1 year. Influenza, chicken pox and pneumococcal vaccines may be given in the absence of contraindications. Live vaccines are contraindicated in children who have undergone liver transplantation.



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Figure 9.14.2 Biliary Atresia—Post Kasai

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It is believed to be due to the deposition of bile acids in the skin or due to increased endogenous opioids like met-enephalins synthesized in the gut. Some of the treatment options are: • Cholestyramine • Colestipol • Phenobarbitone • Ursodeoxycholic acid: Dose 15–30 mg/kg/day • Opioid antagonists: IV naloxone or oral nalmefene • Rifampicin • Antihistamines • Carbamazepine • Plasmapheresis • Ultraviolet B light • External diversion of bile.

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pidemiolgy

Biliary atresia, an important cause of neonatal cholestasis, occurs with estimated frequency of 1 in 8,000 to 15,000 live births. Exact prevalence of PFIC remains unknown, but the estimated incidence varies between 1/50,000 and 1/100,000 births. They exist worldwide with equal sex distribution. As per studies, PFIC represents 10–15% causes of cholestasis in children and 10–15% of liver transplantation indications in children. PFIC1 and PFIC2 represent two-third cases of PFIC, and PFIC3 one-third of cases. Choledochal cyst (CDC), the commonest surgical cause of childhood cholestasis, has an incidence of one in 13,000 to 15,000 births. In Japan, however, it is much more common occurring 1 in 1,000 births. Choledochal cyst for reasons unknown is much more common in females with female male ratios of 3 or 4:1 in most series.

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Alagille syndrome otherwise called paucity of bile ducts is one of the most significant abnormalities of the intralobular bile ducts in children and is essentially a histopathological Table 9.15.1 Etiology of cholestasis in children  

efinition

tiology of holestasis in hildren

Cholestasis is classified as extra or intrahepatic, depending on site of block. It may be acute or chronic. Cholestasis can occur in a wide variety of disorders in childhood (Table 9.15.1). Acute cholestasis can occur due to viral hepatitis (both hepatotropic and non-hepatotropic), drugs, and sepsis; and due to total parenteral nutrition (TPN). Some of the conditions like graft versus host disease and allograft rejection can cause both acute hepatocellular and biliary ductal involvement with cholestasis. Some important causes of childhood cholestasis are discussed below. A

Cholestasis is not a disease, rather, a symptom of many diseases due to a pathologic state of reduced bile formation or flow. Intrahepatic cholestasis, like neonatal hepatitis, inherited and genetic defects of bile formation and secretion like progressive familial intrahepatic cholestasis (PFIC) and extrahepatic biliary obstruction like biliary atresia, choledochal cyst are the most common causes of chronic cholestatic liver disease in children and they form the prime indications for liver transplantation also, in pediatrics.

Cholestasis is defined as the failure of normal bile to reach duodenum due to pathology or block anywhere between the cytoplasm of the hepatocyte and ampulla of Vater. This may occur due to impairment in bile secretion or any condition where there is impediment to bile flow. Clinically, cholestasis is recognized by the presence of jaundice, high colored urine, hypopigmented or frank acholic stools, with or without itching due to retention of pruritogenic substances that are normally excreted in bile. Cholestasis however, is also defined pathologically and morphologically as the accumulation of bile and components of bile in liver cells and biliary passages along with generalized bile acid induced injury in a biopsy. At a biochemical level, cholestasis is defined as any condition in which substances normally excreted into bile are retained in blood. Elevated direct bilirubin is, hence, the usual marker for cholestasis, except in rare inherited syndromes of bilirubin transport defects, like Dubin Johnson and Rotor syndromes, where direct bilirubin may be elevated in blood but not other components of bile.

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Obstructive cholestasis •  Biliary atresia •  Congenital bile duct anomalies – choledochal cysts, stenosis •  Cholelithiasis •  Stricture of common bile duct (CBD) •  Pancreatic pathology with CBD obstruction •  Portal biliopathy •  Biliary ascariasis •  Inspissated bile or mucus •  Hepatolithiasis, Caroli’s disease •  Infectious cholangitis (cholangitis) Cholestasis – Quasi-obstructive causes •  Primary sclerosing cholangitis •  Cholangitis associated with Langerhans cell histiocytosis •  Cholestasis with ductal hypoplasia •  Alagille syndrome – syndromic ductal paucity •  Non-syndromic ductal paucity •  Ductopenic allograft rejection-post-transplant Hepatocellular cholestasis •  Hepatitis (hepatitis A, hepatitis B, hepatitis C, hepatitis E) •  Drug-induced cholestasis •  Progressive familial intrahepatic cholestasis (PFIC) •  Wilson disease •  Indian childhood cirrhosis •  Granulomatous liver disease due to various causes •  Inborn errors of bile acid synthesis •  Total parenteral nutrition – associated cholestasis •  Benign recurrent intrahepatic cholestasis (BRIC) •  Infiltrative diseases like Hodgkin disease, leukemias •  Alpha 1-antitrypsin deficiency

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These are a group of disorders presenting as chronic cholestasis of variable severity, ranging from severe neonatal cholestasis with biliary cirrhosis to benign recurrent cholestasis of youth and adult. Intrahepatic cholestasis of pregnancy too can be due to PFIC. They are all due to molecular level defects in bile transport, based on which they are classified as PFICs type 1, II and III. Type 1, also called PFIC1 (Byler’s disease) was first reported in the Amish community in direct descendants of Jacob Byler and Nancy Kaufmann. It is caused by mutations in the ATP8B1 gene (also designated FIC1 gene) which besides in the hepatocyte, is also expressed in other organs like pancreas, kidney and small intestine. The abnormal protein produced by the mutant gene disturbs bile secretion



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Progressive amilial ntrahepatic holestasis

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Features of chronic cholestasis or chronic liver disease. haracteristic facies: Broad forehead, deep set widely spaced eyes, smaller pointed mandible or chin, flattened malar prominence and prominent ears giving the face a triangular appearance. • ertebral anomalies: Butterfly vertebra. • ardiac anomalies: Usually peripheral pulmonic stenosis. • cular anomalies: Usually posterior embryotoxon. Treatment is directed towards cholestasis and pruritus. Onset of decompensation will require liver transplant. V

• •

especially. ATP dependent aminophospholipid transport across leaflets of biliary canaliculi, resulting in low bile acid concentration in secreted bile. Extrahepatic manifestations include chronic diarrhea, persistent short stature, deafness, and pancreatitis and in some severe forms, increased sweat chloride too, due to faulty expression of the gene in the extrahepatic sites. The multiorgan expression of the disease is one reason why liver transplant is often not curative in this disease. Clinically it can present as neonatal, infantile and childhood cholestasis of variable severity and its mild forme fruste can be present as benign recurrent intermittent cholestasis (BRIC0, intermittent self-limiting cholestasis in adolescents and youth without significant liver damage. Type 2, the second type, called PFIC2, is caused by mutations in the ABCB11 gene (also designated BSEP) which encodes the ATP-dependent canalicular bile salt export pump (BSEP) of human liver and is located on human chromosome 2. Mutations in this protein are responsible for the decreased biliary bile salt secretion described in affected patients, leading to decreased bile flow and accumulation of bile salts inside the hepatocyte with ongoing severe hepatocellular damage, apoptosis and necrosis. This also presents as neonatal hepatitis of variable severity without the extrahepatic manifestations of PFIC1. Both PFIC1 and PFIC2 share similar lab findings of cholestasis and hepatic damage. Low or normal cholesterol and GGTP differentiates PFIC1 and PFIC2 from other causes of cholestasis. PFIC2 often has higher alpha-fetoprotein and transaminases at presentation. Type 3, the third type of PFIC, called PFIC3, is caused by a genetic defect in the ABCB4 gene (also designated MDR3) located on chromosome 7. Class III multidrug resistance (MDR3) P-glycoprotein (P-gp), is a phospholipid translocator involved in biliary phospholipid (phosphatidylcholine) excretion and is predominantly expressed in the canalicular membrane of the hepatocyte. Cholestasis results from the toxicity of bile in which detergent bile salts are not inactivated by phospholipids, leading to bile canalicular, biliary epithelial and hepatocyte injuries. The absence of phospholipids in bile destabilizes the micelles and promotes lithogenicity of bile with crystallization of cholesterol. This favors small bile duct obstruction by calculi and cholangitis, thereby worsening the cholestasis. Unlike PFIC1 and PFIC2, PFIC 3 has elevated gammaglutamyl transpeptidase (GGTP). Cholesterol however stays normal. Clinical presentation again is similar, as neonatal hepatitis of variable severity and relentless progression to biliary cirrhosis of childhood.

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diagnosis. Paucity is said to be present when there is histological evidence of ratio of ducts to portal tracts which is less than 0.5–0.9 ducts to 10 portal triads. That means only one visible functioning bile duct per 10–20 portal ducts on liver biopsy. It is classified as syndromic or non-syndromic type depending on presence or absence of associated anomalies. Alagille syndrome is caused by a mutation in the JAG1 gene on chromosome 20p12a. While paucity of bile ducts and resultant cholestasis is a basic feature, it is a multisystem developmental disorder also characterized by cardiac, musculoskeletal, ocular, facial, renal and neurodevelopmental abnormalities. Alagille non-syndromic type can present as: • Neonatal cholestasis • Chronic childhood cholestasis – jaundice or HCU or pruritus • Hepatosplenomegaly • Chronic liver disease, portal hypertension and/or frank cirrhosis. Non-syndromic types without associated abnormalities tend to have a chronic course, often going on to adulthood. Frank cirrhosis and decompensation are rare in childhood. In the absence of associated abnormalities, diagnosis depends entirely on demonstration of reduced bile ducts on liver biopsy. Alagille syndromic type is characterized by:

Choledochal cysts are congenital bile duct anomalies. These cystic dilatations of the biliary tree can involve the extrahepatic biliary radicles, the intrahepatic biliary radicles, or both. The exact pathogenesis is unknown and probably multifactorial. Defects in epithelialization and recanalization of the developing bile ducts and congenital weakness of 575

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Ultrasonography is the most useful study to diagnose a CDC. The cystic dilatation can be easily visualized. Intrahepatic biliary radicular dilatation is however rare in CDC. Magnetic resonance cholangiopancreatography (MRCP) is currently the investigation of choice to study the extent of intra and extrahepatic biliary involvement and in classification of the cyst. Surgical excision of the cyst with Roux-en-Y hepaticojejunostomy gives excellent long-term results. Long-term follow-up is essential particularly after cysto-enterostomy as there is continued risk of recurrent cholangitis, lithiasis, pancreatitis and possible cholangiocarcinoma. C

Gallstones and holedocholithiasis





Gallbladder (GB) calculi are relatively uncommon in children, but its incidence has dramatically increased following widespread use of USG which picks up silent stones. Most gallstones picked up these days are in children where no pathology can be made out to explain the stones. The extensive use of ceftriaxone (which crystalizes in bile) in pediatric practice has contributed significantly to this increase incidence of GB stones in the absence of any GB pathology. Cholelithiasis in the first years of life needs evaluation for: • Congenital malformation of bile ducts • Hemolytic disease • Lipid abnormalities • Chronic liver disease Other predisposing factors include obesity, trauma, intra-abdominal sepsis, and prolonged immobilization. Pigment stones are generally more common in children. Most GB stones stay asymptomatic. Less than 5% are present with complications secondary to CBD or pancreatic ductal obstruction. Treatment would include long-term ursodeoxycholic acid (UDCA), endotherapy for obstructing stones and elective cholecystectomy if stones persist into adolescence.





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the ductal wall have been implicated in causation of cystic dilatations. Anomalous junction between the common bile duct (CBD) and the pancreatic duct, where the pancreatic duct joins more than 1 cm proximal to ampulla can be demonstrated in many of these children with CDC. Such abnormal union allows efflux of pancreatic secretions into CBD, where, the proenzymes, activated by the bile, could damage bile duct wall predisposing to dilatation and cyst formation. Todani classified CDC into five different types, way back in 1977, and that classification is still followed with few modifications (Fig. 9.15.1). • Type I is the commonest (80–90%). It is a fusiform dilation of a portion or whole of CBD. Intrahepatic ducts however, are normal. • Type II is a diverticulum that projects out of CBD; enlarges and eventually compresses the CBD. • Type III, otherwise called choledochocele, is a dilatation of intraduodenal portion of CBD at the point where pancreatic duct joins CBD. • Type IV has multiple focal dilatations of the intrahepatic and extrahepatic biliary tree. • Type V has focal dilatation of intrahepatic biliary system alone and is called Caroli’s disease. Most patients with CDCs are diagnosed during infancy or childhood, although the condition may be discovered at any age. Approximately 67% of patients present with signs or symptoms referable to the cyst before the age of 10 years. Clinical features vary according to age. When it is symptomatic in neonatal period (<5%), it presents like neonatal hepatitis/biliary atresia. The classical clinical picture of jaundice with abdominal pain and lump at the right hypochondrium is seen, hardly in 15–20% of cases. Most however have at least two of the three above signs. Presentation can also be as pancreatitis, cholangitis, and perforation of bile duct and rarely as biliary cirrhosis with portal hypertension.

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Portal iliopathy

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Figure 9.15.1 Classification of choledochal cysts.,   Courtesy: Dr Frank Gaillard, Royal Melbourne Hospital, Australia  

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Portal biliopathy is a rare but serious complication of portal hypertension of any cause, but commonly due to portal venous thrombosis, which results in development of varices around the gallbladder and CBD, where they cause pressure obstruction, strictures and rarely stones in CBD. Any icterus in extrahepatic portal venous obstruction (EHPVO) should raise suspicion of portal biliopathy, though it is very uncommon below 10 years of age. Diagnosis is by biochemistry confirming cholestasis, and Ultrasound. Ultrasonogram, especially color Doppler flow imaging, can visualize the varices around the GB and CBD well. Doubtful cases can be confirmed by MRCP. Treatment would be endoscopic retrograde cholangio pancreatography (ERCP) with stent placement, balloon dilatation of strictures, stone removal, if present, and in intractable cases, decompression surgery for portal hypertension (PHT) and hepaticojejunostomy.

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Ultrasonography of liver and bile ducts is useful to detect causes of obstructive cholestasis like CDC, CBD stones, Caroli’s disease and pancreatic causes of biliary obstruction. Associated renal anomalies might be picked up by USG, like polycystic kidneys (congenital hepatic fibrosis, Caroli’s disease), single kidneys, and ureteric duplication (Alagille disease). Color flow and Doppler USG picks up varices around gall bladder and CBD in portal biliopathy well. Abdominal CT, ERCP or MRCP scan, endo USG, if USG findings are equivocal.

Liver Biopsy

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Histopathological evidence of cholestasis: • Biliary duplication • Bile within hepatocytes/canaliculi • Cholate induced hepatocellular injury • Paucity of bile ducts in Alagille syndrome • Relatively bland picture in PFIC1 • Giant cell hepatitis.

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Increased serum direct bilirubin levels. Increased total serum bile salt concentration. Increased total serum cholesterol level (except PFIC 1 and 2). Increased serum lipoprotein-X, GGTP, serum alkaline phosphatase, 5’ nucleotidase. Patients with PFIC1 and PFIC2 however, have normal serum GGTP activity. It is usually elevated in PFIC3. Increased fecal fat levels in virtually all cholestatic diseases. Screening for viral markers, especially hepatitis B, A and E, might be needed in short duration cholestasis. Rarely, one might have to consider Mantoux, chest X-ray, HIV serology and investigations for other granulomatous conditions like sarcoidosis, granulomatous disease, etc.

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Treatment of cholestasis is disease specific but many do not respond well to therapy of any sort. In many, symptomatic treatment is all that medicine can offer, short of transplant.

Methods to Improve Bile Flow/Remove Toxic Bile Acids •

Ursodeoxycholic acid (20–30 mg/kg/d), to increases bile salt dependent bile formation and antagonize the effect of hydrophobic toxic bile acids in PFICs.

Flow chart 9.15.1 Complications of cholestasis.  

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Patients with cholestasis may present clinically in many different ways depending on the disease process. • Scleral icterus and high colored urine. • Pruritus: Many conditions like Alagille have significant pruritus before icterus becomes obvious. • Xanthomas and xanthalasmas. • Maldigestion, malabsorption steatorrhea and failure to thrive due to low bile salt levels in intestinal lumen. • Increase of copper in blood. • In acute obstructive causes, the child can present with classic Charcot’s triad of fever, severe abdominal pain and jaundice. • Long-standing cholestasis results in chronic liver disease-biliary cirrhosis (Flow chart 9.15.1).

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Selenium 1–2 mg/kg/day. Zinc 1 mg/kg/day, zinc sulfate, orally. Water soluble vitamins—two times recommended dietary allowance (RDA).

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Treatment of Pruritus

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• Cholestasis is not uncommon problem in childhood. • Choledochal cyst and cases of neonatal hepatitis growing into childhood with the cholestasis are the common causes. • Alagille disease, PFICs and other biliary blocks are other interesting causes of cholestasis in childhood. • Diagnostic modalities have improved considerably last decade with USG, MRCP and biopsy clarifying the cause of cholestasis very well. • Treatment modalities have not kept pace with diagnostic facilities and many childhood medical causes of cholestasis are still not curable. • Advent of liver transplant has revolutionized the outlook for untreatable causes of cholestasis.

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1. Reduce the bile acid pool in the body by: • Decreased ileal reabsorption of excreted bile acids using binding resins like cholestyramine 240 mg/ kg/day or celestipol 500 mg/kg/day. • Increased bile acid excretion using UDCA, pheno­ barbitone, and rifampicin (10 mg/kg/day). 2. Reduce irritation of peripheral nerve endings by pruri togenic factors in bile using • Sedative antihistamines (Diphenhydramine 5 mg/ kg/day, hydroxyzine 2 mg/kg/day) and short course steroids. 3. Decrease propulsion of itch impulses through nerves to CNS using • Opiate antagonists like naltrexone at a dose of 0.25–0.5 mg/kg. • Antiserotonin drugs like ondansetron and its analogs. • Nonspecific neural transmission suppressants like carbamazepine. 4. Central depressants like propofol given as slow subcutaneous infusions can be used in intractable pruritus. Plasmapheresis and biliary diversion are used as last resorts. 5. Liver transplant is of course curative in pruritus.

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Phenobarbitone (5 mg/kg/d) to improve bile salt inde pendent bile flow. Biliary diversion, ileal diversion to remove toxic bile acids in PFIC.

ibliography

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Increased carbohydrate and protein intake. Replace fat with medium-chain triglycerides (MCT) oil or coconut oil with added essential fatty acid (EFA). Parenteral fat soluble vitamin A, K, D periodically or additional oral supplementation. Water soluble vitamin E orally (Tocopherol polyethylene glycol succinate). Calcium 50–100 mg/kg/day, orally. Phosphorus 25–50 mg/kg/day. Iron 3–5 mg/kg/day.



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Nutrition in Cholestasis

1. Cies JJ, Giamalis JN. Treatment of cholestatic pruritus in children. Am J Health-Syst Pharm. 2007;64:1157-62. 2. Davit-Spraul A, Gonzales E, Baussan C, et al. Progressive familial intrahepatic cholestasis. Orphanet J Rare Dis. 2009;4:1. 3. Dhiman RK, Puri P, Chawla Y, et al. Biliary changes in extrahepatic portal venous obstruction: compression by collaterals or ischemic? Gastrointest Endosc. 1999;50:646-52. 4. Kamath BM, Loomes KM, Piccoli DA. Medical Management of Alagille Syndrome. J Pediatr Gastroenterol Nutr. 2010;50:5806. 5. McEvoy CF, Suchy FJ. Biliary tract disease in children. Pediatr Clin North Am. 1996; 43:75-98. 6. Sarin SK, Bhatia V, Makwane U. Portal biliopathy in extrahepatic portal vein obstruction. Indian J Gastroenterol. 1992;2:A82. 7. Tomer G, Shneider BL. Disorders of bile formation and biliary transport. Gastroenterol Clin North Am. 2003;32:839-55.





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tiology

Etiology varies with the age of presentation (Table 9.16.1). The most common causes in neonates and infants are

 

Table 9.16.1 Etiology of fulminant hepatic failure Septicemia Inborn errors of metabolism Tyrosinemia Galactosemia Hemochromatosis Hereditary fructose intolerance Mitochondrial disorders Severe birth asphyxia Perinatal Herpes simplex infection Hemophagocytic lymphohistiocytosis

Viral hepatitis A, B, B + D, E Parvovirus, Adenovirus Herpes simplex Hepatotoxic drugs* Shock, Ischemic hepatitis@ Hematological malignancy Hodgkin’s lymphoma Leukemic infiltrates Autoimmune hepatitis type 2 Wilson disease Inborn errors of metabolism Infections# Industrial poisons        

       

 

Older children

 

Neonates and infants

 

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The Pediatric Acute Liver Failure Study Group proposed the following criteria: • Hepatic coagulopathy not corrected by parenteral administration of vitamin K. • No history of known liver disease. • Prothrombin time (PT) 15–19.9 seconds/INR 1.5–1.9 with encephalopathy; or PT ≥ 20 seconds/INR ≥ 2 without encephalopathy. Hepatic encephalopathy is a state of disturbed neurological function associated with liver disease. Unlike in adults where encephalopathy is central it may be absent, late or unrecognized especially in neonates and infants. Based on the gap between the onset of jaundice and noticing of encephalopathy, O’Grady et al. proposed three subcategories of FHF. FHF is generally described as the development of encephalopathy: • Hyperacute liver failure: Gap is less than 7 days, risk of rapid development of coma but outcome of survival is better. • cute liver failure: Gap is between 7 days and 28 days. Risk of cerebral edema, poor prognosis is without a liver transplantation. • ubacute hepatic failure: Gap is between 4 weeks and 24 weeks. Least incidence of cerebral edema and prognosis is worst. Ascites is an important presentation. • In certain conditions there may be acute decompensation of the diseased liver. This is known as acute on chronic liver failure, e.g. Acute viral hepatitis (AVH) with Wilson disease (WD).

Fulminant hepatic failure is characterized by marked splanchnic and systemic arteriolar vasodilatation along with hyperdynamic circulation and low arteriovenous oxygen content difference. Tissue hypoxia develops despite adequate arterial oxygen and this contributes to the development of multiorgan failure and is a marker of poor prognosis. • Microcirculatory plugging is caused by formation of microthrombi as a consequence of activation and consumption of platelets along with the increased adhesion of leukocytes to the endothelial wall. Increased activity of cGMP results in vasodilatation. • Encephalopathy results from the accumulation of nonmetabolized ammonia, mercaptans, fatty acids and GABA. Production of false neurotransmitters is enhanced due to decreased aromatic and branched chain amino acids in the blood. The cerebral metabolism is altered. • Renal failure of various degrees occurs in FHF patients. Hypovolemia caused by vasodilatation, microcirculatory disturbance and acute tubular necrosis are important contributing factors. • Rapid deterioration in nutritional status with depletion of muscle and fat stores often occurs as a consequence of impaired gluconeogenesis and impaired glycogen

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Definition

Pathophysiology

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Fulminant hepatic failure (FHF) is one of the leading causes of death in hospitalized children in India. It presents acutely, in previously healthy children and progresses rapidly despite the updated protocol of treatment of FHF. Viral hepatitis A and E are common causes of FHF in the developing world. In one study, nearly 50% of all cases of FHF were due to HAV and dual infection (HAV and HEV) was 60% of FHF. About 50% of children qualified for a liver transplant; some had to undergo emergency living donor related liver transplantation. Timely selection of patients with FHF satisfying King’s College criteria using split liver-live donor liver transplantation by eminent teams in several new centers in India show gratifying results.

metabolic liver disease, septicemia, viral infections especially herpes simplex 1, 2 and neonatal hemochromatosis. In children older than 1 year viral hepatitis (most common hepatitis A), drugs, systemic infection and unknown causes are the most common etiologies.

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* Valproic acid, INH, paracetamol, halothane, phenytoin, ketoconazole, carbamazepine, cyclophosphamide, methotrexate, NSAIDs, anti-retroviral drugs, herbal drugs. @ Budd Chiari syndrome, portal vein thrombosis, hepatic veno-occlusive disease. # CMV, Herpes, EBV, leptospira, dengue, typhoid, malaria.

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Fulminant hepatic failure affects previously healthy children with no recognized risk factors for liver disease. Children usually present with hepatitis and worsening of symptoms over a period of several days or weeks. Jaundice is the presenting symptom in most of the children and its day of onset should be noted. A prodrome of flu-like illness may precede jaundice. Fever, anorexia, vomiting, abdominal pain and fetor hepaticus are common. Altered consciousness and mental changes present later. Infants initially may present with poor feeding, irritability and disturbances in sleep rhythm. Hemorrhagic diathesis and ascites may develop later. A detailed history of mental changes, easy bruising, seizures, decreased urine output, contact with infections, injections, blood transfusion, drug intake and family history of WD or autoimmune diseases should be elicited. For neonates and infants presenting with FHF an additional history of developmental delay, consanguinity, perinatal or antenatal infections and neonatal deaths should be sought. Initial physical assessment should include growth, development and nutrition parameters, signs of chronic liver disease, liver and splenic span, ascites, and signs of

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nvestigations Serum bilirubin, ALT, AST, and PT should be performed to assess liver cell injury. PT ≥15 seconds and INR ≥ 1.5 which is not corrected by parenteral vitamin K in 6 hours along with the biochemical evidence of liver injury indicates liver failure. Laboratory monitoring should include charged body potential (CBP), electrolytes, renal function tests, blood glucose, phosphorus, serum ammonia, lactate, arterial blood gas, coagulation profile, and blood culture for infection screening. Specific laboratory screening to identify the cause of FHF based on age of the child should be initiated simultaneously as early treatment results in better recovery. Serum copper, viral serology, autoimmune markers and metabolic screen should be performed as an initial etiology screen.

anagement

Management in an intensive care is mandatory for all patients with more than grade I encephalopathy. Nursing in quiet environment is essential. Barrier nursing should be practised. Specific therapies where treatable etiologies can be identified needs to initiated early. Treatment is supportive but specific for multi-organ dysfunction (Table 9.16.3). Orthotopic liver transplant using whole, split or auxiliary liver from either cadaver or living related donors has shown promising results and is indicated when there is acute deterioration in mental status, stage 3/4 encephalopathy, PT ≥100 sec/INR ≥ 6.5, serum bilirubin ≥17.4 mg/dL, worsening lactic acidosis, HRS or the disease is irreversible (WD, FHF).

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•

coagulopathy, urine output and circulatory adequacy. Neurological assessment for grading of encephalopathy (Table 9.16.2) should be done several times a day. Complications are often encountered in association with grade III and IV encephalopathy. They include cerebral edema, convulsions, hypoglycemia, hypophosphatemia, dyselectrolytemia, metabolic acidosis, hypotension, sepsis, gastrointestinal bleeding, coagulopathy, hepatorenal syndrome (HRS) and multiorgan failure. I

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storage. Hypoglycemia, hypophosphatemia and hypo magnesemia are common. Metabolic acidosis is relatively frequent due to tissue hypoxia, increased peripheral lactate production and renal failure. Reduced hepatic synthesis of clotting factors, increased consumption of clotting factors and platelets contribute to the coagulopathy associated with FHF. Children with FHF are susceptible to infections as a consequence of impaired neutrophils and Kupffer cell phagocytic function with reduced complement levels. Induced bacterial changes in the gut flora may also contribute to this. The common infections that occur are pneumonia, septicemia, urinary tract infections and spontaneous bacterial peritonitis (SBP). A vicious cycle of endotoxemia, circulatory collapse, tissue hypoxia, increased bacteria translocation and leaky intestinal mucosa contribute to multiorgan failure.

Table 9.16.2 Grades of hepatic encephalopathy

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Grades of encephalopathy

Mental status

Behavior

Motor activity

Tone and reflexes

Response to pain

Pupils

Grade I

Alert oriented

Restless, irritable, csonfusion

Incoordination, tremor

Normal

Obeys

Normal

Grade II

Lethargic Confused Irritated

Combative euphoric

Yawning Grimacing Intention tremor

Increased tone, brisk reflexes

Localizes

hyperactive

Grade III

Stupor Arousable

Sleeps all times, Decreased motor marked confusion activity, marked intention tremor

Up planters, clonus

Flexes

Hippus

Grade IV

Not arousable

Unconscious

Sustained clonus

Extends

Dilated, sluggish

Absent

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Colloid, dopamine/dobutamine infusions Avoid fluid overload. Phosphate, magnesium and potassium supplementation

Prevention of stress ulcer

H2 blocker, sucralfate

Sedation

Propofol

Optimize oxygen delivery

Oxygen, N-acetyl cysteine and prostaglandin E1 infusions

Coagulopathy

FFP in active hemorrhage Recombinant factor VIIa if unresponsive bleed: 5–10 µg/kg Packed cell transfusion in hemodynamically destabilizing anemia Platelet concentrate when platelet count becomes less than 20,000 Plasmapheresis

Prevention and correction of hypoglycemia

10–20% dextrose

Prevention of hepatic encephalopathy (Decrease ammonia)

Dietary protein restriction 0.5–1 g/kg/day Lactulose 1 mg/kg/6 hourly till three loose motions per day Sodium benzoate 0.25 g/day

Cerebral edema

Monitor ICP (Subdural transducer or repetitive trans cranial Doppler examination): keep less than 20–25 mm Hg pressure Quiet environment, 30° head elevation, pyrexia control, sedation 20% mannitol infusion Elective ventilation Induction hypernatremia (145–155 mEq/L) by 30% NaCl Induction of hypothermia (Core body temperature 32–33°C)

Subclinical or clinical seizures

Phenytoin infusion, thiopental infusion

Diet

Enteral nutrition/TPN High calorie 30–50 Kcal/kg, 50% non-protein calories High carbohydrate, protein restriction Vegetable protein preferred

Prevention and treatment of infections

IV line care, infection surveillance Prophylactic antibiotics, anti-fungal where indicated

Renal failure

Maintain intravascular volume and pressure Dialysis in established failure

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Prognosis depends upon the underlying cause. Various criteria have been established to prognosticate FHF. Some of the indicators for poor prognosis are INR more than 4, factor V concentration less than 25%, lactic acidosis, hyperphosphatemia, grade 4 encephalopathy, HRS, children less than 2 years of age and WD. The overall mortality exceeds 60%.

1. Arya R, Gulati S, Deopujari S. Management of encephalopathy in children. Post Grad Med J. 2010;86:34-41. 2. Bhatia V, Lodha R. Intensive care management of children with acute liver failure. Indian J Pediatr. 2010;77:1288-95. 3. Cochran JB, Losek JD. Acute liver failure in children. Pediatr Emergency Care. 2007;23(2):129-35. 4. Dhawan A. Etiology and prognosis of acute liver failure in children. Liver Transplantation. 2008;14:S80-4. 5. Faraz W, Dar F, Bartlett A, et al. Auxiliary liver transplantation for acute liver failure in children. Ann Surg. 2010;251:351-6. 6. Pareja E, Cortes M, Bonora A, et al. New alternatives to the treatment of acute liver failure. Transplant Proc. 2010;42:2959-61. 7. Poddar U, Thapa BR, Prasad A, et al. Natural history and risk factors in fulminant hepatic failure. Arch Dis Child. 2002;93:48-51. 8. Shanmugam NP, Bansal S, Greenough A, et al. Neonatal liver failure: aetiologies and management – state of the art. Eur J Pediatr. 2011;170:573-81.



Prognosis

ibliography





Extracorporeal liver assist systems have been developed as a bridge till the native liver regenerates or transplantation is possible. MARS (molecular adsorbent recirculating system) involves usage of albumin-resin dialysate to remove protein bound and low molecular toxins. A single pass albumin dialysis (SPAD) has also been developed. Newer modalities undergoing research are hepatocyte transplantation into portal vein and alginate encapsulated hepatocyte intraperitoneal transfusion.

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Table 9.16.3 Supportive therapy in fulminant hepatic failure

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scites

efinition

Pathophysiology

Ascites is of Greek derivation (askhos) which refers to a ‘bag’ or ‘sack’. The word describes pathologic fluid accumulation within the peritoneal cavity (Fig. 9.17.1).

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Inside the abdomen there is a membrane called the peritoneum which has two layers. One layer lines the abdominal wall and the other layer covers the organs inside the abdominal cavity. The peritoneum produces a fluid that acts as a lubricant and allows the abdominal organs to glide smoothly over one another. Sometimes an excess of this fluid can build up between the two layers and this is called ascites. The accumulation of fluid in the abdominal cavity can be associated with portal hypertension. This means there is an increased blood pressure in the veins draining the liver. The higher pressure can be caused by liver damage. It can also be caused by impaired drainage in the lymph system. This system takes excess fluid and particles away from the liver. Low levels of albumin and other proteins in the blood also contribute to ascites. The force that holds plasma water within the blood vessels is reduced. Plasma water is lost into the abdominal cavity. Albumin in the ascitic fluid pulls yet more fluid across into this cavity. Blood flow to the kidneys might be reduced. This leads to increased secretion of aldosterone. This causes the kidneys to retain salt and water. Urinary output is decreased, and fluid is retained. In some cases, kidney disease contributes to impaired elimination of salt and water. Fluid may leak from capillaries, the pancreas, or the lymph system. Capillary fluid leakage can be caused by inflammation or infection.





ackground

The accumulation of ascitic fluid represents a state of totalbody sodium and water excess, but the event that initiates the unbalance is unclear. Three theories of ascites formation have been proposed. 1. Under filling theory: This suggests that the primary abnormality is inappropriate sequestration of fluid within the splanchnic vascular bed due to portal hypertension and a consequent decrease in effective circulating blood volume. This activates the plasma renin, aldosterone, and sympathetic nervous system, resulting in renal sodium and water retention. 2. verflow theory: This suggests that the primary abnor mality is inappropriate renal retention of sodium and water in the absence of volume depletion. This theory was developed in accordance with the observation that patients with cirrhosis have intravascular hypervolemia rather than hypovolemia. 3. Peripheral arterial vasodilatation hypothesis: This includes components of both of the other theories. It suggests that portal hypertension leads to vasodi latation, which causes decreased effective arterial blood volume. As the natural history of the disease progresses, neurohumoral excitation increases, more renal sodium is retained, and plasma volume expands. This leads to overflow of fluid into the peritoneal cavity. According to the vasodilatation theory, the under filling theory is proposed to be operative early and the overflow theory is proposed to be operative late in the natural history of cirrhosis (Flow chart 9.17.1). Although the sequence of events that occurs between the development of portal hypertension and renal sodium retention is not entirely clear, portal hypertension apparently leads to an increase in nitric oxide levels. Nitric oxide mediates splanchnic and peripheral vasodilatation. Patients with ascites have greater hepatic artery nitric oxide synthase activity compared to patients without ascites. Regardless of the initiating event, a number of factors contribute to the accumulation of fluid in the abdominal cavity. Elevated levels of epinephrine and nor epinephrine are well-documented factors. Hypoalbuminemia and reduced plasma oncotic pressure favor the extravasation of fluid from the plasma to the peritoneal fluid, and, thus, ascites is infrequent in patients with cirrhosis unless both portal hypertension and hypoalbuminemia are present. If the liver is damaged, it may produce less blood protein. This may upset the body’s fluid balance which causes fluid to build up in the body tissues, including the abdomen. Cancer cells can block the lymphatic system. The lymphatic system is a network of fine channels, which

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Figure 9.17.1 Child with ascites

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Flow chart 9.17.1 Pathophysiology of ascites  

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Cardiovascular (20% cases) (failure or poor output) a. Rhythm disturbances: Heart block, auricular tachy cardia b. Cardiac malformation: Hypoplastic left heart, Ebstein’s disease Hematological disorders (10% cases) (Chronic in utero anemia): Isoimmune hemolytic disease, homozygous alpha thalassemia

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Ascites in the newborn (Fig. 9.17.2) can be grouped as: I. Associated with hydrops II. Isolated ascites III. Ascites due to peritonitis

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Increased hydrostatic pressure Cirrhosis (Flow chart 9.17.2) Hepatic vein occlusion (Budd-Chiari syndrome) Inferior vena cava obstruction Constrictive pericarditis Congestive heart failure Decreased colloid osmotic pressure End-stage liver disease with poor protein synthesis Nephrotic syndrome with protein loss Malnutrition Protein-losing enteropathy Increased permeability of peritoneal capillaries Tuberculous peritonitis Bacterial peritonitis Malignant disease of the peritoneum Leakage of fluid into the peritoneal cavity Bile ascites Pancreatic ascites (secondary to a leaking pseudocyst) Chylous ascites Urine ascites Miscellaneous causes Myxedema Ovarian disease (Meigs’ syndrome) Chronic hemodialysis

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Table 9.17.1 Pathogenic mechanisms in ascites formation

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runs throughout the body. One of its functions is to drain off excess fluid, which is eventually got rid of in the urine. If some of these channels are blocked, the system cannot drain efficiently and fluid can build up. The pathophysiologic mechanisms of ascites is shown in Table 9.17.1.

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Flow chart 9.17.2 Ascites formation in cirrhosis

 

Figure 9.17.2 Ascites in neonate

•

Chromosomal (10% cases): Turner syndrome, trisomy 13, 18 and 21 Infection (8% cases): TORCH group, syphilis Renal (5% cases): Nephrosis, posterior urethral valve Pulmonary (5% cases): Diaphragmatic hernia. Gastrointestinal (5% cases): Atresia Maternal conditions (5% cases): Toxemia, diabetes Placenta or cord (rare): Cord compression, chorangioma Miscellaneous (10% cases): Wilms’ tumors, neuroblastoma Storage disease: Mucopolysaccharidosis VIII Skeletal abnormalities: Osteogenesis imperfecta, achondrogenesis Cirrhosis: a-1 antitrypsin deficiency Liver failure: Neonatal hemochromatosis Unknown (20% cases).

• • • • • • • • •

solated scites A

I

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Chylous: Congenital anomaly of lymphatic channels Biliary: Spontaneous perforation of biliary tree Pancreatic duct anomaly.

Figure 9.17.3 Ascites with portal hypertension showing dilated veins  

• • •

Peritonitis Chemical: Bile, meconium Bacterial.



b. Hepatocellular disease: Autoimmune hepatitis, hepatitis B,C, Wilson’s disease, antitrypsin deficiency. c. Toxins: Ethanol, methotrexate, 6-mercaptopurine. d. Miscellaneous: Histiocytosis X, schistosomiasis.

tiology in hildren ssociated with Portal Hypertension ( ig. 9.17.3) F

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Tuberculosis, heart failure, nephrotic syndrome, pancreatitis, chlamydial infection and rheumatoid arthritis. A

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tiology of cute scites

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xtrahepatic disorders: Venous obstruction—Splenic vein thrombosis, portal vein thrombosis/cavernous transformation, Budd-Chiari syndrome, inferior vena cava obstruction. iscellaneous: CHF, AV fistulae 2. ntrahepatic disorders: a. Biliary tract disease: EHBA, cystic fibrosis, choledochal cyst, sclerosing cholangitis, intrahepatic cholestasis 584 syndromes. 1.

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Venous obstruction: Budd-Chiari syndrome, portal vein thrombosis, inferior vena cava obstruction, splenic vein thrombosis, veno-occlusive disease of liver.

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Infections – Bacterial peritonitis – Tuberculous peritonitis – Fungal peritonitis – HIV-associated peritonitis Malignant conditions – Peritoneal carcinomatosis – Primary mesothelioma – Pseudomyxoma peritonei – Hepatocellular carcinoma Other rare conditions – Familial Mediterranean fever – Vasculitis – Granulomatous peritonitis – Eosinophilic peritonitis.

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Ascites needs to be differentiated from abdominal distension due to other causes like gross obesity, gaseous distention, bowel obstruction, abdominal cysts or masses. The clinical manifestations of ascites can vary from an asymptomatic patient to patients complaining of increased abdominal girth, early satiety, and respiratory distress depending on the amount of fluid accumulated in the abdominal cavity. Flank dullness which is present in about 90% of patients, is the most sensitive physical sign. Per abdomen: Increasing weight and abdominal girth (if previous values are available), shifting dullness (Puddle sign), fluid thrill, peritoneal tap (Table 9.17.2). Elicitation of increased flank dullness to percussion with patient supine and shifting dullness (> 1500 m free fluid). The physical examination should focus on the signs of portal hypertension and chronic liver disease. Liver is examined to see if it is enlarged or tender. The liver may be difficult to palpate if a large amount of ascites is present (Table 9.17.3).

–

– –

–

–

–

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onitoring

Simple assessment of the progress of ascites may be made by serial measurements of the abdominal girth. The tape measure must be placed in the same position each time. Serial measurement of weight also indicates fluid gain or loss. This tends to be much faster than gain or loss of fat or lean body mass.

 

Table 9.17.2 Grading of ascites Grade

Severity

Signs

I

Mild

Puddle sign (+) Detected by ultrasound abdomen

II

Moderate

Shifting dullness (+) No fluid thrill

III

Tense

Fluid thrill (+) Respiratory difficulty (+)

–

–

–

–

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–

–

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iseased Peritoneum (

SAA

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–

–

–

•

xamination



•

l

–

l

Portal hypertension (serum-ascites albumin gradient [SAAG] > 1.1 g/d ) – Hepatic congestion, congestive heart failure, constrictive pericarditis, tricuspid insufficiency, Budd-Chiari syndrome Liver disease, cirrhosis, alcoholic hepatitis, fulminant hepatic failure, massive hepatic metastasis Hypoalbuminemia (SAAG < 1.1 g/d ) – Nephrotic syndrome – Protein-losing enteropathy – Severe malnutrition with anasarca Miscellaneous conditions (SAAG < 1.1 g/d ) – Chylous ascites – Pancreatic ascites – Bile ascites – Nephrogenic ascites – Ovarian disease.

L

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•

ormal Peritoneum

Tattoos Habitation or origination from an area endemic for hepatitis. Patients with a history of cancer, especially gastrointestinal cancer, are at risk for malignant ascites. Malignancy-related ascites is frequently painful, whereas cirrhotic ascites is usually painless.





E

tiology of scites in eference to ormal and/or iseased Peritoneum

• •

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ii. Peritonitis: Spontaneous perforation of bile duct iii. Fulminant hepatic failure.

Presentation History

• • • •

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isk actors for iver iseases F

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Chronic viral hepatitis or jaundice Intravenous drug use Sexual promiscuity Transfusions: Hepatitis C has been linked to transfusions

Table 9.17.3 Staging of ascites  

Most cases of ascites are due to liver disease or due to some precipitating factors deteriorating liver functions, e.g. drugs (NSAIDs). History of abdominal distention, increasing weight, respiratory embarrassment, associated pedal edema.

Stage

Signs

1+

Detectable only after careful examination

2+

Easily detectable but of relatively small volume

3+

Obvious ascites but not tense ascites

4+

Tense ascites

585

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Confirming the presence of ascites Finding the cause for the ascites Assessing any complication due to the ascites.

•

B

lood Tests

Complete blood counts Complete urine examination Liver function tests including plasma proteins Clotting screen, especially if invasive investigations are considered. White cell count: Normal ascitic fluid contains fewer than 500 leukocytes/m and fewer than 250 polymorphonuclear leukocytes/m . Any inflammatory condition can cause an elevated white blood cell count. White cell count when greater than 350/microliter is suggestive of infection. A neutrophil count of more than 250 cells/m is highly suggestive of bacterial peritonitis. In tuberculous peritonitis and peritoneal carcinomatosis, a predominance of lymphocytes usually occurs. If most cells are polymorphonuclear, bacterial infection should be suspected. When mononuclear cells predominated, tuberculosis or fungal infection is likely. This is the single most useful test. Only recent trauma gives false results. To correct this, one polymorphonuclear leukocyte (PMN) is subtracted from absolute ascitic fluid PMN count for every 250 RBC. In old trauma, PMN will have lysed so no correction is needed. ed cell count: When greater than 50,000/microliter denotes hemorrhagic ascites, which usually is due to malignancy, tuberculosis or trauma.

•

586

S

maging tudies hest and plain abdominal films: Elevation of the diaphragm, with or without sympathetic pleural effusions (hepatic hydrothorax), is visible in the presence C

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• •

 

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• • •

MRI

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nvestigations

 



of massive ascites. More than 500 mL of fluid is usually required for ascites to be diagnosed based on findings from abdominal films. Many nonspecific signs indicate ascites, such as diffuse abdominal haziness, bulging of the flanks, indistinct psoas margins, poor definition of the intraabdominal organs, erect position density increase, separation of small bowel loops, and centralization of floating gas containing small bowel. The direct signs are more reliable and specific. In 80% of patients with ascites, the lateral liver edge is medially displaced from the thoracoabdominal wall (Hellmer sign). Obliteration of the hepatic angle is visible in 80% of healthy patients. In the pelvis, fluid accumulates in the rectovesical pouch and then spills into the paravesical fossa. The fluid produces symmetric densities on both sides of the bladder, which is termed a “dog’s ear” or “Mickey Mouse” appearance. Medial displacement of the cecum and ascending colon and lateral displacement of the properitoneal fat line are present in more than 90% of patients with significant ascites. Ultrasound: Abdominal ultrasound can be used to detect ascites in morbidly obese, to indicate appropriate site for paracentesis, in patients with multiple abdominal surgical scars and with serum alphafetoprotein, to detect hepatic malignancy. It can detect as little as 100 mL of fluid in the peritoneal cavity. Uncomplicated ascites appears as a homogenous, freely mobile, anechoic collection in the peritoneal cavity that demonstrates deep acoustic enhancement. Free ascites does not displace organs but typically situates itself between them, contouring to organ margins and demonstrating acute angles at the point at which the fluid borders the organ. The smallest amounts of fluid first tend to collect in the Morison pouch and around the liver as a sonolucent band. With massive ascites, the small bowel loops have a characteristic polycyclic, “lollipop,” or arcuate appearance because they are arrayed on either side of the vertically floating mesentery. Certain sonographic findings suggest that the ascites may be infected, inflammatory, or malignant. Findings include coarse internal echoes (blood), fine internal echoes (chyle), multiple septa (tuberculous peritonitis, pseudomyxoma peritonei), loculation or atypical fluid distribution, matting or clumping of bowel loops, and thickening of interfaces between fluid and adjacent structures. In malignant ascites, the bowel loops do not float freely but may be tethered along the posterior abdominal wall plastered to the liver or other organs or they may be surrounded by loculated fluid collections. Upper gastrointestinal endoscopy: To confirm esopha geal/fundal varices. T and : Ascites is demonstrated well on CT scan images. Small amounts of ascitic fluid localize in the right perihepatic space, the posterior subhepatic space (Morison pouch), and the Douglas pouch. A number of C

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eck: Check for jugular venous distention. Heart: Check for tricuspid murmur or signs of heart disease. ungs: Examine for signs of fluid (heart failure). kin: May show cutaneous spider angiomas, palmar erythema, Dupuytren’s contracture, or large veins on the abdomen. sterixis may be present, ascitis may be part of generalized edema. Patients with cardiac disease or nephrotic syndrome may have anasarca. ymph nodes: For enlargement. A pathologic left-sided supraclavicular node (Virchows node) suggests the presence of upper abdominal malignancy. The puddle sign indicates that as little as 120 m of fluid is present. When peritoneal fluid exceeds 500 m , ascites may be demonstrated by the presence of shifting dullness or bulging flanks. A fluid-wave sign is notoriously inaccurate.

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CT features suggest neoplasia. Hepatic, adrenal, splenic, or lymph node lesions associated with masses arising from the gut, ovary, or pancreas are suggestive of malignant ascites. Patients with malignant ascites tend to have proportional fluid collections in the greater and lesser sacs, whereas, in patients with benign ascites, the fluid is observed primarily in the greater sac and not in the lesser omental bursae.

nvasive Procedures

t

Ascitic tap (Abdominal paracentesis).

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Figure 9.17.5 Site of ascitic tap  

A

bdominal Paracentesis





1. Midline site: Below the umbilicus, this is avascular area. 2. When midline site is inappropriate (presence of scar), then a site two-finger breadth medial to the anterior superior iliac spine is chosen. 3. Ultrasonic guidance is needed only in, specific indications.

Technique Needle is inserted, using a Z tract to prevent leakage of fluid. This is achieved by retracting (with one glove hand) the skin approximately 2 cm caudal in relation to the deep abdominal wall and then slowly inserting the paracentesis needle. The skin is not released until the needle has penetrated the peritoneum or fluid flows. When the needle is finally removed at the end to procedure, the skin

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Routine tests optional tests Total protein Gram’s stain and culture Albumin AFB smear and culture Cell count cytology Amylase Lactate dehydrogenase (LDH) Glucose. ab studies: Peritoneal fluid should be sent for cell count, albumin level, culture, total protein, Gram stain, and cytology for new-onset ascites of unknown origin. Gross appearance: Most ascitic fluid is transparent and tinged yellow. This may be attributed to either a traumatic tap or malignancy. Bloody fluid from a traumatic tap is heterogeneously bloody, and the fluid will clot. Nontraumatic bloody fluid is homogeneously red and does not clot because it has already clotted and lysed. Neutrophil counts of more than 50,000 cells/m have a purulent cloudy consistency and indicate infection. It may be red because of presence of red cells more than 10,000/cumm, milky if it is lipid laden, dark-brown because of bilirubin, black/ tea color in pancreatic ascites, cloudy because of absolute neutrophilic count over 5,000/cumm (Table 9.17.4). l

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ite

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or large volume ascites: Supine with head slightly elevated. • or low volume ascites: Lateral decubitus position. • or small volume ascites: Face down position or hand knee position (Fig. 9.17.4). F

•

scitic luid nalysis

A

Position

resumes its original position and seals the needle pathway (Fig. 9.17.5). F

Abdominal paracentesis is the most rapid and perhaps the most cost-effective method of diagnosing the cause of ascites formation. Therapeutic paracentesis may be performed for refractory or tense ascites.

 

Table 9.17.4 Gross appearance of ascites Association

Translucent or yellow

Normal/sterile

Brown

Hyperbilirubinemia (most common) Gallbladder or biliary perforation

Cloudy or tubid

Infection

Pink or blood tinged

Mild trauma at the site

Grossly bloody

Malignancy Abdominal trauma

Milky (“chylous”)  

Cirrhosis Thoracic duct injury Lymphoma

587

 

Figure 9.17.4 Minimal ascites is tapped in knee chest position

Color

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Low gradient (< 1.1 g/d )

Cirrhosis

Tuberculous peritonitis

Hepatitis

Nephrotic syndrome

Fulminant hepatic failure

Pancreatic ascites

Cardiac ascites

Bowel obstruction/infarction

Portal vein thrombosis

Biliary ascites

Veno-occlusive disease

Postoperative lymphatic leak

Myxedema

Serositis in connective tissue diseases

Massive liver metastases

Nephrotic syndrome

l

High gradient (> or = 1.1 g/dL)

l

l

 

Table 9.17.6 Types of ascites according to the level of the serum-ascites albumin gradient (SAAG)

> 250

Positive (one organism)

Culture-negative neutrocytic bacterascites

> 250

Negative

Monomicrobial non-neutrocytic bacterascites

< 250

Positive (one organism)

Polymicrobial bacterascites

< 250

Positive (polymicrobial)

Secondary bacterial peritonitis

> 250

Positive (polymicrobial)

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LD

A

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B C

Indications for Admitting Patients of Chronic Liver Disease with Ascites 1. For investigations of the cause of liver disease 2. Child not responsive to appropriate OPD basis therapy 3. For intensive education of the patient in preparing a diet limited to 88 mmol of sodium per day 4. For careful monitoring of serum and urine electrolytes and serum concentration of urea nitrogen and creatinine 5. Grade III ascites with respiratory difficulty/distress 6. Ascites with suspected spontaneous bacterial peritonitis 7. If a child develops diuretic-induced complications Electrolyte imbalances Hyponatremia: Serum sodium < 125 mEq/L

Spontaneous bacterial peritonitis



PMN count Bacterial (cells/mm3) culture result

PMN, polymorphonuclear neutrophil leukocyte



588





Type



 

Table 9.17.5 Classification of ascitic fluid infection

ulture: The common bacterial infection of ascitic fluid are monomicrobial with a very low bacterial concentration. The sensitivity with bedside inoculation of blood culture bottles with ascites results in 92% detection of bacterial growth in neutrocytic ascites. H: LDH estimation is often helpful in distinguishing spontaneous bacterial peritonitis from gut perforation. Lactate dehydrogenase > 225 mU/L, glucose < 50 mg/dL, total protein > 1 g/dL and multiple organisms on Gram stain suggest secondary bacterial peritonitis (ruptured viscus or loculated abscess). Triglycerides: A high level of triglycerides confirms chylous ascites. mylase: In pancreatitis or gut perforation it is markedly elevated, usually greater than 2000 IU. ilirubin: An elevated bilirubin level suggest biliary or gut perforation. omplications of paracentesis: Include infection, electro lyte imbalances, bleeding, and bowel perforation. Bowel perforation should be considered in any patient with recent paracentesis who develops a new onset of fever and/or abdominal pain. All patients with long-standing ascites are at risk of developing umbilical hernias. Large-volume paracentesis often results in large intravascular fluid shifts. This can be avoided by administering albumin replacement, if more than 5 liters is removed.



SAA



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Total protein: In the past, ascitic fluid has been classified as an exudate if the protein level is greater than or equal to 2.5 g/d . However, the accuracy is only approximately 56% for detecting exudative causes. The total protein level may provide additional clues when used with the SAAG. An elevated SAAG and a high protein level are observed in most cases of ascites due to hepatic congestion. Those patients with malignant ascites have a low SAAG and a high protein level. Gram stain: Gram stain is only 10% sensitive for helping visualize bacteria in early-detected spontaneous bacterial peritonitis. Approximately 10,000 bacteria/m are required for detection by Gram stain; the median concentration of bacteria in spontaneous bacterial peritonitis is 1 organism/ m . ytology: Cytology smear results are reported to be 58– 75% sensitive for helping detect malignant ascites. Positive in peritoneal carcinomatosis. Sensitivity increased by centrifuging large volume. pH when less than 7 suggests bacterial infection. erum ascitis albumin gradient ( G): The SAAG is the best single test for classifying ascites into portal hypertensive (SAAG > 1.1 g/d ) and nonportal hypertensive (SAAG < 1.1 g/d ) causes. Calculated by subtracting the albumin concentration of the ascitic fluid from the albumin concentration of a serum specimen obtained on the same day. Serum ascites albumin gradient (SAAG) = serum albumin ascitic fluid albumin. It correlates directly with portal pressure. The accuracy of the SAAG results is approximately 97% in classifying ascits. High albumin gradient and low albumin gradient should replace the ‘term transudate and exudate’, in the classification of ascites as accuracy is not good in the latter. The test is accurate despite ascitic fluid infection, diuresis, therapeutic paracentesis, albumin infusion and etiology of liver disease (Tables 9.17.5 and 9.17.6).

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Amiloride (Midamor)

rugs iuretics

Spironolactone (Aldactone) For management of edema resulting from excessive aldosterone excretion. Competes with aldosterone for receptor sites in distal renal tubules, increasing water

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C

D

A pyrazine-carbonyl-guanidine unrelated chemically to other known antikaliuretic or diuretic agents. Potassiumconserving (antikaliuretic) drug which, compared with thiazide diuretics, possesses weak natriuretic, diuretic, and antihypertensive activity. ose: Not established fully in pediatric practice. ontraindications: Documented hypersensitivity; elevated serum potassium levels (>5.5 mEq/L); impaired renal function, acute or chronic renal insufficiency, and evidence of diabetic nephropathy. Monitor electrolytes closely if evidence of renal functional impairment is present, BUN >30 mg/100 m , or serum creatinine level >1.5 mg/100 ml. Precautions: Potassium retention associated with use of an antikaliuretic agent accentuated in presence of renal impairment and may result in rapid development of hyperkalemia. Monitor serum potassium level. Mild hyperkalemia usually not associated with abnormal ECG findings.

Metolazone (Mykrox, Zaroxolyn) Helps treat edema in congestive heart failure. Increases excretion of sodium, water, potassium, and hydrogen ions by inhibiting reabsorption of sodium in distal tubules. May be more effective in those with impaired renal function. 589 ose: 5–20 mg/dose PO q24h. D

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ed rest: Upright position increases renin-aldosterone activity, increased retention of sodium or water. Bed rest reduces this activity. edical care: The goals of pharmacotherapy are to reduce morbidity and to prevent complications. iet: Sodium restriction (20–30 mEq/d) and diuretic therapy constitute the standard medial management for ascites and are effective in approximately 95% of patients. Sodium restriction up to 5 mg per day in child 1–4 years, not greater than 20 mEq per day in child 4–11 years, not greater than 30 mEq per day in child 12–14 years. luid restriction: It is the sodium restriction not the fluid restriction, that results in weight loss. Fluid restriction is only indicated when there is persistent hyponatremia, serum sodium < 120 mEq/liter (reduced renal free water clearance). Renal sodium retention is the phenomenon primarily responsible for fluid retention and ascites formation. It occurs months before impairment of renal free water clearance. Measurements of twenty-four hour urinary sodium excretion (with measurement of creatinine to assess completeness of collection). A major goal of treatment is to increase urinary sodium excretion to > 78 mmol/day.

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Initial evaluation Identify and treat the underlying cause Diagnostic ascitic fluid tap Ascitic fluid analysis Treatment of diuretic-sensitive ascites Indications to stop diuretics Treatment of refractory ascites Spontaneous bacterial peritonitis M

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1. 2. 3. 4. 5. 6. 7. 8.

Increases excretion of water by interfering with chloridebinding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in ascending loop of Henle and distal renal tubule. Dose must be individualized to patient. ose: 1–2 mg/kg/dose PO; not to exceed 6 mg/kg/dose; do not administer >q6h 1 mg/kg IV/IM slowly under close supervision; not to exceed 6 mg/kg. When treating infants, titrate in increments of 1 mg/kg/dose until a satisfactory effect is achieved. ontraindications: Documented hypersensitivity; hepatic coma; anuria; state of severe electrolyte depletion. Precautions: Perform frequent serum electrolyte, carbon dioxide, glucose, creatinine, uric acid, calcium, and BUN determinations during first few months of therapy and periodically thereafter. Torasemide is three times more potent and longer acting than furosemide. D

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Principles of Treatment

Furosemide (Lasix)

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excretion while retaining potassium and hydrogen ions. The peak effect of aldactone is approximately 3 days. ose: 2–3 mg/kg/day PO in divided doses q6-24h. ontraindications: Documented hypersensitivity; anuria; renal failure; hyperkalemia. Precautions: Caution in renal and hepatic impairment; may cause gynecomastia and impotence in men.

iseases of Gas roin es inal ys em and iver

Hypokalemia: Serum potassium < 3.0 mEq/L Hyperkalemia: Serum potassium > 6.0 mEq/L 8. Hepatorenal syndrome • Increase in baseline serum creatinine by > 100% or an absolute value of 1.5 mg/d (even if the patient is responding to diuretics) • Urinary Na+ < 10 mEq/L • Creatinine clearance < 0.75 mg/kg/min 9. Hepatic encephalopathy 10. Refractory ascites.

vip.persianss.ir

B

Lowers portal pressure and inhibits renin secretion or combination of these effects, results increased natriuresis. S

Which Diuretics in Pediatrics and When to Increase Dose Diuretics should be initiated in patients who do not respond to sodium restriction. A useful regimen is to start with spironolactone. The addition of loop diuretics may be necessary in some cases to increase the natriuretic effect. If no response occurs after 4–5 days, the dosage may be increased stepwise.

Duration of Diuretics Therapy To treat: Diuretic therapy is continued till ascites. To prevent: In certain conditions like cirrhosis effective doses of diuretics have to continued for months to years, to prevent reaccumulation of fluid.

Indications to Stop Diuretics

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A TIPSS is a side-to-side portal-systemic shunt placed by an interventional radiologist (Figs 9.17.6 and 9.17.7). TIPSS is an efficacious treatment for patients with refractory ascites. Survival may be better than in patients treated with serial large-volume paracentesis. TIPSS is associated with suppression of antinatriuretic systems, and an improvement in renal function and renal response to diuretics. Although the main indication for TIPSS remains variceal bleeding refractory to endoscopic therapy, the procedure reduces the activity of the RAAS and increases natriuresis and GFR. Shunt dysfunction and development of encephalopathy remain the major concerns in this patient group. S

Peritoneovenous hunt Peritoneovenous shunts (e.g. LeVeen [Fig. 9.17.8] or Denver) have been shown to have poor long-term patency. They are associated with excessive complications, including peritoneal fibrosis, and confer no survival advantage relative to standard therapy. It should be reserved for diuretic-resistant patients who are candidates for neither liver transplantation nor serial large-volume paracentesis (because of multiple surgical scars or distance from a physician able to perform paracentesis).

iver Transplantation

This is the ultimate treatment modality available for refractory ascites in end stage liver disease. By replacing the cirrhotic liver, portal hypertension and its underlying mechanisms of ascites are corrected. Ideally

Encephalopathy Serum sodium < 120 mmol/L despite fluid restriction. Serum creatinine > 2.0 mg/d . Clinically significant complications of diuretics. Hyperkalemia and metabolic acidosis (spironolactone). l

• • • • •

urgical

Transjugular nterahepatic Portal- ystemic tent- hunt (T P )

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Inhibits tubular reabsorption of electrolytes by increasing osmotic pressure of glomerular filtrate. Increases urinary output. ose: Mannitol (20%) 2 m /kg every 6 hours for 2 days or 0.5-3.0 g/kg/dose 8th hourly. ontraindications: Documented hypersensitivity, anuria, severe pulmonary congestion, progressive renal damage, severe dehydration, active intracranial bleeding, and progressive heart failure. Precautions: Carefully evaluate cardiovascular status before rapid administration because a sudden increase in extracellular fluid may lead to fulminating CHF. Avoid pseudoagglutination. When blood is given simultaneously, add at least 20 mEq of sodium chloride to each liter of mannitol solution. Do not give electrolyte-free mannitol solutions with blood.

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b- lockers (Propranolol)

Mannitol (Osmitrol)

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ontraindications: Documented hypersensitivity; hepatic coma or anuria. Precautions: Caution in hepatic or renal disease, diabetes mellitus, gout, or lupus erythematosus.

Diuretic-Resistant Ascites

Figure 9.17.6 Liver explaint showing metal mesh of a TIPS  

For ascites resistant to medical therapy treatment options include: • Therapeutic paracentesis • LeVeen or Denver (peritoneovenous) shunt • Liver transplantation • Extracorporeal ultrafiltration of ascitic fluid with reinfusion • Transjugular intrahepatic portosystemic stent shunt.

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transplantation should be done before hepato-renal syndrome sets in. Scarcity of facility and exorbitant costs are currently the limiting factors in our country. A patient with cirrhosis, the development of ascites refractory to standard medical therapy is associated with an approximately 50% 6-month survival, and an approximately 25% 12-month survival.

to determine the sodium balance which can be approximated by monitoring intake (diet, sodium containing medications and intravenous solutions) and urinary excretion because, a negative sodium balance is a predictor of weight loss. • A reasonable goal for a patient without peripheral edema is a negative sodium balance with a weight loss of 0.5 kg per day. esponse to therapy is indicated by the following parameters: 1. Optimal decrease in body weight is 0.5–1% every 24 hours as compared to the previous day’s weight. Weight loss more than this would be harmful and indicates rapid shift of body fluids and calls for immediate reduction of diuretic dose. 2. Relief of abdominal distention as evidenced by improve ment of distress and decreasing abdominal girth. • Achieving a negative sodium balance (when the patient is excreting more sodium than the intake) indicates good diuretic response. Inadequate sodium restriction is an important cause of diuretic resistant ascites and can be suspected if the patient does not lose weight and fluid despite an appropriate natriuresis.

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When a patient is responding to medical treatment, hospitalization is not necessary. • The best method of assessing the effectiveness of diuretic therapy is by monitoring body weight and urinary sodium levels. • In general, the goal of diuretic treatment should be to achieve weight loss of 300–500 g/d in patients without edema and 800–1000 g/d in patients with 591 edema. l

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Patients can actually be maintained free of ascites if sodium intake is limited to 10 mmol/d . Twenty-four hours urinary sodium measurements are useful in patients with ascites related to portal hypertension in order to assess the degree of sodium avidity, monitor the response to diuretics, and assess compliance with diet. For grade 3 or 4 ascites, therapeutic paracentesis may be necessary intermittently. At hospital it is important to monitor body weight and the intake and output of fluids. Fluid restriction is only necessary if the serum sodium concentration drops below 120 mmol per liter. It is also important

F

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F

Portocaval shunt operation involves the anastomosis of the portal vein and the inferior vena cava, consequently reducing the portal pressure. The shunt also produces a marked diuresis and natriuresis. However, despite reported efficacy, surgical portosystemic shunts are rarely used in the treatment of advanced cirrhotic ascites, because of the high incidence of post-shunt encephalopathy. In addition, surgical shunts may cause technical difficulties during subsequent orthotopic liver transplantation.



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urgical Portosystemic hunting

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Figure 9.17.8 Peritoneovenous (LeVeen) shunt

 

Figure 9.17.7 TIPS shunt from hepatic vein to portal vein

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Diagnosis A diagnosis of SBP is made when an ascitic fluid bacterial culture is positive (e.g. Escherichia coli, Klebsiella pneumoniae, or Pneumococcus) with an elevated ascitic fluid absolute polymorphonuclear leukocyte count >250 cells/mm3, and symptoms and/or signs consistent with infection (temperature >100° F, chills, abdominal pain, rebound tenderness, reduced bowel sounds) without an evident intra-abdominal and surgically treatable source of infection. A missed or delayed diagnosis of spontaneous bacterial peritonitis (SBP) could potentially lead to sepsis and significant morbidity and mortality.

Treatment



Patients with a definitive diagnosis or presumptive diagnosis of SBP, should be treated with antibiotics. Treatment should not be delayed in those with a presumptive diagnosis until a positive culture is obtained. Those with positive ascitic fluid cultures in the absence of a neutrophil response should also be treated with antibiotics, if symptoms and/or signs of infection are present. When treating empirically a broad spectrum, nonnephrotoxic, antibiotic is administered intravenously, e.g. cefotaxime (third-generation cephalosporin). In well-characterized patients with SBP a 5-day course is as efficacious as a 10-day course of intravenous antibiotics. Lack of antibiotic-induced clinical improvement is an indication for repeat diagnostic paracentesis. If the ascitic fluid PMN leukocyte count is lower and the culture negative, a further course of antibiotic is given. If the ascitic fluid PMN leukocyte count is higher and culture yields a new organism, a different antibiotic is chosen. Alternatively, if reculture yields the same organism secondary bacterial peritonitis is suspected. Co-treatment with intravenous albumin, 1.5 g/kg at the time of diagnosis and 1 g/kg on day 3, reduces the incidence 592 of renal impairment and improves survival.



Prevention Cirrhotic patients, with low ascitic fluid total protein levels (< 1 g/d ) or gastrointestinal hemorrhage or those who have recovered from an episode of SBP, are at high risk of developing SBP and are candidates for long-term prophylactic therapy with oral antibiotics. Oral antibiotic primary prophylaxis, with norfloxacin, ciprofloxacin or cotrimoxazole, appears to be effective in preventing an initial episode of SBP or a recurrence of SBP. The emergence of infections caused by bacteria resistant to specific antibiotics is a potential problem.

Prognosis Depends on the underlying disorder, the degree of reversibility of a given disease process, and the response to treatment.

Patient ducation The most important aspect of patient education is determining when therapy is failing and recognizing the need to see a physician. Unfortunately, in most cases, liver failure has a dismal prognosis. All patients must be taught which complications are potentially fatal and the signs and symptoms that precede them. Abdominal distention and/or pain despite maximal diuretic therapy are common problems, and patients must realize the importance of seeing a physician immediately.

onitoring of the Patient

The treatment of ascites depends on it’s cause. In the majority of patients, cirrhosis leading to portal hypertension is the major cause. A particular value of recognizing portal hypertension as a cause of ascites is that medical management using diuretics and salt restriction is often effective in portal hypertensive patients. Conversely, ascites due to peritoneal inflammation or malignancy alone does not respond to salt restriction and diuretics.

ow lbumin Gradient scites A

B

pontaneous acterial Peritonitis

The prognosis in patients who develop SBP is so poor, that liver transplantation should be considered in all survivors of SBP.

l

Pleural effusion, particularly on the right side can develop in some patients with ascites. It occurs due to passage of fluid through small holes in the diaphragm. These effusions may be very large.

Liver Transplantation

E

Hydrothorax

Necessary only if there are atypical features (symptoms, clinical setting, ascitic fluid analysis, organism(s), response to therapy) suggestive of secondary peritonitis.

A

Some patients may develop or may show an increase in the size of already existent umbilical hernia. Most hernias recur after surgical repair unless the ascites is controlled.

Follow-up Paracentesis



Umbilical Hernia

M

omplications of scites

Oral ofloxacin has been reported to be as efficacious as intravenous cefotaxime in the treatment of patients with SBP, who are not azotemic, vomiting or in shock. However, until more data are available, an intravenous antibiotic regimen is preferred.

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Once ascites has disappeared, diuretic treatment should be adjusted to maintain the patient free of ascites. Body weight, orthostatic symptoms, and serum electrolytes, urea and creatinine are monitored. A

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These patients usually do not have portal hypertension and do not respond to salt restriction and diuretics. Patients

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Serial Large-Volume Paracentesis

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Serial large-volume paracentesis (6–10 L) are safe and effective in controlling refractory ascites. Therapeutic paracentesis volume of fluid to be tapped: Up to 100 m /kg safely at any time. How frequently one should tap: large volume tap is indicated in one sitting then frequent taps.

Mechanism of Relief by Paracentesis



Taking out fluid from peritoneal cavity decreases systemic venous congestion, increases GFR and renal plasma flow which helps in producing diuresis. Advanced cirrhosis is associated with a hyperdynamic circulation characterized by reduced systemic vascular resistance secondary to splanchnic vasodilatation, which leads to effective hypovolemia. Intense activation of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system, and nonosmotic release of vasopressin occur, with consequent renal hypoperfusion. This becomes more accentuated as patients progress from decompensated cirrhosis to the hepatorenal syndrome (HRS).

A

Atrial Natriuretic Peptide Atrial natriuretic peptide (ANP) normally increases glomerular filtration rate (GFR) and natriuresis. Patients with advanced cirrhosis and ascites have a reduced natriuretic response to ANP despite elevated levels. Exogenous ANP administration, together with the splanchnic vasoconstrictor terlipressin to counter the hypotensive effect of ANP, increases renal blood flow, GFR and natriuresis in patients with refractory ascites.

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ovel Treatments in scites

Other Agents Although not tested specifically for refractory ascites, a number of agents have been tried in humans which may increase diuresis in cirrhotic patients with ascites. These include the V2 receptor antagonist, OPC-3126, Niravoline, a k-opioid antagonist, and the adenosine-1-receptor antagonist FK352. Future studies using these novel agents may provide further information regarding their efficacy in refractory ascites.

hylous scites

Turbid, milky or creamy peritoneal fluid due to the presence of thoracic or intestinal lymph having triglyceride (fat) concentration of more than 1000 mg/d . If patient has nothing by mouth, then milky color will fade and the fluid will look like transudate with predominance of lymphocytes (85%). l

M



Defined as fluid overload that is non-responsive to restriction of dietary sodium to 88 mmol/day and maximal dose diuretic therapy (furosemide + spironolactone), in the absence of ingestion of prostaglandin inhibitors, such as non-steroidal anti-inflammatory drugs. Ascites is also considered to be refractory when there is intolerance of diuretic therapy. Indications of failure of diuretic therapy include minimal or no weight loss, together with inadequate urinary sodium excretion (< 78 mmol/day). Less than 10% of patients with ascites complicating cirrhosis meet the criteria of the definition of refractory ascites.

A

efinition

N

A

efractory scites

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R

Twenty-four hours urinary sodium measurement is a helpful parameter. When patient has no urinary sodium excretion despite diuretics, recommend an alternative treatmentparacentesis.

C

S

Urinary odium

In patients with no urinary sodium excretion and a dietary intake of 88 mmol sodium daily, the required frequency is about every two weeks. The frequency is influenced by the degree of compliance with the low sodium diet. The sodium content of ascitic fluid is about 130 mmol/L. Thus, a 6 L paracentesis removes 780 mmol sodium. Patients, who ingest 88 mmol sodium per day and excrete 10 mmol sodium in non-urinary losses and no sodium in the urine, retain 78 mmol sodium per day. Accordingly, a 6 L paracentesis removes the sodium retained over a period of 10 days, and a 10 L paracentesis removes the sodium retained over approximately 17 days. Intravenous colloid replacement, e.g. albumin 6 to 8 g/L ascitic fluid removed is recommended immediately following a large-volume paracentesis (>5 L), to minimize intravascular hypovolemia, activation of vasoconstrictor and antinatriuretic systems, and impairment of renal function. Dextran 70 is less efficacious than albumin. If a paracentesis is <5 L, colloid replacement appears to be unnecessary.

iseases of Gas roin es inal ys em and iver

with ‘Tuberculous peritonitis’ are cured by antituberculous therapy. Pancreatic ascites may resolve spontaneously, require endoscopic stenting or operative intervention or need ‘somatostatin’ therapy. Lymph leak usually resolves spontaneously or may require surgical intervention or peritoneovenous shunting: Chlamydial peritonitis requires tetracycline therapy. Nephrotic and lupus ascites may require steroids. Malignant requires surgical debulking and chemotherapy. Ascites may respond to aggressive dialysis.

auses

Congenital anomaly of lymphatics lymphangiectasis, obstruction of duct within its abdominal portion from trauma, tumor, large lymph nodes, rupture of major lymphatic channel, tuberculosis, filariasis, nephrotic 593 syndrome, cirrhosis, rheumatoid arthritis, other serositis.

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anagement





a. Dietary: i. Low fat diet - containing medium chain triglycerides, because these are absorbed directly into the portal circulation. ii. High protein diet, and iii. Parenteral nutrition supplementation. b. Paracentesis: Duration of treatment may require several months for effective medical management. Surgical approach abdominal exploration to detect the site of the leak.

S

A

In chronic peritonitis/persistent ascites fluid have some what similar color, from the degeneration of inflammatory products (leukocytes/tumor cell), and may be confused with chylous fluid (Table 9.17.7).

ummary

The circulatory disturbances seen in advanced cirrhosis lead to the development of ascites, which can become refractory to diet and medical therapy. These abnormalities may progress and cause a functional renal failure known as the hepatorenal syndrome. Management of refractory ascites and hepatorenal syndrome is a therapeutic challenge, and if appropriate, liver transplantation remains the best treatment. New therapeutic options have recently appeared, including the transjugular intrahepatic portosystemic shunt and selective splanchnic vasoconstrictor agents, which may improve renal function and act as a bridge to transplantation. B





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complications. Thus their monitoring is more intense and repeated every 48 hours.

Pseudochylous scites

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M

onitoring during iuretic Therapy



The main concern during diuretic therapy is whether there is too rapid fluid mobilization and diuretic induced complications. In OPD settings the patient needs to be assessed after one week of starting therapy and thereafter every two weeks. At each visit compliance for low sodium diet, bed rest and diuretic doses should be ascertained. Examination for changes in weight, abdominal girth, pedal edema, ascitic grading and subtle signs of spontaneous bacterial peritonitis should be done. Weight loss of more than 1% per day or 4–6% per week of the previous weight would indicate too rapid fluid mobilization and natriuresis. This cautions us to evaluate renal functions along with reduction in the dose of diuretics. Evaluation of serum Na, K, blood urea and creatinine and liver function tests would be useful in assessing diuretic response and its attendant complications. Serial measurement of fractional excretion of sodium is an objective measure of the effectiveness of the diuretic response. This requires simultaneous estimation of serum and spot urinary sodium and creatinine concentrations. At the earliest suspicion of spontaneous bacterial peritonitis, an ascitic tap should be performed and antibiotic therapy instituted. Admitted patients are usually those who have resistant ascites or have developed diuretic induced

 

Table 9.17.7 Difference between true and pseudochylous fluid True chylous fluid

Pseudochylous fluid



Ether test- top thick layers becomes clear Turbidity is unchanged fluid

594

Alkali test- no change in color

Becomes clear (dissolves cellular protein)

Fat globules stained by Sudan

Not stained

ibliography

1. Albornoz L, Motta A, Alvarez D, et al. Nitric oxide synthase activity in the splanchnic vasculature of patients with cirrhosis: relationship with hemodynamic disturbances. J Hepatol. 2001;35(4):452-6. 2. Arrovo V, Esptein M, Gallus G et al. Refractory ascites in cirrhosis. Mechanism and treatment. Gastroenterology. 1989;2:195. 3. Arroyo V, Gines P, Gerbes AL, Dudley FJ, Gentilini P, Laffi G, Reynolds TB, Larsen HR, Scholmerich J. Definition and diagnostic criteria of refractory ascites and hepato-renal syndrome in cirrhosis. Hepatology. 1996;23(1):164-76. 4. Bernadi M, Santini C, Trevisani F. Renal function impairment induced by change of posture in patients with cirrhosis and ascites. Gut. 1985;26:629-35. 5. Cardenas A, Bataller R, Arroyo V. Mechanisms of ascites formation. Clin Liver Dis. 2000;4(2):447-65. 6. Casado M, Bosch J, Garcia-Pagan JC, et al. Clinical events after transjugular intrahepatic portosystemic shunt: correlation with hemodynamic findings. Gastroenterology. 1998;1114:1296-1303. 7. D’Amico G, Luca A, Morabito A, Miraglia R, D’Amico M. Uncovered transjugular intrahepatic portosystemic shunt for refractory ascites: a meta-analysis. Gastroenterology. 2005;129(4):1282-93. 8. D’Amico G, Morabito A, Pagliaro L, Marublni E. Survival and prognostic indicators in compensated and decompensated cirrhosis. Dig Dis Sci. 1986;31:468-75. 9. Diseases of the peritoneum, mesentery and omentum. In: Wynngaarden JB, Smith LH, Bennet JC (Eds). Cecil Textbook of Medicine, 20th edition. W B Saunders ny, 1996. 10. Garcia-Tsao G. Current management of the complications of cirrhosis and portal hypertension: variceal hemorrhage, ascites, and spontaneous bacterial peritonitis. Gastroenterology. 2001;120(3):726-48. 11. Gerbes AL. Medical treatment of ascites in cirrhosis. J Hepatol. 1993;17(suppl):S4-S9. 12. Gines P, Cardenas A, Arroyo V, Rodes J. Management of cirrhosis and ascites. N Engl J Med. 2004;350:1646-54. 13. Hardikar W. Ascites and encephalopathy in chronic liver disease. Indian J Ped. 2002;69:169-73.

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31. Runyon B. Approach to the patient with ascites. In: Yamada T, Alpers DH, Laine L, Owyang C, Powell DW, (Eds). Textbook of Gastroenterology, 3rd edition Philadelphia, Pa: Lippincott Williams and Wilkins; 1999; 966-91. 32. Runyon BA, Antillon MR, Akriviadis EA, et al. Bed side inoculation of food culture bottles with ascitic fluid is superior to delayed inoculation in detection for spontaneous bacterial peritonitis. J Clin Microbio. 1991;28:2811. 33. Runyon BA, Montano AA, Akriviadis EA, et al. The serumascites gradient is superior to the exudate-transudate concept in differential diagnosis of ascites. Ann Intern Med. 1992;117:215. 34. Runyon BA, Montano AA, Alkriviadis EA, et al. The serum ascites albumin gradient in the differential diagnosis of ascites is superior to the exudate/transudate concept. Ann Intern Med. 1992;117:215. 35. Runyon BA. Care of patients with ascites. N Engl J Med. 1994;330(5):337-41. 36. Runyon BA. Care of patients with ascites. New England J Medicine. 1994;330:337. 37. Runyon BA. Management of adult patients with ascites caused by cirrhosis. Hepatology. 1998;27:264-72. 38. Runyon BA. Paracentesis of ascitic fluid: a safe procedure. Arch Intern Med. 1986;146:2259. 39. Schiff ER, Sorrell MF, Maddrey WC. Ascites and spontaneous bacterial peritonitis. In: Schiff ER, Sorrell MF, Maddrey WC (Eds). Schiff’s Disease of the Liver, 8th edition. Philadelphia, Pa: Lippincott Raven. 1999.pp.503-44. 40. Sherlock S, Senewiratne B, Scott A, Walker JG. Complications of diuretic therapy in hepatic cirrhosis. Lancet. 1966;1:1049-53. 41. Surgaila I, Bartie W, Walker S. Spironolactone pharmaco kinetics and pharmacodynamics in cirrhosis with ascites. Gastroenterology. 1992;102:168. 42. Turkel SH. Congenital ascites Clin Perinatol. 1988;9:613. 43. Valla D, Flejou JF, Labrec D. Portal hypertension and ascites in acute hepatitis. Clinical hemodynamics and histologic correlations. Hepatology 1978;10:482-87. (http://www. medstudents.com.br/medint/medint3.htm) 44. Wallerstedt S, Olsson R, Simrén M, Broomé U, Wahlin S, Lööf L. Abdominal tenderness in ascites patients indicates spontaneous bacterial peritonitis. Eur J Intern Med. 2007;18(1):44-7. 45. Witte CL, Witte MH, Dumont AE. Lymph imbalance in the genesis and perpetuation of the ascites syndrome in hepatic cirrhosis. Gastroenterology. 1980;78:1059-68. 46. Wong F, Blendis L. Hepatorenal failure. Clin Liver Disease. 2000;4(1):169-89.

iseases of Gas roin es inal ys em and iver

14. Hardy SC, Kleinman RE. In: Erederick JS (Eds). Cirrhosis and Chronic Live Failure in Liver Diseases in Children 1st edition Mosby 1994.pp.229-30. 15. Heneghan MA, Harrison PM. Pathogenesis of ascites in cirrhosis and portal hypertension. Med Sci Monit. 2000;6(4):807-16. 16. Idem. Low protein concentration ascitic fluid is predisposed to spontaneous bacterial peritonitis. Gastroenterology. 1986;91:1343-46. 17. Inturri P, Graziotto A, Rossaro L. Treatment of ascites: old and new remedies. Dig Dis. 1996;14:145-56. 18. Jeffery J, Murphy MJ. Ascitic fluid analysis: the role of biochemistry and haematology. Hisp Med. 2001; 62(5):28286. 19. Levy M. Pathophysiology of ascites formation. In: Epstein M (Ed). The Kidney in Liver Disease, 3rd edition. Williams and Wilkins, Baltimore. 1988.pp.209-43. 20. Lieberman FL, Denison EK, Reynolds TB. The relationship of plasma volume, portal hypertension, ascites and renal sodium retention in cirrhosis: the overflow theory of ascites formation. Ann NY Acad Sci. 1970;170:202-12. 21. Mathur P, Oberoi A, Arora NK. Management of ascites in children with chronic liver disease. Indian J Practical Pediatrics. 2002;4(4):329-37. 22. McGillivroy BC. Neonatal ascites. Pediatr Pev. 1987;9:197. 23. McVay PA, Toy PTCY. Lack of increased bleeding after paracentesis and thoracocentesis in patients with mild coagulation abnormalities. Transfusion. 1991;31:164-71. 24. Pare P, Talbot J, Hoefs JC. Serum ascites albumin concentration gradient: A physiologic approach to the differential diagnosis. Gastroenterology. 1983;85:240. 25. Parsons SL, Watson SA, Streele RJ. Malignant ascites. Br J Surg. 1996;83:6-14. 26. Press OW, Press NO, Kaufman SD. Evaluation and management of chylous ascites. Ann intern Med. 1982;96:358. 27. Rector WG Jr, Reynolds TB. Superiority of the serumascites albumin difference over the ascites total protein concentration in separation of “Transudative” and Exudative” ascites. Am J Med. 1984;77:83-85. 28. Reynolds TB. Ascites. Clin Liver Dis. 2000;4(1):151-68. 29. Rimola AD, Garcia-Tsao G, Navasa M, et al. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club. J Hepatol. 2000;32(1):142-53. 30. Rossle K, Ochs A, Gulberg V, et al. A comparison of paracentesis, and transjugular intrahepatic portosystemic shunting in patients with ascites. NEJM. 2000;342:1701-07.

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ommon Metabolic Liver isorders in hildren

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Wilson isease

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Liver plays a central role in innumerable metabolic processes in the body, and hence is affected primarily or secondarily in many inborn errors of metabolism; these are referred to as metabolic liver disorders (MLDs). Metabolic liver disorders now account for up to 40% of all chronic liver admissions to large medical centers in India. A strong index of suspicion is the key to making a definitive diagnosis. The commonest MLDs seen in India are Wilson disease (WD), glycogen storage disease (GSD) and galactosemia. Not all of them have a specific therapy but in some like Wilson disease (WD), glycogen storage disease (GSD), galactosemia, etc. medical therapy or dietary manipulations, are important to sustain a normal life. The possibility of a metabolic liver disease should be considered if any of the following are present: • Family history of liver disease or consanguinity • Unexplained hepatomegaly without jaundice • Any unexplained chronic liver disease • Associated rickets, failure to thrive and dysmorphism • Associated renal, respiratory or neurological disease • Recurrent episodes of liver disease • Liver failure in early infancy, severe uncorrectable coagulopathy.

iagnostic hallenges No single test is diagnostic by itself, and a group of appropriate tests of copper metabolism need to be done in order to make the diagnosis. • erum ceruloplasmin: The level of ceruloplasmin in normal individuals is 20–40 mg/dL. Serum ceruloplasmin is reduced in most patients with WD. However 5–40% of WD may have a normal ceruloplasmin. • 24-hour urine copper: n symptomatic patients with WD, the 24 hour urinary Cu excretion is more than 100 µg/day (normal < 40 µg/day). However, similar high values have also been documented in non WD chronic hepatitis, Indian childhood cirrhosis, chronic cholestatic liver disease, acute liver failure of any etiology and Cu contaminated urine samples. • ayser- leischer ring: t appears as a golden brown or greenish yellow discoloration in the limbus of the cornea. A slit lamp examination is necessary for detection. In India, kayser Fleischer (KF) ring is seen at an earlier age and also in a significant number of hepatic cases. • Hepatic copper: ormal values are less than 50 µg/g of dry weight of liver. It is the single best predictive marker for WD and considered the gold standard, with values usually above 250 µg/g dry weight. Disorders like Indian childhood cirrhosis and chronic cholestatic disorders also give rise to high hepatic coppers but can be clinically differentiated from WD. • Genetic studies: irect genetic diagnosis is difficult because of the occurrence of more than 200 mutations, each of which is rare. The WD mutations in different regions of India suggest high genetic heterogeneity and the absence of a single or a limited number of common founder mutations. S

ntroduction

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Management • iet: t is advisable to avoid high Cu containing foods like organ meats (liver), chocolates, nuts and dry fruits. • rugs: ontinuous lifelong drug therapy is essential in the management of WD. Treatment comprises of an initial phase where Cu is reduced to subtoxic threshold. D penicillamine (DP) or trientine with/without zinc is used as initial therapy, and a maintenance phase to maintain a slightly negative Cu balance so as to prevent D

The clinical manifestations are a result of the deposition of copper in various organs and the age of presentation can vary from 4 years to 60 years. The manifestations are more likely to be hepatic in early childhood and neurological in ad­ olescents; however other forms of presentation are also seen. The spectrum of hepatic manifestations includes all forms of chronic or acute liver disease. In Indian children, neurological manifestations can begin even in the first decade. They can be equally varied and include clumsiness, speech difficulties, scholastic deterioration, behavior problems, choreoathetoid and dystonic movements. Other presentations are “osseo­ muscular” with bony deformities (knock knees) suggestive of 596 resistant rickets. Hemolytic anemia can occur due to eryth­ rocyte membrane injury from the free copper in the serum.

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linical Manifestations

iagnostic pproach In a neurological setting, diagnosis of WD is made by presence of ayser Fleischer (KF) ring with either a low ceruloplasmin or high urinary copper. In liver disease, WD is strongly suggested by any two of the following: low ceruloplasmin, high urinary copper or presence of KF rings, and confirmed by a high hepatic Cu. k

C

Wilson disease is an inborn error of metabolism characte­ rized by toxic accumulation of copper in liver, brain, cornea and other tissues. It is an autosomal recessive disorder and occurs worldwide with an estimated prevalence of 1 in 30– 50,000. It is one of the leading causes of chronic liver disease in Indian children. The gene responsible has been identified as the ATP 7 B gene located on chromosome 13q.

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1. Bavdekar AR. Therapeutic and management challenges in Wilson’s disease. J Gastroenterol Hepatol. 2004;19:S391 6. 2. Bavdekar AR, Tanner MS. Indian childhood cirrhosis and other metabolic liver diseases. In: Dhavendra Kumar (Ed). Genetic Disorders of the Indian subcontinent. Nederlands, Dordrecht: Kluwer Academic Publishers; 2004. pp. 223 45. 3. Ghishan FK, Ballew MP. Inborn errors of carbohydrate metabolism. In: Suchy SJ, Sokol RJ, Balistreri WF (Eds). Liver Disease in Children, 2nd edition. Philadelphia: Lippincott Williams and Wilkins; 2001. pp. 565 72. 4. Gupta A, Chattopadhyay I, Dey S, et al. Molecular pathogenesis of Wilson disease among Indians: a perspective on mutation spectrum in ATP7B gene, prevalent defects, clinical heterogeneity and implication towards diagnosis. Cell Mol Neurobiol. 2007;27(8):1023 33. 5. Roberts EA, Schilsky ML. AASLD Practice Guidelines. Diagnosis and treatment of Wilson’s disease: an update. Hepatology. 2008;47(6):2089 111. 6. Segal S. Galactosemia today: the enigma and the challenge. J Inherit Metab Dis. 1998;21:455 71.

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IX

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Management of Glycogen torage isease Treatment of GSD I is aimed at preventing hypoglycemia by frequent daytime feeding with slowly resorbed carbohydrates (starch, glucose polymers) and continuous nocturnal feeding. Liver transplant is the only available option for GSD IV but may not prevent progression of extrahepatic disease.

ibliography

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Glycogen torage isease Types and These GSDs are due to defect in the hepatic phosphorylase system. The disorders are fairly benign and long term outlook for growth and liver function are good. D

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Glycogen torage isease Type This rare disorder occurs due to a defect in glycogen branching enzyme. Patients are normal at birth. Hepatomegaly and failure to thrive are seen in infancy. Cirrhosis and splenomegaly soon become manifest and death from liver cell failure usually occur before 3 years of age. Liver biopsy shows cirrhosis and abnormal glycogen, which is diastase resistant. S

ey Messages

• Metabolic liver diseases (MLDs) account for up to 40% of chronic liver diseases in Indian children. • Presentation may be in early infancy or in childhood. • Wilson disease, glycogen storage disease and gala­ ctosemia are the commonest MLDs. • Early diagnosis is essential for appropriate treatment and favorable outcome.

Glycogen storage disease III is due to abnormal activity of debrancher enzyme – amylo 1 6 glucosidase. Type IIIa is associated with progressive (cardio) myopathy while IIIb has mainly liver disease. In infancy, presentation is similar to GSD I, but milder with hepatomegaly and hypoglycemia. Gradually hepatomegaly decreases and fasting hypoglycemia improves. This is the commonest GSD in India.

S

and Liver

Glycogen torage isease Type

ys e

Glucose 6 phosphatase deficiency is the most severe form of hepatic GSD and results in defective gluconeogenesis. Patients present in infancy with doll like facies, truncal obesity, massive hepatomegaly, nephromegaly, failure to thrive, hypoglycemia and lactic acidosis after short fasting intervals. Serum triglycerides, cholesterol and uric acid are moderately elevated. The kidneys are enlarged on ultrasound due to increased glycogen content. Liver biopsy shows markedly increased fat and glycogen without fibrosis.

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Glycogen storage diseases are a heterogeneous group of entities classified on the basis of specific enzyme defects in various steps of glycogen synthesis or breakdown. Types I, III, IV, VI and IX have liver involvement.



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1 phosphate uridyltransferase (GALT) (which is the most common) or uridine diphosphate galactose 4 epimerase. Galactose 1 phosphate uridyltransferase deficiency should be suspected in any of the following presentations in neonatal period: jaundice, hepatomegaly, hypoglycemia, cirrhosis, ascites, liver failure, coagulopathy, cataracts and Escherichia coli sepsis. If untreated, these children go onto develop liver failure or chronic liver disease. The laboratory findings besides those of deranged liver function include elevated blood galactose and galactose 1 phosphate, hypoglycemia, hyperglycosuria, hyperchloremic metabolic acidosis, albuminuria and hyperaminoaciduria. Urine reducing substances have been the traditional screening test, but the recommended diagnostic method is RBC gal 1 PUT, for which the Buetler screening test is widely used. Elimination of dietary galactose is the only available treatment. In neonates and small infants, the preparation used is lactose free casein hydrolysates or soya bean milks. In older children, diets restricted to less than 125 mg galactose are advised.

iseases of Gas roin es ina

Cu accumulation and toxicity. D penicillamine, trientine or zinc has been traditionally used for this phase. • Liver transplant: iver transplant is the treatment of choice in children with acute liver failure or decompensated cirrhosis unresponsive to medical therapy. One year survival ranges from 79% to 87%.

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It is an autosomal recessive disorder of galactose metabolism due to deficiency of enzymes galactokinase and Galactose

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cute Pancreatitis in hildren D Nirmala

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Abdominal pain with nausea and vomiting is the hallmark of pancreatitis in children as well as in adults. It is characteristically a sharp and steady epigastric pain of sudden onset, commonly aggravated by eating and improved by drawing the knees up to the chest. Radiation of pain to the back or pain in other sites of abdomen is rare in children unlike adults. The pain increases in intensity over 24–48 hours and the patient may require hospitalization. On physical examination, the child usually appears anxious and uncomfortable, particularly with any movement. Tachycardia and fever are common; diffuse abdominal tenderness, more marked in the upper abdomen, and quiet bowel sounds are the rule. However, the diagnosis is not always obvious, and the symptoms can easily be attributed to other acute abdominal emergencies. Other possible findings include signs of pancreatic ascites, an epigastric mass suggestive of phlegmon or a pseudocyst formation, and bluish flanks (Grey Turner’s sign) or umbilicus (Cullen’s sign), indicating hemorrhagic pancreatitis. Evidence of pleural effusion or dyspnea in the presence of acute respiratory distress syndrome (ARDS) may be found on examination of the chest. Severe acute pancreatitis is rare in children. In this life threatening condition the patient may be acutely ill with severe abdominal pain and vomiting progressing to

tiology

­



The causes of pancreatitis are as diverse or even more in children compared to adults as shown in the Table 9.19.1 below. Drugs and blunt trauma were the leading causes for acute pancreatitis in children followed by gallstone disease, tuberculosis, mumps, viral hepatitis and hyper triglyceridemia and hereditary, according to one Indian study and the cause was not known in 35% of cases according to this study.



Pathogenesis



E



The frequency and true incidence of pancreatitis in children are unknown due to limited case reporting and underdiagnosis by physicians; but recent studies have demonstrated that the incidence of acute pancreatitis has increased even in pediatrics. Buntain et al. after a review of pancreatitis in childhood over a 15 years period concluded that pancreatitis was not rare in childhood and had a significant overall mortality rate of 30% or greater as compared to 12% in adults. Pseudocysts complicate acute pancreatitis in approximately 10–23% of cases. The incidence of pancreatic pseudocysts is greater than 50% when associated with traumatic injury to the abdomen.

F

E

Acute pancreatitis is an acute inflammatory process of the pancreas resulting in edema, hemorrhagic or fatty necrosis of pancreatic acinar cells and peripancreatic tissues and even remote organ involvement, which are often reversible. Mild acute pancreatitis is the term reserved for pancreatitis with minimal or no organ dysfunction whereas severe pancreatitis should be considered if there is evidence of life-threatening complications such as organ failure (shock, pulmonary insufficiency and renal failure) or local complications like necrosis, abscess or pseudocyst.



efinitions

its lytic enzymes by a series of highly compartmented systems. At each step of their formation and secretion the enzymes are totally sequestrated in a membrane-bound space. The various potent inhibitors of proteolytic enzymes present in many body fluids, and tissues constitute a second line of protection, defending the organism against inappropriate activation of the digestive proenzymes of the pancreas. These inhibitors bind strongly to the proteases and render them inactive. Till now, the exact mechanisms of the development of acute pancreatitis are a matter of debate. The most common and widely accepted theory is that pancreatitis develops because of an injury to the pancreatic acini or disruption of the pancreatic duct, which permits the leakage of pancreatic enzymes (trypsin, chymotrypsin and elastase) into pancre atic tissue. The leaked enzymes become activated in the tissue, initiating autodigestion and acute pancreatitis. The activated proteases (trypsin and elastase) and lipase break down tissue and cell membranes, causing edema, vascular damage, hemorrhage, ischemia inflammation and necrosis with release of toxic factors in both pancreatic and peripancreatic tissues leading to systemic effects such as multiorgan failure (Flow chart 9.19.1).

C

Acute pancreatitis is a disorder of varied etiology with obscure pathogenesis presenting both as mild disease and multiorgan failure, and is difficult to treat with no specific treatment and has commonly an unpredictable outcome. Pancreatitis, although is relatively uncommon during childhood, there is a significant morbidity and mortality associated with it. D

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9.19

598 Acute pancreatitis usually follows a complex cascade of

events. The pancreas is protected from the harmful effects of

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Drugs •  L-asparaginase •  Azathioprine •  Corticosteroids •  Didanosine •  Estrogens •  Ethacrynic acid •  Furosemide •  Procainamide •  Sulphasalazine •  Sulphonamides •  Tetracyclines •  Thiazides •  Valproate •  Zalcitabine

Infections •  Campylobacter •  Cryptosporidium •  Leptospira •  Mycoplasma •  Salmonella typhi •  Toxoplasma •  Viruses like mumps, coxsackie, cytomegalovirus, herpes simplex virus, hepatitis B and varicellazoster viru

Miscellaneous •  Graft-versus-host disease •  Hereditary •  Idiopathic •  Renal transplantation











  

 

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adiologic indings F



High index of suspicion with a history of abdominal even trivial trauma, drugs or acute infections is stressed. Screening of family for hereditary or metabolic disorders associated with pancreatitis will help. White blood cell counts may be increased with increased band counts and these findings do not imply infection always. An increased hematocrit secondary to hemoconcentration, secondary to volume depletion may be found. Also, 15% of children with pancreatitis develop hypocalcemia, and up to 25% have hyperglycemia during the acute attack. Blood urea nitrogen may be increased due to prerenal azotemia or acute renal injury, metabolic acidosis due to circulatory failure and hypoxemia due to respiratory insufficiency. The serum amylase concentration is elevated in at least 75% of cases of acute pancreatitis on the initial day of

symptoms and remains elevated in most patients for 5–10 days. Protracted elevations of serum amylase are suggestive of pseudocyst or other complications of pancreatitis. The serum lipase level is also usually elevated in acute pancreatitis, and serum lipase measurement is preferable to serum amylase because of its equal sensitivity and greater specificity because almost all lipase originates from the pancreas. Urinary lipase levels may remain elevated for a few days longer than serum levels. Additional tests, which have been used in the diagnosis of acute pancreatitis include immunoreactive trypsinogen, elastase, ribonuclease and phospolipase A, but no particular advantage. Levels of cationic trypsin are said to be a more sensitive early marker of pancreatic inflammation. R

D

iagnosis



t



shock, high fever, jaundice, ascites and pleural effusion. The mortality is highly related to systemic inflammatory response syndrome with multiple organ dysfunctions like shock, renal failure, ARDS, disseminated intravascular coagulation (DIC) and systemic infection.

t

Biliary tract obstruction •  Biliary tract anomalies •  Choledochal cyst •  Gallstones •  Parasites (Ascaris) Vasculitis •  Henoch-Schonlein purpura •  Kawasaki disease •  Systemic lupus erythematosus

t

Toxins •  Alcohol •  Boric acid •  Carbamate •  Organophosphorus •  Yellow scorpion sting Nutritional problems •  Hyperalimentation •  Malnutrition •  Rapid refeeding after starvation

t

Multisystem diseases •  Crohn’s disease •  Hemolytic uremic syndrome •  Reye’s syndrome •  Sepsis •  Sarcoidosis •  Shock (hypoperfusion)



Pancreatic-flow obstruction disorders •  Cystic fibrosis   Pancreas divisum •  Pancreatic/ductal anomalies •  Annular pancreas

S

 

Metabolic disorders •  Hyperlipidemia (primary type 1and1V) •  Diabetes mellitus •  Hypercalcemia •  Hyperparathyroidism •  Uremia



Physical injury •  Abdominal trauma(blunt or penetrating) •  Abdominal surgery •  Endoscopic retrograde cholangiopancreatography •  Posterior penetrating duodenal ulcer

iseases of Gas roin es inal ys em and iver

Table 9.19.1 Etiology of acute pancreatitis

Though the abdominal plain film can be completely normal in patients with acute pancreatitis, the most commonly recognized radiologic signs associated with acute pancreatitis include the following: • Air in the duodenal C-loop • The sentinel loop sign, which represents a focal dilated 599 proximal jejunal loop in the left upper quadrant

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Flow chart 9.19.1 Acute pancreatitis - pathogenesis

• •

The colon cut off sign, which represents distention of the colon up to the transverse colon with a paucity of gas distal to the splenic flexure (Fig. 9.19.1) One fifth of children may show evidence of pleural effusion on chest films.

•

Contrast-Enhanced Computed Tomography • •

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•

Local complications include pancreatic pseudocyst, necrosis and phlegmon or abscess formation, splenic artery pseudoaneurysms, hemorrhage from erosions into splenic artery and vein, thrombosis of the splenic vein, superior mesenteric vein and portal veins (in descending order of frequency), duodenal obstruction, common bile duct obstruction and progression to chronic pancreatitis. Systemic complications include ARDS, DIC, hypocal cemia (from fat saponification), hyperglycemia, multiple organ dysfunction syndrome, and insulin-dependent diabetes mellitus (from pancreatic insulin-producing beta cell damage). ­



•

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It is the standard imaging modality for the evaluation of acute pancreatitis and its complications. Using noncontrastenhanced CT, clinicians can establish the diagnosis and demonstrate fluid collections but cannot evaluate for pancreatic necrosis or vascular complications. Typical CT findings in acute pancreatitis include focal or diffuse enlargement of the pancreas, heterogeneous enhancement of the gland, irregular or shaggy contour of the pancreatic margins, blurring of peripancreatic fat planes with streaky soft tissue stranding densities, thickening of fascial planes, and the presence of intraperitoneal or retroperitoneal fluid collections. The fluid collections most commonly are found in the peripancreatic and anterior pararenal spaces but can extend from the mediastinum down to the pelvis. (Fig. 9.19.2) Complications of acute pancreatitis, such as pseudocysts, abscess, necrosis, venous thrombosis, pseudoaneurysms and hemorrhage, can be recognized with contrastenhanced computed tomography (CECT). Other adjunctive imaging modalities include ultra 600 sonography, MRI and angiography:

Ultrasonography is especially useful in the diagnosis of gallstones and follow-up observation of pseudocysts. Ultrasonography also can be used to detect pancreatic pseudoaneurysms. An enlarged, edematous-appearing pancreas usually suggests pancreatitis on ultrasound but the pancreas may appear completely normal in mild cases of acute pancreatitis. The diagnostic efficacy of MRI is comparable to that of CECT, although MRI examination is more time consuming and costly. Angiography is primarily used to help diagnose the vascular complications of acute pancreatitis.

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DeBanto et al. developed a prognostic scoring system to assess the severity of acute pancreatitis in children. The factors identified in this study were age less than 7 years, weight less than 23 kg, admission WBC more than 18,500, an admission lactate dehydrogenase (LDH) more than 2,000, ionized calcium of less than 8.3 mg/dL at 48 hours,

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Pain ontrol Meperidine (Demerol) is preferred to morphine for pain control because it is less likely to cause spasm of the sphincter of Oddi, which can worsen the pancreatitis. S

asogastric uction

Nasogastric suction is useful only when persistent vomiting or ileus is present.

Treatment of nfection I

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There are several scoring indices that have been used as predictors of survival. Two such scoring systems are the Ranson’s criteria and Acute Physiology and Chronic Health Evaluation (APACHE II) indices. Most but not all studies report that the APACHE score may be more accurate. These scoring systems are meant for adults and not well validated in children.

In the management of acute pancreatitis, the treatment is to stop feeding the patient, giving him or her nothing by mouth, and giving IV fluids to prevent dehydration. Fluid administration must be sufficient to replace “third spacing” and to maintain good urine output. In prolonged cases, peripheral or central IV nutrition may be necessary because of the high metabolic rate that accompanies pancreatitis. Recently, there has been a shift in the management paradigm from total parenteral nutrition (TPN) to early enteral feeding. The advantage of enteral feeding is that it is more physiological, prevents gut mucosal atrophy, and is free from the side effects of TPN.

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The mainstay of treatment is supportive with fluid resusci tation, analgesia and attention to nutritional needs and to limit systemic complications, prevents pancreatic necrosis and infection once necrosis has occurred (Flow chart 9.19.2).

Figure 9.19.2 Edematous necrotic pancreas

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Figure 9.19.1 Absence of colonic gas shadow beyond splenic flexure colon cut off sign

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Developed in the early 1990s by Balthazar et al. the Computed Tomography Severity Index (CTSI) is a grading system used to determine the severity of acute pancreatitis. The numerical CTSI has a maximum of ten points, and is the sum of the Balthazar grade points and pancreatic necrosis grade points Computed Tomography Severity Index staging of acute pancreatitis severity has been shown by a number of studies to provide more accurate assessment than APACHE II, Ranson and CRP level. However, a few studies indicate that CTSI is neither significantly associated with the prognosis of hospitalization in patients with pancreatic necrosis nor is it an accurate predictor of acute pancreatitis severity.

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althazar coring

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trough albumin less than 2.6 g/dL at 48 hours, 48-hour fluid sequestration more than 75 mL/kg/48 hours and a 48-hour rise in BUN more than 5 mg/dL. When the cut-off for predicting a severe outcome was set at three or more the author’s prediction rule was found to be more sensitive for predicting severe acute pancreatitis than Ranson scores (70% vs. 30%).

The role of antibiotics is controversial. Antibiotics are generally unnecessary, even in the presence of elevated white blood cell counts and fever; they should be used only 601 when infection is strongly suspected.

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Flow chart 9.19.2 Algorithm for management of acute pancreatitis

In severe pancreatitis, which forms a small percentage in children, the patient should be transferred to an intensive care unit for close monitoring. Fluid resuscitation helps to prevent hypotension and renal insufficiency, crystalloids may suffice but colloids may be necessary if there is hypoalbuminemia consequent to protein loss into the peritoneum. Cardiorespiratory monitoring is necessary to prevent hypoxemia, adult respiratory syndrome and cardiac complications like heart failure, myocardial infarction, cardiac arrhythmia and shock. S

urgical Treatment 602 Surgical management of acute pancreatitis is rarely

required. Surgical intervention is only needed if the

symptoms are severe and prolonged or complicated by necrosis or abscess formation that requires debridement. Peritoneal lavage has been used in adults in an effort to reduce the incidence of secondary infection; however, this has not been through trials with children to test its efficacy. If underlying pancreaticobiliary disease is present, surgical intervention is required for cure. Surgery for pancreatic ductal disruption or compromise (i.e. acute traumatic pancreatitis with ductal injury) is indicated after medical failure. Acute pancreatic pseudocysts, which are smaller than 5 cm in diameter, are managed with observation for 4–6 weeks. Most of them resolve spontaneously. Pancreatic pseudocysts larger than 5 cm in diameter may require surgical intervention.

anagement of evere Pancreatitis S

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Abbreviation: TPN, Total parenteral nutrition

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1. Balthazar EJ. CT diagnosis and staging of acute pancreatitis. Radiol Clin North Am. 1989;27:19-37. 2. Das S, Arora NK, Gupta DK, et al. Pancreatic diseases in children in a north Indian referral hospital. Indian Pediatr. 2004;41:704-10. 3. Gupta PK, al-Kawas FH. Acute pancreatitis: diagnosis and management. Am Fam Physician. 1995;52:435-43. 4. Weizman Z, Durie PR. Acute pancreatitis in childhood. J Pediatr. 1988;113(1 pt 1):24-31.



• Acute pancreatitis though rare in children, there is an increased incidence due to increased awareness among physicians. • Causes are plenty but blunt trauma, systemic causes and drugs are common etiologies.



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Cases of uncomplicated acute pancreatitis usually resolve within 2–4 days but severe acute pancreatitis may require parenteral nutrition for long. Diagnosis of the specific cause of pancreatitis is important to elucidate as there is a 9% recurrence rate, most of which are diagnosed with idiopathic recurrent pancreatitis or structural anomalies.

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• Pathogenesis still remains obscure in spite of many theories. • Diagnosis is possible in the presence of clinical suspicion with elevated amylase and lipase, which is then confirmed by imaging. • Management is essentially medical consisting of supportive care and prevention of complications and surgery is rarely needed. • Mild acute pancreatitis carries good prognosis though severe pancreatitis carries high mortality.

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Endoscopic sphincterotomy with stone extraction is the treatment of choice for pancreatitis secondary to obstruction of gallstone at the ampulla though it is found to be rare in children.

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hronic Pancreatitis in hildren Seema Alam

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Chronic pancreatitis is a progressive inflammatory disease of the pancreas leading to slow destruction of pancreatic parenchyma and progressive fibrosis. It causes exocrine and endocrine insufficiency eventually resulting in malabsorption of dietary nutrients, malnutrition, diabetes and severe unrelenting abdominal pain. Two forms are recognized: (1) a large-duct calcifying type and (2) a small-duct variant. Traditionally, CP has been classified as fundamentally different from acute pancreatitis—the latter is usually characterized by restoration of normal pancreatic histology after full clinical recovery. However, acute, recurrent acute and CP are now regarded as a disease continuum and there is an overlap in causative factors, both genetic and environmental.

pidemiology

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From the adult data it is apparent that the disease is uncommon in Europe, USA and Japan but the prevalence (114–200 per 100,000) is considerably higher in south India. Pancreatitis is rarely seen in children and the underlying etiologies differ greatly from those in adults. The number of cases seen per year ranged from 28 to 46 and the median age at first presentation was 12.5 years in a center in USA. Yachha et al. in the only Indian study have reported seven cases of CP in a decade at a tertiary center.

tiopathogenesis

It has been seen in experimental studies that an attack of pancreatitis begins as pancreastasis, prevention of apical exocytosis in the pancreatic acinar cell. The acinar cell quickly releases newly synthesized enzyme via the basolateral membrane into lymphatics, by way of the interstitium, and directly into the bloodstream. Some zymogen granules 604 also release their stored enzyme basolaterally. Oxidative stress has been implicated in the pathophysiology of CP. These events result in inflammation. Reactive oxygen



Tropical alcific Pancreatitis C

efinition

species are the trigger of so-called pancreastasis and as the potentiator of inflammation by activating signaling cascades that convert the damaged acinar cell into a factory for chemokines and cytokines. With time the secretory parenchyma is destroyed and replaced by fibrous tissue leading to malnutrition and diabetes. Pancreatitis in children is being increasingly recognized particularly in patients with multisystem disease. In adults the most common causes of pancreatitis are alcohol and biliary tract disease. Although most published pediatric series contain relatively few patients, it is clear that the etiologies of pancreatitis are quite varied in childhood. Unlike adults, most children have a single, self-limited episode of pancreatitis. Except for patients with cystic fibrosis, hereditary pancreatitis, and pancreatitis secondary to congenital malformations, few cases progress to chronicity. The most common etiologies found in a study were biliary tract disease, structural defects and hereditary whereas the rest of the children with CP were idiopathic. It is a controversial issue whether structural defect like pancreas divisum (PD) induces pancreatitis. The PD rate was significantly higher for all/chronic/recurrent idiopathic pancreatitis patients (35%/43%/33%) than for subjects in the community group (2.6%), but was not higher for acute pancreatitis (13%).

Tropical calcific pancreatitis (TCP) is another entity, which is common in the second decade of life. Tropical calcific pancreatitis is a juvenile form of chronic calcific, nonalcoholic pancreatitis, prevalent almost exclusively in the developing countries of the tropical world. Some of its distinctive features are younger onset, presence of large intraductal calculi, exocrine insufficiency, high prevalence of diabetes, accelerated course of the disease and high susceptibility to pancreatic cancer. As described before in the hereditary pancreatitis, the activation of trypsinogen to trypsin was shown to play a key role in the pathogenesis. In addition, various sites of trypsinogen, serine protease 1 mutations have been reported. The serine protease inhibitor Kazal type 1 secreted from pancreatic acinar cells into the pancreatic juice, is a potent trypsin inhibitor that prevents the trypsin-catalyzed premature activation of zymogens in the pancreas and pancreatic duct. However, mutations in trypsinogen gene do not play an important role in causing CP in Asia Pacific region. Cystic fibrosis transmembrane conductance regulator gene, which is also known as another causative gene in chronic pancreatitis, should also be looked though the incidence should be very low in Indian children. Alpha 1-antitrypsin is of particular interest because it may prevent pancreatic autodigestion by inhibiting protease activity.

Chronic pancreatitis (CP) is an uncommon clinical problem in pediatric gastroenterology practice. More than 50% of children with CP present initially with episodes of acute pancreatitis and subsequently with recurrences by 10–12 years of age and the rest will have an insidious onset with or without abdominal pain. It is a chronic disorder of complex etiopathogenesis. Though many classification systems have been proposed for CP in adults, an ideal, simple, objective and reproducible classification for childhood CP is still awaited. The staging of CP reflects the extent of the damage at a particular time point and has primarily a prognostic implication. D

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An Indian study emphasized the role of multidisciplinary approach in management of such cases (please refer Yachha et al. in suggested to read section). The management of CPis focused on the following (Table 9.20.1).

lleviation of Pain

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Tests of Pancreatic tructure

An abdominal radiograph will show pancreatic calculi in at least 30% of patients overall and 90% of patients with tropical pancreatitis. Abnormalities in the pancreatic duct system on MRCP and ERCP are the most efficient diagnostic techniques with the former substantially better at detecting small-duct disease than the latter. Multidetector CT, which provides excellent images of the main pancreatic duct but not always of the side-branch, changes as shown by ERCP; secretin-enhanced MRCP, which also shows duodenal filling by pancreatobiliary secretions, is more accurate than standard MRCP in identifying small-duct disease; secretin enhanced MRCP has a sensitivity of 73.3% in diagnosing PD (Figs 9.20.1A to C). Endoscopic ultrasound (EUS) identifies both parenchymal and ductal alterations but is observerdependent. Finally the clinician should suspect hereditary pancreatitis and start a search for genetic mutations (refer to etiopathogenesis).

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An abnormal liver function profile suggests sclerosing cholangitis, gallstones or constriction of the intrapancreatic bile duct in autoimmune pancreatitis.

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Presenting features of CP usually fall into one of the three groups: 1. Apparent acute or recurrent acute pancreatitis with constant pain 2. Symptoms and signs of local complications of the disease (e.g. pseudocyst, obstruction of adjacent organs or vascular thrombosis) 3. Complaints that suggest exocrine or endocrine pancreatic failure, or both, by which stage pancreatic calculi are often present. Pain is the over-riding symptom in all but 10–15% of cases of CP. Those who do not present with pain could be those with idiopathic disease or patients with autoimmune pancreatitis who might present with steatorrhea, diabetes or jaundice. The pain occurs in episodes that last about 1 week, or is constant. It starts in the epigastrium and moves through the dorsal spine or localizes to the left hypochondrium, radiating to the left infrascapular region. The pain is sometimes associated with nausea and vomiting and can be partially eased by sitting up and leaning forward or by application of local heat or other counterirritants to the dorsal spine or epigastrium. The pain can be so severe that patient fears food and loses weight. Erythema ab igne is a useful pointer for diagnosis of CP. An epigastric swelling suggests a pseudocyst or an inflammatory mass. Patients with multisystem involvement usually have the autoimmune form of CP. Although the risk of pancreatic cancer is especially high in patients with hereditary pancreatitis, they do not have a higher mortality risk than the general population.

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linical eatures

If autoimmune disease is a possibility, serology will show raised concentrations of IgG4 predominantly, and antilactoferrin, anticarbonic anhydrase, rheumatoid factor and antinuclear antibody. Imaging tests show distinctive changes in autoimmune pancreatitis.

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An association has been suggested investigating alpha 1-antitrypsin phenotypes or serum levels in patients with pancreatitis.

Ultrasonography Computed tomography Endoscopic retrograde cholangiopancreatography. Endoscopic ultrasonography. F

Tests of Pancreatic unction Tests of exocrine pancreatic function – Sudan Black staining for fat globules in stool – Fecal elastase – Fecal chymotrypsin Tests of endocrine pancreatic function: glucose tolerance test. –

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ipid Profile and erum alcium for Type-1 Hyperlipidemia and Hypercalcemia Lipid profile and serum calcium for type-1 hyperlipidemia and hypercalcemia respectively should be looked for in patients with suspected chronic pancreatitis.

Pain is the most common and most disabling symptom of CP, and is the cause of frequent hospitalizations. In initial evaluation of pain, associated conditions should be identified, which have a specific therapy like pseudocyst, pancreatic fistula and ascites, duodenal or biliary compression and gastroparesis. Modalities for pain relief are medical, endoscopic, interventional or surgical. ­

• • • •

Medical Therapy •

Analgesics and pancreatic enzyme supplements are mainstay in relieving pain of pancreatitis. Most CP patients need some form of analgesia in the form of nonopioid narcotics (acetaminophen, aspirin) but usually these agents fail. In the opioid group, agents with least potency should be used, like propoxyphene, tramadol or meperidine. Tramadol is a dual action analgesic 605 with mu-opioid and monoaminergic properties, higher doses produce analgesia similar to morphine. The dose

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Figures 9.20.1A to C (A) MRI showing atrophied pancreas with dilated main pancreatic duct; (B and C) Magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography of the same patient showing a dilated main pancreatic duct

•

• •

606

is gradually increased to an acceptable pain level rather than complete pain relief. During each acute painful attack in CP, pancreas is “put to rest” with no oral feeding and use of IV fluids and electrolytes for initial 1–2 days, followed by gradual reintroduction of feeds. Adjunctive more potent agents include selective serotonin reuptake inhibitors like fluoxetine and duloxetine. Role of these agents in small children is less well established. Pancreatic enzyme supplements are also used to alleviate pain of CP. The basis for their use is ability to activate the feed-back control to reduce pancreatic secretion. Randomized controlled trials in adults showed effectiveness in relieving pain with nonentericcoated enzyme preparations, but no benefit with enteric-coated microsphere preparations. The basis for this difference is that feed-back sensitive part of small bowel is the most proximal portion, and entericcoated preparations may not release most of their proteases until they reach the more distal small bowel. As the nonenteric coated preparations are destroyed by gastric acid, concomitant acid suppression with

•

H2 receptor blockers (H2RA) like ranitidine (3–5 mg/ kg/dose 2–3 times a day) or PPI, like omeprazole in a dose of 0.7–0.33 mg/kg/day in 1–2 divided doses) are recommended. The dose of pancreatic enzyme supplements is calculated according to lipase content (pediatric dosage children is 1000–2500 U of lipase/kg/ meal). Nonenteric coated preparations are not available in India. Other medical therapies of benefit are antioxidants (selenium, beta-carotene, vitamins C and E, methionine) and octreotide. Octreotide acts by decreasing pancreatic secretion and reducing circulating cholecystokinin levels. Steroids are indicated only in autoimmune pancreatitis in a dose of 30–40 mg/day (2 mg/kg/day) with gradual taper over 3 months period and a maintenance dose of 5–7.5 mg/day (0.1–0.2 mg/kg/day).

Endoscopic Therapy The goal of endoscopic therapy is to improve pancreatic ductal drainage by relieving obstruction. The potential application of endoscopic therapy is applicable to limited subgroup of patients with large duct CP with dilated

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Table 9.20.1 Modalities for management of chronic pancreatitis and complications

Others

Antioxidants Octreotide Steroids for autoimmune pancreatitis

Relief of pain

Pancreatic duct sphincterotomy Stent placement Stone removal Basket retrieval with or without lithotripsy (mechanical or extracorporeal shock-wave lithotripsy)

Drainage of pseudocyst

Transpapillary Transluminal Cystoduodenostomy Cystogastrostomy

Pancreas divisum

Minor papillotomy and stent placement

Biliary stricture and obstruction

Papillotomy and biliary stenting

Gastric or esophageal variceal bleed

Endotherapy for varices (banding, sclerotherapy or glue)

Pancreatic fistula

Stent placement in pancreatic duct over site of ductal disruption

Drainage of pseudocyst

Percutaneous - CT guided

Pseudoaneurysm

Angiographic demonstration and coil embolization

Drainage procedures

Side-to-side pancreaticojejunostomy (Puestow’s) Distal pancreaticojejunostomy (Duvale’s)

Pseudocyst

Cyst excision with drainage procedure

Biliary obstruction

Bypass - Hepatojejunostomy or choledochojejunostomy

These modalities are used in adults with intractable pain. Combination of glucocorticoids and bupivacaine is used for celiac plexus block, whereas absolute alcohol is used for neurolysis. The procedure can be done under CT or endoscopic ultrasound (EUS) guidance.

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anagement of Pancreatic xocrine ysfunction Malabsorption and steatorrhea with related nutritional deficits: maldigestion, steatorrhea and nutritional defi

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Diabetes in TCP usually develops before development of exocrine insufficiency and the severity is proportional to number and size of pancreatic calculi and calcifications. Management of diabetes in TCP is similar as in any other diabetic except that liberal caloric and protein intake is advised because of underlying malnutrition, and these patients are more prone to hypoglycemic episodes. Oral hypoglycemic agents may be used in the initial phase, but most patients ultimately require insulin. Microvascular complications of diabetes should be looked for in follow up. M

Surgical Therapy Indications for surgery in cases with CP include intractable abdominal pain or associated complications of chronic pancreatitis. Drainage procedures are commonly used; side-to-side pancreaticojejunostomy (Puestow) or distal pancreaticojejunostomy (Duvale) either alone or combined with localized pancreatic resection.

anagement of iabetes and ts omplications C

Nerve Blocks and Neurolysis

ciencies: pancreatic enzyme supplements are advised with a dose of lipase being 1,000–2,500 U of lipase/kg/meal (30,000 U/meal for adults). Enteric coated preparations are preferred, which are given along with H2RA or proton pump inhibitor (PPI), and should be spread over each meal. Efficacy of treatment is assessed by change in stool consistency, loss of visible fat and improvement in weight. Fat soluble vitamins (A, D, E and K) should be supplemented in a dose 2–3 times of recommended dietary allowance. I

pancreatic duct with or without dominant stricture or obstructing stone in pancreatic duct. The modalities include pancreatic duct sphincterotomy, stent placement and stone removal. Usually a combination of modalities is needed in most of the patients. Patients with PD presenting with CP and upstream ductal dilatation usually benefit from minor sphincter papillotomy and stent placement.

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Pancreatic enzyme supplements

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Nonopioids: NSAIDs like aspirin Opioids: Propoxyphene, tramadol, meperidine Pain modulators: Fluoxetine, duloxetine, gabapentin, pregabalin

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Analgesics

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Pancreatic Pseudocyst

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Pseudocyst occurs in 25% of cases of adults with chronic pancreatitis, but the prevalence is not known in children.

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Children should be educated not to take alcohol or smoke as alcohol increases the pain and severity of CP, and smoking doubles the risk of pancreatic malignancy in hereditary pancreatitis.

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1. Garg PK, Tandon RK. Survey on chronic pancreatitis in the AsiaPacific region. J Gastroenterol Hepatol. 2004;19:998-1004. 2. Gonoi W, Akai H, Hagiwara K, et al. Pancreas divisum as a predisposing factor for chronic and recurrent idiopathic pancreatitis: initial in vivo survey. Gut. 2011;60(8):1103-8. . 3. Gullo L, Migliori M, Olah A, et al. Acute pancreatitis in five European countries: etiology and mortality. Pancreas. 2002;24(3):223-7. 4. Lopez M. The changing incidence of acute pancreatitis in children: a single-institution perspective. J Pediatr. 2002;140(5):622-4. 5. Tandon RK. Tropical Pancreatitis. J Gastroenterol. 2007;42:141-7. 6. Werlin SL, Kugathasan S, Frautschy BC. Pancreatitis in children. J Pediatr Gastroenterol Nutr. 2003:37:591-5. 7. Yachha SK, Chetri K, Saraswat VA, et al. Management of childhood pancreatic disorders: a multidisciplinary approach. J Pediatr Gastroenterol Nutr. 2003:36:206-12.



ibliography





Healthy Lifestyles



easures



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• Chronic pancreatitis should be differential diagnosis of patients with recurrent abdominal pain of the upper abdomen and periumbilical especially where it is associated with weight loss. • All these cases should undergo CT scan, MRCP and ERCP for diagnosis and etiologic workup. • All cases should be assessed for pancreatic exocrine and endocrine dysfunction. • Pain alleviation, pancreatic enzyme replacement therapy and drainage of the local complications like pancreatic pseudocyst are the mainstay of treatment.

Other Complications Rarely, complications like bile duct obstruction, duodenal obstruction or stenosis and pancreatic fistula may develop. Biliary obstruction is usually managed with endoscopic therapy and stent exchange. Surgery in the form of bypass is indicated for most of them as definite therapy. Pancreatic fistulas may be external or internal. External fistulas usually develop following surgery or percutaneous drainage, and may take weeks to heal. Internal fistulas usually occur after rupture of pseudocyst and may track to peritoneal cavity (pancreatic ascites) or pleural space (pancreatic pleural effusion). Diagnosis is established through documentation of high amylase levels in respective fluids. Complete bowel rest, hyperalimentation and octreotide are indicated for management of both types of fistulas. Additionally, endoscopic stent placement across the site of ductal disruption effectively closes the fistula rapidly.

Genetic mutations are important to look for in idiopathic chronic pancreatitis (for details see the etiopathogenesis). Newer radioimaging modalities (e.g. EUS, secretin enhanced magnetic resonance cholangiopanc reatography (MRCP) and multidetector computed tomography (MDCT) would give better yield for diagnosis of CP and structural defects like PD. ­

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Bleeding in the setting of CP may occur because of bleeding in pseudocyst, rupture of pseudoaneurysm, variceal bleed secondary to portal or splenic vein thrombosis or because of nonsteroidal anti-inflammatory drug (NSAID) related ulcer or gastric erosions. Bleeding within pseudocyst or rupture of pseudoaneurysm may be slow, intermittent or acute and massive, which may remain confined to peritoneal or retroperitoneal compartments or may manifest as hemosuccus pancreaticus (bleed into pancreatic duct presenting as pain, jaundice and melena). Therapeutic options are either embolization or surgery.

Considering 50 and 17 times increased risk of pancreatic cancer in hereditary and tropical pancreatitis, respectively, children should be screened for malignancy in follow-up. Age to start screening has been recommended to begin from 35 years or 10 years before onset of malignancy, in cases with family history of pancreatic cancer. Diagnostic screening modality is either CT or EUS.



Gastrointestinal Bleeding

Screening for Malignancy



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Complications include compression of surrounding viscera or vessels, infection, hemorrhage, pseudoaneurysm or pancreatic fistula formation with resultant pancreatic ascites or pleural effusion. Therapy is indicated for symptomatic, enlarging or complicated pseudocyst and includes CT guided percutaneous or endoscopic drainage or surgery. Endoscopic drainage procedures may be done either through the papilla (transpapillary) or through the wall of stomach (cystogastrostomy) or small intestine (cystoduodenostomy or -jejunostomy). Surgical drainage for cyst is usually combined with ductal drainage procedures.

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Section

10 Diseases of Kidney and Urinary Tract Section Editor : Arvind Bagga

































10.1 10.2 10.3 10.4 10.5 10.6 10.7 10.8 10.9 10.10 10.11 10.12 10.13 10.14

The Kidney: Structure and Function: BR Nammalwar Diagnostic Evaluation of Kidney and Urinary Tract: RN Srivastava Developmental Anomalies: Susan Uthup Glomerulonephritis: Kamran Afzal Renal Vasculitis and Lupus Nephritis: Sushmita Banerjee Acute Kidney Injury: Arvind Bagga Nephrotic Syndrome: Arvind Bagga Urinary Tract Infection, Vesicoureteric Reflux and Reflux Nephropathy: M Vijayakumar Disorders of Micturition and Obstructive Uropathy: Madhuri Kanitkar Chronic Kidney Disease, Renal Replacement Therapies: Kishore D Phadke Renal Tubular Diseases: Aditi Sinha Asymptomatic Hematuria: Indira Agarwal Nephrolithiasis: Uma Ali Hypertension: Pankaj Hari

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The Kidney: Structure and Function BR Nammalwar

The kidneys maintain the extracellular volume, osmolality, and electrolyte and acid base balance. They regulate arterial blood pressure and calcium, phosphorus and magnesium metabolism, remove metabolic nitrogenous waste pro­ ducts, toxins and drugs, and produce hormones, vitamin D, erythropoietin, renin and vasoactive amines.

Gross Anatomy

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The kidneys are paired organs that lie on the posterior wall of the abdomen behind the peritoneum on either side of the vertebral column. They grow rapidly in the first year of life, from 4.5 cm in length at birth to 6.5 cm and to 11 cm in adulthood. The renal artery, vein and nerves enter the kidney on its medial aspect. The renal tissue is divided into an outer region called cortex, and an inner medulla composed of nephrons, blood vessels, lymphatics and nerves. The medulla is divided into conical masses called renal pyramids with intervening columns. The bases of the pyramids originate at the corticomedullary border and the apices are the papillae, which project into the minor calyces, wherein urine is collected from the papillae. The minor calyces are cup like structures that join to form three or four major calyces within each kidney. In turn, the major calyces unite to form the pelvis, the upper expanded region of the ureter, which carries urine to the urinary bladder.

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Renal Vascular System

The nephron consists of a glomerulus, proximal tubule, loop of Henle, distal tubule and collecting duct system (Fig. 10.1.1). The glomerulus is responsible for filtering the blood, providing a barrier to the passage of protein and cells into the urine. It consists of a network of capillaries supplied by the afferent arteriole and drained by the efferent arteriole. These capillaries press into the closed end of the proximal tubule that forms the Bowman’s capsule of the glomerulus. The capillaries are covered by epithelial cells called podocytes, which form the visceral layer of the Bowman’s capsule. The visceral cells continue at the vascular pole to form the parietal layer of the Bowman’s capsule. The space between the visceral and the parietal layer is the Bowman’s space, which becomes the lumen of the proximal tubule at the urinary pole of the glomerulus (Fig. 10.1.2). The endothelial cells of the glomerular capillaries are covered by a basement membrane, which is surrounded by podocytes. The capillary endothelium, basement membrane and foot processes of podocytes form the filtration barrier. The endothelium is fenestrated and is freely permeable to water, small solutes and most proteins but impermeable to cellular components. The endothelial cells have negatively charged glycoproteins on their surface, which retard filtration of anionic proteins into Bowman’s space. These cells synthesize several vasoactive substances, angiotensin, prostaglandins, nitric acid, endothelin 1, bradykinins and glucocorticoids that are important in controlling renal flow. The basement

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The renal artery divides into five segments, which sub­ sequently branch along the pyramids to form interlobar arteries, arcuate arteries, the interlobular arteries and the afferent arterioles, which form the glomerular capillaries. Glomerular capillaries come together to form the efferent arteriole, which leads into a second capillary network, the peritubular capillaries, which supply blood to the remainder of the nephron. The vessels of the venous system run parallel to the arterial vessels and progressively form the interlobular, arcuate, interlobar and renal veins.

Nervous System

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Sympathetic fibers originating in the lower splanchnic nerves travel through the lumbar ganglion to the kidney. Stimulation of the sympathetic nervous system reduces renal blood flow by causing intrarenal vasoconstriction. It also stimulates the local renin angiotensin aldosterone system and enhances sodium reabsorption.

Structure and Function of the Nephron Figure 10.1.1 Diagrammatic presentation of segments of the nephron (1—afferent arteriole; 2—glomerular capillary network; 3—efferent arteriole)  

The functional unit of the kidney is the nephron. Each

610 human kidney contains approximately 1.2 million nephrons.

vip.persianss.ir

iseases of



idne and rinar

-

ract



-

-

-



yT

-

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K



collecting duct. Numerous collecting ducts join and open through the ducts of Bellini into a minor calyx at the papillary tip of the pyramid. The filtrate produced by the glomerulus enters the tubule where reabsorption and secretion of fluid and electrolytes adjust the urinary composition to maintain homeostasis of body fluids. Each segment of the nephron has specific transport functions (Table 10.1.1). The processes of reabsorption of solutes and water from the tubular lumen across the tubular cell membrane to the peritubular capillary blood and secretion into tubular fluid are mediated by diffusion, channels or specialized membrane carrier proteins called “transporters”. Active transporters include Na+/K+ ATPase, Ca2+ ATPase, H+/K+ ATPase and H+ ATPase. The passive transporters are Na+/K+/ Cl and Na+ glucose co transporters and Ca2+/Na+ and H+/ Na+ exchanger. Almost all cells in the nephron have a single nonmotile primary cilium that protrudes into the tubular lumen. These cilia function as mechanosensors, sensing changes in flow rate of the tubule fluid, and chemosensors, sensing or responding to compounds in the surrounding fluids to initiate calcium dependent signaling pathways including those that control nephron function, proliferation, differen­ tiation and apoptosis. Nephrons are classified by their location as superficial and juxtamedullary. The glomeruli of superficial nephrons are located in the outer cortex. These nephrons have short loops of Henle, and have efferent arterioles that branch into peritubular capillaries surrounding adjacent nephrons in addition to their own segments. This capillary network provides a pathway for the return of reabsorbed water and solutes to the circulatory system. The glomeruli of

D

membrane is a porous matrix of anionic proteins that includes type IV collagen, laminin, the proteoglycans agrin and perlecan and fibronectin, and is an important barrier to filtration of plasma proteins that functions primarily as charge selectivity filter. The podocytes have long finger like foot processes that interdigitate to cover the basement membrane and are separated by apparent gaps called filtration slits. Each filtration slit is bridged by a thin diaphragm that contains pores (Fig. 10.1.2). The slit diaphragm is composed of several proteins including nephrin, podocin, alpha actinin 4 and CD2AP. These filtration slits function primarily as a size selective filter that retards the filtration of proteins and macromolecules. In addition to phagocytosis of the proteins, podocytes are involved in the production and maintenance of the glomerular basement membrane (GBM) through a well developed Golgi apparatus. The proximal tubule initially forms several coils, followed by a straight piece that descends toward the medulla. The loop of Henle is composed of the straight part of the proximal tubule, a descending thin limb, which ends in a hairpin turn, an ascending thin limb and a thick ascending limb. The juxtaglomerular apparatus is located at the end of the ascending limb where the nephron passes between the afferent and the efferent arterioles of the same nephron. This consists of an area of thickened epithelial cells of the afferent arteriole, the granular cells, an area of specialized cells lining the wall of the distal tubule, the macula densa cells and the extraglomerular mesangial cells. The juxtaglomerular apparatus activates the renin angiotensin aldosterone axis and participates in sodium conservation. The distal tubules of two or more nephrons join to form a cortical collecting duct, which continues as the medullary

 

Figure 10.1.2 Diagrammatic presentation of structure of the glomerulus. Inset shows electron microscopic presentation of glomerular capillary wall showing the components of the filtration barrier

611

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Sites Proximal tubule

of ook e

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T x b

Function Reabsorption

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ediatrics

Table 10.1.1 Tubular functions

Henle’s loop •  Thin descending limb •  Thin ascending limb •  Thick ascending limb

Secretion

Bicarbonate (80%) Calcium (70%) Phosphorous (80%) Magnesium (15%) Potassium (67%) Proteins as amino acids (100%) Sodium and chloride (67%) Urea (67%) Water (67%) Urea

Water (15%) Sodium chloride (25%) Bicarbonate (10%) Calcium Magnesium (60%) Potassium (20%) Ammonium (variable) Calcium (20%) Sodium chloride (25%)

Distal tubule

Bicarbonate (10%) Calcium (9%) Magnesium (5%) Phosphorus (10%) Sodium chloride (5%)

Collecting duct

Bicarbonate (4%) Potassium (Nil) Sodium chloride (3%) Urea (variable) Water (variable)

Ammonium (variable) Bicarbonate in metabolic alkalosis Potassium (0–70%) Urea (variable)

1. Eaton DC, Pooler JP. Vander’s Renal Physiology, 7th edition. New York: McGraw Hill; 2009. 2. Koepen BM, Stanton BA. Renal Physiology, 4th edition. Philadelphia: Mosby; 2009.



ibliography





juxtamedullary nephron are located at the corticomedullary junction while their loops of Henle are long and extend deep into the medulla. Their efferent arterioles form a network of peritubular capillaries as well as several vascular loops called the vasa recta deep in the medulla. The long loops of Henle and their vasa recta help to concentrate the urine.

B

Source: Koeppen BM, Stanton BA. Renal Physiology, 4th edition. Philadelphia: Mosby, Elsevier; 2007. pp. 19-30.

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Diagnostic valuation of Kidney and Urinary Tract E





Diseases of Ki ney an Urinary Trac

10.2

RN Srivastava

dema

O

Facial edema is an important feature of renal disease and is often ignored unless acute and associated with other abnormalities such as gross hematuria or oliguria. Nephrotic syndrome characteristically manifests with gradually increasing periorbital edema, which is often mistakenly attributed to an allergic or eye problem. In acute glomerulonephritis (GN), edema is turgid and persistent whereas in nephrotic syndrome, the swelling is soft and pits on pressure. Nephrotic syndrome is easily differentiated from other causes of edema such as congestive cardiac failure and cirrhosis of liver.

liguria

A decrease in urine volume denotes renal dysfunction. Oliguria is defined as a urine output less than 500 mL/ day/1.73 m2 or less than 0.5 mL/kg/hour (< 1 mL/kg/hour in newborns). Anuria may result from severe dehydration and hypovolemia, complete obstruction of the urinary tract or profound renal parenchymal injury.

A

d d t

bdominal Pain

A

Flank pain is often present in acute pyelonephritis and nephrolithiasis. Young children may not be able to localize the pain. Ultrasonography is a useful tool for evaluation of the anatomy of kidneys and urinary tract.

bnormalities of Micturition

Constant bedwetting, weak urinary stream, dribbling and crying during micturition are abnormal and require evaluation. Distal obstruction, most commonly from posterior urethral valve, should be excluded in male infants. Persistent dribbling suggests abnormal ureteric insertion distal to bladder neck. Spinal dysraphism should be excluded in patients with neurogenic bladder.

nuresis and Daytime ymptoms S

E

Hematuria Urine color may vary from frank red to shades of brown, described as cola or tea colored. A small amount of blood (1 mL in 1 L of urine) is sufficient to make urine appear red. Concentrated urine looks like mustard oil, and is often mistakenly reported as hematuria. Myoglobinuria, porphyria or alkaptonuria may cause brown discoloration of urine, while administration of rifampicin and pyridium and ingestion of sugar beet or red dyes impart a reddish orange color. Hematuria should be confirmed by micro­ scopy, and is differentiated from hemoglobinuria and methemoglobinuria. Important causes of hematuria and steps of evaluation are listed in Chapter “Asymptomatic Hematuria”.

Urine outputs in excess of 4–6 mL/kg/day reflect impaired urinary concentration. Polydipsia is often associated. Conditions causing excessive solute excretion (osmotic diuresis, e.g. diabetes mellitus) or reduced proximal tubular reabsorption (Fanconi syndrome and isolated hyper­ calciuria) lead to mild polyuria. Impaired distal concentration due to vasopressin deficiency (central diabetes insipidus) or lack of tubular response to vasopressin (nephrogenic diabetes insipidus) will lead to profound water losses. Distal tubular dysfunction may result from obstructive uropathy, chronic hypokalemia or interstitial nephritis. Polyuria and polydipsia are important features of nephronophthisis, a familial nephropathy that manifests during infancy.

E

Common presenting features suggestive of an underlying renal disease include gross hematuria, edema, dysuria, flank pain and decrease in urine output.

Polyuria

Involuntary voiding occurring only at night and being the only complaint (monosymptomatic nocturnal enuresis) is quite common in young children, and does not require detailed investigation. Voiding problems during daytime, such as urgency, frequency or holding maneuvers, suggest an underlying bladder dysfunction. Detailed history and examination including neurological evaluation (anal tone, sensory loss over the perineum) are carried out. Recurrent urinary tract infections (UTIs) are commonly associated. Urine flowmetry and study of bladder function may be required. A

linical eatures F

C

There are only a few specific manifestations of renal diseases in infants and children. Other clinical features are subtle or vague and do not lead to a suspicion of an underlying renal disorder. Kidney diseases should be considered in children with failure to thrive, unexplained fever, obscure anemia, rickets and dyselectrolytemia and acid base abnormalities. A family history of renal disease should always be obtained.

bnormalities on Urinalysis

Microscopic hematuria [more than 5 RBC/high power field (HPF)] is not uncommon in an asymptomatic child on routine urinalysis. It may be associated with mild to moderate proteinuria. The presence of these abnormalities should be confirmed on repeated, careful urine examination.

613

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Timed Urine ollection

B

F

Presence of dysuria, flank pain and cloudy urine suggests UTIs. Tenderness in the renal angle and fever indicate pyelonephritis. Features suggestive of chronic kidney dis­ ease (CKD) include hypertension, growth retardation and normocytic normochromic anemia. Presence of palpable kidney(s) may suggest multicystic dysplastic kidney, poly­ cystic kidney disease, pelviureteric junction obstruction or Wilms tumor.

-

Because of difficulties in accurately collecting all specimens of urine, 12 hour or 24 hour collections are undertaken when definitely needed, e.g. for quantitative measurement of calcium, phosphate, creatinine, magnesium or oxalate for the diagnosis of metabolic abnormalities underlying urolithiasis (see Chapter 10.13) or in evaluation of tubular dysfunction (see Chapter 10.11). -

ther eatures

more accurately, in a counting chamber. More than five neutrophils/HPF with bacteriuria suggest UTI. Microscopic hematuria is defined as the presence of more than five red cells/HPF in a centrifuged specimen. Phase contrast microscopy is helpful to examine red cell morphology, casts and crystals. Red cell casts indicate glomerular inflammation. Clumping of neutrophils (white cell casts) suggests acute pyelonephritis. C

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O

lood Tests

Proteinuria

Glomerular filtration rate =

E

Microscopic xamination Fresh, centrifuged specimen should be examined. Red

614 blood cells and leukocytes can be counted under HPF, and



k × height (in cm) Serum creatinine (mg/dL)

-





-



Where k = 0.42 for preterm infants; 0.45 for children less than 2 year old; 0.55 for older children. Serum albumin is reduced in patients with nephrotic syndrome proteinuria, occasionally below 1.5 g/dL. In children with nephrotic syndrome, hypercholesterolemia is typically present. The levels of complement factor 3 (C3) in blood are reduced in postinfectious GN, membranoproliferative glom­ erulonephritis (MPGN) and lupus nephritis. In systemic lupus erythematosus (SLE), C3 levels reflect disease activity; the normal range is between 70 mg/dL and 120 mg/dL. Antinuclear antibodies (ANA) are antibodies directed against chromatin associated or ribonucleoprotein par­ ticles. They are not specific and may be increased in many autoimmune diseases like SLE, juvenile rheumatoid arthri­ tis, polyarteritis nodosa (PAN) and autoimmune hepatitis. Antibodies to double stranded DNA (anti dsDNA) is specific to SLE, while increased titer of antineutrophil cytoplasmic -

-

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Urine protein is estimated with heat precipitation or sulfosalicylic acid as turbidity that is graded from trace, 1+ to 4+. Dipstick testing is more convenient and is graded similarly (trace: 15 mg/dL; 1+: 30 mg/dL; 2+:100 g/dL; 3+:300 mg/dL; 4+:2 g/dL). Composite sticks are available for examining pH, glucose, protein, RBCs, leukocyte esterase and nitrite. The latter two tests help in the diagnosis of UTI. Normal children excrete less than 100 mg/m2/day of protein in urine, which is chiefly tubular Tamm Horsfall protein. Since collection of 24 hour urine specimens is often difficult, the ratio of protein to creatinine in a random sample can be used. Normal values are less than 0.5 in infants and less than 0.2 in older children; values more than 2 suggest nephrotic range proteinuria.







Urinalysis

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E

Laboratory valuation



A detailed examination of urine is crucial in the evaluation of renal disease. The first morning specimen is more concentrated and preferred since formed elements lyse quickly in dilute urine. It is examined promptly or stored at 4°C. A midstream specimen can be obtained in older children, but in neonates and infants, transurethral catheterization or suprapubic bladder puncture may be carried out. Examination of urine specific gravity aids the evaluation for polyuria while the measurement of urine pH assists in determining tubular acidification abnormalities.

The normal level of blood urea ranges between 20 mg/ dL and 40 mg/dL. Factors that reduce renal perfusion can cause a reversible increase in blood urea levels. The levels are also increased in excessive tissue breakdown, trauma, gastrointestinal bleeding and use of corticosteroids and tetracycline. Urea levels are low in presence of hepatic failure and on a low protein diet. The level of serum creatinine varies inversely with the glomerular filtration rate (GFR) of which it is a better indicator than blood urea. Serum creatinine is not readily affected by prerenal factors. However, serum creatinine depends on muscle mass and may overestimate GFR in presence of malnutrition. Hyperbilirubinemia (bilirubin level > 5 mg/dL) interferes with the measurement of creatinine. Glomerular filtration rate may be estimated in children as follows:



t

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Tex boo of Pe ia rics

Microscopic hematuria associated with proteinuria suggests an underlying glomerular, or occasionally tubulointerstitial abnormality. Isolated microscopic hematuria is most commonly due to idiopathic hypercalciuria (defined as random urine calcium: creatinine ratio of > 0.2 or 24 hour urine calcium more than 4 mg/kg body weight). Transient, mild proteinuria may be observed during fever following exercise, and during infections. Persistent proteinuria is most commonly due to renal disease and should always be investigated to find the cause.

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Performance of diagnostic imaging in children requires expertise, experience and patience. Appropriate sedation should be used whenever required. Care is taken to minimize exposure to both radiation and radiocontrast. Common imaging techniques used are listed below. A

X

Plain -ray of the bdomen

d

d

The micturating cystourethrogram (MCU) is useful for the diagnosis and grading of vesicoureteric reflux (VUR) (Fig. 10.2.1), and detection of bladder and urethral abnormalities. Following urinary catheterization, radiocontrast agent is introduced into the bladder; films are taken while the child is voiding. Strict aseptic precautions are required. Oral amoxicillin or parenteral gentamicin (administered 30–60 minutes prior to the procedure and 6 hours afterward) may be administered prophylactically.

Ultrasonography Ultrasound gives excellent information on anatomical aspects (Fig. 10.2.2). It is especially suited for children since it is painless, requires no sedation or radiocontrast administration, and can be repeated safely. Ultrasound is useful in guiding procedures such as renal biopsy or fine needle aspiration. The major limitation of ultrasonography is that it is operator dependent; interpretation in children requires considerable experience. The renal cortical echotexture is compared with liver, spleen and renal medulla; nonspecific changes may occur with renal parenchymal disease. Measurement of renal size helps assess its growth. Doppler evaluation is useful for assessment of blood flow.

The use of intravenous pyelography (IVP) or excretory urography has declined due to the advent of ultrasonography and radionuclide studies. It is currently indicated for detailed evaluation of structural anomalies, e.g. duplex kidneys and horseshoe kidneys, and for ureteric calculi. Intravenous pyelography requires bowel preparation and administration of an ionic contrast

 

Figure 10.2.1 Micturating cystourethrogram showing bilateral grade V vesicoureteric reflux in a 3-year-old boy with recurrent urinary tract infections. The urethra is not visualized

ntenatal Ultrasound

Evaluation in antenatal period allows detection of common abnormalities such as unilateral or bilateral hydronephrosis

Figure 10.2.2 Ultrasound study in a 6-year-old boy showing hydronephrosis; note enlarged kidney and dilated renal pelvis  

ntravenous Pyelography

A

I



A plain radiograph has limited utility, chiefly in detecting small renal calculi and ureteric calculi without proximal ureteral dilatation. Radiographs also assist in the evaluation of the spine in children with neurogenic bladder, assess­ ment for changes of renal osteodystrophy and screening for metastatic bone disease.

Micturating ystourethrogram

t

maging tudies S

I

Testing for specific tubular function is indicated by clinical features. For example, children with polyuria may require water deprivation testing and vasopressin administration, and bicarbonate or ammonium chloride loading tests are performed in those with impaired urinary acidification. These tests are discussed in Chapter 10.11.

C

F

Tests of Tubular unction

(urograffin, 3–4 mL/kg) with films taken at 1–5 minutes, 10–15 minutes and a late pelvic film for the bladder. Hydration is necessary to avoid contrast nephropathy. The test is avoided in neonates since urinary concentration of the contrast is inadequate.

Diseases of Ki ney an Urinary Trac

antibody (ANCA) is seen in a group of small vessel vasculitis, including microscopic polyangiitis, Wegener’s granuloma­ tosis and renal limited vasculitis.

615

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Noncontrast helical computerized tomography (CT) scan­ ning is useful in identifying very small calculi, which might not be detected on ultrasonography. CT provides excellent anatomical details, which is especially useful in evaluating abdominal masses (e.g. tumor or abscess). Disadvantages include radiation exposure, the need for sedation and risks of contrast nephropathy.

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-

-

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learance tudies

Agents such as 51Cr ethylenediamine tetra acetic acid (EDTA) and 99mTc DTPA are used for estimation of total and differential glomerular filtration. 131I ortho iodohippurate helps determine effective renal plasma flow.

a

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Renography or renal perfusion study monitors the arrival, uptake and elimination of a radiopharmaceutical by the kidney. Agents used include 99mTc labeled diethylene­

-

enography

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R

C

Radionuclide methods are increasingly replacing conven­ tional radiocontrast studies such as IVP and angiography, since they are noninvasive, highly sensitive and involve lower radiation exposures. They are used to assess differential renal function and renal perfusion, and to identify cortical scars, intrarenal masses and upper tract dilatation. Important techniques are described.

Renal static imaging provides a two dimensional depiction of the concentration and distribution of radionuclide. 99m Tc labeled dimercaptosuccinic acid (DMSA) and gluco­ heptonate (GHA) provide excellent quality of images. 99mTc DTPA visualizes the pelvicalyceal collecting system and ureters well. Due to its concentration in the renal cortex and a slow rate of urinary excretion, DMSA is particularly useful for demonstration of renal scarring (Fig. 10.2.4), identification of ectopic kidneys and in detecting damage from trauma. Imaging with GHA is useful when evaluating abnormalities in both the cortex and collecting system since it is filtered, partially reabsorbed and retained in proximal tubular cells.

-

I

adionuclide maging

enal tatic maging

S

-

Magnetic resonance imaging (MRI) is used for the detection of spinal abnormalities such as tethered cord. MRI provides superior resolution and avoids radiation. However, the procedure requires sedation. The use of gadolinium based contrast in patients with impaired renal function carries the risk of nephrogenic systemic fibrosis. R



I

R

Magnetic esonance maging

S

C

omputerized Tomography

triamine penta acetic acid (DTPA), an agent excreted purely by glomerular filtration, and mercaptotriacetylglycine (MAG 3) and LL ethylene cysteine dimer (LL EC), excreted by glomerular filtration and tubular secretion. Figures 10.2.3A and B show the three phases of a normal renogram. The peak of the curve depends on renal blood flow, renal function, tubular transit and excretion. Therefore, the peak is delayed in renal artery stenosis, renal parenchymal disease, oliguria and with obstruction. Dynamic scans are useful in identification of pelviureteric junction obstruction and renovascular stenosis, evaluation of differential and total renal function, assessment of allograft function and perfusion. A diuretic renogram helps differentiate obstructive dilatation of the upper urinary tract from nonobstructive hydronephrosis; in the latter, the radionuclide clears promptly following the injection of frusemide. By temporarily reducing the renal blood flow and GFR, administration of captopril facilitates the diagnosis of renal arterial stenosis. R

t

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and multicystic dysplastic kidney. Particular attention is di­ rected toward the amount of amniotic fluid, anteroposterior diameter of renal pelvis and pelviectasis, renal echotexture, appearance of the ureters and urinary bladder. Distended bladder with bilateral hydronephrosis suggests distal ob­ struction as seen with posterior urethral valves, while uni­ lateral hydronephrosis with normal ureters and bladder suggests pelviureteric junction obstruction.

B

 

616 Figures 10.2.3A and B Diethylenetriamine-penta-acetic acid scintigraphy showing normal concentration and excretion of the radiolabeled agent through both kidneys. Note the three phases: (i) a rapid rise and fall due to first pass perfusion; (ii) slow rise to a peak due to arrival of the agent into the kidney and (iii) declining amplitude due to excretion. Delayed image shows clearing of the radionuclide from both kidneys and its presence in urinary bladder

vip.persianss.ir

Diseases of Ki ney an Urinary Trac

 

Table 10.2.1 Indications for renal biopsy

 

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­

Evaluation of renal histology is an important tool for the diagnosis of various renal parenchymal diseases involving glomeruli or tubulointerstitium. Indications for kidney biopsy are listed under specific conditions in Table 10.2.1. A renal biopsy is not necessary in uncomplicated cases of poststreptococcal GN and corticosteroid responsive nephrotic syndrome. The procedure must be performed early in case of rapidly progressive glomerulonephritis (RPGN), suspected SLE nephritis and renal vasculitis, where early institution of specific therapy may improve outcome. The availability of disposable automatic devices (biopsy gun) and ultrasonographic guidance have improved the yield

t



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B

enal iopsy



Direct radionuclide cystography (DRNC) is a reliable and sensitive technique for the detection of VUR. It is performed by instilling radionuclide through a urethral catheter or by its injection into the bladder. Thereafter, rapid sequence images of the bladder are obtained while the patient voids. These provide a visual representation of the rate of bladder emptying, residual urine volume and evidence of reflux. Compared to MCU, the technique involves lower radiation exposure, making it suitable for repeated follow up examinations.

of the procedure, with relatively less risks. Prior to biopsy, a normal coagulation profile and normal blood pressure must be ensured to reduce the risk of bleeding. Patients with marked azotemia should be dialyzed and receive intranasal desmopressin 30–60 minutes prior to the procedure. The procedure is performed on an empty stomach (4 hour fasting) under light sedation using intravenous midazolam with ketamine; atropine administration reduces the risk of secretions. The child lies in the prone position with a folded towel or bedsheet placed under his lower ribs and epigastrium to push the kidney posteriorly and stabilize its position. The biopsy site is the angle made by the lower edge of the 12th rib and the lateral border of sacrospinalis. The kidney is localized with a “probing” 23 gauge needle or visualized directly by ultrasound. The entry of the biopsy needle into the kidney when it pierces the renal capsule is indicated by slight resistance. Following biopsy, vital signs should be monitored closely for the next 6–8 hours. Complications include local pain, gross hematuria, perinephric hematoma, infection, and rarely, formation of traumatic arteriovenous fistula. Strenuous exercise should be avoided for a few days. The renal histology is examined by light microscopy and immunofluorescence. Electron microscopic examination is useful for precise diagnosis of Alport syndrome, MPGN and thin GBM disease. -

C

R

Direct adionuclide ystogram

d

Less useful •  Chronic renal failure, to ascertain etiology •  Non-nephrotic range proteinuria •  Microscopic hematuria •  Steroid sensitive nephrotic syndrome

Figure 10.2.4 Dimercaptosuccinic acid scan showing bilateral cortical scarring in a 7-year-old girl with recurrent urinary tract infections

R

d



Common or usually indicated •  Steroid resistant nephrotic syndrome •  Acute renal failure of unknown cause •  Rapidly progressive renal failure •  Systemic disease (Henoch-Schönlein purpura, lupus, hemolytic uremic syndrome, IgA nephropathy) •  Inherited nephropathies, e.g. Alport syndrome •  Renal allograft dysfunction •  Detection of calcineurin toxicity

617

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D



evelopmental nomalies Susan Uthup

 

Table 10.3.1 Clues suggesting renal anomalies









•  Oligohydramnios •  Fetal compression syndrome (Potter sequence: flat facies, low set malformed ears, pulmonary hypoplasia, limb anomalies) •  Chromosomal disorders: trisomy 13; trisomy 18; Turner syndrome •  Tuberous sclerosis •  Prune belly syndrome (absent abdominal muscles, cryptorchidism •  Meningomyelocele •  Anorectal malformations •  Aniridia (Wilms tumor) •  Family history of renal disease (Alport syndrome, polycystic kidney disease)     

enal ysplasia D

R

The hypoplastic kidney is small in size but the shape and structure are normal. The functioning renal parenchyma is reduced as there is reduction in the number of nephrons. Hypoplastic kidney may be unilateral or bilateral. Bilateral renal hypoplasia is an important cause of kidney failure in the first decade of life.

There is abnormal differentiation of renal parenchyma with development of cysts, undifferentiated mesenchymal tissue, cartilage, primitive glomeruli and primitive tubules. Dysplasia may be unilateral or bilateral and may be associated with other developmental abnormalities of the urinary tract. Intrauterine obstruction of the urinary tract may cause severe bilateral renal dysplasia. Severe bilateral dysplasia presents as Potter sequence and is incompatible with life.

C

ystic Lesions K

D

Multicystic ysplastic idney This is the most common renal cystic disease. The kidney is enlarged and presents as an abdominal mass in neonates. There is severe cystic renal dysplasia with no functioning renal tissue. The cysts are randomly arranged. Multicystic dysplastic kidneys may be associated with developmental abnormalities of the urinary tract. Surgical removal is seldom necessary as the dysplastic kidney usually involutes. D

Polycystic idney isease K

A

Renal agenesis is the complete absence of identifiable renal tissue due to failure of development of ureteric bud or metanephros. It may be unilateral or bilateral. Renal agenesis occurs in 1 in 500–1,000 births. Typically the ureter and ipsilateral trigone of urinary bladder are absent. In unilateral renal agenesis, the contralateral normal kidney hypertrophies. Bilateral renal agenesis, with an incidence of 1 in 3,000 births, is incompatible with life. It is associated with pulmonary hypoplasia and facial appearance characterized by wide set eyes, squashed flattened nose, receding chin, large low set ears, small mandible and deficiency of cartilage. The absent renal echoes and urinary bladder can be detected at 12 weeks of gestation on ultrasound. Death occurs in the perinatal period due to respiratory insufficiency.

R

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R

enal genesis

enal Hypoplasia

Inherited polycystic kidney disease is an important cause of end stage renal disease. Two distinct patterns of inheritance -

Congenital anomalies of the kidney and urinary tract (CAKUT) represent a broad range of disorders. Severe structural fetal anomalies occur in 1% of pregnancies and defects of renal development might account for 30% of chronic kidney failure in children. Clues suggesting renal anomalies are given in Table 10.3.1. The development of kidneys begins at the fifth week of gestation from the intermediate mesoderm which differentiates into pronephros, mesonephros and metanephros. Pronephros and mesonephros degenerate. The definitive fetal kidneys develop from the metanephros. The ureteric bud, originating from the mesonephric (Wolffian) duct, penetrates the metanephric blastema and induces its differentiation into renal parenchyma. In the absence of ureteric bud, metanephric kidneys will not form. The kidneys ascend from sacral to lumbar region, and nephrogenesis is complete by 36 weeks of gestation. Embryologically, the ureter begins development as a solid cord. As the collecting system lengthens and canalizes, anomalies can lead to transient or permanent, partial or complete obstruction to urine flow. This obstructive process, if significant and persistent, results in varying degrees of cystic dysplasia and renal dysfunction. The fetal kidneys start producing urine by the ninth week of gestation and contribute to the amniotic fluid. An adequate amniotic fluid volume is essential for normal lung development. Patients with oligohydramnios show pulmonary hypoplasia, deformities of the skeleton and soft tissues. Developmental anomalies of kidneys include malfor­ mation of the renal parenchyma, abnormalities of migration or in the development of collecting system.

t

t

Tex book of Pedia rics

10.3

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1. Elder JE. Congenital anomalies and dysgenesis of kidneys. In: Nelson Textbook of Pediatrics, 18th edition. Saunders; 2007. pp. 2221 3. 2. Goodyer P. Renal dysplasia/hypoplasia. In: Avner E, Harmon W, Niaudet P (Eds). Pediatric Nephrology, 5th edition. Philadelphia: Lippincott Williams and Wilkins; 2004. pp. 83 92. 3. Nammalwar BR, Vijayakumar M. Genetic and developmental renal disease. In: Principles and Practice of Pediatric Nephrology. New Delhi: Jaypee Brothers; 2004. pp. 424 34. 4. Pohl M, Bhatnagar V, Mendoza SA, et al. Toward an etiological classification of developmental disorders of the kidney and upper urinary tract: Perspectives in Basic Science. Kidney Int. 2002;61:10 9. -

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Antenatal ultrasonography can detect anomalies of kidneys as early as 16 weeks of gestation. Hydronephrosis is the most common renal anomaly detected on ultrasound in

ibliography

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ntenatal Hydronephrosis

A



During the ascent, one kidney may cross the midline and fuse with the other. Patients with this condition often show anomalies of the collecting system, including reflux and obstruction.

t

B

E

rossed used ctopia F

C

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In horseshoe kidneys, the lower poles of kidneys, commonly fuse in the midline. This anomaly occurs in 1 in 400 births. One third of patients with Turner syndrome have horseshoe kidneys. Reflux, obstruction, infection and stone formation are common; there is increased risk of Wilms tumor. Skeletal, cardiovascular, neural tube defects and anorectal malformations are associated.



K

Horseshoe idney



During development, kidneys ascend and rotate so that renal pelvis faces medially. Renal ectopia occurs in 1 in 800 births. Pelviureteric junction obstruction and VUR may occur in kidneys that fail to ascend.



enal ctopia, Malrotation

3–5% pregnancies. The dilatation may involve the calyces (caliectasis) or pelvis (pelviectasis) or both. Antenatally detected hydronephrosis may be the result of obstruction or nonobstructive causes (Table 10.3.2). Obstructive lesions, particularly bilateral lesions are harmful to the developing kidneys. The anteroposterior diameter of the fetal renal pelvis more than 4 mm below 20 weeks, and more than 7 mm above 20 weeks of gestation, is considered significant. In most cases (60%), antenatal hydronephrosis is physiological and resolves by the first year of life. Amniotic fluid volume is the chief determinant of fetal survival in these babies, oligohydramnios being associated with pulmonary hypoplasia. Oligohydramnios beyond the second trimester indicates urinary obstruc­ tion or renal failure in the fetus. The presence of bilateral upper tract dilatation and persistently distended bladder suggest the possibility of posterior urethral valves. Oligohydramnios and brightly echogenic kidneys, if detected on ultrasound prior to 24 weeks of gastation, predict fetal ESRD syndrome and poor postnatal survival. In such cases, termination of pregnancy may be contemplated. Careful postnatal follow up is needed in all children with CAKUT.



bnormalities in Position E

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Autosomal recessive polycystic kidney disease, linked to chromosome 6, has more severe clinical course than ADPKD. It may present as Potter sequence with pulmonary hypoplasia, CKD during childhood or with liver disease in older survivors. The kidneys are enlarged with multiple cysts. The reniform shape is maintained.

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Physiological Obstructive lesions Pelviureteric junction obstruction Posterior urethral valve Vesicoureteric reflux –  Primary –  Secondary to duplex collecting system, ectopic ureter, prune belly syndrome •  Nonobstructive nonrefluxing ureters •  Primary megaureter 

•  •  •  •  •     



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Autosomal Recessive Polycystic Kidney Disease

iseases of idney and Urinary Trac

Table 10.3.2 Causes of antenatal hydronephrosis

Autosomal Dominant Polycystic Kidney Disease Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common inherited human disorders and the most frequent genetic cause of renal failure in adults. It often presents in adults but can occasionally be detected in children. Chief manifestations include palpable kidneys, hematuria, hypertension, UTIs and renal stones. The genetic loci are on chromosomes 16 and 4. The kidneys are enlarged with multiple cysts. Hepatic cysts, cysts in pancreas, spleen and cerebral aneurysms may also occur. End stage kidney disease occurs in the fifth or sixth decade. Screening ultrasound examination of parents and siblings should be done.

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have been described, autosomal dominant and recessive, each with different characteristics.

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Glomerulonephritis kamran Afzal

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Most cases of GN are due to an immunologic response to a variety of etiologic agents. Poststreptococcal glomeru­ lonephritis is associated with throat or skin infection with nephritogenic strains of group A streptococci. Their nephritogenicity is related to the M protein serotype: types 2, 49, 56 and 60 are associated with pyoderma and PSGN, while 1, 4, 12 and 25 are associated with throat infection and PSGN. The process of renal injury begins with deposition

 

Table 10.4.1 Etiology of acute glomerulonephritis

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Postinfectious •  Bacteria: Streptococci (group A, beta-hemolytic), staphylococci, pneumococci, meningococci, Treponema pallidum, Salmonella typhi, leptospira •  Viruses: Hepatitis B and C, cytomegalovirus, parvovirus, Ebstein-Barr virus, coxsackie virus, echovirus, varicella, rubella, rickettsiae and mumps •  Parasites: Plasmodium malariae, P. falciparum, Toxoplasma, filariasis, Schistosoma mansoni •  Others: infection of shunts and prosthesis, infective endocarditis Noninfectious •  Primary renal diseases   –  IgA nephropathy   –  Membranoproliferative glomerulonephritis   –  Mesangial proliferative glomerulonephritis   –  Hereditary nephropathy •  Systemic diseases   –  Vasculitis: Henoch-Schönlein purpura, microscopic polyangiitis, Wegener’s granulomatosis   –  Collagen vascular disorder: Systemic lupus erythematosus

Light microscopy shows diffuse proliferative and exudative changes with polymorphonuclear infiltrate and variable mesangial matrix expansion. There is endothelial and mesangial cell proliferation, resulting in obliteration of glomerular tuft. Severe injury results in proliferation of parietal and visceral epithelial cells resulting in crescents. Immunofluorescence reveals irregular IgG and C3 deposits along the capillary wall in early stages (starry sky appearance) and the mesangium later. Garland pattern of confluent deposits along capillaries correlates with heavy proteinuria.

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Pathogenesis

Pathology

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Acute GN, or the acute nephritic syndrome, is defined as sudden onset of hematuria and proteinuria, accompanied by hypertension, edema and impaired renal function. Postinfectious GN is the most common cause, and nearly 80% cases are poststreptococcal glomerulonephritis (PSGN), (Table 10.4.1). Immunoglobulin A (IgA) nephropathy is the most common primary GN worldwide; the disease is frequent in Japan and Korea.

Poststreptococcal glomerulonephritis affects children in the age group of 5–12 years (rare below 2 years), with male preponderance. Asymptomatic disease is 4–5 times more common among sporadic PSGN, although less frequently during epidemics. Subclinical cases have microscopic hematuria, and low complement with or without hyper­ tension. Symptomatic cases have an abrupt onset with hematuria, proteinuria and variable edema and hypertension. History of streptococcal infection may precede clinical disease onset by 1–2 weeks for throat infections and 3–4 weeks for skin infections. Anuria is rare, though transient oliguria may be noted. The occurrence of similar symptoms within 3–4 days of a respiratory or gastrointestinal infection suggests IgA nephropathy or Alport syndrome. The presence of rash, arthralgia, abdominal pain and hemoptysis suggests diag­ noses other than postinfectious GN (Table 10.4.2). Family history of renal disease suggests hereditary nephropathies such as Alport syndrome or thin basement membrane disease. Systemic features are seen with systemic vasculitis and systemic lupus erythematosus.

cute Glomerulonephritis

of immune complexes formed either in the circulation or in situ by binding of antibodies to antigens trapped in the glomerulus or native glomerular components. The immune complexes and streptococcal antigens activate the complement pathways with recruitment of leukocytes and macrophages, and release of growth factors and cytokines that together initiate and propagate glomerular inflammation and injury. The early phase of PSGN is associated with C3 nephritic factor activation of alternate pathway and depletion of plasma C3.

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Glomerulonephritis (GN) refers to disorders in which an immunologic insult triggers inflammation and proliferation of glomerular tissue with damage to the GBM, mesangium, or capillary endothelium. Glomerulonephritis may be primary (confined to the kidney) or secondary (part of a systemic disorder). Depending on duration of disease onset and the rate of progression, GN could be acute, rapidly progressive or chronic. A

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omplications

An occasional patient may present with nephrotic range proteinuria or hypertensive emergency. The latter is characterized by stage 2 hypertension, with clinical evidence

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Table 10.4.2 Clues to underlying etiology of glomerulonephritis Investigations

Diagnosis

Purpura, joint pain, abdominal pain, nausea, vomiting

Skin biopsy: leukocytoclastic vasculitis, IgA and C3 deposits   Renal biopsy: proliferative GN; mesangial IgA deposits

Henoch Schönlein purpura

Recurrent hematuria, proteinuria, following respiratory tract infection

Mesangial IgA deposits

IgA nephropathy

Hematuria following respiratory infections; sensorineural deafness; lenticonus, retinopathy; family history

Electron microscopy: Irregular thickening, splitting and lamination of glomerular basement membrane

Alport syndrome

Arthralgia, malar rash, nephritis

Positive ANA, dsDNA; low C3

SLE

Sinusitis, pulmonary infiltrates and nephritis

Positive for c-ANCA Biopsy: Pauci-immune necrotizing GN

Wegener’s granulomatosis

Nephritis, fever, weight loss; rash, arthralgia, pulmonary hemorrhage

Positive for p-ANCA Biopsy: Pauci-immune necrotizing GN

Microscopic polyangiitis

Hemoptysis; pulmonary hemorrhage

Anti-GBM antibody in serum, biopsy

Good pasture syndrome

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Postinfectious GN

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Clinical presentation

Preceding sore throat/skin infection, abscess, Hematuria; high blood creatinine; low serum endocarditis, infected shunt, prosthetic valves, C3, C4; ASO, anti-DNase B, antihyaluronidase indwelling catheters

Abbreviations: GN, Glomerulonephritis; ASO, Antistreptolysin O; ANA, Antinuclear antibody; dsDNA, Double stranded DNA; ANCA, Antineutrophil cytoplasmic antibody



Treatment Therapy is essentially symptomatic with mild cases of PSGN, requiring home based treatment. Hospital admission is required for those with oligoanuria, moderate to severe edema or hypertension and impaired renal functions.

 

Table 10.4.3 Indications for renal biopsy in acute glomeru­ lonephritis

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During early phase of disease •  Latent period between streptococcal infection and acute glomeru lonephritis of less than 1 week; no serologic evidence of streptococcal infection; normal serum complement C3 •  Extrarenal manifestations of systemic disease: rash, joint pain, fever, hepatosplenomegaly, lymphadenopathy, hemoptysis •  Anuria and/or rapidly deteriorating renal function During recovery phase •  Persistent hypertension or nephrotic range proteinuria beyond 2 weeks •  No improvement/continued decrease in the glomerular filtration rate beyond 2 weeks •  Persistent hypocomplementemia beyond 12 weeks •  Persistent gross hematuria more than 1 month, microscopic hematuria more than 18 months 





Dilutional anemia (normocytic, normochromic) correlates with expansion of the extracellular fluid. The presence of thrombocytopenia requires investigations for lupus or hemolytic uremic syndrome (HUS). On urinalysis, gross hematuria is present; dysmorphic red cells, and red cell and hyaline casts may be seen. While proteinuria is often mild, occasionally nephrotic range proteinuria may be observed. The finding of neutrophils on microscopy does not suggest a UTI. Although most patients have mild to modest elevations in the serum concentrations of creatinine and urea, the spectrum could range from severe azotemia to even normal levels at presentation. Hyperkalemia, metabolic acidosis and hyponatremia are only present in patients with significant renal function impairment. Antistreptolysin O titers are elevated in up to 80% of cases suggesting preceding streptococcal infection, although antibiotic treatment may attenuate this response. Total hemolytic complement and some components are low during acute PSGN suggesting activation of the alternative pathway of the complement system. The concentration of C3 has been found to be low in more than 90% patients and normalizes by 6–8 weeks. The level of C3 does not have any prognostic significance, but persistent hypocomplementemia suggests an alternative



iagnosis

diagnosis like lupus, MPGN or postinfectious GN, bacterial endocarditis, visceral abscess and shunt nephritis. Kidney biopsy is not needed to confirm the diagnosis of PSGN. It is indicated in those with heavy proteinuria, suspected crescentic GN or significant deviation from the natural course of the disease (Table 10.4.3).



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of heart failure, pulmonary edema or encephalopathy. Rarely there is progressive worsening of renal functions with hypertension and oligoanuria.

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apidly rogressive ( rescentic) Glomerulonephritis

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Acute GN can rarely show rapid progression GN (RPGN) characterized by hematuria, edema, hypertension, oligo anuria and azotemia. Extensive crescents on renal biopsy are the histological hallmark. Crescents are two or more layers of segmental to circumferential proliferation of parietal or visceral epithelial cells that completely or partially obliterate the Bowman’s space. Crescentic GN is labeled when 50% or more glomeruli have crescents. Crescents can evolve rapidly from cellular to fibrocellular and fibrous especially in the event of delayed treatment. Crescentic GN is rare in children. Its causes are cate­ gorized based on findings on renal immunofluorescence: immune, pauci immune and anti GBM disease, reflecting different mechanisms of glomerular injury (Table 10.4.4). Immune complex GN is common in children. F

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There is variable degree of gross hematuria, hypertension, oligo anuria and edema. Systemic complaints (cough, sinusitis, vasculitic rash, arthritis, neurological manifestations) are more common with pauci immune disease. Hemoptysis and pulmonary hemorrhage are seen in anti GBM disease, but may occur in lupus, Henoch Schönlein purpura (HSP), Wegener’s granulomatosis or any GN with pulmonary edema. -

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Attempts to identify the etiology of postinfectious GN are prudent. Although the course and prognosis for PSGN is well known and almost always favorable, this is not always so with non streptococcal forms of the condition. Edema usually resolves in 5–10 days, and the blood pressure returns to normal after 2–3 weeks, though persistence of elevated blood pressure for up to 6 weeks is compatible with complete resolution. Urinary abnormalities resolve at various times after onset: gross hematuria and proteinuria resolve early but microscopic hematuria could continue for 6–12 months. C3 concentration returns to normal in more

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than 95% patients by 8–10 weeks. Clinical manifestations of the disease rarely recur, and second episodes of PSGN are rare.

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Penicillin for 7 days may be used in those with residual pharyngitis or pyoderma, prevents spread of streptococci to others but does not alter disease course in the index case. Those with oliguria/anuria require strict control of fluid intake to insensible water losses along with replacement of urine output. Prudent use of diuretics (frusemide 1–3 mg/kg) helps to manage fluid overload and circulatory congestion. Salt and fluid intake should be limited in those with significant hypertension, edema or renal failure. Dialysis is required in patients with refractory or worsening acute renal failure. Mild hypertension is treated with oral diuretics, beta adrenergic blockers or angiotensin converting enzyme inhibitors. Severe hypertension requires oral/IV frusemide and oral or sublingual nifedipine. For those presenting with hypertensive emergencies, IV short acting antihypertensive (sodium nitroprusside, labetalol or nicardipine) are used for controlled reduction in blood pressure. Specific therapy is not available for most other causes except infections. Those with heavy proteinuria or rapidly progressive RPGN require prompt therapy (see below). Patients with IgA nephropathy and microscopic or recurrent gross hematuria but subnephrotic range proteinuria (< 1 g/1.73 m2) do not require specific treatment.

iagnosis

Investigations include blood counts, urinalysis (hematuria, proteinuria, red cell casts), blood levels of urea, creatinine and C3 (low in PSGN, lupus and MPGN). Serology includes

 

Table 10.4.4 Common causes and histology of crescentic glomerulonephritis Cause (prevalence)

Histology

Cellular, fibrocellular crescents Immune complex GN (50–70%) Postinfectious (streptococci, staphylococci, infective endocarditis, Immunofluorescence: Granular deposits of complement and immune complexes along capillary wall and mesangium shunt nephritis, visceral abscess, hepatitis B and C, HIV) Systemic diseases (systemic lupus, Henoch-Schönlein purpura, rheumatoid arthritis, dermatomyosistis, Behcet syndrome) Primary renal disease (IgA nephropathy, membranoproliferative GN) Focal necrotizing GN with crescents; vasculitis; fibrinoid necrosis Pauci-immune (15–30%) Systemic vasculitis (microscopic polyangiitis, Wegener’s in glomeruli, blood vessels Immunofluorescence: Minimal, no immune deposits granulomatosis) Without vasculitis (renal-limited disease)

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Anti-GBM antibody (uncommon) Good pasture syndrome (lung, kidney involvement) Anti-GBM disease (only kidney involvement) Postrenal transplant in Alport syndrome

Severe histological disease; crescents in most glomeruli Immunofluorescence: linear deposits of anti-GBM antibodies

Abbreviations: GN, Glomerulonephritis; GBM, Glomerular basement membrane

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iagnosis

Laboratory workup includes urinalysis (hematuria, pro­ teinuria and RBC casts), and estimation of blood levels of creatinine, electrolytes, calcium, phosphorus and alkaline phosphatase. Renal ultrasound is done to assess kidney size, followed by biopsy.

Treatment

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Antiproteinuric treatment with angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blocker (ARB) may be used to reduce heavy proteinuria and retard disease progression. For those with nephrotic range proteinuria, oral prednisolone has been used with variable success.

Prognosis

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The outcome depends on the etiology, stage of disease and renal histology. Those with significant obsolescent and sclerosed glomeruli with tubulointerstitial fibrosis fare worse with progression to end stage renal disease.

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Early diagnosis and treatment are necessary, given the risk of poor outcome and progression to end stage renal disease (ESRD). The initial therapy is with IV methylprednisolone (15–20 mg/kg, maximum 1 g/day) for 3–6 days, followed by oral prednisolone (1.5 mg/kg daily) for 4 weeks, with tapering to 0.5 mg/kg daily by 3 months, and alternate day prednisolone for 12 months. IV cyclophosphamide (500–750 mg/m2) is administered monthly for 6 doses. Plasmapheresis for 10–14 days is recommended for pauci immune and anti GBM disease, but may be effective in refractory lupus nephritis, HSP and severe proliferative GN. Maintenance immunosuppression with azathioprine (2 mg/ kg) and alternate day prednisolone is needed for 2–3 years in most patients with ANCA associated crescentic GN. Therapy for immune complex disease depends on the underlying etiology. Other agents include mycophenolate mofetil, cyclosporine, anti CD20 antibodies and IV immunoglobulin.

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Patients have variable combinations of proteinuria, hematuria, edema and hypertension. Cause specific symptoms can help determine the etiology. Once CKD sets in, there is progressive decline in GFR and uremia with its associated complications. -

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Treatment

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from basement membrane (double contour of GBM on silver methenamine stain). MPGN type II has electron dense deposits of IgG and C3 in basement membrane. In advanced stage, the glomeruli are hyalinized and obsolescent, with tubulointerstitial fibrosis and arteriolar sclerosis.

iseases of idney and Urinary Trac

antistreptolysin O in preceding streptococcal infection; and antinuclear and anti dsDNA autoantibodies in lupus. Anti­ nuclear cytoplasmic antibodies with specificity for protein­ ase 3 produce cytoplasmic staining on immunofluorescence (c ANCA), e.g. Wegener’s granulomatosis. Myeloperoxidase specific ANCA produces perinuclear staining on immunoflu­ orescence (p ANCA) in renal limited vasculitis, microscopic polyangiitis and drug induced pauci immune GN. Renal biopsy with light, immunofluorescence and electron microscopy is needed in all since occasionally diffuse proliferative GN or thrombotic microangiopathy (TMA) may have similar clinical presentation.

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hronic Glomerulonephritis

Chronic GN (CGN) is characterized by progressive glomerular and tubulointerstitial fibrosis, ultimately leading to a reduction in GFR and retention of uremic toxins. If disease progression is not halted, the net result is chronic kidney disease and end stage renal disease. Almost all the causes listed in Table 10.4.1 can progress to CGN. Common causes include crescentic GN, membranoproliferative GN and mesangial proliferative GN. Nearly 20% patients with IgA nephropathy or lupus nephritis can evolve into chronic GN. Mesangial proliferative GN (MPGN) is characterized by mesangial cell proliferation and matrix expansion with IgM and C3 deposits. In MPGN type I, glomeruli show subendothelial and mesangial deposits and separation of endothelial cell

1. Bagga A, Menon S. Rapidly progressive glomerulonephritis. In: Geary DF, Schafer F (Eds). Comprehensive Pediatric Nephrology. Philadelphia: Mosby; 2008. pp. 319 27. 2. Bagga A, Srivastava RN. Acute and rapidly progressive glomerulonephritis. In: Srivastava RN, Bagga A (Eds). Pediatric Nephrology, 5th edition. New Delhi: Jaypee Brothers; 2011. pp. 130 52. 3. Brogan P, Eleftheriou D, Dillon MJ. Small vessel vasculitis. Pediatr Nephrol. 2010;25:1025 35. 4. Eison TM, Ault BH, Jones DP, et al. Post streptococcal acute glomerulonephritis in children: clinical features and pathogenesis. Pediatr Nephrol. 2011;26:165 80. 5. Sulyok E. Acute proliferative glomerulonephritis. In: Avner ED, Harmon WE, Niaudet P (Eds). Pediatric Nephrology, 5th edition. Philadelphia: Lippincotts Williams and Wilkins; 2005. pp. 601 14. 6. Vamvakopoulos J, Savage CO, Harper L. ANCA associated vasculitides lessons from the adult literature. Pediatr Nephrol. 2010;25:1397 1407. 7. Yoshizawa N, Yamakami K, Fujino M, et al. Nephritis associated plasmin receptor and acute poststreptococcal glomerulonephritis: characterization of the antigen and associated immune response. J Am Soc Nephrol. 2004;15:1785 93.



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Prognosis depends on: • tiology: PSGN fares better than pauci immune or anti GBM nephritis, • Fibrous crescents fare worse than cellular or fibrocellular crescents and • Severity of renal failure and promptness of initiating therapy.

ibliography



Prognosis

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enal Vasculitis and Lupus Nephritis

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Sushmita Banerjee

Vasculitis is an inflammation of blood vessel walls that often results in ischemic injury to the end organ or tissue. Different vasculitides have predilection for involving specific organ systems, and the kidney is commonly affected. The vasculitic syndromes are classified according to the dimension of vessel affected (Table 10.5.1). The majority of vasculitides do not have a proven etiology. Evidence suggests a genetic predisposition with diseases precipitated by an environmental trigger, resulting in an abnormal immune response. Multiple ANA are found in SLE, of which anti-dsDNA is the most specific. Activation of the classical pathway of complement results in low levels of C3 and C4 and the deposition of C3, C4 and C1q in renal tissue. Antineutrophil cytoplasmic antibodies have a role in pathogenesis of vasculitides and correlate with disease activity. There are two types: 1. Protoplasmic ANCA (p-ANCA or perinuclear pattern of staining on indirect immunofluorescence) with antimyeloperoxidase (anti-MPO) specificity on ELISA, and 2. Classical ANCA (c-ANCA with diffusely granular, cytoplasmic staining) and anti-protease 3 (anti-PR3) specificity.

Table 10.5.2 Criteria for diagnosis of different vasculitic syndromes  

enal Vasculitis

Disease

Criteria

Henoch-Schönlein purpura

Purpura or petechiae (mandatory) with lower limb predominance plus one of four criteria: (i) abdominal pain; (ii) histological evidence of IgA deposition; (iii) arthritis or arthralgia; (iv) renal involvement

Polyarteritis nodosa Systemic inflammatory disease with evidence of necrotizing vasculitis, or angiographic abnormalities of medium/small sized arteries (mandatory criterion) plus one of five criteria: (i) skin involvement; (ii) myalgia/muscle tenderness; (iii) hypertension; (iv) peripheral neuropathy; (v) renal involvement Wegener’s granulomatosis

Three of six criteria: (i) histopathological evidence of granulomatous inflammation; (ii) upper airway involvement; (iii) laryngotracheobronchial involvement; (iv) pulmonary involvement (X-ray/ CT); (v) positive antineutrophilic cytoplasmic antibody; (vi) renal involvement

Takayasu arteritis

Typical angiographic abnormalities of the aorta or its main branches and pulmonary arteries (mandatory criterion) plus one of five criteria: (i) pulse deficit or claudication; (ii) blood pressure discrepancy in any limb; (iii) bruits; (iv) hypertension; (v) elevated acute phase reactants

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Most vasculitides involve several organ systems resulting in variable patterns of clinical involvement (Table 10.5.2). Anemia, fever, malaise and weight loss may be present along with arthritis, skin rashes, purpura (Fig. 10.5.1), abdominal

Source: European League Against Rheumatism, Paediatric Rheumatology International Trials Organisation, Paediatric Rheumatology European Society.

 

Table 10.5.1 European League Against Rheumatism, Paediatric Rheumatology European Society: classification of childhood vasculitis Disease

Large

Takayasu arteritis

Medium

Kawasaki disease Polyarteritis nodosa

Small

Nongranulomatous Henoch-Schönlein purpura Microscopic polyangiitis Granulomatous Wegener’s granulomatosis Churg-Strauss syndrome

Others

Connective tissue disease associated Infection, malignancy, drug hypersensitivity associated Behcet disease Cogan syndrome

Figure 10.5.1 Henoch-Schönlein purpura  

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nvestigations Patients show evidence of raised acute phase reactants. Investigation of extrarenal manifestations is guided by clinical features, and may include chest X-ray, lung CT, brain imaging and echocardiography. Biopsies of upper respiratory tract mucosa are performed for the diagnosis of Wegener’s granulomatosis where they show a granulomatous necrotizing vasculitis. Skin biopsies show leukocytoclastic vasculitis with IgA deposition in HSP and necrotizing vasculitis in microscopic PAN. Angiography shows changes such as thickening and narrowing of the aorta and its branches in Takayasu disease; or intrarenal aneurysms or vascular pruning in PAN (Figs 10.5.2 and 10.5.3). Urinalysis might show active sediment with hematuria, proteinuria and casts. Urea and creatinine may be raised. ANA, anti-dsDNA and ANCA serology, and complement levels are useful in ascertaining the diagnosis. In ANCA associated vasculitis, renal biopsy shows pauci-immune crescentic GN (Fig. 10.5.4).

Henoch-Schönlein pupura is the most common childhood vasculitis. Renal involvement is reported to occur in 20– 30% patients with risk of progression to ESRD in 1–3%. Occasional late progression up to 2 years after onset has been documented in patients who have initially improved, making long-term follow-up essential. The chief renal finding is microscopic hematuria. The presence of renal insufficiency,

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with steroids and other immunosuppressive agents with regular monitoring to keep disease activity under control. Renal revascularization procedures (stenting, grafting or autotransplantation) may be required in patients developing arterial stenosis or dilatation.

iseases of id ey a d Uri ary Trac

pain, uveitis and mucosal ulcers. Large vessel disease can cause absent or asymmetric pulses and claudication. Hypertension is a common finding; patients with Takayasu arteritis often have abdominal bruit due to renal artery stenosis. Intrarenal involvement causes an acute nephritic or nephritic-nephrotic presentation with hematuria and edema.

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Henoch- chönlein Purpura Nephritis

Management

Figure 10.5.3 Renal aneurysms in polyarteritis nodosa

Figure 10.5.2 Takayasu arteritis with left renal artery stenosis

Figure 10.5.4 Crescentic glomerulonephritis

 

 

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Supportive management with antipyretics, antibiotics and antihypertensive agents are used as required. Renal failure is managed with salt, potassium and fluid restriction and dialysis when indicated. Management of extrarenal symptoms is done simultaneously. The specific management of the renal disease in the majority of these conditions (PAN, Takayasu disease, and ANCA related vasculitis) involves therapy

 

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Table 10.5.3 Histopathological grading of systemic lupus erythematosus nephritis



Class I: Minimal changes on light microscopy Class II: Mesangial proliferative glomerulonephritis Class III: Focal segmental proliferative glomerulonephritis Class IV: Diffuse proliferative glomerulonephritis with or without crescents Class V: Membraneous changes Class VI: Sclerosed lesions



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1. Brogan P, Eleftheriou D, Dillon M. Small vessel vasculitis. Pediatr Nephrol. 2010;25:1025-35. 2. Brunner HI, Huggins J, Klein-Gitelman MS. Pediatric SLE: towards a comprehensive management plan. Nat Rev Rheumatol. 2011;7:225-33. 3. Dillon MJ, Eleftheriou D, Brogan PA. Medium-size-vessel vasculitis. Pediatr Nephrol. 2010;25:1641-52. 4. Gulati A, Bagga A. Large vessel vasculitis. Pediatr Nephrol. 2010;25:1037-48. 5. Khubchandani RP, Viswanathan V. Pediatric vasculitides: a generalists approach. Indian J Pediatr. 2010;77:1165-71. 6. Ozen S, Pistorio A, Iusan SM, et al. EULAR/PRINTO/PRES criteria for Henoch Schönlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: Final classification criteria. Ann Rheum Dis. 2010;69:798-806. 7. Ozen S, Ruperto N, Bagga A, et al. EULAR/PReS endorsed consensus criteria for the classification of childhood vasculitides. Ann Rheum Dis. 2006;65:936-41.





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ibliography





Systemic lupus erythematosus is a multisystem disease with renal involvement occurring in 60–80% children, the majority (90%) within the first year of presentation. Lupus nephritis is characterized by variable grades of hematuria, proteinuria, hypertension and renal functional impairment. Renal tubular dysfunction occurs rarely. A renal biopsy is indicated in all patients with renal involvement, as there might be unsatisfactory correlation of clinical findings, serology and pathology. The deposition of IgG, IgA and IgM immune-complexes, C3, C4 and C1q indicates a full house on immunofluorescence, characteristic of SLE nephritis. Histological grading influences manage ment and prognosis (Table 10.5.3). Class IV or diffuse proliferative GN is most common and may have a rapidly progressive course with devastating consequences if untreated. Class I-II lupus nephritis is treated with corticosteroids, with management aimed more at extrarenal disease. Patients with class III-IV nephritis with high activity indices are treated aggressively with combinations of high dose steroids and cytotoxic agents. Commonly used protocols include high dose IV or oral corticosteroids and

cyclophosphamide. The use of drugs like azathioprine or mycophenolate mofetil for long-term maintenance either primarily or after induction of remission may be effective and associated with fewer side effects. Treatment options in patients with refractory illness include plasmapheresis, IV immunoglobulin and rituximab.



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Nephritis ssociated with ystemic Lupus rythematosus

Note: Each class is further subdivided according to extent of lesions and activity and chronicity markers



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hypertension or significant proteinuria indicates a poorer prognosis with increased likelihood of persistence and progression. Renal biopsy findings vary from mesangial and/ or endocapillary proliferation to severe involvement with crescentic GN, with deposits of IgA and C3. A short course of corticosteroids is recommended in patients with severe abdominal symptoms. The presence of microscopic hematuria alone does not warrant specific treatment. Therapy with corticosteroids does not reduce the risk of HSP nephritis. Patients with severe HSP nephritis, particularly RPGN, are treated with combinations of oral or IV corticosteroids, immunosuppressive agents (azathioprine, cyclophosphamide, mycophenolate mofetil), dipyridamole, IVIG and plasma exchange.

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Diseases of Ki ney an Urinary Trac

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Arvind Bagga

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The etiology of ARF is classified as prerenal, intrinsic renal or postrenal. A number of indices aid in differentiating prerenal from renal azotemia, the most useful being the fractional excretion of sodium. Patients with prerenal illness show a low fractional excretion of sodium (< 1%); higher values are seen with acute tubular necrosis. The chief causes of AKI include acute tubular necrosis secondary to hypovolemia, sepsis and nephrotoxic agents, acute GN and HUS (Table 10.6.2).

valuation

A careful history provides clues to the underlying cause. A history of diarrhea, vomiting, fluid or blood loss should be sought and an assessment of fluid intake in the previous 24-hour be made. Important investigations in patients with ARF include:

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Complete blood counts, urea, creatinine, sodium, potassium, calcium, phosphate, pH, bicarbonate • Urinalysis; culture; sodium, osmolality, fractional excretion of sodium • Chest X-ray (for fluid overload, cardiomegaly) • Abdominal ultrasonography (identify urinary tract dilatation, obstruction) • Peripheral smear examination, platelet and reticulocyte count, complement (C3), LDH levels; stool culture (suspected HUS) • Blood ASO, C3, ANA, ANCA (suspected acute or RPGN) • Doppler ultrasonography (suspected arterial or venous thrombosis). A kidney biopsy is not required in most patients with ARF. Indications for kidney biopsy are: RPGN or nonresolving GN; ARF associated with a systemic disease, e.g. systemic lupus, HSP; suspected interstitial nephritis or if the underlying cause of ARF is not apparent on clinical features and investigations.

Management Specific management of the underlying disorder is possible in some cases (Table 10.6.3). Patients with urinary tract obstruction need to be managed urgently. It is important to manage life-threatening complications including hyperkalemia, pulmonary edema, hypertensive emergencies, severe acidosis and anemia (Table 10.6.4). Hyperkalemia is a serious emergency. Urgent treatment is instituted depending on blood potassium levels and ECG changes. Concomitant metabolic acidosis should be corrected. While sodium bicarbonate, glucose, insulin and salbutamol reduce the extracellular concentration of potassium by moving the ion into the cells, calcium infusion decreases membrane irritability without altering serum potassium levels. The action of Kayexalate (sodium polystyrene sulfonate) or calcium resonium, which exchanges ­

tiology

•



E

Acute renal failure (ARF) or acute kidney injury (AKI) occurs in a variety of settings with clinical features ranging from mild elevation in serum creatinine to anuric renal failure. Acute kidney injury is considered to be present when there is an abrupt (within 48-hour) reduction in kidney function, defined as absolute increase in serum creatinine of either more than or equal to 0.3 mg/dL or a percentage increase of more than or equal to 50% or reduction in urine output (oliguria of < 0.5 mL/kg/hour for > 6-hour). These criteria include both an absolute and a percentage change in creatinine, to accommodate variations related to age, gender and body mass index and reduce the need for a baseline level of serum creatinine. If the diagnosis of AKI is based on the urine output criterion alone, urinary tract obstruction and other reversible causes of oliguria (hydration status and diuretic use), should be excluded. Patients meeting the definition of AKI can be staged from stage 1 to stage 3 (Table 10.6.1).

 

Table 10.6.1 Staging of acute kidney injury* Stage

Serum creatinine criteria

1

Increase in serum creatinine of ≥ 0.3 mg/dL or ≥ 150–200% (1.5- to Less than 0.5 mL/kg/hour for > 6-hour 2-fold) from baseline

2

Increase in serum creatinine to more than 200–300% (> 2- to 3-fold) from Less than 0.5 mL/kg/hour for > 12-hour baseline

3**

Increase in serum creatinine to more than 300% (> 3-fold) from baseline Less than 0.3 mL/kg/hour for 24-hour, or (or serum creatinine of ≥ 4.0 mg/dL with acute increase of ≥ 0.5 mg/dL) anuria for 12-hour

*Only one criterion (creatinine or urine output) is required for staging **Patients receiving renal replacement therapy are considered in stage 3

Urine output criteria

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Abbreviations: ACE, Angiotensin converting enzyme; NSAIDs, Nonsteroidal anti-inflammatory drugs; SLE, Systemic lupus erythematosus



potassium for sodium or calcium ions, is slow and not useful in emergencies. Peritoneal or hemodialysis (HD) is the most effective method to remove excess potassium from the body. Hypertension is commonly observed in cases of GN and HUS. The symptoms of hypertensive encephalopathy are related to rapidity of rise rather than absolute value of the blood pressure. These include headache, blurring of vision, convulsions, papilledema, cranial nerve palsies, vomiting and altered sensorium. Blood pressure should be reduced with sodium nitroprusside (0.5–8 µg/kg/minute) infusion. In asymptomatic hypertension, nifedipine, amlodipine, prazosin and labetalol may be used.

Fluid and electrolyte intake in a patient with ARF should be regulated based on a clinical examination of extracellular fluid volume status, urine output and daily weights. The daily fluid requirement amounts to insensible water losses (300–400 mL/m2), urinary output and extrarenal fluid losses. Insensible fluid losses are replaced with 5–10% dextrose/ glucose solution. Urine output should be measured without resorting to catheterization. Urinary losses and those from extrarenal sources should have their composition analyzed and replaced accordingly. It is preferable to administer the required amounts of fluid by mouth, whenever feasible. If there is persistent vomiting, intravenous route may be necessary. Potassium containing fluids should not be given to patients with oliguria. Ongoing treatment is guided by intake-output analysis, daily weight, physical examination and serum sodium. If fluid in an appropriate volume and composition has been given, the patient should lose 0.5– 1% of his weight every day. This weight loss is the result of caloric deprivation and not inadequate fluid therapy. Serum sodium concentrations should be maintained within the normal range. A rapid weight loss and increasing level of serum sodium suggest inadequate free water replacement. On the other hand, an absence of weight loss and hypo natremia indicate excessive free water replacement. The types of fluids used are mostly crystalloids, e.g. saline, Ringer lactate. There is no conclusive evidence that crystalloids are better or worse than colloids in resuscitating patients with sepsis. However, the use of colloids in the care of patients with sepsis reduces the risk of occurrence of edema. ­

 

 

 

 

Postrenal failure Posterior urethral valves, urethral stricture Bilateral pelviureteric junction obstruction Ureteral obstruction (stenosis, stone, ureterocele) Neurogenic bladder

luid and utrition



 

 

 

 

 

 

 

 

 

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Intrinsic renal failure Acute tubular necrosis Prolonged prerenal insult (see above) Medications: Aminoglycosides, radiocontrast, NSAIDs Exogenous toxins: Diethylene glycol, methanol Intravascular hemolysis, hemoglobinuria Tumor lysis syndrome Hemolytic uremic syndrome: Diarrhea associated (D+) and atypical (D–) forms Glomerulonephritis   • Postinfectious glomerulonephritis   • Systemic disorders: SLE, Henoch-Schönlein purpura, microscopic polyangiitis   • Membranoproliferative glomerulonephritis Interstitial nephritis (drug-induced, idiopathic) Bilateral renal vessel occlusion (arterial, venous)

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Prerenal failure Hypovolemia (dehydration, blood loss, diabetic ketoacidosis) Third space losses (septicemia, nephrotic syndrome) Congestive heart failure Perinatal asphyxia Drugs (ACE inhibitors, diuretics)

Hyponatremia (sodium < 130 mEq/L) is usually the result of excessive fluid administration rather than salt loss. Patients with blood sodium concentration more than 125 mEq/L are rarely symptomatic. Hyponatremia is best managed by fluid restriction; patients with resistant hyponatremia can be satisfactorily managed by dialysis. Treatment with hypertonic saline (3%) is reserved for those with symptomatic hyponatremia (encephalopathy, lethargy and seizures), but should be used cautiously because of potential complications of fluid overload, hypertension and intraventricular hemorrhage.

Tex boo of Pe ia rics

Table 10.6.2 Important causes of acute kidney injury

 

Table 10.6.3 Management of conditions causing acute kidney injury

628

Prerenal acute kidney injury

Administer fluids; avoid NSAIDs, ACE inhibitors; inotropes (for cardiac failure)

Acute tubular necrosis

Supportive care; treat infections, cause of circulatory failure

Glomerulonephritis

Supportive care; plasma exchange; immunosuppressive medications

Hemolytic uremic syndrome

Supportive care; plasma infusions; plasma exchange

Vasculitis

Immunosuppressive medications

Interstitial nephritis

Discontinue offending drug; consider steroid therapy

Renal artery, vein occlusion

Anticoagulation; thrombolysis or surgery

Urinary tract obstruction

Bladder catheter; nephrostomy; surgical treatment

Abbreviations: ACE, Angiotensin converting enzyme; NSAIDs, Nonsteroidal anti-inflammatory drugs

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Diseases of Ki ney an Urinary Trac

 

Table 10.6.4 Management of complications Complication

Treatment

Fluid overload

Fluid restriction: Insensible losses (400 mL/m²/d); add urine Monitor other losses and replace as appropriate, consider output, other losses; 5% dextrose for insensible losses; N/5 dialysis saline for urine

Remarks

Pulmonary edema

Oxygen; frusemide 2–4 mg/kg

Hypertension

Symptomatic: Sodium nitroprusside 0.5–8 µg/kg/minute In emergency, reduce blood pressure by one-third of the infusion; frusemide 2–4 mg/kg ; nifedipine 0.3–0.5 mg/kg desired reduction during first 6–8 hours, one-third over next 12–24 hours and the final one-third slowly over 2–3 days oral/sublingual Asymptomatic: Amlodepine, prazosin, labetalol, clonidine

Metabolic acidosis

Sodium bicarbonate (IV or oral) if bicarbonate levels < 18 mEq/L Watch for fluid overload, hypernatremia, hypocalcemia; consider dialysis

Hyperkalemia

Calcium gluconate (10%) 0.5–1 mL/kg over 5–10 minutes Salbutamol 5–10 mg nebulized Sodium bicarbonate (7.5%) 1–2 mL/kg over 15 minutes Dextrose (10%) 0.5–1 g/kg and insulin 0.1–0.2 U/kg Calcium or sodium resonium (Kayexalate) 1 g/kg/day

Hyponatremia

Fluid restriction; if sensorial alteration or seizures give 3% saline Hyponatremia is usually dilutional; 12 mL/kg of 3% saline raises 6–12 mL/kg over 30–90 minutes sodium by 10 mEq/L

Severe anemia

Packed red cells 3–5 mL/kg; consider exchange transfusion

Monitor blood pressure, fluid overload

High phosphate

Phosphate binders (calcium carbonate; aluminum hydroxide)

Reduce dietary phosphate; avoid milk products; high protein diet



Indications for initiating RRT include severe or persistent hyperkalemia (> 7 mEq/L), fluid overload (pulmonary edema, severe hypertension), uremic encephalopathy, and severe metabolic acidosis (TCO2 < 10–12 mEq/L), hyponatremia (120 mEq/L or symptomatic) or hypernatremia. The initial renal replacement therapy (RRT) of choice in sick and unstable patients is often intermittent peritoneal dialysis (PD). It is easy to initiate in children

d d t

Hemolytic Uremic yndrome Hemolytic uremic syndrome characterized by microangio pathic hemolytic anemia, thrombocytopenia and renal impairment is one of the most common causes of AKI in children. The diarrhea associated (classic) HUS occurs in childhood, usually caused by shigatoxin (verotoxin) producing bacteria (Escherichia coli 0157:H7, Shigella dysenteriae) and is associated with a satisfactory prognosis. 629 More than 90% children recover normal renal function ­

enal eplacement Therapy R

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Diuretics may be useful in instances where high urine flow is required to prevent intratubular precipitation as with intravascular hemolysis, hyperuricemia and myoglobinuria. Drugs that increase severity of renal damage, delay recovery of function or reduce perfusion, e.g. aminogly cosides, radiocontrast media, NSAIDs, amphotericin B, ACE inhibitors and indomethacin, should be avoided. Standard charts are used for modifying the dose and dosing interval of antibiotics, depending on the severity of renal injury. There is no beneficial effect of dopamine infusion on the outcome of AKI. Its routine use for prevention or treatment of acute tubular necrosis is therefore not recommended. The role of other medications, including fenoldopam, atrial natriuretic peptide, calcium channel blockers (CCBs) and other medications is investigational.

of all ages, including neonates. Peritoneal access can be obtained using a stiff catheter and trocar. While PD can be effectively performed with these catheters, these should be removed after 48–72 hours beyond which the risk of infection is very high. If the duration of ARF is prolonged, chronic peritoneal dialysis may be performed, either manually (continuous ambulatory peritoneal dialysis) or with the use of an automated device (continuous cycling peritoneal dialysis). Hemodialysis is more efficient for correction of fluid and electrolyte abnormalities. However, it is expensive to institute, requires expertise and skilled nursing and is not available at most centers in our country. It is not suited for patients with hemodynamic instability, bleeding tendency and in very young children where vascular access might be difficult. Continuous renal replacement therapy (CRRT) is useful when large amount of fluids have to be removed in sick and unstable patients. Special equipment and trained staff are necessary to provide CCRT in children. Hemodialysis is less expensive than CRRT, and should be the first RRT of choice in centers where it is available. S

Diuretics and Drugs

Stabilizes cell membranes; prevents arrhythmias Shifts potassium into cells Requires monitoring of blood glucose Given orally or rectally, can be repeated every 4 hours



­



Adequate nutritional support is preferred with maxi mization of caloric intake. A diet containing 1.2–2 g/kg of protein in infants and 0.8–1.2 g/kg in older children, and 60– 80 Cal/kg should be given. Once dialysis is initiated, dietary protein, fluid and electrolyte intake should be increased.

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Monitor using CVP; consider dialysis

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1. Ariceta G, Besbas N, Johnson S, et al. Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol. 2009;24:68796. 2. Bagga A, Bakkaloglu A, Devarajan P, et al. Improving outcomes from acute kidney injury: report of an initiative. Pediatr Nephrol. 2007;22:1655-8. 3. Noris M, Remuzzi G. Atypical hemolytic uremic syndrome. N Engl J Med. 2009;361:1676-87. 4. Ricci Z, Cruz D, Ronco C. The RIFLE criteria and mortality in acute kidney injury: a systematic review. Kidney Int. 2008;73:538-46.



ibliography



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Therapy for HUS includes the management of ARF. Specific management includes treatment of hematological complications, avoiding antidiarrheal drugs and monitoring for extrarenal involvement. Transfusion of packed red blood cells is needed in patients with severe anemia (hemoglobin < 6 g/dL). Careful monitoring of blood pressure, urine output and respiratory rate is necessary. Platelet transfusions are limited to children with active bleeding since they might contribute to microthrombi formation and promote tissue ischemia. While there are no specific evidence based guidelines on therapy for HUS, there is consensus on the need for plasmapheresis and infusion of fresh frozen plasma. Patients with anti-CFH autoantibodies may additionally benefit from administration of intravenous immunoglobulin. Therapy with monoclonal antibodies targeting B cells and immunosuppressive medications might be useful in this subset of patients. Monoclonal antibodies against factor 5 (eculizumab) have been used in patients with the atypical and, more recently, the diarrheal forms of HUS. Plasma infusions are effective in patients with deficiency of complement factors, CFH and CFI.



t

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with supportive therapy. Atypical (non-diarrheal) HUS is a heterogeneous disorder with less favorable outcome. This condition is distinguished from classic HUS by absence of diarrheal prodrome, a chronic and relapsing course, high mortality and risk of ESRD. The diagnosis of HUS is made in presence of azotemia, thrombocytopenia (< 100,000/mm3) and hemolysis, occurring with or without history of preceding diarrhea or dysentery. The underlying histological lesion is a TMA involving capillaries and small arterioles in the kidney. While histological changes are most marked in the kidneys, evidence of TMA might be present in the brain, heart, lungs, gastrointestinal tract and pancreas. Activation of the alternative complement pathway is important in an important proportion of cases. Defects in the genes for multiple components have been identified. These include loss of function mutations in factor H (CFH), membrane cofactor protein (MCP, CD46), factor I (CFI), factor H related proteins 1-5 (CFHR1-5) and thrombomodulin, and gain of function mutations in factor B and C3. About 10–15% cases have been associated with autoantibodies against factor H (anti-CFH antibodies), particularly in the background of mutations in the CFHR1/3 (complement factor H related 1, 3) gene. Deficiency of a metalloproteinase with thrombospondin motifs-13 (ADAMTS13) and defective cobalamin metabolism are also rarely pathogenic. Enterohemorrhagic E. coli (EHEC) or S. dysenteriae is the likely cause of HUS in patients older than 6 months with history of diarrhea or bloody diarrhea in the preceding 2 weeks. Serum levels of complement factors C3 and C4 should be estimated. A low level of C3 in a patient with normal C4 indicates selective activation of the alternative pathway. Where possible, blood samples are taken for estimation of CFH, CFI, CFB, CD46 and anti-CFH antibodies, before instituting plasmapheresis or infusing blood products.

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Arvind Bagga

 

Table 10.7.2 Investigations at the first episode of nephrotic syndrome

Most children with nephrotic syndrome do not require a biopsy during the disease course. A biopsy is indicated at the onset of nephrotic syndrome if a cause other than minimal change nephrotic syndrome is likely, e.g. (i) age

 

Table 10.7.1 Important definitions to clarify course of nephrotic syndrome Remission: Urine albumin nil or trace (or proteinuria < 4 mg/m2/hour) for three consecutive early morning specimens Relapse: Urine albumin 3+ or 4+ (or proteinuria > 40 mg/m2/hour) for three consecutive early morning specimens, having been in remission previously Frequent relapses: Two or more relapses in initial 6 months or more than three relapses in any 12 months Steroid dependence: Two consecutive relapses when on alternate day steroids or within 14 days of its discontinuation Steroid resistance: Absence of remission despite therapy with daily prednisolone at a dose of 2 mg/kg/day for 4 weeks

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Management of the nitial pisode

-

The adequacy of treatment of the initial episode, in terms of dose and duration of corticosteroids, is an important determinant of long term course. A

ndications for Biopsy

at onset less than 1 year or more than 16 years; (ii) gross or persistent microscopic hematuria, or low C3; (iii) renal failure, not attributed to hypovolemia; (iv) suspected secondary cause and (v) sustained hypertension. A biopsy is considered later in steroid resistance and proposed use of calcineurin inhibitors.

gents

Prednisolone and prednisone are of proven benefit in patients with nephrotic syndrome. Other agents such as deflazacort, methylprednisolone, dexamethasone or triamcinolone should not be used. Prednisolone is given after meals to reduce GI side effects; administration of antacids is usually not required.

Dose and Duration Prednisolone is given at a dose of 2 mg/kg/day (maximum 60 mg) in single or divided doses for 6 weeks, followed by 1.5 mg/kg (maximum 40 mg) as a single morning dose on alternate days for the next 6 weeks. Therapy with corti­ costeroids is then stopped. Evidence from controlled studies suggests that pro­ longed initial steroid therapy (for 12 weeks or longer) is associated with reduced risk for relapses. Some experts suggest that therapy should not be stopped abruptly, but tapered over 8–12 weeks. The risk of steroid adverse effects with prolonged therapy must be recognized. Based on 631 available evidence and opinion, and while awaiting results ­

I

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Evaluation of a patient with suspected nephrotic syndrome includes history and physical examination, with attention to etiology, prior therapies, edema, blood pressure, anthropometry and evidence of infections. Heavy (nephrotic range) proteinuria is presence of 3–4+ (300–1000 mg/ dL) urine protein by dipstick on early morning urine for 3 consecutive days, a spot urine protein/creatinine ratio more than 2 mg/m2, or protein excretion more than 40 mg/m2 per hour on a timed sample. A precise quantitative assessment of proteinuria is not necessary. Relevant investigations are listed in Table 10.7.2.

If required •  C3 and antistreptolysin O (gross or persistent microscopic hematuria) •  Chest X-ray (positive tuberculin test; history of contact with tube rculosis) •  Hepatitis B surface antigen (if recent jaundice, raised levels of trans aminases) •  Antinuclear antibodies (if features of systemic lupus erythematosus) •  Urine culture (if clinical features of urinary tract infection)



valuation at nset O

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Essential •  Urinalysis: Proteinuria, red cells, casts •  Blood levels of urea, creatinine, albumin, cholesterol •  Complete blood counts •  Tuberculin test

t

Nephrotic syndrome is characterized by heavy proteinuria, hypoalbuminemia (albumin < 2.5 g/dL), hyperlipidemia (cholesterol > 200 mg/dL) and edema. The large majority is primary (idiopathic); a secondary cause (amyloidosis, lupus, HSP) is rare. Most (> 80%) children with idiopathic nephrotic syn­ drome show remission following therapy with oral corticosteroids (steroid sensitive). The prognosis in these cases is favorable, contrasted to patients who do not respond (steroid resistance). The disease course is variable. While a few children have none (20%) or 1–2 relapses a year (20–25%), others show frequent relapses (40%). A small proportion shows resistance after initial steroid responsiveness (late resistance). Table 10.7.1 lists definitions that clarify the course of nephrotic syndrome.

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Diseases of Ki ney an Urinary Trac

10.7

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Therapy for elapse

Steroid Sparing Agents

Alternative agents are recommended if: (i) prednisolone threshold more than 0.5–0.7 mg/kg on alternate days; (ii) features of corticosteroid toxicity (growth failure, hyper­ tension and cataract) appear. The agents used are listed below:

C

-

A

Levamisole • Dose and duration: 2–2.5 mg/kg on alternate days for 12–24 months. • dverse effects: Flu like symptoms, neutropenia, hepatotoxicity, convulsions, skin rash. • Monitoring: Monitor total and differential leukocyte count every 3–4 months. • oncomitant steroid therapy: The dose of predniso­ lone is tapered to 0.25–0.5 mg/kg on alternate days. While therapy with prednisolone may be discontinued in some cases, many patients require a small dose of prednisolone. 632

F

A

C

A

C

C

alcineurin nhibitors [ yclosporine ( s ), Tacrolimus] These agents are indicated in patients with steroid depen­ dence that fails to benefit with levamisole, cyclophospha­ mide and/or MMF. I

n U

Following treatment of a relapse, prednisolone is tapered to a dose of 0.3–0.7 mg/kg on alternate days, which is given for 9–18 months.

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Long-term, Alternate Day Steroids

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These patients require prolonged treatment in order to maintain disease remission. The strategies are summarized below.

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Mycophenolate Mofetil (MM ) • Dose and duration: 600–1000 mg/m2/day; 20–30 mg/ kg/day for 12–24 months. • dverse effects: Uncommon; gastrointestinal discom­ fort, diarrhea and leukopenia. • Monitoring: (i) Leukocyte counts are monitored every 1–2 months; treatment is withheld if count falls below 4,000/mm3; (ii) side effects mimic infectious gastroenteritis. • oncomitant steroid therapy: The agent has moderate steroid sparing potential; tapering doses of prednisolone are given for 6–12 months.

• Dose and duration: CsA 4–5 mg/kg/day; Tacrolimus 0.1–0.2 mg/kg/day for 12–24 months. • dverse effects: Nephrotoxicity; hirsutism, gum hyper­ plasia; hypertension; hypercholesterolemia; hyperglyce­ mia; neurotoxicity with headache and seizures; diarrhea. • Monitoring: Monitor (i) renal function every 3 months; (ii) trough levels (CsA 80–120 ng/mL; tacrolimus 3–7 ng/mL) particularly if response is unsatisfactory, noncompliance is suspected and if nephrotoxicity; (iii) lipid profile and blood sugar; (iv) repeat biopsy after 2–3 years of therapy, particularly if further therapy is planned. Relapses during therapy are treated with daily steroids, followed by tapering doses of prednisolone on alternate days. The occurrence of frequent relapses despite use of alternative agent is an indication for use of another agent. Flow chart 10.7.1 summarizes the protocol for management of patients with frequent relapses and steroid dependence. A

requent elapses and teroid Dependence R

F

Patients suffering from three or fewer relapses a year should receive treatment for each disease relapse as described above, i.e. prednisolone at 2 mg/kg/day (single or divided doses) until remission, followed by the same agent given in a single morning dose of 1.5 mg/kg on alternate days for 4 weeks. Therapy is then discontinued.

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nfrequent elapses



I

Relapses are often triggered by minor infections. Sympto­ matic therapy of infectious illness often results in remission of 1+/2+ proteinuria. However, persistence of 3+/4+ proteinuria with infections requires therapy. Prednisolone is given at a dose of 2 mg/kg/day until urine protein is trace or nil for three consecutive days (remission), and subsequently as a single morning dose of 1.5 mg/kg on alternate days for 4 weeks. Treatment for a relapse usually lasts for 5–6 weeks. The subsequent management of a patient with steroid sensitive nephrotic syndrome depends on the course of the illness. R

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yclophosphamide • Dose and duration: 2–2.5 mg/kg/day for 8–12 weeks. • dverse effects: Leukopenia, alopecia, vomiting, hem­ orrhagic cystitis; gonadal toxicity, malignancies. • Monitoring: (i) Cumulative dose should not exceed 168 mg/kg; repeat courses are avoided; (ii) leukocyte counts should be monitored every 2 weeks; cyclophosphamide is stopped if less than 4000/cu mm; (iii) fluid intake should be increased; patients are encouraged to void frequently. • oncomitant steroid therapy: Cyclophosphamide has a potent steroid sparing potential, allowing discontinuation of steroids. The dose of prednisolone is maintained at 1 mg/kg during cyclophosphamide therapy; subsequently prednisolone is tapered and discontinued. • Patient selection: This agent is preferred in patients with: (i) significant steroid toxicity; (ii) severe relapses with episodes of hypovolemia, life threatening infections or thrombosis and (iii) poor compliance or difficult follow up.

of ongoing prospective studies, initial therapy with oral steroids is recommended for 12 weeks. Failure to achieve remission of proteinuria despite treatment with daily prednisolone for 4 weeks is labeled as steroid resistant nephrotic syndrome (SRNS).

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Genetic tudies

Patients with SRNS might show mutations in genes enco­ ding podocyte proteins: podocin (NPHS2), nephrin (NPHS1) and Wilms tumor (WT1) genes. The illness is unresponsive to immunosuppressive medications, progresses rapidly to ESRD, and unlike nongenetic FSGS (which recurs after transplantation in 30%), does not recur. Where facilities exist, mutational analysis should be offered to patients with: (i) congenital nephrotic syndrome, (ii) family history of SRNS, (iii) sporadic initial resistance that does not respond to therapy with cyclophosphamide or calcineurin inhibitors and (iv) girls with steroid resistant FSGS.

Management Patients with idiopathic SRNS secondary to MCD, FSGS or mesangioproliferative GN are treated similarly. The chief factor predicting outcome is the response of proteinuria to therapy rather than the renal histology.



t

Calcineurin Inhibitors Treatment with CsA or tacrolimus results in complete or partial remission of SRNS in almost 60–85% children. Adverse effects require close monitoring (see Table 10.7.3).

Cyclophosphamide Oral cyclophosphamide has limited efficacy in inducing remission. Intravenous cyclophosphamide has modest success, when given monthly for 6 doses with tapering doses of prednisolone, inducing remission in 30–40%.

Pulse Corticosteroids with Oral Cyclophosphamide Pulses of IV methylprednisolone or dexamethasone have been used in combination with oral cyclophosphamide with moderate efficacy. The risk of steroid toxicity is high, and patients show systemic infections, hypertension and electrolyte abnormalities. Significantly higher remission is seen with calcineurin inhibitors as compared to other agents. Other therapies include rituximab (anti CD20 monoclonal antibody), combi­ nation of cyclosporine and mycophenolate mofetil, and plasmapheresis. -



ti e

The aim of therapy in patients is to induce and maintain remission of proteinuria, while avoiding medication adverse effects. Most regimens use a combination of an immunosuppressive agent with prednisolone and enalapril (Table 10.7.3).



S

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Initial resistance is defined by the lack of remission at the first episode of nephrotic syndrome, and late resistance is considered in patients who are steroid sensitive initially, but show steroid resistance during a subsequent relapse. Children with steroid resistant nephrotic syndrome (SRNS) (initial or late) should undergo renal biopsy before instituting specific treatment. Histology shows minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) in 30– 40% patients each, and mesangioproliferative GN in a small group. Patients with MCD show a satisfactory response to therapy; FSGS with chronic tubulointerstitial changes is associated with less satisfactory outcomes.

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Diseases of Ki ney an Urinary Trac

Flow chart 10.7.1 Alternative agents in steroid sensitive nephrotic syndrome

Prednisolone Prednisolone is a component of all regimens used in therapy of SRNS. The agent is given on alternate days at 1 mg/kg/ 633 day for 1–3 months, following which the dose is tapered.

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Intravenous cyclophosphamide

500–750 mg/ m2

6 pulses

40–50

Tex

Oral cyclophosphamide

2–2.5 mg/kg/ day

12 weeks

20–25

Dose

Cyclosporine (CsA) Tacrolimus (Tac)

Duration

Efficacy (%)

Adverse effects

4–5 mg/kg/day 12–36 months

50–80

0.1–0.2 mg/ kg/day

70–85

Acute and chronic nephrotoxicity; hirsutism and gum hyperplasia (CsA > Tac); hypertension; hypercholes terolemia (CsA > Tac); hyperglycemia (Tac); elevated transaminases; neurotoxicity (headache, seizures; Tac > CsA) ­

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Agent

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Table 10.7.3 Agents used in the management of steroid resistant nephrotic syndrome

Leukopenia; alopecia; nausea and vomiting (IV > oral); gonadal toxicity; hemorrhagic cystitis (IV > oral)

Methylprednisolone Dexamethasone

20–30 mg/kg IV 4–5 mg/kg/day IV Pulses on alternate days x 6; once weekly x 8, fortnightly x 4, monthly x 8, bimonthly x 4 [abbreviated protocols also used]

Prednisolone

Tapering doses x 18 months* PO

Cyclophosphamide

2–2.5 mg/kg/day x 12 weeks** PO

30–50

Hypertension, hypokalemia, hyperglycemia, steroid psy chosis, systemic infections

­

High Dose Corticosteroids with Cyclophosphamide

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Effects of cyclophosphamide and prolonged steroid therapy

*Prednisolone 1.5 mg/kg on alternate days x 4 weeks; 1.25 mg/kg x 4 weeks; 1 mg/kg x 4 months; 0.5–0.75 mg/kg x 12–18 months **Cyclophosphamide is given during weeks 3–15



S

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Congenital nephrotic syndrome is defined as the presence of nephrotic syndrome within the first 3 months of life. This condition has diverse etiologies. While the Finnish type and other inherited defects are common forms, rare causes include intrauterine infections and maternal drugs. Genomic sequencing of NPHS1 enables diagnosis of the Finnish nephrotic syndrome. Mutations in other genes (NPHS2, WT1 and LAMB2) might be important in other cases. A correct diagnosis is important for prognosis, therapy and genetic counseling. Immunosuppression has no role in managing infants with congenital nephrotic syndrome. Angiotensin converting enzyme inhibitors [ACEIs (enalapril 0.2–0.5 mg/kg/day)] are effective in reducing proteinuria. C

upportive are and Management of omplications S

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Patients are monitored for proteinuria (dipstick, spot samples), blood levels of creatinine and albumin, and edema every 2–3 months. While the aim of treatment is complete remission, the occurrence of partial remission is satisfactory. Most patients who respond to treatment do so within 2–3 months. Therapy should be considered not effective and discontinued if nephrotic range proteinuria persists beyond 6 months. Patients that fail therapy with one regimen may show response to different agents. Monitoring for drug levels is recommended when using CsA or tacrolimus, because variable bioavailability might result in either subtherapeutic or toxic levels. Trough level (sample drawn 15–30 minutes prior to due dose) is estimated 2 weeks after introduction of therapy, or suspecting toxicity or poor compliance. Trough levels of 80–120 ng/mL for CsA and 3–7 ng/mL for tacrolimus are acceptable. Examination of renal histology is required in patients with persistent decline in renal function (creatinine > 50% 634 above baseline) despite reduced dose or discontinued

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Therapy with ACE inhibitors (enalapril 0.3–0.6 mg/kg/ day; ramipril 6 mg/m2 q24h is associated with decrease in proteinuria and control of hypertension. Adverse effects include dry cough, hyperkalemia and decline in renal function. Angiotensin receptor blockers (losartan, valsartan) may be used in case of persistent dry cough or as add on for better antiproteinuric effect.

treatment. Since prolonged therapy might show histological nephrotoxicity, in presence of normal levels of creatinine, biopsy is advised in patients receiving therapy with CsA or tacrolimus for 2–3 years.

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Angiotensin Converting Enzyme Inhibitors, Angiotensin Receptor Blockers

dema

Daily administration of corticosteroids results in diuresis within 2–4 days. Therapy for edema is therefore not required in most patients with steroid sensitive nephrotic syndrome. Patients with significant edema require treatment with diuretics. Anasarca results in discomfort and an increased risk of infections should be avoided.

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Patients with SRNS may show persistent dyslipidemia that requires treatment, usually with atorvastatin (10–20 mg/day).

Thrombosis

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Live vaccines (oral polio, varicella) are deferred until the child is off immunosuppressive medications for at least 4 weeks. Two doses of the varicella vaccine are given 4 weeks apart, while the child is in remission and off immunosuppressive medications. Injectable polio vaccine should be administered to children with nephrotic syndrome and their siblings. The administration of pneumococcal vaccine is desirable. Children below 2 years of age should receive the pneumo­ coccal conjugate vaccine. Above 2 years of age, 1 dose of the polysaccharide vaccine (PPV23) is administered, following a dose of the conjugate vaccine. Children who continue to have relapses of nephrotic syndrome may receive one repeat dose of PPV23, 5 years after the primary vaccination. N

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Table 10.7.4 provides a summary of management of common bacterial infections in patients with nephrotic syndrome. During serious infections, steroids should be administered daily at stress doses (see below). Varicella may be life threatening illness in immunocompromised patients. All patients should receive oral acyclovir (80 mg/kg/day in 4 doses) for 7 days; severe illness requires admission and administration of IV acyclovir. Administration of varicella

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Children with nephrotic syndrome are predisposed to venous thrombosis during relapses, due to loss of antithrombin III, low intravascular volume, immobilization, indwelling vascular catheters and puncture of deep vessels. Diagnosis requires confirmation with ultrasonography, Doppler studies and cranial MRI if required. Therapy includes heparin or low molecular weight heparin initially, followed by oral anticoagulants.

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Hypovolemia may occur during a disease relapse or follo­ wing administration of diuretics, particularly in children with poor oral intake, diarrhea and vomiting. Patients complain of abdominal pain, lethargy, dizziness and leg cramps. Signs include the presence of tachycardia, hypotension, delayed capillary refill, low volume pulses and cold peripheries. An elevated ratio of blood urea to creatinine, rising hematocrit and urine sodium less than 20 mEq/L suggest the presence of hypovolemia. Patients require admission and rapid infusion of normal saline (10–20 mL/kg) over 20–30 minutes. Patients who do not respond to two saline boluses should receive infusion of 5% albumin (10–15 mL/kg).

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zoster immunoglobulin (in a single dose within 96 hours of exposure), or intravenous immunoglobulin (400 mg/ kg, single dose) might prevent or lessen the severity of the disease in susceptible individuals exposed to varicella. Children with nephrotic syndrome and positive tuberculin test in absence of evidence of tuberculosis should receive prophylaxis with isoniazid for 6 months.

Diseases of Ki ney an Urinary Trac

Short term therapy with frusemide (1–3 mg/kg/day, in 1–2 doses) is effective; therapy beyond 3–4 days is rarely necessary. Edema that does not respond to maximal doses of frusemide requires coadministration of a thiazide. If frusemide is used for prolonged duration or at high doses, therapy with spironolactone (2–4 mg/kg/day) prevents the occurrence of hypokalemia. Patients with refractory edema are hospitalized and given IV frusemide either as bolus injections (1–3 mg/kg/ dose, infused over 15–20 minutes) or as infusions (0.1–1 mg/kg/hour), under monitoring. Infusions of albumin (20% albumin, 0.5–1 g/kg over 2–4 hours), with IV frusemide, administered at the end of the infusion, are useful in severe hypoalbuminemia (albumin < 1.5 g/dL). The effect is transient, and repeat administration of albumin is often required. Albumin infusions should be given carefully in patients with respiratory distress, hypertension and impaired kidney functions.

utrition

During remission, children should eat a balanced, nutritious diet. Salt restriction is advised in patients with anasarca; undue restrictions that make food unpalatable are not required. Patients with persistent or recurrent proteinuria

 

Table 10.7.4 Management of systemic bacterial infections in nephrotic syndrome Infection

Drug (Dose)

Duration

Peritonitis

IV Cefotaxime (100–150 mg/kg/day); IV Ceftriaxone (75–100 mg/kg/day); or IV Ampicillin (100 mg/kg/day) with IV Amikacin (15 mg/kg/day)

7–10 days

Cellulitis

IV Cloxacillin (100–200 mg/kg/day) + IV Ceftriaxone (50–100 mg/kg/day) 10 days Shift to oral cloxacillin (100 mg/kg/day) or Coamoxiclav (30–40 mg/kg/day) and cefixime (8 mg/kg/day) once erythema and induration resolve

Pneumonia

Coamoxiclav (30–40 mg/kg/day); Cephadroxil (30 mg/kg/day) Atypical, nonsevere: Azithromycin (10 mg/kg/day) if atypical pathogens likely Severe: IV Cefotaxime (100–150 mg/kg/day); Ceftriaxone (75–100 mg/kg/day) Severe infection with S. aureus: Teicoplanin (10 mg/kg/day) or Vancomycin (40–60 mg/kg/ day) with Amikacin (15 mg/kg/day)

7–10 days 3–5 days 7–10 days 10–14 days

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The parents are briefly told about the natural history of the disease, and the likely adverse effects of repeated courses of high dose steroid therapy and other medications. The patient should return for follow up at 4 weeks of therapy of the initial episode, or any relapse. The need to examine urine protein at home (dipstick, boiling method) is emphasized. Parents should maintain a diary, recording the protein excretion, intake of medications and intercurrent



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1. Bagga A, Mantan M. Nephrotic syndrome in children. Indian J Med Res. 2005;122:13 28. 2. Benoit G, Machuca E, Antignac C. Hereditary nephrotic syndrome: a systematic approach for genetic testing. Pediatr Nephrol. 2010;25:1621 32. 3. Gulati A, Bagga A. On behalf of the Indian Society of Pediatric Nephrology. Guidelines for management of children with steroid resistant nephrotic syndrome. Indian Pediatr. 2009;46:35 47. 4. Hodson EM, Willis NS, Craig JC. Corticosteroid therapy for nephrotic syndrome in children. Cochrane Database Syst Rev. 2007;4:CD001533. 5. Hodson EM, Willis NS, Craig JC. Interventions for idiopathic steroid resistant nephrotic syndrome in children. Cochrane Database Syst Rev. 2010;(11):CD003594. 6. Indian Society of Pediatric Nephrology. Management of steroid sensitive nephrotic syndrome: Revised guidelines. Indian Pediatr. 2008;45:203 14. 7. Jalanko H. Congenital nephrotic syndrome. Pediatr Nephrol. 2009;24:2121 8.



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Patients who have received steroids at high doses for more than 2 weeks in the past year are at risk of suppression of the hypothalamic pituitary adrenal axis. These children require steroid supplements during surgery, anesthesia or serious infections, which are given as parenteral hydrocortisone (2–4 mg/kg/day) followed by oral prednisolone (0.3–0.6 mg/kg/day). The medications are given for the duration of stress and tapered rapidly.



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illnesses. The record provides useful assessment of patient’s disease status and course, including steroid threshold for relapses.



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should increase their daily intake of proteins to 2–2.5 g/kg. Those receiving prolonged (> 3 months) steroid therapy should receive supplements of calcium carbonate (250–500 mg) and vitamin D (125–250 IU).

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Diagnosis

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Definitions The diagnosis of UTI requires demonstration of significant bacteriuria on urine culture in the presence of symptoms. • Significant bacteriuria refers to a colony count of more than 105 CFU/mL of a single bacterial species in a midstream clean catch sample • Significant bacteriuria without symptoms of UTI is called asymptomatic bacteriuria • Recurrent UTI denotes a second episode of UTI • A complicated UTI is diagnosed in the presence of fever more than 39°C, systemic toxicity, persistent vomiting, dehydration, renal angle tenderness and raised serum creatinine • Children with simple UTI may have dysuria, frequency or urgency with or without fever, and none of the symptoms of complicated UTI • The term complicated UTI implies upper tract infection or acute pyelonephritis, while dysuria and frequency indicate lower tract involvement (cystitis, urethritis).

Detection of leukocytes (> 5 WBC/HPF in centrifuged urine) and bacteria on microscopic examination of a carefully collected fresh sample of urine suggests UTI. Enhanced urinalysis using uncentrifuged urine sample for leukocyturia (> 10 WBC/mm3) in Neubauer counting chamber along with Gram staining of sediment for bacteria is useful. Rapid tests like Greiss test and nitrite and leukocyte esterase tests are popular but may have false positivity and negativity. The bacterial enzyme nitrate reductase can convert urinary nitrate to nitrite. Children with urinary frequency may show false negative tests due to insufficient time for incubation of bacteria with urine. False negative results are also seen if the UTI is caused by a bacterium that does not contain nitrate reductase, e.g. streptococcal species. Similarly, leukocyte esterase detects leukocytes in urine, which can be present in UTI or in conditions like interstitial nephritis and GN. A combination of the two tests (leukocyte esterase and nitrite) is more useful. A combined positive test in a child with positive clinical features suggests upper tract UTI. Similarly, a positive rapid test in combination with positive enhanced urinalysis indicates UTI in 95% of cases. The criteria for the diagnosis of UTI depend on the method of collection of urine. On culture of urine collected by a standard midstream clean catch specimen, a colony count of more than 105CFU/mL should be documented. A colony count below 104 is usually due to urinary contamination unless the child has polyuria or has received antimicrobial therapy. If urine sample is obtained by suprapubic aspiration (e.g. infants), any number of pathogens can indicate UTI. On samples collected by urethral catheterization, a colony count of more than 5 X 104 CFU/mL indicates UTI.

Newborns with UTI present with septicemia, jaundice, vomiting and shock. In infancy, symptoms are nonspecific, such as unexplained fever, diarrhea, vomiting and failure to thrive. Older children have dysuria, frequency and suprapubic pain. Fever, flank pain and toxic appearance suggest renal parenchymal involvement (complicated UTI). Examination should include evaluation for features suggesting underlying structural abnormalities, such as distended bladder, palpable enlarged kidney(s), tight phimosis in a boy, vulval synechiae in a girl, palpable fecal mass in the colon, patulous anus, neurological deficit in lower limbs, urinary incontinence and

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Urinary tract infections (UTI) are among the most common infections of childhood. The risk of occurrence of UTI before the age of 14 years is approximately 1–3% in boys and 3–10% in girls. During infancy, the male to female ratio is 3–5:1. Beyond 1–2 years, there is a female preponderance with male to female ratio of 1:10. The diagnosis of UTI is often missed in infants and young children since symptoms are minimal and nonspecific. Prompt identification and adequate management are mandatory to prevent renal cortical scarring, which can lead to progressive parenchymal damage and hypertension. Young age, delayed or inadequate antibacterial therapy, recurrent infections, voiding dysfunction and associated high grades of vesicoureteric reflux (VUR) are risk factors for renal scarring in young children.

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evidence of previous surgery of the urinary tract, anorectal malformation or meningomyelocele.

Urinary Tract nfections

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Urinary Tract nfection, Vesicoureteric eflux and eflux ephropathy

10.8

tiology

The most common causative organism in children is E. coli (60–80%); Proteus, Klebsiella, Staphylococcus saprophyticus, Enterococcus and Enterobacter are the other common organisms identified.

Management Prompt treatment is needed to reduce the morbidity of infection, minimize renal damage and subsequent complications. The decision for hospital admission is based on factors such as young age (< 3 months), presence of systemic toxicity (complicated UTI) or dehydration, inability to retain orally and the likelihood of noncompliance to 637

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All children with UTI require some form of renal imaging (Flow chart 10.8.1). Infants presenting with the first episode of UTI should undergo an ultrasound study, dimercaptosuccinic

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Flow chart 10.8.1 Evaluation following initial febrile urinary tract infection#

Any child with recurrent UTI should be evaluated for complicating factors like VUR, obstruction of the urinary system, neurogenic bladder and bowel bladder dysfunction (voiding dysfunction). A thorough clinical examination and review of the imaging studies are mandatory. Features that can suggest bowel bladder dysfunction include recurrent febrile UTIs, persistent high grade VUR, constipation, impacted stools, maneuvers to postpone voiding (holding maneuvers, e.g. Vincent curtsy, squatting), voiding less than 3 or more than 8 times a day, straining or poor urinary stream, thickened bladder wall (> 2 mm), postvoid residue more than 20 mL and spinning top configuration of bladder on MCU. Children with VUR, bowel bladder dysfunction, obstruction and neurogenic bladder require a multidisciplinary approach to their management, involving consultations with both urology and nephrology.

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hemoprophylaxis

Following treatment of UTI, prophylactic antibiotic therapy is initiated in children below 1 year of age, until appropriate imaging of the urinary tract is completed. Drugs used include cotrimoxazole (1–2 mg/kg/day), cephalexin (10 mg/kg/ day), cefadroxil (5 mg/kg/day) or nitrofurantoin (1–2 mg/ kg/day), administered in a single dose at bedtime. The chief intent is to keep the bladder urine sterile in patient with VUR. Chemoprophylaxis is administered for 6–24 months, depending upon the associated anomalies and UTI recurrence.

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acid (DMSA) scan and MCU. Ultrasonography is usually performed during acute illness and may demonstrate renal anomalies, dilated or irregular pelvicalyceal system and severe parenchymal scarring. Dimercaptosuccinic acid is done to identify acute pyelonephritis during the acute phase of UTI and also to identify cortical scars on follow up. The timing of DMSA at 2–3 months following the UTI helps to detect scarring. Micturating cystourethrogram should be performed only after adequate control of infection. Children between 1 year and 5 years should undergo ultrasonography and DMSA scan following the first episode of UTI, and an MCU only if USG or DMSA scan is abnormal. Children above 5 years of age with the first attack may be evaluated with an ultrasound alone; MCU and DMSA are needed if the ultrasound is abnormal. Findings on MCU may include VUR, bladder thickening due to lower tract obstruction or posterior urethral valves. MCU and ultrasound also allow the assessment of residual urine. Direct radionuclide cystogram, instead of contrast MCU, is a useful test for repeat evaluations to document resolution of VUR on follow up. It is not recommended as the initial screening test as it may not provide details of the anatomy of bladder and urethra.



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therapy. Parenteral antibiotics used include ceftriaxone, cefotaxime, amikacin, gentamicin and coamoxiclav. Some advocate single daily dose of aminoglycoside in children with normal renal function. The treatment is modified later according to antimicrobial sensitivity. Oral antibiotics are started once clinical improvement is noted, after 48–72 hours of parenteral therapy. Oral medications used include cefixime, coamoxiclav, cipro­ floxacin, ofloxacin and cephalexin. Children with simple UTI and those above 3 months of age are treated with oral antibiotics. With adequate therapy, resolution of fever and reduction of symptoms are noted by 48–72 hours. Failure to respond to therapy may be due to resistant pathogens, complicating factors or noncompliance, and these children require re evaluation. The duration of therapy is 10–14 days for complicated UTI and 7–10 days for simple UTI. Supportive therapy includes maintenance of adequate hydration and control of fever. Parenteral fluids are indicated in febrile children with inadequate oral intake or dehydration. A repeat urine culture is not necessary, unless there is persistence of fever and toxicity despite 72 hours of adequate antibiotic therapy.

Screening of normal school children may occasionally reveal significant bacteriuria. These organisms are of low virulence that colonize the lower tract, and no treatment is necessary. However, adolescent females presenting with asymptomatic bacteriuria need ultrasonographic evaluation to rule out renal anomalies, since they may be at risk of acute pyelonephritis during pregnancy.

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Abbreviations: MCU, Micturating cystourethrogram; DMSA, Dimercapto­ succinic acid # From ISPN revised guidelines on UTI, 2011 *All children with recurrent UTI need detailed evaluation with ultrasono­ graphy, DMSA scan and MCU

Vesicoureteric reflux implies passage of urine into the ureter during micturition. Normally, the long submucosal and intravesical segment of the ureter at the ureterovesical

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Diseases of Ki ney an Urinary Trac

junction closes when bladder contracts, effectively preven­ ting VUR. Incompetence of ureterovesical junction due to shortening and lack of obliquity of the submucosal and intravesical segments results in VUR. Primary VUR is an isolated defect that has a genetic basis and may occur in siblings. VUR may be secondary to bladder outflow obstruction (e.g. posterior urethral valves), neurogenic bladder or a functional voiding disorder. During micturition, VUR allows the rise in intravesical pressure to be transmitted to the ureter and renal pelvis, which enables urine to enter papillary collecting ducts and renal tubules (intrarenal reflux). Thus, pathogenic organisms present in the bladder can reach the renal parenchyma and initiate inflammation and subsequent scarring. However, renal damage may occur even in sterile urine, possibly due to the transmitted pressure or by immunological mechanisms. Vesicoureteric reflux is present in 30–50% of children with recurrent febrile UTI and renal cortical scarring. Low grades (I III) of VUR are likely to resolve over time. Moderate to severe VUR, particularly if bilateral, is an important risk factor for pyelonephritis and renal scarring, which leads to hypertension, proteinuria and progressive kidney disease. The risk of scarring is highest among infants. Intrauterine VUR, even in the absence of infection, can result in renal dysplasia or hypoplasia.



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The severity of VUR is graded using the International Study Classification from Grade I to V, based on the appearance of the urinary tract on contrast MCU. Mild to moderate VUR (grades I–III) is characterized by reflux into the nondilated or dilated ureter and upper collecting system. In severe VUR (grades IV V), there is reflux into grossly dilated and distorted ureter (s), pelvis and calyces. Radionuclide cystogram is more sensitive and specific for the detection of VUR than MCU, but cannot delineate anatomic abnormalities, and the grading is not reliable. Hence, the use of DRCG is limited to follow up studies (Fig. 10.8.1). The DMSA renal scan is a sensitive technique to detect renal scarring in reflux nephropathy. Patients with imaging evidence of scars on the background of VUR require evaluation for evidence of hypertension or proteinuria. R

Management of Vesicoureteric eflux -

Children with VUR and otherwise normal urinary tract are treated with long term chemoprophylaxis with

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Diagnosis



Children with VUR may present with recurrent febrile UTI with or without structural anomaly of the urinary tract. Patients with reflux nephropathy and severe parenchymal scarring may present with chronic acidosis, hypertension and renal failure.

nitrofurantoin, cotrimoxazole, cephalexin or cefadroxil. Infants with VUR grades I and II receive antibiotic prophy­ laxis up to 1 year of age, and continue to be followed up till 5–7 years of age. Children with grades III–V VUR should receive antibiotic prophylaxis up to 5 years of age. Beyond 5 years, prophylaxis is continued if there is bowel bladder dysfunction. In all categories, antibiotic prophylaxis is restarted if breakthrough febrile UTI is noted. Training the child for double or triple voiding reduces the residual urine and is beneficial. Urine microscopy and culture are performed whenever UTI is suspected. Radionuclide cystography can be repeated every 1–2 years to assess for resolution of VUR, especially in patients with VUR grades III–V. Most cases of grades I–III VUR resolve; higher grades of reflux may disappear in a small percentage of patients. Surgery for reflux is indicated in patients with recurrent breakthrough febrile UTIs while on prophylaxis, nonresolution of grades III–V VUR by 5 years of age, VUR grades III–V associated with bilateral renal scarring beyond 2 years of age and by parental choice (remote residence, anxiety). There are two surgical options for correction of VUR. Subureteric injection of Deflux or Macroplastique is a day care technique which is 70% effective in eliminating VUR in grade III or IV. A day care minimal access extravesical ureteric reimplant technique is also suitable for Grade III or IV VUR. Cost of the implant and risk of failure, particularly in inexperienced hands or with bladder bowel dysfunction, limit its utility. The most effective method of reflux elimination is surgery by ureteric reimplantation. Voiding dysfunction is an important reason for recurre­ nces of UTI, particularly in children with VUR. Failure to manage this condition is a common cause of failure of antibiotic prophylaxis as well as surgical management. Treatment of constipation and voiding dysfunction is an important component of the management of VUR in children.

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Figure 10.8.1 Radionuclide scintigraphy in a 4 year old with bilateral Grade V vesicoureteric reflux on micturating cystourethrogram performed at 18 months. The images suggest persistence of severe reflux on the right side

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1. Bensman A, Dunand O, Ulinski T. Urinary tract infections. In: Avner ED, Harmon WE, Niaudet P, Yoshikawa N; Eds. Pediatric Nephrology, 6th edition. Springer Verlag, Berlin Heidelberg; 2009.pp.1299 1310. 2. Srivastava RN, Bagga A. Urinary tract infection. In: Pediatric Nephrology, 5th edition. New Delhi: Jaypee Brothers; 2011. pp. 273 300. 3. Vijayakumar M, Kanitkar M, Nammalwar BR, et al. Revised statement on management of urinary tract infections. Indian Pediatr. 2011; 48: 709 17. 4. Vijayakumar M, Prahlad N. Urinary tract infection in children. In: Vijayakumar M, Nammalwar BR (Eds). Principles and Practice of Pediatric Nephrology. New Delhi: Jaypee Brothers; 2004. pp. 348 57. 5. Vijayakumar M, Prahlad N, Sharma NL, et al. Urinary tract infection. In: Gupte S (Ed). Recent Advances in Pediatrics 17. New Delhi: Jaypee Brothers; 2007. pp. 240 60.

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Children with renal scar (reflux nephropathy) are counseled regarding the need for early diagnosis and therapy of UTI, and regular follow up. Physical growth and blood pressure should be monitored every 6–12 months through adolescence. Investigations include urinalysis for proteinuria and estimation of serum creatinine. Yearly ultrasound examinations are done to monitor renal growth. Patients with proteinuria and hypertension benefit from treatment with ACEIs and ARBs.





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Reflux is inherited in an autosomal dominant manner with incomplete penetrance. About 27% of siblings and 35% of offsprings of patients may have reflux. Ultrasonography is the modality of choice to screen these individuals. Further imaging is required if ultrasonography is abnormal or upon occurrence of febrile UTI.

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10.9

Madhuri Kanitkar The common embryological origin of the bladder and rectum (from the cloaca) results in functional dis­ orders that affect both organs, termed bowel bladder dysfunction (BBD). Functional voiding disorders may be either overactive bladder when it is a filling phase disorder or dysfunctional voiding when it is an evacuation phase disorder due to bladder sphincter dysynergia. A longs­ tanding dysynergic bladder may result in an overstretched low pressure underactive bladder leading to overflow incontinence. Severe bladder sphincter dysynergia is noted in the Hinman syndrome where the urinary bladder is trabeculated, develops high pressure with bilateral VUR akin to neurogenic bladder without any obvious structural abnormality. Constipation is a major aggravating factor for bladder dysfunction.

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The urinary bladder functions as a compliant compartment with adequate capacity and a competent sphincter. This process is controlled by the somatic and autonomic nervous system and the brain. The nomenclature for symptoms has been recently standardized (Table 10.9.1). While continuous incontinence is almost always due to an underlying anatomical or neurological anomaly, intermittent incontinence is mostly functional.

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The continuous process of urine formation ends in an intermittent act of micturition due to the storage capacity of the urinary bladder. The bladder can empty to completion at an appropriate time and place, once control is achieved by 5 years of age. An aberration of this function results in a wet child, or a child who cannot void to completion. The disorders are classified as primary functional voiding disorders, which occur in the presence of an intact neuronal pathway and no congenital or anatomical abnormality of the urinary tract; or may be secondary to a neurological or structural anomaly. Disorders of micturition are associated with recurrent UTIs and VUR. High bladder pressures combined with poor emptying result in stasis and infection, and back pressure changes affect the pelvicalyceal system and the kidneys, which is an important cause for CKD in children.

More than 85% children have complete bladder control by 5 years of age. A child having bedwetting at least twice a month after the fifth year has enuresis and warrants attention. It is termed primary when the child has never been dry and secondary when bedwetting starts after a minimum period of 6 months of dryness at night. It is termed monosymptomatic if it is not accompanied by any lower urinary tract symptoms. This should be differentiated

 

Table 10.9.1 Classification of disorders of micturition Term Incontinence Continuous Intermittent Storage symptoms Frequency Urgency Nocturia

Definition

Uncontrollable leakage of urine Constant leakage of urine usually due to anatomical/neurological causes Urine leak in discrete amounts: daytime (functional voiding disorder); night time (enuresis) Increased if more than 8 times/day; decreased if less than 3 times/day Sudden and unexpected experience of immediate need to void Child awakens at night to void

Voiding symptoms Hesitancy

Difficult initiation of voiding or child waits a considerable period before voiding starts

Weak stream

Passage of urine with a weak force, relevant from infancy

Straining

Child applies abdominal pressure to initiate and maintain voiding

Intermittency

Micturition in several discrete spurts

Holding maneuvers

Strategies used to postpone voiding or suppress urgency such as standing on tiptoe, forcefully crossing the legs or squatting with the heel pressed into the perineum

Voiding postponement

Daytime incontinence with habitual postponement of micturition

Vaginal reflux

Toilet trained prepubertal girls who experience incontinence in moderate amounts, consistently occurring within 10 minutes after normal voiding

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A functional voiding disorder presents with daytime wetting or recurrent UTI. Children with enuresis refractive to therapy or a persistent VUR may also have voiding dysfunction. A wet child requires systematic evaluation in a stepwise manner (Flow chart 10.9.1). Clinical examination should include the lower back to look for clues suggesting spinal and sacral anomalies and the abdomen for palpable bladder and kidneys. The lower limbs are assessed for tone, power and sensations, and the perineum for ectopic ureters or epispadias. A voiding diary is requested to include a frequency volume charting of urine output and oral fluid intake for 2–3 days with record of accidents/wetting. The voided volume of urine each time is then compared to the expected capacity of the bladder. Ultrasonography of the abdomen is done to examine for dilatation of the upper tract, bladder wall thickness and the presence of postvoid residual urine. An MRI scan of the spine helps to detect an occult problem of the spinal cord, which might result in a neurogenic bladder. An MCU helps to determine the presence of and severity of VUR and delineates the posterior urethra if the patient has recurrent UTI. A urodynamic study is required in some cases, especially those with daytime symptoms, holding maneuvers and abnormal voiding pattern with postvoiding residue. A uroflow study combined with EMG for pelvic floor muscles is less invasive and can delineate most children requiring further evaluation. Treatment of UTI and (re) institution of structured voiding patterns with appropriate hydration, hygiene and timed voiding is important. Constipation should be corrected. In patients with overactive bladder, an anticholinergic medication (e.g. oxybutynin) is effective. Biofeedback therapy and computer games help in training children to develop relaxed voiding. In children with dysfunctional voiding with large postvoid residues, clean intermittent catheterization is advised.

 

Table 10.9.2 Medications used for enuresis Dose

Side effects

Age for use

DDAVP nasal spray

10–40 mg/day

Nasal stuffiness, Any if hyponatremia, seizures supervised

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Drug

Headache, epistaxis, nausea

Any

Oxybutynin

5–20 mg/day

Dryness of mouth, flushing, palpitations blurring of vision

Any

Tolterodine

2 mg at bedtime Similar to oxybutynin but milder

>5 years

Imipramine

0.9–1.5 mg/kg/ day

>7 years

Anxiety, personality change palpitations

bstructive Uropathy

This term is used to refer to a group of disorders characterized by either prevesical or bladder outlet obstruction (anatomical or functional) resulting in pelvicalyceal dilatation, increased back pressure and renal damage. Stasis due to post void residual urine results in recurrent UTI that results in progressive increased renal damage. The long term outcome depends on timing and severity of the obstruction and its relief. Common causes for obstructive uropathy are enumerated in Table 10.9.3. -

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DDAVP tablets 0.2–0.6 mg/day

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Timely treatment of nocturnal enuresis prevents psycho­ logical distress. Dry bed training includes emptying the bladder before retiring to bed, encouraging bedtime resolution and keeping a chart of wet and dry nights. The child should be rewarded for active cooperation in the therapy and not just for dry nights. Behavioral changes significantly improve the outcome and advice is given to drink more water during the daytime, avoid extra fluids after dinner, prevent constipation and increase physical activity. The child is encouraged for timely voiding. Studies have shown that neither bladder holding nor stretching exercises are efficacious. The alarm device is used to elicit a conditioned res­ ponse of awakening to the sensation of a full bladder. A number of medications are used for treatment of nocturnal enuresis (Table 10.9.2). Therapy once initiated is continued for 2 weeks before assessing efficacy and adjusting the dose. Once the child is dry the dose is maintained for 3–6 months and then weaned over 3–4 weeks. Anticholinergic drugs are useful in children who manifest urge symptoms. Desmopressin (DDAVP) is used in patients showing high nocturnal urine production. The spray should be admi­ nistered under the supervision to prevent accidental or intentional overdose. Water restriction is recommended when using DDAVP to prevent hyponatremia. Tricyclic

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Treatment

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antidepressants are used if other therapeutic options have failed. The use of alarm is preferred in patients who do not respond to dry bed training and behavioral modifications. If the child is unresponsive to the alarm, DDAVP may be used as an adjunct. The latter is used initially if short term benefits are necessary.



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from voiding disorders when enuresis is accompanied with daytime urge symptoms. Some of the factors responsible for enuresis are maturational delay, deep sleep and a loss of circadian rhythm of the antidiuretic hormone (ADH) secretion. A genetic basis is well known. Less than 5% children with primary monosymptomatic enuresis have an organic basis and most require no evaluation other than a urinalysis. History and clinical examination exclude an anatomical or neurological cause for incontinence. A voiding diary helps rule out voiding dysfunction, since the history of daytime symptoms may not be forthcoming.

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Diseases of Ki ney an Urinary Trac

Flow chart 10.9.1 A stepwise systemic evaluation

 

Table 10.9.3 Etiology and diagnosis of obstructive uropathy Bladder outlet obstruction

Suspect

Posterior urethral valves

Micturating cystourethrogram (MCU) Antenatal hydronephrosis Weak stream, dribbling; recurrent urinary tract Cystoscopy infections (UTI); palpable kidneys, urinary bladder; postvoid residue

Diagnosis

Urethral strictures/atresia

Straining, weak stream; history of urethral mani­ Cystoscopy pulations and/or trauma MCU

Urogenital sinus anomalies Bladder agenesis Anorectal malformations

Continuous incontinence; abnormal external genitalia; MCU, cystoscopy recurrent UTI Magnetic resonance urography

Neurogenic bladder

Sacral dimple, tuft of hair or pad of fat; meningo­ MRI spine myelocele; neurological deficits; incontinence; weak MCU urinary stream Urodynamic studies

Prune belly syndrome

Poorly developed abdominal muscles

MCU

Supravesical obstruction

Suspect

Diagnosis

Pelviureteric junction obstruction Vesicoureteric junction obstruction

Antenatal hydronephrosis; recurrent UTI; abdominal DTPA scintigraphy mass Intravenous pyelography (IVP)

Recurrent ureteric calculi

Ureteric colic; hematuria; recurrent UTI

DTPA scintigraphy IVP High resolution CT

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1. Kanitkar M. Disorders of micturition. In: Srivastava RN, Bagga A (Eds). Pediatric Nephrology, 5th edition. New Delhi: Jaypee Brothers; 2011. pp. 464 90.



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ibliography





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2. Nevéus T, von Gontard A, Hoebeke P, et al. The standardization of terminology of lower urinary tract function in children and adolescents: report from the standardization committee of the International Children’s Continence Society. J Urol. 2006;176:314 24. 3. Nunes VD, O’Flynn N, Evans J, et al. Management of bedwetting in children and young people: summary of NICE guidance. BMJ. 2010;341:936 8. 4. Ramamurthy HR, Kanitkar M. Noninvasive urodynamic assessment in children are they reliable? Indian J Pediatr. 2010;77:1400 4.

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The aim of treatment is preservation of renal function and prevention of UTI. Long term follow up is necessary and should comprise annual ultrasound, physical examination for growth, controlling blood pressure, urinalysis for proteinuria and estimation of blood creatinine.

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hronic Kidney Disease, enal eplacement Therapies

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Diseases of Ki ney an Urinary Trac

10.10

Kishore D Phadke

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Table 10.10.2 Features suggesting chronic kidney disease

d

Failure to thrive, not explained by nutrition Unexplained anemia Bony deformities Recurrent urinary tract infections Positive family history of renal disease Exposure to nephrotoxic drugs Systemic disease with known renal involvement Hypertension Persistent proteinuria, abnormal urinalysis Abnormal renal imaging

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tiology

linical eatures F

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Congenital malformations of the kidneys (hypoplastic, dysplastic kidneys, obstructive uropathy and posterior urethral valves) or genetic disorders (hyperoxaluria, poly cystic kidney disease, congenital nephrotic syndrome, and Wilms tumor) are causes of CKD in young children. Glomerular diseases (FSGS, HUS, chronic GN and Alport disease) or tubulointerstitial diseases (tubulointerstitial nephritis, cystinosis, nephronophthisis and nephrotoxic drugs) predominate in older children.

Chronic kidney disease may be asymptomatic especially in the early stages. The manifestations may be subtle, posing challenges in recognition (Table 10.10.2).

E



Chronic kidney disease (CKD) is as an abnormality of kidney function or structure as determined by laboratory tests, urinalysis or imaging tests, with or without reduced GFR less than 60 mL/min/1.73 m2, which has been present for at least 3 months. It is usually of gradual onset, irreversible and has tendency to progress. Chronic kidney disease results in significant societal burden due to its complication, disability and economic cost involved. Early recognition and appropriate management of CKD can reduce its morbidity. The staging of CKD as proposed by National Kidney Foundation—Kidney Disease Outcome Quality Initiative is useful to standardize definitions (Table 10.10.1). Glomerular filtration rate is estimated by the Schwartz formula [k x height (cm)/creatinine (mg/dL)], k is a constant (0.45 for infants < 2 years; 0.55 for older children). Patients with stage 5 CKD may have life-threatening biochemical abnormalities, requiring renal replacement therapies (RRT), e.g. dialysis or transplantation for survival.

valuation

t

Urine Tests The degree of proteinuria and hematuria increases as CKD progresses. Urinary findings depend on the stage of CKD and the type of primary renal disease. The protein/ creatinine ratio on a random sample of urine gives an idea of quantitative urinary protein excretion.

Blood Tests Blood urea and creatinine are commonly used to screen and monitor CKD. As function deteriorates, blood levels of these markers rise. Disproportionately-high blood urea levels are seen during dehydration, high protein intake or hypercatabolic states (high fever, gastrointestinal bleed, steroid therapy, sepsis). Serum calcium, phosphate, alkaline phosphatase and parathyroid hormone (PTH) levels assess the mineral bone disease (MBD). Electrolyte and bicarbonate levels are useful to assess electrolyte and acid base disturbances. Serum cystatin C levels can be used instead of serum creatinine as these are independent of muscle mass. The GFR is estimated with help of serum creatinine, using the Schwartz formula. Radiolabeled iothalamate, DTPA or EDTA are exogenous biomarkers used to estimate GFR.

 

Table 10.10.1 Stages of chronic kidney disease Stage

Description

GFR (mL/min/1.73 m2)

1

Kidney damage with normal or increased GFR

≥ 90

2

Kidney damage with mild decrease in GFR

60–89

3

Moderate decrease in GFR

30–59

4

Severe decrease in GFR

15–29

5

Kidney failure, end stage renal disease

< 15 (or dialysis)

Abbreviation: GFR, Glomerular filtration rate

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A percutaneous renal biopsy may be indicated in early course of CKD. In advanced stages of CKD, renal histopathology is not useful in determining the etiology as findings of glomerulosclerosis, tubular atrophy and interstitial fibrosis are nonspecific.

C

Management

Dietary Management The diet aims at controlling hypertension, edema and electrolyte disturbances, and retarding progression of renal failure while promoting growth and development. The diet should provide recommended dietary allowances (for age and height) of calories and high biological value proteins. Restriction of sodium and fluid is necessary in oliguric or anuric renal failure. Children with polyuric renal failure often require sodium and water supplementation. Potassium restriction is required for children with CKD stage 5.

nemia

­

Growth ailure Factors contributing to growth failure are inadequate nutrition, secondary hyperparathyroidism, anemia, meta bolic acidosis, salt depletion and abnormalities of the growth hormone-insulin like growth factor (GH-IGF) axis. Short stature is therefore managed by nutritional rehabilitation and correction of acidosis, anemia and bone disease. If growth retardation persists, these children are offered human recombinant growth hormone; its cost is a limiting factor for routine use.

ther ssues

Control of hypertension helps to slow the progression of renal disease. Angiotensin converting enzyme inhibitors and receptor blockers have the advantage of reducing intraglomerular hypertension; renal functions and potas sium levels are monitored. Other drugs include CCBs, betaadrenergic or alpha blockers and clonidine. Metabolic acidosis should be corrected to maintain bicarbonate levels at 20 mEq/L. Patients with CKD should receive complete vaccinations in order to prevent infec tion associated morbidity. Drugs should be used with appropriate dosage modification and nephrotoxic agents should be avoided. The management of a child with CKD requires a team approach. It is helpful to have a medical social worker involved in the care of the child and the family. The social

­



­

The anemia of CKD is normocytic and normochromic. Causative factors include reduced erythropoietin synthesis, iron and folate deficiencies, occult blood losses, bone marrow suppression, decreased life span of red cells and secondary

Causes of CKD-MBD include phosphate retention, hypo calcemia, hyperparathyroidism, impaired renal calcitriol synthesis and aluminum toxicity. Controlling serum phosphorus requires dietary intervention and use of phosphate binders, which may be either calcium containing (carbonate, acetate) or calcium free (sevelamer, lanthanum carbonate). Aluminum based phosphate binders are avoided for fear of its toxicity. The product of calcium and phosphorus should not exceed 65 in older children and 55 in children less than 12 years. Calcium supplements and vitamin D and its analogs such as calcitriol or paracalcitol are used to suppress PTH. Calcimimetic agents (cinacalcet) act on calcium sensing receptors, and reduce levels of PTH.

­



The clinical action pyramid for various stages of CKD is summarized in Figure 10.10.1.

hronic Kidney Disease-Mineral Bone Disease

F

The aims of conservative management are: • Correct reversible component of renal dysfunction • Slow rate of progression of renal disease • Treat metabolic derangements • Optimize growth and development • Prepare for treatment of ESRD, plan RRT.

A

 

enal Biopsy

I

S

I R

Renal ultrasound is a noninvasive technique that provides useful information about the size, shape, echotexture, presence of cysts, evidence of obstruction and renal stones. Renal scans are used to diagnose specific conditions, e.g. renal scars and differential renal functions.

hyperparathyroidism. Anemia results in fatigue, anorexia, exercise intolerance and poor cognitive performance, and is an important cardiovascular risk factor. Oral iron is poorly absorbed in CKD. As GFR declines, parenteral iron may be needed to maintain the transferrin saturation index above 30%. The hemoglobin target should be selected in the range of 11– 12 g/dL. The initial dose of recombinant human erythropoietin is 50–150 IU/kg/dose thrice a week given subcutaneously. The dose is titrated to obtain the desired response, while maintaining adequate iron stores. Darbopoetin alpha has a longer half-life, allowing administration once 1–2 weeks. Blood transfusions are avoided for fear of exposure to infectious agents and to avoid sensitization, increasing the risk of rejection following transplantation.

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Figure 10.10.1 Clinical action pyramid  

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Peritoneal dialysis is the preferred modality of dialysis in young children. The peritoneum functions as the semipermeable membrane across which exchange of solutes and fluids occurs. This is a continuous form of RRT in contrast to intermittent HD. The development of automated PD has made home dialysis possible. The main complication is peritonitis. The child and the parents are trained to perform the exchanges.

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1. KDOQI; National Kidney Foundation. Clinical practice recommendations for anemia in chronic kidney disease in children. Am J Kidney Dis. 2006;47:S86-108. 2. KDOQI Work Group. KDOQI Clinical Practice Guideline for Nutrition in Children with CKD: 2008 update. Am J Kidney Dis. 2009;53(3 Suppl 2):S11-104. 3. Klaus G, Watson A, Edefonti A, et al. Prevention and treatment of renal osteodystrophy in children on chronic renal failure: European guidelines. Pediatr Nephrol. 2006;21:151-9. 4. Srivastava RN, Bagga A (Eds). Pediatric Nephrology, 5th edition. New Delhi: Jaypee Brothers; 2011. pp. 360-85.

Peritoneal Dialysis

Bibliography



Dialysis should be initiated when the GFR is below 10 mL/ min/1.73 m2 or when symptoms of uremia appear. Two types of dialysis are available: PD (peritoneal dialysis) and HD (hemodialysis).



Dialysis Treatment

An adult kidney can be successfully transplanted into a child. The choice of kidney donor is either living related from a close blood relative (usually parents) or a deceased donor. The Indian Government has passed a Human Organ Transplantation Act in 1994, defining brain death, paving the way for deceased donor organ transplantation. Patients need-life-long immunosuppressive medications to prevent rejection of the allograft. Complications after transplantation include rejection of graft, infections, vascular thrombosis, recurrence of original disease, hypertension, drug toxicities and malignancy. The results of pediatric transplantation in experienced centers are excellent with 1-year and 5-year graft survival of more than 90% and more than 70% respectively. Excellent rehabilitation is expected in children with functioning grafts. Transplantation provides children with ESRD, a good quality of prolonged life.



­

End stage renal disease is the term used when the child in stage 5 CKD needs RRTs for survival. It generally corresponds to the level of GFR less than 15 mL/min/1.73 m2. Renal transplantation is the preferred modality of RRT in children. Dialysis treatment should be used as a bridge toward transplantation; awaiting transplantation or if transplan tation cannot be performed.

enal Transplantation



enal eplacement Therapies R

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The modifiable factors for retarding progression of CKD include hyperfiltration, proteinuria, hypertension, hyper parathyroidism, dyslipidemia and nephrotoxic drugs. Every effort should be made to control these modifiable factors. Lowering blood pressures to target systolic and diastolic blood pressures below 90th percentile is important. Angiotensin converting enzyme inhibitors and ARBs have renoprotective effects by reducing proteinuria, lowering intraglomerular pressure and by their antifibrotic effects.

Hemodialysis is performed in a dialysis center. Vascular access remains a challenge in children, especially since arteriovenous fistulae are difficult to make. The catheter is placed in the internal jugular vein. Hemodialysis needs technical expertise, availability of dialysis machine, dialyzers (artificial kidneys), heparinization and continuous monitoring during the procedure. Children on HD require dietary restrictions. The procedure is performed for a total duration of 10–12 hours, three times a week.



S

lowing Down the Progression

Hemodialysis

Diseases of Ki ney an Urinary Trac

worker will address issues such as compliance, adherence to treatment, regular follow-ups, financial issues, preparing the child and the family for the future and discussing options for RRTs. The child should be encouraged to participate in age appropriate activities and attend regular school.

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enal Tubular iseases

Renal tubular acidosis (RTA) include conditions characte­ rized by a defect of renal acidification resulting in impaired capacity for net acid excretion and hyperchloremic metabolic acidosis, in the presence of normal glomerular function. Transport defects are usually secondary to reduced proximal tubular reabsorption of bicarbonate (HCO3–), as in proximal RTA, or the distal secretion of protons (hydrogen ion, H+), as in distal RTA. A third variety called type IV RTA is distinguished by the presence of hyperkalemia. These conditions may be primary, with or without known genetic defects, or secondary to other causes (Table 10.11.2).

Pathophysiology

 

Table 10.11.1 Presenting features in tubular disorders

enal Tubular cidosis A

In comparison to glomerular diseases, tubular disorders are less common. A high index of suspicion and correct diagnosis allow specific management in many patients. Tubulopathies should be suspected in children presenting with symptoms listed in Table 10.11.1. The diagnosis of a primary tubular disorder implies that there is no significant impairment of glomerular function or tubulointerstitial inflammation. The disorder may be congenital or acquired and involve a single tubular function (renal glucosuria, nephrogenic diabetes insipidus) or multiple functions (Fanconi syndrome). Most disorders can be diagnosed following careful interpretation of specific urine and plasma biochemical tests.

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10.11

Growth retardation, failure to thrive Delayed gross motor milestones Polyuria, excessive thirst Recurrent episodes of dehydration, vomiting, fever Rickets, bone pains Episodic weakness Constipation Craving for salt and savory foods

The excretion of acid and the reabsorption of filtered bicar­ bonate are mediated by tubular secretion of hydrogen ions (H+). In the proximal tubule, filtered HCO3– is reabsorbed through carbonic anhydrase in the tubular brush border. The primary defect in proximal (type II) RTA is reduced renal threshold for HCO3– reabsorption leading to bicarbonaturia. Fanconi syndrome refers to a generalized proximal tubular dysfunction characterized by tubular proteinuria, amino­ aciduria and variable bicarbonaturia, phosphaturia and glucosuria.

 

Table 10.11.2 Inherited and acquired forms of renal tubular acidosis

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Type of RTA

Inherited

Acquired

Type 1 (Distal) RTA

Autosomal dominant Autosomal recessive With hemolytic anemia With hearing loss

Systemic lupus erythematosus, Sjögren syndrome Obstructive uropathy, reflux nephropathy Sickle cell anemia Amphotericin B toxicity

Type 2 (proximal) RTA: isolated

Carbonic anhydrase inhibitors (acetazolamide) Autosomal dominant Autosomal recessive (with ocular abnormalities: band keratopathy, cataracts or glaucoma; defective dental enamel; intellectual impairment; basal ganglia calcification)

Multiple tubular dysfunction Fanconi syndrome

Autosomal dominant, autosomal recessive X-linked (Dent disease) Syndromic: Cystinosis; galactosemia; tyrosinemia; Wilson disease; hereditary fructose intolerance; Lowe syndrome; glycogen storage disease type I; mitochondrial disorders)*

Type 3 (combined)

Autosomal recessive (with osteopetrosis; blindness, deafness)

Type 4 (hyperkalemic)

Autosomal dominant Pseudohypoaldosteronism type 1 (PHA) PHA type 2 Congenital adrenal hyperplasia

Vitamin D dependent rickets Primary hyperparathyroidism Acute tubulointerstitial nephritis with uveitis Drugs: Ifosfamide, Cisplatin, aminoglycosides Toxins: Lead, cadmium, mercury, toluene Aldosterone deficiency without renal disease (Addison disease; adrenal tuberculosis; necrosis) Chronic renal insufficiency (Obstructive uropathy, interstitial nephritis) Aldosterone resistance (amiloride, spironolactone)

*Syndromic forms of Fanconi syndrome are inherited in autosomal recessive pattern, except Lowe syndrome which has X linked recessive inheritance

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Metabolic acidosis may result from either increased endogenous acid synthesis (e.g. ketoacidosis, lactic acidosis) or enhanced bicarbonate losses (diarrhea, intestinal tube drainage or fistula, ureterosigmoidostomy, cholestyramine). Since all types of RTA are associated with hyperchloremic metabolic acidosis, the initial step is the determination of the plasma anion gap, which is normal (8–12 mEq/L) in all types of RTA. Table 10.11.3 lists important steps of evaluation. Elevated excretion of urinary NH4+ in patients with metabolic acidosis suggests extrarenal HCO3– losses (diar­ rhea), while low excretion points to RTA. Since the difference between urinary unmeasured anions (sulfates, phosphates, organic anions) and cations (calcium, magnesium) is relatively constant (at ~80 mEq/L), the measurement of important ions as urine anion gap (UAG; urine net charge) effectively estimates NH4+ excretion. Loading with sodium bicarbonate, performed orally (2–4 mEq/kg/day for 3 days) or intravenously (0.5 mEq/ mL at 3 mL/minute) to achieve urine pH more than 7.5 and normal serum HCO3– (> 22 mEq/L), allows simultaneous measurement of fractional excretion of bicarbonate and urine to blood CO2 gradient, reflecting proximal bicarbonate handling and distal tubular acidification, respectively. Table 10.11.4 summarizes the differences among various types of RTA. Additional tests are required depen­ ding on the type suspected. In patients with proximal RTA, other proximal functions are evaluated, including for aminoaciduria, glucosuria, low molecular weight prote­ inuria, and calculation of fractional excretion of phosphate (FEPO4) and tubular maximum for phosphate. Patients are screened for cystinosis, Lowe syndrome, galactosemia and Wilson disease. Evaluation in patients with distal RTA includes ultrasonography (nephrocalcinosis, renal calculi) and measurement of urinary calcium and citrate excretion. All patients should undergo a hearing evaluation; older children are evaluated for secondary causes. Workup in patients with type 4 RTA should include renal function tests and ultrasonography to identify structural or parenchymal disease. Measurement of plasma renin activity and aldosterone levels are required. Transtubular potassium gradient is a useful test in diagnosing type 4 RTA. When coupled to a mineralocorticoid challenge, this test allows distinction between aldosterone deficiency and resistance.

Treatment Management of RTA involves correction of acidosis through administration of alkali supplements (Polycitra, Shohl solution) and provision of adequate nutrition, fluids and deficient electrolytes. Patients with distal RTA require 2–3 mEq/kg/day of alkali. Urinary potassium losses decrease with correction of acidosis, but some patients require prolonged potas­ sium supplementation. Similarly, rickets improve with

-

-

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Features that suggest RTA are listed in Table 10.11.1. Chil­ dren with proximal RTA present with failure to thrive, irritability, anorexia, listlessness, and uncommonly, with symptoms of hypokalemia (weakness, paralysis). Patients with Fanconi syndrome may have features of the underlying disorder (Table 10.11.2), as in patients with cystinosis (presentation in infancy, photophobia, hepatosplenomegaly, blond hair) or Lowe syndrome (presentation in infancy, severe rickets, cataract, buphth­ almos, hypotonia and developmental delay). Features in distal RTA include impaired growth, polyuria, nephrocalcinosis or nephrolithiasis, symptoms of hypokalemia and/or hearing loss. Children with type 4 RTA have milder acidosis without nephrocalcinosis, urolithiasis or bone lesions. Underlying tubulointerstitial disease may be evident. The autosomal recessive form of pseudohypoaldosteronism (PHA) type 1 is an important differential diagnoses in infants presenting with salt loss, hypotension, hyperkalemia and metabolic acidosis. The autosomal dominant form of PHA type 1 involves only the kidney and is less severe than the recessive form, which is systemic, affecting sweat and salivary glands and colon.

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In the distal tubule, secreted H+ ions combine with sodium hydrogen phosphate (Na2HPO4) and ammonia (NH3) to form NaH2PO4 and NH4+, measured as titratable acidity and urinary ammonium ion, respectively. Additional factors that influence H+ secretion and HCO3– reabsorption include extracellular fluid volume, potassium balance and plasma aldosterone. Distal RTA is characterized by decreased distal tubular secretion of H+ ions, leading to low rates of excretion of ammonium (NH4+) ions and titratable acidity. Hypokalemic distal (classic or type 1) RTA occurs due to a secretory (rate) defect, with decreased secretion of H+ due to impaired function of an ion channel (H+ ATPase, H+/K+ ATPase or Cl /HCO3– exchanger), or a gradient (permeability) defect, where an increased back leak of normally secreted protons dissipates the pH gradient. In both forms, the urine pH cannot reach maximal acidity (i.e. remains > 5.5) despite acidemia. Hypokalemia is attributed to increased urinary losses of K+, partially secondary to hyperaldosteronism in response to volume contraction and urinary losses of Na+. Distal RTA with hyperkalemia may result from a voltage defect (hyperkalemic distal RTA), secondary to insufficient negative intratubular potential in the cortical collecting duct, or a rate defect, due to aldosterone deficiency or resistance (type 4 RTA). Other than normo or hyperkalemia, the findings in hyperkalemic distal RTA resemble classic distal RTA. Aldosterone resistance or deficiency decreases distal reabsorption of Na+, which lowers the transtubular potential gradient for H+ secretion. In addition, lack of aldosterone action decreases urinary excretion of K+. Hyperkalemia in turn reduces ammoniagenesis. In type 4 RTA, maximally acidic urine (< 5.5) can be formed, indicating intact ability to establish a maximal H+ gradient.

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Step

Test

Comment

1

Plasma anion gap

Calculated as [Na+ - (Cl- + HCO3–)] Normal (8–12 mEq/L) in renal tubular acidosis (RTA) and diarrhea Elevated in patients with ketoacidosis, lactic acidosis, inborn errors of metabolism, poisoning or uremia

2

Urine anion gap (UAG) or UAG = Urinary Na+ + K+ - Clurine net charge Urinary NH4+ = 80 – UAG During systemic acidosis, negative UAG suggests extrarenal (diarrheal) HCO3– losses and positive UAG reflects impaired urinary acidification (RTA); UAG is positive in normal conditions

3

Urine pH

Is measured on fresh voided specimen with pH meter, not dipstick Estimates < 1% of urinary proton excretion During systemic acidosis, pH > 5.5 suggests distal RTA; value < 5.5 suggests extrarenal cause and RTA type 2 or 4

4

Fractional excretion of bicar bonate (FEHCO3)

FEHCO3 (%) = urine bicarbonate × plasma creatinine × 100 plasma bicarbonate × urine creatinine After bicarbonate loading, value is > 15% in proximal RTA; < 5% in normal persons and classic distal RTA

5

Urine to blood pCO2 gradient Urine pCO2 sensitively reflects distal H+ secretion, rising to > 70 mm Hg during alkalosis (U-B CO2) U-B CO2 = Urine pCO2- blood pCO2 After bicarbonate loading, value < 10 mm Hg suggest classical type 1 RTA; value is > 20 mm Hg in normal individuals; patients with permeability and voltage defects; types 1 and 4 RTA

     

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t

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Table 10.11.3 Evaluation in patients with suspected renal tubular acidosis



management of acidosis. Urinary calcium excretion should be monitored; patients with persistent hypercalciuria require thiazides. The requirement of alkali supplements is higher (5–20 mEq/kg/day) in patients with proximal RTA. This is given Table 10.11.4 Investigations to differentiate types of renal tubular acidosis Proximal RTA

Distal RTA

Type 4 RTA

Classic

Hyperkalemic

Normal/ low

Normal/ low

High

High

Urine pH

< 5.5

> 5.5

> 5.5

< 5.5

Urine anion gap

Positive

Positive

Positive

Positive

Urine NH4+

Low

Low

Low

Low

< 5%

> 5–10%

< 20

20

> 20

Tubulopathies with Urinary hloride Wasting C

Plasma K

Bartter and Gitelman syndromes are caused by defects in ion transporters resulting in increased urinary losses of chloride, accompanied by potassium and sodium wasting. B

+

Fractional HCO3 excretion

–

> 10–15% < 5%

U-B pCO2 mm Hg > 20 Normal

High

High

Normal/ low

Other tubular defects

Often present

Absent

Absent

Absent

Nephrocalcinosis

Absent

Present

Present

Absent

Bone disease

Common

Often present

Uncommon

Absent

Patients present with failure to thrive, polyuria, polydipsia and recurrent episodes of dehydration. The neonatal form is particularly severe with maternal polyhydramnios, polyuria, dehydration, hypercalciuria and nephrocalcinosis. Hypokalemia is marked with hypochloremic metabolic alkalosis and increased levels of plasma renin and aldos­ terone. Bartter syndrome is differentiated from other conditions with persistent hypokalemic metabolic alkalosis by the presence of normal blood pressure, and high urinary excretion of chloride and calcium. Further characterization of the molecular defect is based on genetic testing. Differences in presentation may help characterize the defect (Table 10.11.5).

Urine Ca2+

artter yndrome S

Investigations

as a combination of sodium and potassium citrate, with restriction of dietary sodium. Administration of hydro­ chlorothiazide causes contraction of extracellular fluid volume and increased proximal HCO3– reabsorption. Supple­ ments of phosphate (neutral phosphate, Joulie solution) are necessary in Fanconi syndrome. Small doses of vitamin D may enable healing of rickets. Specific treatment may be useful, such as therapy with cysteamine in patients with cystinosis, penicillamine in Wilson disease and dietary interventions (galactosemia, hereditary fructose intolerance).

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Abbreviations: RTA, Renal tubular acidosis; U-B pCO2, Urine to blood pCO2 gradient

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Presentation

Antenatal Bartter syndrome (aBS): Types 1, 2 and 4

Polyhydramnios, prematurity Neonatal: Failure to thrive, nephrocalcinosis Sensorineural deafness in type 4 Bartter syndrome

Classic Bartter syndrome (cBS; type 3)

Growth retardation, hypercalciuria, no nephrocalcinosis, normal serum magnesium

Type 5 Bartter syndrome*

As classic; hypomagnesemia

Gitelman syndrome

Episodic muscle weakness; mild polyuria; hypocalciuria, hypomagnesemia, chondrocalcinosis

*Inherited in autosomal recessive manner, except type 5 Bartter syndrome that is autosomal dominant

Polyuria



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Polyuria is defined as urine output exceeding 6 mL/kg/hour or 2 L/m2 in children. Polyuria may accompany structural renal disorders including juvenile nephronophthisis, renal dysplasia (reflux nephropathy, obstructive uropathy) and chronic tubulointerstitial nephritis, or solute losses (RTA, Bartter like syndromes and diabetes mellitus). Nephrogenic diabetes insipidus is a rare condition characterized by tubular unresponsiveness to the antidiuretic hormone (ADH, vasopressin). Most cases are inherited in an X linked recessive pattern with mutations in the gene for the arginine vasopressin V2 receptor (AVPR2); 10% cases are inherited autosomally through mutations in the aquaporin 2 gene. Infants present with irritability, failure to thrive, recurrent episodes of dehydrations and intermittent fever. Nephrogenic diabetes insipidus may be acquired, as with obstructive uropathy, analgesic nephropathy, sickle cell disease, chronic pyelonephritis, hypercalcemia, hypokalemia, sarcoidosis and with use of lithium and tetracyclines. Diagnosis of diabetes insipidus requires confirmation of polyuria and exclusion of differential diagnoses. Useful

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efractory ickets R

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Patients with Gitelman syndrome have abnormalities similar to Bartter syndrome, including hypokalemia, metabolic alkalosis and hypomagnesemia. However, symptoms, including polyuria and growth retardation, are milder and appear in older children. Episodes of weakness, vomiting, abdominal pain and tetany may occur. The underlying mechanism is a defect in the thiazide sensitive, sodium chloride cotransporter in the distal tubule. Urinary calcium excretion is low but magnesium wasting is prominent. Treatment is with supplementation of potassium and magnesium (as oral magnesium chloride, gluconate, oxide or hydroxide).

Rickets results from a lack of adequate mineralization of growing bones. The diagnosis is based on clinical findings, radiological features and blood biochemistry. The term refractory rickets is used for patients who fail to show radiological healing and normalization of biochemical abnormalities, despite therapy with two large doses of vitamin D. The causes of refractory rickets are grouped into two categories according to the underlying defect, abnormal vitamin D metabolism or impaired renal tubular phosphate handling (Table 10.11.6). The former is characterized by low serum levels of calcium and phosphate, aminoaciduria and high PTH. The latter shows hypophosphatemia with normal serum calcium and PTH. Rickets in distal RTA is attributed to impaired renal hydroxylation of calcidiol and a negative calcium balance secondary to persistent metabolic acidosis. Presentation varies by cause and severity. Patients with vitamin D dependent rickets (VDDR) have onset in infancy with tetany, seizures, delayed dentition and hypocalcemia. Patients with VDDR type 1 show enamel hypoplasia; those with VDDR type 2 may have alopecia and ectodermal defects (oligodontia, epidermal cysts). Presentation of 651 hypophosphatemic rickets includes short stature, lower limb deformities and dental abnormalities (pulp defor­

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Gitelman yndrome

investigations include measurement of urine osmolality, electrolytes, sugar and ketones; blood electrolytes, pH, bicarbonate, sugar, calcium and creatinine, and renal ultra­ sonography. Upon water deprivation, diabetes insipidus is suggested by plasma sodium of more than 145 mEq/L, plasma osmolality more than 295 mEq/kg and urine osmolality less than 300 mEq/kg. A rise in urine osmolality to more than 150% of baseline following administration of desmopressin (DDAVP) suggests complete central diabetes insipidus, while no change (< 110% baseline) suggests complete nephrogenic diabetes insipidus. Patients with diabetes insipidus require an adequate intake of water. Restriction of dietary sodium to 1 mEq/kg/ day and administration of hydrochlorothiazide (2–4 mg/kg/ day), with or without amiloride (0.3 mg/kg/day) help reduce polyuria in patients with nephrogenic diabetes insipidus. Indomethacin (2 mg/kg/day) is also useful.





Management of Bartter syndrome includes fluid replacement and supplementation of potassium chloride (1–3 mEq/kg/day). Administration of indomethacin (2–3 mg/kg/day) or ibuprofen (30 mg/kg/day) decreases elevated prostaglandins and ameliorates polyuria. Potassium sparing diuretics and ACE inhibitors may aid potassium retention.

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Disorder

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Table 10.11.5 Tubular diseases presenting with hypochloremic metabolic alkalosis with hypokalemia and normal or low blood pressure

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Flow chart 10.11.1 Evaluation in patients with refractory rickets

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Chronic kidney disease mineral bone disease





Distal renal tubular acidosis

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Hypophosphatemic rickets X-linked familial Autosomal dominant Autosomal recessive Hypophosphatemic rickets with hypercalciuria Dent disease Fanconi syndrome

1. Bagga A, Bajpai A, Menon S. Approach to renal tubular disorders. Indian J Pediatr. 2005;72:771 6. 2. Bagga A, Sinha A. Evaluation of renal tubular acidosis. Indian J Pediatr. 2007;74:679 86. 3. Hoppe B, Kemper MJ. Diagnostic examination of the child with urolithiasis or nephrocalcinosis. Pediatr Nephrol. 2010;25:403 13. 4. Nicoletta JA, Lande MB. Medical evaluation and treatment of urolithiasis. Pediatr Clin N Am. 2006;53:479 91. 5. Pettifor JM. What’s new in hypophosphataemic rickets? Eur J Pediatr. 2008;167:493 9. 6. Tanaka ST, Pope IV JC. Pediatric stone disease. Current Urology Reports. 2009;10:138 43.

Calcipenic rickets Vitamin D dependent rickets, type 1 Vitamin D dependent rickets, type 2

ibliography

 

Table 10.11.6 Causes of refractory rickets

phosphate. Requirement of calcitriol is higher (0.05–0.2 µg/ kg/day) in patients with VDDR type 2. These patients may benefit from administration of high dose calcium infusions. The rickets in RTA responds satisfactorily to correction of acidosis; patients with proximal RTA additionally require supplements of oral phosphate with or without vitamin D. Management of hypophosphatemic rickets involves supplementation of phosphate (30–50 mg/kg/day) as neutral phosphate or acid phosphate (Joulie solution). Patients with X linked hypophosphatemic rickets also require small doses of calcitriol (25–50 ng/kg/day; 0.25–0.5 µg daily). Management of MBD associated with CKD relies on control of hyperphosphatemia (dietary restriction, use of oral phosphate binders) and therapy with active vitamin D analogs.





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mities, abscess). Patients with hypercalciuric variant of hypophosphatemic rickets, distal RTA or Dent disease may show nephrocalcinosis or nephrolithiasis. Presentation of RTA and Fanconi has been discussed. Evaluation should include estimation of blood levels of calcium, phosphorous, alkaline phosphatase, creatinine, pH, electrolytes, bicarbonate, 25 hydroxyvitamin D and PTH; urinalysis; estimation of timed excretion of calcium, phosphate, protein and creatinine; and ultrasonography of kidneys. Flow chart 10.11.1 provides an approach to diagnosis. The therapy of rickets is tailored to the underlying cause. Patients with VDDR type 1 are treated with calcidiol or calcitriol (1–2 µg daily) and supplements of calcium and

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Diseases of Ki ney an Urinary Trac

10.12

symptomatic Hematuria Indira Agarwal

pidemiology



The prevalence of gross hematuria is 0.1% with more than half being due to identifiable causes. Asymptomatic microscopic hematuria is tenfold as prevalent as gross hematuria; most often it is transient and on repeated evaluation the prevalence decreases to less than 0.5%. The first step is to identify the site of bleeding: glomerular or nonglomerular. If bleeding occurs in the

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upper tract the color of the urine is “cola colored” or “tea colored” and shows dysmorphic RBC (> 30% by phase contrast microscopy). Urine from the lower tract is bright red, has clots and eumorphic RBC. Beets, dyes, medications (phenazopyridine), uric acid and porphyrins can color urine red or pink. Causes of glomerular hematuria include postinfectious GN, IgA nephropathy, systemic lupus, HSP, HUS, MPGN, in­ fections (malaria, leptospirosis and endocarditis), benign familial hematuria and Alport syndrome. Nonglomerular causes include nephrolithiasis, hypercalciuria, viral hemor­ rhagic cystitis, UTI and vascular abnormalities.

A history of facial puffiness, oliguria, hypertension and impaired renal function suggests a glomerular disease. IgA nephropathy can mimic postinfectious GN but can be differentiated by symptoms being “synpharyngitic”, normal C3 and recurrent episodes with normal urine in between. Presence of fever, rash, joint pains with or without abdominal pain suggests an underlying systemic disorder. Patients with collagen vascular disorders may occasionally present with RPGN and require urgent intervention (Flow charts 10.12.1 and 10.12.2).

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Microscopic hematuria is often detected on routine urina­ lysis. Gross hematuria though uncommon may be more serious as it often originates from glomeruli or the urinary tract and needs immediate attention. The persistent finding of five or more red cells per HPF on a centrifuged urine specimen performed over 2–3 weeks warrants evaluation. Dipsticks have a sensitivity of 100% and specificity of 99% in detecting 1–5 RBC/HPF but need confirmation by microscopy of the centrifuged specimen. Presence of RBC and granular casts with proteinuria >2+ suggest a glomerular cause. A positive dipstick reaction in the absence of RBC and RBC casts in the urine suggests hemoglobinuria or myoglobinuria. This can be differentiated from hematuria by centrifugation where a clear pink supernatant with minimal or no deposits suggests hemoglobinuria while cloudy red or dark brown supernatant suggests hematuria.

 

Flow chart 10.12.1 Gross hematuria

Abbreviations: PSGN, Poststreptococcal glomerulonephritis; UTI, Urinary tract infections; CBC, Complete blood counts; ASO, Antistreptolysin O Source: Evaluation of hematuria. In: Kaplan BS, Kevin EC (Eds). Pediatric Nephrology and Urology: The Requisites in Pediatrics. Philadelphia: Elsevier Mosby; 2005. pp. 95-102.

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Flow chart 10.12.2 Microscopic hematuria

Source: Evaluation of hematuria. In: Kaplan BS, Kevin EC (Eds). Pediatric Nephrology and Urology: The Requisites in Pediatrics. Philadelphia: Elsevier Mosby; 2005. pp. 95-102.





poststreptococcal GN. C3 levels are low in lupus nephritis, MPGN and cryoglobulinemia. If there is no evidence of streptococcal infection, other infections or alternative glomerular disease needs to be considered. If hematuria is persistent and accompanied by heavy proteinuria and reduced renal function, renal biopsy with electron micro­ scopy differentiates glomerular disease from an inherited nephropathy. Minor trauma can precipitate hematuria in children with renal cysts and hydronephrosis. Arteriovenous malfor­ mations and hemangiomas, which cause episodic gross hematuria, may be difficult to diagnose even by cystoscopy or angiography. Eumorphic RBC suggests nonglomerular hematuria. If white cells are present, a clean catch urine culture is indicated. If genitourinary tuberculosis is suspected, urine is cultured for acid fast bacilli. Urine calcium/creatinine ratio is estimated for hypercalciuria. If calculi are not visualized by ultrasound abdomen, a spiral CT scan should be done. Stone analysis is useful but a metabolic workup is necessary to determine the underlying cause.

ibliography

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1. Moore GP, Robinson M. Do urine dipsticks reliably predict microhematuria? The bloody truth! Ann Emerg Med. 1988;17:257 60. 2. Phadke KD, Vijayakumar M, Sharma J, et al. Consensus statement on evaluation of hematuria. Indian Pediatr. 2006;43:965 73. -



Urinalysis and complete blood count is the first step in evaluation, followed by electrolytes, creatinine, complement levels (C3, C4) and ASO. Low C3 and evidence of streptococcal infection confirms the diagnosis of



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In the absence of systemic signs and symptoms, conditions like benign familial hematuria or Alport syndrome should be considered. Urinalysis of family members, and eye (anterior lenticonus) and hearing assessments (high tone hearing deafness) are advised. Hematological conditions like sickle cell disease and trait, coagulopathies and thrombocytopenia may occasionally present with hematuria. Loin pain hematuria presents with recurrent episodes of loin pain (unilateral, bilateral) and hematuria (microscopic, gross) where investigations do not reveal any abnormality. Nutcracker syndrome due to entrapment of left renal vein between aorta and superior mesenteric artery presents similarly. Patients with hematuria due to a disorder in the lower tract have symptoms of dysuria, burning, frequency or hesitancy. Terminal hematuria suggests cystitis, while at initiation suggests urethritis. Urinary tract infections present with fever; adenovirus infection may result in hemorrhagic cystitis. Children with nephrolithiasis present with renal colic, gross or asymptomatic microhematuria while those with hypercalciuria have hematuria without evident calculi. Interstitial nephritis may present with malaise, fatigue and variable volumes of urine output.

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tiology

Investigations for nephrolithiasis include: (a) imaging studies; (b) urinalysis and culture; (c) urine and serum biochemistry and (d) stone composition. I

Nephrolithiasis may result from varied causes, including inherited metabolic defects, infections, structural urological abnormalities and drugs (Table 10.13.1).

Pathogenesis

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maging tudies

The aim of imaging is to confirm the presence, size and location of the stone, and to identify underlying urological abnormalities or associated obstruction.

Ultrasonography Ultrasonography is the modality of choice since it is safe, easily available and lacks radiation exposure. It is also useful for the evaluation of renal anatomy and for obstruction, and a convenient method for follow-up monitoring. Ultrasound has a sensitivity of 96% and specificity of almost 100% for stones above 5 mm; however, the sensitivity and specificity are lower for ureteric stones.

Radiography of the Kidney, Ureter and Bladder

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Crystals may form due to supersaturation of urine with solutes due to their excessive excretion (calcium oxalate, sodium urate or cystine), a decrease in urinary volume (poor water intake; excessive intestinal or renal losses) or a decrease in the urinary inhibitors of crystallization (citrate, magnesium or pyrophosphate). Damage to the uroepithelial lining with formation of calcium phosphate plaques leading to crystal adherence and growth is another mechanism of stone formation. Irrespective of the etiology, high protein or salt intakes increase the risk of nephrolithiasis.

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is a feature of ureteric calculi; it may radiate from loin to groin, or mimic appendicitis or diverticulitis. Bladder stones present with dysuria, urgency, incontinence, interrupted stream, strangury and, rarely, acute retention of urine.

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Stones in the kidneys and urinary tract are not uncommon in childhood. Children are at a high risk for recurrent stone formation and an underlying metabolic disorder may be found in 50–75% cases. A family history of renal stones is present in approximately 40% patients.

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10.13

Nephrolithiasis is often silent and detected incidentally during imaging for unrelated symptoms. Presentations include gross hematuria and complications such as UTI or obstruction. Pain

 

Table 10.13.1 Causes of nephrolithiasis

Radiography of KUB is a poor modality for detecting stones with a sensitivity of 77% and specificity of 87%. Its chief role is in differentiating radiolucent from radiopaque stones, which may suggest stone composition; while calcium oxalate and phosphate stones are radiopaque, uric acid and drug stones are radiolucent.

Etiology

Cause

Metabolic Hypercalciuria

With hypercalcemia: vitamin D overdose; hyperpara­ thyroidism With normal serum calcium: idiopathic; distal renal tubular acidosis; Dent’s disease; familial hypophos­ phatemia with hypercalciuria

Hyperoxaluria

Primary hyperoxaluria types 1 and 2; increased intes­ tinal absorption

Hyperuricosuria

Lesch Nyhan syndrome; Glycogen storage disease type 1

Others

Cystinuria; xanthinuria

Struvite

Urinary tract infections, usually in the presence of a structural abnormality (pelviureteric obstruction, vesicoureteric reflux, neurogenic bladder, bladder exstrophy)

Drugs

Indinavir, ceftriaxone

Intravenous Urography Intravenous urography formerly considered the gold standard for the diagnosis of nephrolithiasis has high specificity (92–100%) but low sensitivity (as low as 51% in some studies). Its utility is restricted to defining anatomical abnormalities preoperatively, if required.

Noncontrast Computerized Tomography Noncontrast computerized tomography (NCCT) is the current gold standard for the diagnosis of nephrolithiasis since its sensitivity and specificity are close to 100%. Uric acid and xanthine stones that are radiolucent on KUB can be diagnosed on NCCT. Chief limitations include cost and radiation. While anatomic delineation is excellent, radiation dose is very high with an enhanced CT. The risk from radiation is reduced by using low doses of contrast. Anatomical and functional delineation is limited in absence 655 of contrast.

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Magnetic resonance urography cannot identify calculi, but can provide good anatomical delineation without radiation exposure. Its use is limited by cost and availability. Caution should be exercised in minimizing radiation exposure during repeated imaging done for monitoring for recurrence of nephrolithiasis.

Urinalysis and ulture

spectroscopy. Analysis is useful in the identification of rare stones such as cystine, uric acid and drug-induced stones and has implications for management.

Treatment Medical Management Acute Management

Urine and erum iochemistry

Long-term Management

Biochemical investigations are required to evaluate renal function and to identify underlying metabolic abnormalities with an excess of solutes (e.g. hypercalcemia, hyper uricosemia, RTA) or decrease in inhibitors of crystallization (e.g. hypocitraturia). Blood investigations include urea, creatinine, calcium, phosphorous, alkaline phosphatase, uric acid, magnesium, venous blood pH, bicarbonate and electrolytes. Timed (12- or 24-hour) urine collection is required to estimate the excretion of calcium, oxalate, uric acid, cystine and citrate. In younger children in whom timed collections are difficult, spot samples of urine solute/ creatinine can be used (Table 10.13.2).

Pharmacological and nonpharmacological measures are used to prevent recurrence of stones and prevent renal damage. General measures include increasing fluid intake and dietary modifications. Increasing urine volume reduces supersaturation of crystals, while a urine output of over 1 mL/kg/hour prevents formation of calcium crystals; larger outputs are required for insoluble substances such as cystine and xanthine. Patients with hypercalciuria should take calcium within the accepted recommended daily allowance; medications containing calcium are avoided. Restricting the intake of animal proteins and salt reduces the rate of calcium excretion as natural sources of citrate, fruits and vegetables are beneficial. Patients with hyperoxaluria should restrict the intake of foods rich in oxalate, such as chocolates, tea, coffee, green leafy vegetable and nuts. Pharmacological measures are targeted to the under lying cause. The solubility of the incriminated solute may be modified by altering the urine pH, e.g. alkalinization enhances the solubility of uric acid and cystine. Increasing urinary citrate may enhance the solubility of calcium. Drugs may decrease production of solutes, e.g. allopurinol for uric acid stones (Table 10.13.3).

Stones excreted in the urine or removed surgically should be analyzed using X-ray diffraction or near infra-red

 

Table 10.13.2 Normal values of solutes in 24-hour urine Value

Calcium

< 4 mg/kg

Oxalate

< 40 mg/1.73 m2; < 2 mg/kg

Uric acid

< 800/1.73 m2 ; < 35 mg/kg

Cystine

< 60 mg/1.73 m2

Xanthine

30–90 µg

Citrate

> 180 mg/g creatinine

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Children presenting with renal colic are managed with antiemetics, nonsteroidal anti-inflammatory drugs, and in severe pain, opioids. Forced intravenous hydration may facilitate nonsurgical expulsion of stone in distal ureteric stones less than 4 mm in size. The efficacy of alpha blockers and CCBs, used in adults to facilitate stone expulsion, has not been established in children.

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Routine urinalysis may show hematuria, pyuria or crystals. Pyuria or fever suggests UTI, but requires confirmation by culture. While crystals of calcium oxalate, calcium phosphate or uric acid are often present in urine of normal individuals, the finding of crystals such as hexagonal cystine crystals or drug crystals may provide clues to etiology. S

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urgical Management

Stone removal may be indicated as an emergency due to acute obstruction or performed electively. The choice of modality for stone removal depends on the size, number

 

Table 10.13.3 Medications used in the treatment of nephrolithiasis

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Medication

Dose

Indication

Allopurinol

10 mg/kg/day in 2–3 divided doses

Hyperuricosuria

Captopril

0.5–2 mg/kg dose 2–4 times a day

Cystinuria

Hydrochlorothiazide

1–2 mg/kg/day in 1–2 divided doses

Hypercalciuria

Potassium Citrate

0.5–2 mEq/kg/day in 3 doses

Hypercalciuria, Hyperuricosuria

Pyridoxine

3–5 mg/kg/day in one daily dose

Primary hyperoxaluria

D Penicillamine

30 mg/kg/day div in 4 doses

Cystinuria

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Surgical Approaches

Extracorporeal shock wave lithotripsy focuses shock wave energy at the calculus. It is the preferred treatment in children with calculi below 20 mm in size. Success rates are lower with hard cystine stones and stones in the lower calyx.

Including laparoscopic or open surgery are required in more than 5% cases, chiefly for large stones, multiple stones and those associated with structural abnormalities.



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Percutaneous Nephrolithotomy

1. Alon US. Medical treatment of pediatric urolithiasis. Pediatr Nephrol. 2009;24:2129-35. 2. Gurgoze MK, Sari MY. Results of medical treatment and metabolic risk factors in children with urolithiasis. Pediatr Nephrol. 2011;26:933-7. 3. Straub M, Gschwend J, Zorn C. Pediatric urolithiasis: the current surgical management. Pediatr Nephrol. 2010;25:1239-44. 4. Turk C, Knoll T, Petrik A, et al. Guidelines on Urolithiasis; European Association of Urology 2011. Available from www. uroweb.org/guidelines/online-guidelines.

Ureterorenoscopy is ideally suited for calculi in the mid and distal ureter. With the availability of smaller scopes, it is now feasible in children.

ibliography



Ureterorenoscopy

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ultrasonic guidance and the instrument inserted under fluoroscopic guidance to fragment and remove the stones.

Diseases of Ki ney an Urinary Trac

and location of stone and the presence of obstructive uropathy or underlying urological abnormalities.

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Hypertension

 

Table 10.14.1 Definition and staging of hypertension in children Prehypertension

SBP or DBP 90th–95th percentile or > 120/80 mm Hg

Hypertension

SBP or DBP > 95th percentile

Stage I hypertension

SBP or DBP between 95th percentile and 99th percentile + 5 mm Hg

Stage II hypertension

SBP or DBP > 99th percentile + 5 mm Hg

Abbreviations: SBP, Systolic blood pressure; DBP, Diastolic blood pressure

Measurement of lood Pressure Table 10.14.2 shows a comparison of various techniques for measurement of blood pressure. Blood pressure measurement in children should be performed after adequate rest while sitting in an upright position with the back supported, and the cubital fossa at the level of the heart. The right arm is preferred to avoid falsely low readings in patients with coarctation of the aorta and for consistency. At least three measurements are taken on a visit, for confirming reproducibility of the result and for decreasing the effect of white coat hypertension. An appropriate cuff size with an inflatable bladder width that is at least 40% of the arm circumference, and bladder length sufficient to cover 80–100% of the arm circumference should be used. Ambulatory blood pressure monitoring refers to the continuous recordings of blood pressure over 12- or 24hour; it is believed to reflect true blood pressures accura tely, is more reproducible and correlates with target organ damage. Data are assessed in terms of mean blood pressure load (percentage of readings above the ambulatory 95th ­

Normative data on blood pressure values, based on gender, age and height percentiles, should be used to assess and interpret the diastolic and systolic blood pressures using the guidelines on definition of hypertension proposed in the Fourth US Task Force Report on Hypertension (Table 10.14.1). Based on normative blood pressure, Figures 10.14.1 and 10.14.2 provide charts for screening and staging of hypertension in boys and girls respectively. • White coat hypertension refers to high office blood pressures in patients who have normal blood pressures in familiar setting. • Masked hypertension refers to situations where office blood pressures are normal but the child is actually hypertensive.

Blood pressure should be measured in all children and adolescents more than or equal to 3-year-old at all medical encounters, and in children less than 3-year-old at risk for hypertension. These include those born premature, having acute or chronic renal disease or systemic illnesses associated with hypertension (neurofibromatosis, tuberous sclerosis). Blood pressure either systolic or diastolic more than the 95th percentile should be documented on at least three separate occasions to diagnose hypertension. B

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The prevalence of hypertension has increased in children. Children with severe hypertension are at increased risk of acute and chronic adverse outcomes, like hypertensive encephalopathy, congestive heart failure, retinopathy and renal failure.

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Table 10.14.2 Blood pressure monitoring techniques

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Technique

Advantages

Drawbacks

Auscultatory (mercury sphygmomanometer)

Most evidence based Noninvasive; quick to perform; easily available

White coat effect Observer bias Terminal digit preference Safety hazard: mercury spill

Aneroid manometry

Easily portable; mercury free

Needs frequent calibration

Oscillometric devices

Easy to use Useful in infants, where auscultation is difficult No observer bias

Limited reference data Values of diastolic pressure derived from mean pressure; may be inaccurate Requires repeated validation Cost and availability

Ambulatory blood pressure monitoring (ABPM)

For white coat, masked hypertension; data on Considerable cost diurnal variability Needs patient cooperation; training

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Figures 10.14.1A and B Blood pressure levels for boys at 50th percentile for height. Chart depicting 90th (closed diamonds), 95th (open squares) and 99th + 5 mm (closed triangles) percentile values for (A) systolic and (B) diastolic blood pressures, representing cut-off values for the diagnosis of prehypertension, stage I and stage II hypertension respectively in boys (based on the Fourth US Task Force Report on Hypertension) Source: Bagga A, Jain R, Vijayakumar M, et al. Management of Hypertension. Indian Pediatr. 2007;44:103-21.

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B Figures 10.14.2A and B Blood pressure levels for girls at 50th percentile for height. Chart depicting 90th (closed diamonds), 95th (open squares) and 99th + 5 mm (closed triangles) percentile values for (A) systolic and (B) diastolic blood pressures, representing cut-off values for the diagnosis of prehypertension, stage I and stage II hypertension respectively in girls (based on the Fourth US Task Force Report on Hypertension). Source: Bagga A, Jain R, Vijayakumar M, et al. Evaluation and management of Hypertension. Indian Pediatr. 2007;44:103-21.

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Careful history and physical examination may provide important clues to the underlying etiology (Table 10.14.4). Family history is taken for hypertension, diabetes, dysli pidemia, obesity, premature cardiovascular or cerebro vascular disease and renal disorders. Assessment of body mass index and measurement of blood pressure in all four limbs are necessary.

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Patients with prehypertension and stage 1 hypertension are usually asymptomatic or may have nonspecific symptoms such as headache, epistaxis, flush, visual disturbances, vertigo or a decline in school performance.

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Sustained hypertension in children is often secondary to an underlying renal disease (Table 10.14.3); renal parenchymal disease is the chief cause. In recent years, essential hypertension has become an important health concern. Patients with essential hypertension are usually postpubertal and overweight and typically show stage 1 hypertension.



E

tiology

Hypertensive crises: some patients with stage 2 hypertension may present with severe hypertension, or hypertensive crises, which are classified as emergencies or urgencies. Hypertensive emergencies are associated with acute target organ damage such as encephalopathy, intracranial hemorrhage, acute left ventricular failure with pulmonary edema, dissecting aortic aneurysm, papilledema and ARF. Hypertensive urgency is severe hypertension without end organ damage. The occurrence of these complications is related to the rate of rise and duration of hypertension, rather than absolute blood pressure values. Complications of sustained hypertension include hyper tensive retinopathy, albuminuria, left ventricular hyper trophy, diastolic dysfunction and premature atherosclerosis as evidenced by increased carotid intima media thickness.

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percentile) and nocturnal dipping (percent day-night difference). Ambulatory blood pressure monitoring is indicated for diagnosis of masked hypertension, white coat hypertension, nocturnal hypertension and evaluation for control of hypertension.

 

Table 10.14.3 Causes of hypertension

 

 

 

 

Acute renal failure; Acute glomerulonephritis Increased intracranial pressure Acute intermittent porphyria Guillain Barré syndrome Hyperthyroidism

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Transient hypertension

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Since the majority of patients with hypertension have underlying renal or renovascular etiology, screening tests are designed to evaluate for these conditions (Table 10.14.2). Patients with hypertension should also be screened for target organ damage. Based on clinical features and initial evaluation, a cause for hypertension is suggested in most instances. Confirmation of the diagnosis requires specific investigations tailored to specific needs (Table 10.14.5).

Persistent hypertension

 

 

 

 

Renal parenchymal disease Glomerulonephritis Reflux nephropathy; obstructive uropathy Polycystic kidney disease, renal dysplasia Post kidney transplant

Management

Cardiovascular Coarctation of aorta

­

 

Therapeutic lifestyle modification is important for manage ment of hypertension. The indications for drug therapy are listed in Table 10.14.6.

 

 

Primary (essential) hypertension Isolated With metabolic syndrome

 

 

Tumors Renal: Wilms tumor(nephroblastoma), reninoma, hemangiopericy toma, hamartoma Extrarenal: Pheochromocytoma, neuroblastoma, paraganglioma

­

 

 

 

 

In children, guidelines recommend lowering blood pressure to below 95th percentile, unless comorbidity is present, in which case the target is below the 90th percentile. In children with CKD, the blood pressure should be targeted between 50 and 75th percentile.

Prehypertension These patients are managed by lifestyle modifications (see below) and re-evaluated 6 months later. Medications are not required unless the patient has comorbid conditions.

 

 

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ssential Hypertension

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Medications/Iatrogenic Corticosteroids Substance abuse Nasal decongestants (phenylephrine, pseudoephedrine, oxymeta zoline) Nonsteroidal anti-inflammatory drugs Others: Erythropoietin, calcineurin inhibitors, theophylline, caffeine, antidepressants

Target lood Pressure B

Endocrine Cushing syndrome Congenital adrenal hyperplasia, primary hyperaldosteronism Hyperthyroidism, hypothyroidism Liddle syndrome, syndrome of apparent mineralocorticoid excess, glucocorticoid remediable aldosteronism

Patients with essential hypertension are initially managed with lifestyle modifications, and pharmacological therapy 661 is initiated later. Thiazide diuretics and beta-blockers, especially in combination, should be avoided due to

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Condition

Clinical features

Investigations

Glomerulonephritis

Facial puffiness, edema, hematuria

Urinalysis, 24-hour urine protein, C3, antinuclear antibody, antineutrophil cytoplasmic antibody, renal biopsy

Reflux nephropathy

Dysuria, frequency, history of urinary tract infections

Renal ultrasound, Micturating cystourethrography, renal scintigraphy

Renovascular disease

Asymmetric pulses, abdominal/neck bruit, weak femoral Doppler ultrasound, captopril renography, CT/MR angio artery pulses graphy or digital subtraction angiography (DSA)

Coarctation of aorta

Weak femoral artery pulses

Echocardiography, DSA

Metabolic syndrome

Adolescent age, obesity

Blood sugars, HbA1C, lipid profile

Endocrine

Muscle weakness, cramps; episodic fever, flushing, tachycardia; Plasma renin; aldosterone; plasma and urinary cortisol, polyuria, polydipsia, failure to thrive; ambiguous genitalia urinary catecholamine MIBG scan; CT/MRI scan

 

Table 10.14.5 Diagnostic workup Evaluation for cause

Screen for target organ damage

Hemogram

Retina fundus examination

Blood urea, creatinine, electrolytes

Urine spot protein to creatinine ratio

Fasting lipids, glucose, uric acid

Chest X-ray

Urinalysis, culture; 24-hour protein

ECG

Chest X-ray

Echocardiography

with the recommended initial dose of the medication, increase the dose until the desired blood pressure target or the maximum dose is reached. A second medication with a complementary mechanism of action should be added if blood pressure control is still not achieved and dose increased to maximum if necessary. If blood pressure not controlled, a third antihypertensive drug of a different class may be added. Therapy in children is often started with a CCB or ACEI. The choice of medication depends on the cause of hypertension and associated complications. F

Renal ultrasonography

Stage 2 hypertension Symptomatic hypertension Secondary hypertension Target organ damage Diabetes types I and II Persistent hypertension despite non-pharmacological measures

S

their significant diabetogenic potential. Therapy may be initiated with a CCB or ACE inhibitor (ACEI). Screening for dyslipidemia and impaired glucose tolerance is done.

econdary Hypertension

D

Patients with sustained secondary hypertension require therapy with antihypertensive agents. The treatment plan should incorporate non-pharmacological measures in all patients.

rug Therapy

There is limited long-term data on benefits or adverse effects of antihypertensive medications in children. Dosing recommendations are shown in Table 10.14.7. Therapy should be initiated with a single agent from any of the drug classes. Drugs with a longer duration of action are preferred for better compliance. When required, dose adjustment 662 should be made once in 2–3 days. A stepped-care approach should be followed. In this approach, one should begin

ollow-up and Monitoring

After initiation of drug therapy, follow-up visits should be frequent until blood pressure is controlled. Home blood pressure monitoring and assessment for side-effects are reviewed at each visit. After successful blood pressure control, “step down” of therapy may be attempted. Monitoring for target organ damage should be done at regular intervals.

Management of Hypertensive rises C

 

Table 10.14.6 Indications for drug therapy

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Table 10.14.4 Clinical features and investigations for secondary hypertension

Hypertensive emergency requires immediate reduction in blood pressure in order to prevent or limit target organ damage, and constant monitoring and supportive care, necessitating hospitalization. A hypertensive emergency is treated with a potent intravenous antihypertensive titrated to produce a controlled reduction in blood pressure, with the aim of decreasing the blood pressure by up to 25% over the first 8 hours of presentation and then gradually to the upper limit of normal (95th percentile) over 24–48 hours. Overly rapid control of hypertension may compromise blood flow to important organs causing ischemic damage, especially since autoregulation may be impaired or altered. Therapy with oral antihypertensives should be commenced as soon as patient can take orally, in order to permit withdrawal of intravenous therapy. The drug therapy of hypertensive emergency is summarized in Table 10.14.8. The drug of choice is IV nitroprusside or labetolol. Alternatively intravenous nicardipine or esmolol may be used. Hypertensive urgency can be treated in a non-ICU setting with oral medications over 24–48 hours.

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Side effects/comments

0.3–6 mg/kg/d 0.1–0.6 mg/kg/d 0.06–0.6 mg/kg/d 6 mg/m2

Use cautiously if GFR < 30 mL/min/1.73 m2 Avoid in renal artery stenosis Use smaller doses in neonates Monitor serum potassium, creatinine, contraindicated in pregnancy

Angiotensin receptor blockers (ARB) Losartan Olmesartan Valsartan Candesartan

0.75–1.4 mg/kg/d 10–40 mg/d 0.2–4 mg/kg/d 0.16–0.5 mg/kg/d

Similar to ACEI; cough, angioedema not seen

Calcium channel blockers Amlodepine Nifedipine Isradepine

0.05–0.5 mg/kg/d 0.25–3 mg/kg/d 0.15–0.8 mg/kg/d

Headache, flushing, tachycardia, edema, dizziness May increase proteinuria

Beta blockers Atenolol Labetolol Metoprolol

0.5–2.0 mg/kg/d 1–40 mg/kg/d 1–6 mg/kg/d

Avoid in asthma, heart failure Reduce dose of atenolol in renal dysfunction

Central alpha agonist Clonidine

5–25 µg/kg/d

Rebound hypertension when withdrawn

Peripheral alpha antagonists Prazosin

0.05–0.5 mg/kg/d

Syncope

Diuretics Hydrochlorothiazide Frusemide Amiloride Spironolactone

1–3 mg/kg/d 0.5–6 mg/kg/d 0.4–0.6 mg/kg/d 1–3 mg/kg/d

Thiazide: Hyperuricemia, hyperlipidemia, hyperglycemia, hypokalemia, ineffective at GFR < 30 mL/min/1.73 m2 Loop diuretics: Alkalosis, hypokalemia Potassium sparing diuretics: Hyperkalemia especially with ACEI, ARB

Vasodilators Hydralazine Minoxidil

1–8 mg/kg/d 0.1–1.0 mg/kg/d

Headache, palpitation Hypertrichosis, fluid retention, pericardial effusion

                                         

t

Dose

Angiotensin converting enzyme inhibitors (ACEI) Captopril Enalapril Lisinopril Ramipril  

Agents

K

 

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Table 10.14.7 Commonly used drugs for treatment of hypertension in children

 

Table 10.14.8 Commonly used drugs for hypertensive emergency Drug

Onset

Route

Dose

Labetalol

5–10 min

IV infusion

0.25–3 mg/kg/hour

Side effects

IV bolus

Orthostatic hypotension, bradycardia, pallor, 0.2–1 mg/kg/dose q 5–10 min (max 40 mg) abdominal pain, diarrhea

Sodium nitroprusside 30 sec

IV infusion

0.5–8 µg/kg/min (in 5% dextrose)

Nausea, vomiting, headache, tachycardia, cyanide toxicity (dizziness, confusion, seizures, jaw stiffness and lactic acidosis)

Nicardipine

IV infusion

0.5–4 µg/kg/min (max 5 mg/hour)

IV bolus

30 μg/kg (max 2 mg/dose) q 15 min

Flushing, reflex tachycardia, phlebitis, edema, headache, nausea, vomiting

1–10 min

Esmolol

60 sec

IV infusion

Loading with 100–500 μg/kg over 1–2 min; Bradycardia, orthostatic hypotension, pallor then maintain at 25–100 μg/kg/min

Sodium nitroglycerine

2–5 min

IV infusion

1–3 µg/kg/min

Phentolamine

10 min

IV bolus

0.1–0.2 mg/kg (max 5 mg) q 2–4 hours if Reflex tachycardia, abdominal pain required

Nifedipine

10–30 min

Oral

0.2–0.5 mg/kg (max 10 mg) q 4–6 hours

Methemoglobinemia, headache, tachycardia

Excessive hypotension, peripheral edema

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B

1. Bagga A, Jain R, Vijayakumar M, et al. Evaluation and management of hypertension. Indian Pediatr. 2007;44:10321. 2. Lande MB, Flynn JT. Treatment of hypertension in children and adolescents. Pediatr Nephrol. 2009;24:1939-49. 3. Linakis J. The assessment and management of hypertensive emergencies and urgencies in children. Pediatr Emerg Care. 2005;21:391-6.

4. Lurbe E, Cifkova R, J Cruickshankd K, et al. Management of high blood pressure in children and adolescents: recommendations of the European Society of Hypertension. J Hypertens. 2009;27:1719-42. 5. National Heart, Lung and Blood Institute Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. The Seventh Report of the Joint National Committee on prevention, detection, evaluation and treatment of high blood pressure: The JNC 7 report. JAMA. 2003; 89:2560-72.

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ibliography

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Section

11 Diseases of Blood Section Editor : MR Lokeshwar

































11.1 11.2 11.3 11.4 11.5 11.6 11.7 11.8 11.9 11.10 11.11 11.12 11.13 11.14

An Approach to Anemia in the Newborn: Ved Prakash Choudhry An Approach to Diagnosis of Anemia in Children: Ved Prakash Choudhry Nutritional Anemias in Infancy and Childhood: Niranjan Shendurnikar Bone Marrow Failure Syndrome: Nitin Shah Thalassemia Syndromes: MR Lokeshwar Sickle Cell Disease: Vibhawari S Dani Red Cell Membrane Disorders: Rashmi Dalvi Red Cell Enzymopathies: Jagdish Chandra Autoimmune Hemolytic Anemia: Bharat Agarwal Coagulation Disorders and Hemophilia: Sunil Gomber Platelet and Vascular Disorders: Sunil Gomber Evaluation of a Child with Thrombosis: Tulika Seth Disseminated Intravascular Coagulation: Anupam Sachdeva Transfusion Medicine and Component Therapy: Deepak Bansal

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An Approach to Anemia in the Newborn





Ved Prakash Choudhry

Introduction

 

Table 11.1.1 Hemorrhage in newborn (blood loss)

Etiology The three major causes of anemia are: • Blood loss • Hemolysis • Reduced red cell production. Blood loss leading to anemia may occur prenatally during delivery or over first 7 days (Table 11.1.1).

• Obstetric causes – Cesarean section – Placenta previa, abruptio placentae and rupture of umbilical cord – Intrauterine manipulation or placenta removal • Fetomaternal transfusion • Amniocentesis in third trimester • External cephalic version • Fetofetal transfusion—Transfusion from one twin to other • Spontaneous hemorrhage • Internal hemorrhage—Intracranial or retroperitoneal, rupture of organs • Iatrogenic—Multiple sampling 

Anemia is a unique problem in neonates. Development of anemia within 7 days of life is termed as “early onset anemia”, while anemia occurring after 7 days is called “late onset anemia”. The causes of anemia in these two groups are quite different and so is the treatment.



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Fetomaternal Transfusion Fetomaternal transfusion occurs in nearly 50% of pregnancies and in most cases it is minimal without any consequences. But in conditions like abruptio placentae and manual extraction of placenta, there is significant fetomaternal transfusion.

 

Figure 11.1.1 Anemia in newborn Courtesy: Dr MR Lokeshwar and Dr VP Choudhry

Clinical Presentation It depends upon the amount of hemorrhage and rapidity of bleed. In acute hemorrhage the neonate is pale and sluggish, develops gasping respiration and signs of circulatory shock (Fig. 11.1.1). Clinical presentation of acute and chronic blood loss along with treatment are given in Table 11.1.2.

The Kleihauer-Betke test is a blood test used to measure the amount of fetal hemoglobin (Hb) transferred from a fetus to a mother’s bloodstream (Fig. 11.1.2). Even though it is usually done as a positive screening test on all Rh negative mothers of Rh positive infants, it is indicated in all cases of maternal trauma.

 

Table 11.1.2 Acute and chronic blood loss in neonates

666

Clinical features

Acute blood loss

Chronic blood loss

Physical signs

Pallor Shallow rapid and irregular breathing Tachycardia No organomegaly

Significant pallor Hepatomegaly Signs of congestive failure depending upon the Hb level

Venous pressure

Low

Normal or elevated

Hemoglobin level

Normal initially and decreases within 24 hours

Low at birth

Red cell morphology

Normocytic, normochromic

Microcytic, hypochromic

Coomb’s test

Negative

Negative

Fetal cells in maternal blood

Present

Significantly present

Treatment

Pack cell transfusion

Pack cell transfusion if anemia is severe

Iron therapy

Later

Immediate

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Special culture media requiring minimal blood Use of transcutaneous monitoring techniques (analysis of blood gases, electrolytes, etc).

iseases

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• •

Fetofetal Transfusion It occurs in monozygotic twins with monochorial placenta. Nearly 20% of these transfusions are associated with twin to twin transfusion. Donor neonate has anemia, while recipient twin is polycythemic. Clinical presentation depends upon the volume of blood transfusion and whether the process has been acute or chronic. The anemic twin may develop pallor and congestive heart failure (CHF). Plethoric twin may develop hyperviscosity, hyperbilirubinemia or disseminated intravascular coagulopathy.

d

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Normal red cell survival in term neonate is 60–80 days while it is 20–30 days in preterm neonate born between 30 weeks and 32 weeks. Most neonates with hemolytic anemia develop jaundice as liver is unable to conjugate and excrete the bilirubin. Symptoms depend upon the level of Hb as described earlier. High reticulocyte counts are seen in the absence of hemorrhage. The common causes of hemolytic states in newborn are given in Table 11.1.3 and Figures 11.1.3A and B. Table 11.1.3 Causes of neonatal hemolytic states  

 

Figure 11.1.2 A fetomaternal transfusion: Kleihauer-Betke test on mother’s blood

o Bloo

Hemolytic Anemia in Newborn

• Drug induced • Red cell enzyme deficiencies: Glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency • Disorders of red cell membrane: Hereditary spherocytosis, hereditary elliptocytosis, hereditary stomatocytosis • Hemoglobinopathies: Alpha-thalassemia, Beta-thalassemia, sickle cell anemia • Infection or septicemia: Gram-positive and Gram-negative, intrauterine infections (TORCH), Malaria (Figs 11.1.3A and B) • Disseminated intravascular coagulopathy • Galactosemia

Internal Hemorrhage



Neonates may develop anemia within 24 hours of birth in the absence of jaundice, often secondary to internal hemorrhage. These forms of bleed occur in difficult deliveries following vacuum or forceps extraction. These deliveries are associated with subdural and subarachnoid hemorrhage or cephalohematoma. Breech deliveries are associated with internal hemorrhage of kidneys, spleen, liver or other organs. Bleeding is severe in presence of vitamin K deficiency. Subarachnoid or intraventricular bleeding has been observed in half of babies with birth weight below 1,500 g. Many neonates are asymptomatic. These babies may be lethargic and have poor sucking, sluggish neonatal reflexes, and pallor and/or breathing problems. Bleeding can be confirmed by CT of head.

a

Iatrogenic Hemorrhage

B Figures 11.1.3A and B (A) Anemia in a neonate following malarial infection due to Plasmodium vivax; (B) The peripheral smear shows the malarial parasite Courtesy: Dr MR Lokeshwar and Dr VP Choudhry  

A major cause of anemia in critically ill neonates in ICU is secondary to frequent blood sampling especially in very low-birth weight (LBW) babies (< 1500 g). About 1 mL of blood represents 1% of total blood volume in these neonates. Approaches used to reduce the amount of blood drawn in ICU include the following: • Use of micromethods • Use of close method to allow return of initial sample drawn • To draw the minimum blood required for tests

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O

L

ate nset of Anemia



Red Cell Enzyme Deficiency Glucose-6-Phosphate Dehydrogenase Deficiency Deficiency of glucose-6-phosphate dehydrogenase (G6PD) in red cells is common among Asians and accounts for 5–20% in different ethnic groups. This deficiency is inherited as X-linked recessive state. Hemolysis often occurs following exposure to drugs or infections. Neonate may receive the offending drug transplacentally or through breast milk. Besides hemolysis there is reduced glucuronidation of bilirubin in presence of G6PD deficiency in hepatocytes. Methemoglobin reduction is a simple screening test. However, G6PD levels can be measured. During acute episodes the test is negative (normal activity) as G6PD deficient cells have been hemolyzed. Anemia with high retic count along with jaundice may occur during neonatal period. Usually its course is mild but may be severe enough to require exchange transfusion (ET). Pyruvate kinase (PK) deficiency is uncommon but its clinical course is mild.



Anemia developing after 7 days of life is termed as late onset anemia. The causes of anemia during this period include: • Physiologic anemia of prematurity • Reduced red cell production • Hemolytic anemia • Mild form of Rh isoimmune hemolytic anemia and ABO incompatibility. [These may manifest before 7 days, while other causes of hemolytic anemia (Table 11.1.3) often present after 7 days] Septicemia causes anemia by two mechanisms, viz. 1. Hemolysis 2. Inhibiting erythropoietic activity. Repeated blood sampling during neonatal period is also a major cause of late onset of anemia.

generally is low along with presence of the Hemoglobin H (HbH) disease. It presents as late onset of anemia. Hemoglobin H disease is more severe and is a result of inheritance of three gene deletions. Neonates with HbH disease have high levels of Hb Barts with anemia and jaundice. Hydrops fetalis is a result of four gene deletion and results in death of the affected fetus or soon after birth. Peripheral blood shows marked hypochromia, poikilocytosis and target cells. A negative Coomb’s test and presence of intracellular crystals of the Hb Barts with supravital staining confirms the diagnosis. Anemia in this condition is of early onset. The β chain mutations often do not present in newborn period. Sickle cell hemoglobinopathies may present in neonatal period. In homozygous form, sickle cell concentration at birth is around 20%. These neonates may present with fever, jaundice, pallor and respiratory distress. Hyperbilirubinemia is more common among neonates with sickle cell anemia. Sickle cell disease can be diagnosed by Hb electrophoresis.



Among the various causes of hemolytic anemia, immunemediated disorders are most common such as Rh and ABO incompatibility. Most infants have hyperbilirubinemia, which usually does not exceed 12 mg/dL. Rh hemolytic disease is due to Rh (Rhesus) incompatibility between mother and neonate. Its prevalence in Indian neonates is about 5%. It occurs as fetal red cells from Rh positive neonate cross into maternal circulation in an Rh negative mother. She produces antibody response to fetal red cells (Rh positive) and these antibodies cross the placenta resulting in fetal red cell hemolysis. The neonate develops jaundice, high retic count and positive direct Coomb’s test. ABO hemolytic disease in India is common but the disease is generally milder. The mother has usually O blood group while fetus has A or B blood group. Hemolysis is more severe in OA incompatibility than OB incompatibility. Fetomaternal incompatibility has been observed in nearly 25% of pregnancies. However, significant hemolysis occurs only in 10% of such cases. The diagnosis can be suspected by high serum bilirubin levels in cord blood and confirmed by the presence of maternal IgG anti-A or anti-B antibodies, antibody dependent cell-mediated cytotoxicity along with high retic count, presence of spherocytes on peripheral blood smear and increased fragility of red cells. Direct Coomb’s test is generally negative or only weekly positive.

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Hemolytic Disease of the Newborn





Disorders of Red Cell Membrane

Hemoglobinopathies in Newborn Period

668

Among various hemoglobinopathies, alpha and gamma chain defects are more frequent in neonatal period than β chain defects. Alpha chain disorders are common as it is part of all Hbs at birth. These disorders are detected on routine neonatal screening. In newborns hemolytic disease occurs with homozygous α-thalassemia. It occurs with defect in two genes or more. Mean corpuscular volume (MCV) is

Hereditary spherocytosis (HS) is the most common form but usually it presents in later life. It presents with pallor, high retic count and high bilirubin levels along with mild splenomegaly. Peripheral smear shows spherocytosis. Another cause of spherocytosis and splenomegaly is ABO incompatibility in the newborn.

Reduced Red Cell Production Several conditions such as pure red cell aplasia, Diamond Blackfan syndrome and Pearson syndrome are uncommon disorders characterized by reduced erythropoiesis but

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Flow chart 11.1.1 Diagnostic approach to neonatal anemia

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Abbreviations: LBW, Low-birth weight; G6PD, Glucose 6-phosphatase dehydrogenase; PK, Pyruvate kinase; PRCA, Pure red cell aplasia; MCV, Mean corpuscular volume; MCH, Mean corpuscular hemoglobin.

Physiological Anemia of Prematurity Hemoglobin level in term infants decreases over first few weeks of life. Premature neonates have greater fall in Hb resulting in “physiological anemia of prematurity”. Hemoglobin levels may decrease to 8 g/dL at 4–8 weeks of life in premature neonates with birth weight of less than 1,500 g. The decrease in Hb is primarily due to decrease in red cell mass rather than Hb dilutional effect. Other factors which contribute to development of anemia include: • Reduced red cell survival • Reduced hematopoietic activity as evident by decrease in reticulocyte count. The premature neonates are able to make physiological adjustments to such a low Hb levels by: 669 • Increasing the cardiac output

­

with normal white cells and platelets. Low-birth weight is observed in 10% of these cases. • Babies with Diamond-Blackfan syndrome have micro cephaly, cleft palate, and anomalies of eye, web neck and thumb. It has autosomal recessive inheritance pattern. Neonates are likely to respond to steroids if diagnosed early • The Pearson syndrome is characterized by presence of vacuoles in bone marrow precursor cells along with sideroblastic anemia and exocrine pancreatic dysfunction • Impaired red cell production has also been observed in intrauterine infections with rubella, cytomegalovirus, adenovirus and human parvovirus • Congenital leukemia and Down syndrome have been associated with impaired erythropoiesis and are uncommon causes of late onset of anemia in the neonate.

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Recombinant Erythropoietin and Anemia of Prematurity ­

Several studies have clearly shown that use of erythro poietin in anemia of prematurity reduces the need of red cell transfusions in the premature or neonates with birth weight of 1,000 g at birth. However, in our country, use of erythropoietin may not be cost effective. However, neonates receiving blood transfusions are at higher risk of developing transfusion transmitted infections. K

The causes of anemia in the neonate are variable with different pathogenesis: • A detailed history of antenatal events including presence of anemia along with treatment received by the mother is essential • Detailed family history of hemoglobinopathies is helpful • Physical examination particularly presence of congenital anomalies and hepatosplenomegaly, stigmata of intrauterine infections, birth weight and development of jaundice, etc. are helpful for correct diagnosis • Initial laboratory studies should include complete blood counts along with red cell indices (MCV and mean corpuscular Hb), reticulocyte count, examination of peripheral blood smear and Coomb’s test (direct and indirect) • A simple algorithm based on reticulocyte count and red cell indices is given in Flow chart 11.1.1 • Subsequently specific tests can be undertaken for conformation of diagnosis • Correct diagnosis and prompt appropriate treatment plays a major role for survival.

• Anemia in the neonatal period is quite common especially in premature, LBW babies and sick neonates requiring intensive care • Anemia in neonatal period is associated with high morbidity and mortality • Causes of neonatal anemia are variable. Detailed history of antenatal events, history of maternal diseases and drug intake is essential along with complete clinical evaluation of the newborn • Use of retic count, red cell indices and peripheral smear examination along with Coomb’s test is useful for an approach to neonatal anemia • Prompt treatment of underlying cause of anemia plays a major role for better survival.

Recent Advances Autologous Transfusion

Delayed Clamping of Cord Several studies have shown that neonates with delayed cord clamping tend to have high Hb levels than those in

Bibliography

1. Luban NL. Management of anemia in the newborn. Early Hum Dev. 2008;84(8):493-8. 2. Nathan DG, Oski SH. Anemia in the newborn. In: Nathan DG, Orkin SH (Eds). Nathan and Oski’s Hematology of Infancy and Childhood, 5th edition. Philadelphian: WB Saunders. 1997. pp.34-52. 3. Singh M. Anemia. In: Singh M (Ed). Care of the Newborn, 7th edition: Sagar Publications. 2010.pp.362-5.

It has been observed that cord blood contains 75–125 mL of blood at birth (one-third of fetal blood). Autologous transfusions are safe provided red cells are collected aseptically and stored properly in the blood bank. Autologous transfusions are useful in premature babies requiring neonatal intensive care facilities, iatrogenic anemia and septicemia.

ey Messages



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Diagnostic Approach to Anemia in Newborn

whom clamping was not delayed. Reduced blood volume is associated with increased mortality among premature infants who develop respiratory distress syndrome. Similarly, it has been observed that delayed cord clamping in premature infants is associated with reduced blood transfusion requirements and better survival.



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Improving oxygen unloading capacity Redistribution of blood flow Increased oxygen extraction by increase in 2, 3-DPG levels of red cells Gradual rightward shift in the oxyhemoglobin dissoci ation curve by decrease in fetal Hb levels.

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n pproach to Diagnosis of nemia in Children

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Diseases of Bloo

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A person is considered anemic when the amount of Hb, the oxygen carrying pigment of the red blood cells (RBCs), is reduced from the normal value for that age and gender. Anemia is characterized by abnormally low levels of healthy RBCs, reduced Hb or red cell blood volume (hematocrit). The reduction of any or all of the three blood parameters affects the oxygen carrying capability of blood adversely. Table 11.2.1 provides the mean Hb concentration levels along with 2 SD below the mean for normal population for gender and age, defined as normal blood levels by the World Health Organization (WHO), the United Nations Children’s Fund and United Nations University. The levels of Hb below which child is considered to have anemia as per the WHO criteria are given in Table 11.2.2. E

pidemiology

Anemia is widely prevalent and is a major cause of morbidity. Globally anemia affects 1.62 billion people which correspond to 24.8% of the population. The highest prevalence is seen in preschool-age children (47.4%), and the lowest prevalence is seen in men (12.7%). Various surveys including the National Family Health Survey (NFHS) have revealed that anemia is highest in children below 6–35 months of age. The data given in Table 11.2.3 indicates that prevalence of anemia in India has increased over the last decade. It is more common in rural areas as compared to urban population.

tiology

The etiology of anemia is variable. It may occur because of: • Decreased erythropoiesis either due to deficiency of nutrition or defect in erythropoiesis • Increased blood loss • Diminished red cell survival as result of immune disorders and chronic infections. The etiology of anemia is given in Table 11.2.4.

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Ved Prakash Choudhry

Classification It is preferable to classify anemia based on the pathophysiologic effects for its better understanding (Table 11.2.5). The classification based on red cell morphology (red cell size and Hb content) is useful in determining the etiology and is helpful in investigating the cause of anemia with minimal investigations (Flow charts 11.2.1 to 11.2.4).

Clinical Picture Presence of anemia is associated with significant morbidity and mortality. The symptoms depend on the severity of anemia and whether it develops over a short or long period of time. Children may remain asymptomatic for long duration if the onset of anemia is insidious. When the onset of anemia is acute, children develop significant pallor, exertional dyspnea and restlessness. Severe anemia

 

Table 11.2.1 Normal hemoglobin, hematocrit or packed cell volume at different ages Age

Hb (g/dL)

RCC (1012/L)

PCV (%)

Mean

±2SD

±2SD

Mean

±2SD

Birth (cord blood)

16.5

13.5

51

42

4.7

3.9

1–3 days

18.5

14.5

56

45

5.3

4.0

Mean

7 days

17.5

13.5

54

42

5.1

3.9

14 days

16.5

12.5

51

39

4.9

3.6

1 month

14.0

10.0

43

31

4.2

3.0

2 months

11.5

9.0

35

28

3.8

2.7

6 months

11.5

9.5

35

29

3.8

3.1

1 year

12.0

10.5

36

33

4.5

3.7

2–6 years

12.5

11.5

37

34

4.6

3.9

6–12 years

13.5

11.5

40

35

4.6

4.0

Girls

14.0

12.0

41

36

4.6

4.1

oys

14.5

13.0

43

37

4.9

4.5

b

12–18 years

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Age/gender groups

Hb (g/dL)

Children 6 months–5 years

< 11

Children 6–14 years

< 12

Adult males

< 13

Females (Non-pregnant)

< 12

Females (Pregnant)

< 11

Table 11.2.3 Prevalence of anemia in different groups as per surveys in India  

Tex

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Table 11.2.2 WHO criteria for hemoglobin below which person is anemic

Group Early childhood

Reference NFHS II, 1998-99

Prevalence (%) 74

Pre-school children (6–35 months) Adolescent girls

NFHS III, 2006-7 Seshadri, 1999, Rural Gujarat

79 62

Seshadri, 1999, Urban affluent

22

ICMR, 2001, Rural India

90

Abbreviation: ICMR, Indian Council of Medical Research

 

Table 11.2.4 Etiology of anemia Inadequate dietary intake of iron and other nutrients (Vitamin B12 and folic acid).

2.

Inadequate supply of iron at birth: Prenatal or maternal nutrition deficiency, prematurity, low birth weight, or multiple births, prenatal blood loss.

3.

Inadequate absorption of iron: Gluten-induced enteropathy, atrophic gastritis, and post-gastrectomy, presence of phytates and calcium in the diet, and presence of recurrent or chronic diarrhea.

4.

Excessive physiological demands of iron associated with rapid growth periods—Prematurity, preschool period and adolescence.

5.

Hemolytic anemias: a. Extracorpuscular: Autoimmune hemolytic anemia, microangiopathic hemolytic anemia, toxic effects due to infection, due to splenomegaly, paroxysmal nocturnal hemoglobinuria, hematopoietic disorders (e.g. leukemia, aplastic anemia, myelodysplastic anemia), Blood loss (acute or chronic), chronic illnesses like juvenile rheumatoid arthritis, renal disease, heart diseases, poisoning (lead, arsenic and other heavy metals.) b. Intracorpuscular: Red cell membrane disorders (hereditary spherocytosis, hereditary elliptocytosis, hereditary stomatocytosis), red cell enzyme deficiencies (G6PD deficiency, PK deficiency), thalassemia, and hemoglobinopathies.

6.

Hematopoietic disorders (leukemia, aplastic anemia and myelodysplastic anemia).

7.

Blood loss (acute or chronic), secondary to parasitic infections like hookworm, giardiasis, gastritis, peptic ulcer, polyps, etc.

8.

Chronic illnesses like juvenile rheumatoid arthritis, renal disease, heart diseases, etc.

9.

Poisoning: Lead, arsenic and other heavy metals.





1.

Table 11.2.5 Pathophysiologic classification of anemia

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Anemia due to increase blood loss

1. Acute posthemorrhagic anemia 2. Chronic blood loss due to some chronic disease, e.g. hookworm infestation, ulcerative colitis, polyps, etc.

Anemia due to impaired red cell production

1. 2. 3. 4. 5. 6.

Deficient heme synthesis: iron deficiency anemia Vitamin B12 or folic acid deficiency (megaloblastic anemia) Deficient globin synthesis: Thalassemia Aplastic anemia (acquired or hereditary) Pure red cell aplasia Anemia of chronic disorders (chronic renal failure, cardiac disorders)

Anemia due to increased red cell destruction (hemolytic anemia)

1. 2. 3. 4.

Sickle cell anemia, thalassemia, hemoglobinopathies Autoimmune hemolytic anemia Hereditary spherocytosis Paroxysmal nocturnal hemoglobinuria

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Flow chart 11.2.1 Clinical approach to a child with anemia

 

Abbreviations: ITP, Immune thrombocytopenic purpura; DIC, Dissemenated intravascular coagulopathy; MDS, Myelodysplastic syndrome

 

Flow chart 11.2.2 Algorithm for microcytic and hypochromic picture on peripheral blood

power and coordination with behavioral effects. The IQ of children may be reduced by 5–7 points. Persistence of anemia has adverse impact on the bactericidal activity of neutrophils and impairs cell immunity leading to recurrent infections. In addition children may develop lymph node enlargement, petechiae, ecchymosis or bleeding symptoms. Presence of liver and spleen enlargement should be observed during the examination 673 of child.



also leads to cardiac enlargement, flow murmurs and even CHF. The tongue papillae are atrophied. The structural changes in the intestine may result in malabsorption and even protein enteropathy. Nails may become brittle and flat with longitudinal ridges (koilonychia). The work capacity or the activity of the child gets impaired. Persistence of anemia leads to neurophysiological and developmental deficits. Children may have reduced motor development, muscle

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Flow chart 11.2.3 Algorithm for macrocytic picture on peripheral blood

 

Abbreviations: CDA, Congenital dyserythropoietic anemia; AIHA, Autoimmune hemolytic anemia

 

Flow chart 11.2.4 Algorithm for normocytic and normochromic picture on peripheral blood

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Abbreviations: CDA, Congential dyserythropoietic anemia; CRF, Chronic renal failure; G6PD, Glucose 6-phosphate dehydrogenase

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RDW

Low MCV

Normal MCV

High MCV

RDW < 15

Thalassemia trait Heterozygous HbE, HbC, etc. ACD

ACD Heterozygous HbE, HbS, HbC, etc. Hereditary spherocytosis Acute hemorrhage

Aplastic anemia MDS Myeloma Liver disease Hyperthyroidism

RDW > 15

Iron deficiency anemia Thalassemia intermedia Sideroblastic anemia ACD RBC fragmentation

Early nutritional deficiency Myelodysplasia Myelophthisic anemia Sickle cell disease

B12 deficiency Folate deficiency AIHA Drugs: Hydroxyurea

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Table 11.2.6 Diagnosis of anemia on mean corpuscular volume and red cell distribution width

Abbreviations: ACD, Anemia of chronic disease; MDS, Myelodysplastic syndrome; AIHA, Autoimmune hemolytic anemia; MCV, Mean corpuscular volume; RDW, Red cell distribution width

 

Table 11.2.7 Abnormal cells on peripheral smear and underlying disorders

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Clinical pproach to nemia

Characteristics

Underlying disorders

Spherocytes

Hereditary spherocytosis Autoimmune hemolytic anemia Hemolytic transfusion reactions Severe burns Hypersplenism Clostridium welchii septicemia

Target cells

Hemoglobinopathies S, C, D and E Thalassemia Post-splenectomy

Elliptocytes

Hereditary elliptocytosis Thalassemias Myelofibrosis Myelophthisic anemia

Schistocytes and fragmental red cells

Disseminated intravascular coagulopathy Hemolytic uremic syndrome Prosthetic heart valve Malignant hypertension

Basophilic stippling

Thalassemia Poisoning (arsenic or lead) Sideroblastic anemia Unstable hemoglobins Hemolytic anemias

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aboratory pproach to nemia A

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The causes of anemia are variable hence family history of anemia, jaundice, race and area of origin should be recorded. Detailed clinical history should be taken including dietary habits and chronic diarrhea. Evaluation of growth retardation and organomegaly is of utmost importance. A simple algorithm for clinical diagnosis in given in Flow chart 11.2.1.



ecent dvances A

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Detailed history, clinical examination and complete blood counts along with a peripheral blood examination and various algorithms aids in reaching a diagnosis. These children may be subjected to few additional tests for confirmation of etiology of anemia (Table 11.2.8).

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Hepcidin ole in ron Metabolism R

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The objectives of laboratory tests are to determine the type, severity and the etiology of anemia. The severity of anemia is determined by the Hb level. The examination of peripheral blood film (PBF) identifies the morphological type of anemia. Based on the red cell morphology and red cell indices such as MCV, the anemia has been classified as microcytic hypochromic, macrocytic and normocytic normochromic. Simple algorithms toward the diagnosis of various etiological conditions are given in Flow charts 11.2.2 to 11.2.4. Reticulocyte count indicates the erythropoietic activity and serves as useful indicator for diagnosis. Recently red cell distribution width (RDW) is provided by most cell counters. Red cell distribution width along with MCV helps in differentiating various etiological conditions (Table 11.2.6). Detailed peripheral smear examination is of utmost importance. This not only helps in classification of anemia but presence of red cell abnormalities gives clue to the underlying diagnosis. • Presence of spherocytes in high number (15–20/100 RBC) is suggestive of HS or immune hemolytic anemia, while presence of a few spherocytes is suggestive of other states (Table 11.2.7) • Presence of schistocytes suggests life-threatening conditions such as disseminated intravascular coagulo pathy or hemolytic uremic syndrome • Presence of basophilic stippling is suggestive of various types of hemolytic anemia, lead or arsenic poisoning and sideroblastic anemia (Table 11.2.7). Based on the peripheral blood examination one may proceed to undertake specific tests to confirm the etiology of the disease process.

Several studies have demonstrated that hepcidin controls the release of iron from variety of cells such as macrophages, hepatocytes and enterocytes into plasma. However, the recycling of iron from RBC lysis and release of iron from tissue iron stores are carried by 675 the interaction of hepcidin with ferroportin which is a

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Bone marrow aspiration

Type of erythropoiesis (normocytic or megaloblastic) leukemia, hemolytic anemia, etc. and marrow iron stores

Bone biopsy

Aplastic anemia , infiltrative disorders (lymphoma or secondaries), myelofibrosis

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Iron deficiency anemia

Megaloblastic anemia

Serum folate levels Serum vitamin B12 levels Schilling test of vitamin B12 absorption

Pernicious anemia

Estimation of intrinsic factor in gastric juice Intrinsic factor antibodies levels Parietal cell antibodies Plasma (or serum) vitamin B12 binding capacity

Hemolytic anemia

Estimation of serum haptoglobin levels Demonstration of hemosiderin in urine Serum bilirubin, total and indirect, serum urobilinogen Serum lactic dehydrogenase levels

Hereditary hemolytic anemia

Detection of enzyme deficiency like G6PD assay, pyruvate kinase assay Glutathione stability test for G6PD deficient patients Coomb’s test (direct and indirect) Hemoglobin electrophoresis (high pressure liquid chromatography) Hemoglobin fetal and hemoglobin A2 estimation

Acquired-hemolytic anemia

Warm and cold autoantibodies detection Detection of incomplete antibodies by the Coomb’s test Ham test for paroxysmal nocturnal hemoglobinuria Flow cytometry evaluation of G-PI linked proteins on neutrophils CD-55 and CD-59 markers

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Serum iron, Total iron binding capacity Percent saturation transferrin Serum ferritin Serum transferrin receptor assays Red cell protoporphyrin levels

increased risk of infections. The iron acquisition by the microbes and their virulence is determined by various host and microbial mechanisms which are given below: • Reduced neutrophil function with decreased enzymatic activity • Impaired natural killer cell activity and impaired bactericidal activity • Depression of T-lymphocyte numbers/defective T-lymphocyte response, impaired interleukin–2 production • Reduced production of macrophage migration inhibition factor • Impaired delayed cutaneous hypersensitivity tuberculin reactivity.

Developmental and Neurophysiological Deficits in ron Deficiency Recently iron deficiency has been shown to have effect on brain metabolism, neurotransmitter function and myeli nation. These changes lead to neurophysiological and developmental deficits in infants and children, which may have adverse effect even during adulthood. Motor development and coordination are reduced. In addition there is impaired language development, scholastic achievement, psychological and behavioral effects such as ­

Children, particularly infants living in developing countries are highly vulnerable to infectious diseases. Iron deficiency is associated with impairment of innate (natural) immunity and cell-mediated immunity, thereby contributing to

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nfections and nemia A

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cellular iron exporter in vertebrates. It has been shown that release of ferroportin is primarily expressed by enterocytes and macrophages, which is also controlled by hepcidin. Iron homeostasis in the body is controlled by very complex mechanism and the main components include: (i) erythropoietic activity, (ii) hypoxia, (iii) iron stores and (iv) inflammation. All these components act through common pathways of hepcidin. Enhanced erythropoiesis and presence of tissue hypoxia decreases the hepcidin production by the liver resulting in enhanced iron absorption. In contrast, increased iron stores and presence of infection reduces the hepcidin production by the liver which causes internalization and degradation of ferroportin by the target cells, leading to decrease or total inhibition of iron absorption by the enterocytes and release of iron by the macrophages and other cells. Thus hepcidin primarily controls the iron absorption.

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Table 11.2.8 Diagnostic tests to confirm the etiology of anemia

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1. Choudhry VP. Hematological disorders. In: Ghai OP, Gupta P, Paul VK (Eds). Essential Pediatrics, 6th edition. New Delhi: CBS Publishers & Distributers; 2004. pp. 298-307. 2. Choudhry VP. Hepcidin and its role in iron metabolism. Indian J Pediatr. 2010;77(7):787-8. 3. Kumar V, Choudhry VP. Iron deficiency and infection. Indian J Pediatr. 2010;77(7):789-93. 4. Madan N, Rusia U, Sikka M, et al. Developmental and neurophysiologic deficits in iron deficiency in children. Indian J Pediatr. 2011;78(1):58-64. 5. NFHS-3. National family health survey—3 (2005–2006). Institute for Population Sciences (IIPS) Mumbai & Macro International 2007: Status of Children in India. 6. Oski FA, Brugnara C, Nathan DG. A diagnostic approach to the anemic patient. In: Nathan DG, Orkin SH (Eds). Hematology of Infancy and Childhood, 5th edition. Philadelphia: WB Saunders; 1997. pp. 375-84. 7. World Health Organization. Nutritional Anemia; Report of WHO Scientific Group. WHO Technical Report Series No. 405. Geneva; 1968. 8. Yadav S, Chandra J. Iron deficiency: beyond anemia. Indian J Pediatr. 2011;78(1):65-72.

• Anemia is widely prevalent in the World. It is more common in the developing countries • Children and women are worst affected • Iron deficiency anemia (IDA) is the most common cause of anemia • Persistence of severe IDA has adverse effects in adult life • Detailed history, examination and use of simple tests are essential for early diagnosis • Simple algorithms are helpful for early diagnosis of anemia.

Bibliography



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insecurity, fatigue, poor attention, etc. These children have decreased physical activity. Changes in brain iron content caused by early iron deficiency are not reversible on iron therapy in animals in spite of correction of anemia and other tissue iron deficits. These observations provide explanation why some effects of iron deficiency are irreversible even after complete correction of iron deficiency. Thus the timing of iron deficiency during infancy and its severity have critical impact even in adult life.

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Nutritional nemias in nfancy and hildhood

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ntroduction

The majority of body iron is in the form of Hb with about 10% in iron containing proteins in non heme tissues (myoglobin and cytochromes) Further 10–15% is stored intracellularly as ferritin or its degradation product, hemosiderin Iron requirements are highest in infancy during period of rapid growth and these are also increased during adolescence, menstruation, pregnancy and lactation. -

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Niranjan Shendurnikar

Nutritional anemias are conditions in which Hb concen­ tration of a given individual is below the normal level due to the deficiency of one or more nutrients needed for hematopoiesis and the Hb can be increased by the supplementation of the deficient nutrient/s. World Health Organization criteria for the diagnosis of anemia are Hb levels less than 11 g/dL in children between 6 months and 6 years and below 12 g/dL in children between 6 years and 14 years. The main nutrients are iron, folate, vitamin B12, proteins and vitamin E.

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Iron deficiency anemia is currently the most widespread micronutrient deficiency and affects nearly 1.5 billion people globally. Presently available data have shown that about one third of world population suffers from IDA of which 90% lives in the third world countries. Infants, preschool children, adolescents and women of child bearing age are at a greatest risk of developing iron deficiency and its resultant anemia. Around 74% of children between the ages of 6 months and 35 months are anemic. The WHO estimates that roughly 50% of anemia prevalence can be attributed to iron deficiency. The Third National Family Health Survey (NFHS 3) in 2005–06 found that the prevalence of anemia among under 5 children approaches 70%. The high prevalence of IDA is accounted for by the combination of limited iron stores at birth, timing of umbilical cord clamping at birth, delayed introduction of complementary foods and the frequency of infections. If not corrected, it leads to increasing severity of anemia, reduced work capacity, increased susceptibility to infections and greater risk of death associated with pregnancy and child birth.

Normal body loss of iron is about 20 µg/kg/day, but this may increase manifold during episodes of diarrhea, dysentery and parasitic infestations. Factors such as preferential delivery of iron to fetus during third trimester, delayed cord clamping and exclusive breastfeeding in first 6 months of life protect infants from becoming iron deficient. Malnutrition, chronic infections and worm infestations also contribute to a high prevalence of anemia.

tiology

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The dietary iron comes from two sources: heme and non heme iron. The major source of iron is in the diet and is found in variable degrees in foods of plant origin. Heme iron is present in meat, fish and poultry but the intake of these

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The causes of IDA are listed in Table 11.3.1.

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ron equirements during hildhood Understanding the requirements, intake and bioavailability of iron is essential to explain the vulnerability of some individuals to develop IDA. The iron released from senescent red cells during the first 8–12 weeks of life (a period of quiescent erythropoiesis) is stored in the body and helps to maintain erythropoiesis up to 4–6 months in a normal term baby and up to 2 months in an LBW baby. • Normal infants have about 75 mg of iron per kg body weight, two thirds of which is present in RBCs • Infants and young children should continue to absorb 0.8–1.0 mg of iron daily to reach the adult level of stores of 4–5 g 678

 

Table 11.3.1 Causes of iron deficiency • • • •

Decreased iron stores: – Preterm – Small for date babies – Twins Decreased intake/assimilation: – Delayed introduction of complementary feeds – Malnutrition/Iron-poor diet/malabsorption syndromes – Chronic infection/chronic diarrhea – Gastrointestinal surgery Increased losses: – GI bleeding – Malaria – Hookworm infestation – Peptic ulcer – Diverticulitis – Bleeding diathesis – Fetomaternal hemorrhage – Repeated venous sampling Increased demands: – Prematurity – LBW babies – Recovering from protein energy malnutrition (PEM) – Adolescents

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Iron deficiency is a systemic disorder involving multiple systems rather than being an isolated hematological condition associated with anemia. The peak incidence of iron deficiency in children occurs between 6 months and 3 years followed by adolescents 11–17 years. Children between 6 months and 24 months are a particularly high risk group for development of iron deficiency due to the low content of bioavailable iron in the weaning foods in developing countries. The appearance of symptoms depends upon the rate of fall of Hb and hemostatic adjustment of various organs systems. As the fall of Hb is often gradual, the onset of symptoms is insidious. Given the gradual development of IDA, pediatric patients rarely exhibit significant physiological consequences of decompensation. Initial manifestations include irritability, anorexia and pallor. Later hyperdynamic circulation leads to palpitation, shortness of breath, easy fatigability, reduced exercise tolerance and heart failure. Gradual onset of pallor may escape notice even when the Hb falls to 4 g/dL. Platonychia, koilonychias, glossitis, stomatitis, and angular cheilitis may be observed, especially with long standing anemia (Fig 11.3.1). The triad of dysphagia due to esophageal webs, koilonychia and splenomegaly in a child with IDA is known as Plummer Vinson or Paterson Kelly syndrome and are not -



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common in children. Mild hepatosplenomegaly is also not uncommon in IDA. Pica is well documented feature of anemia in children and manifested as craving for inedible things such as dirt, clay (geophagia), ice (pagophagia), laundry starch (amylophagia), salt, cardboard, etc. Pica is seen in almost 70–80% of patients and is usually cured by prompt iron therapy. Growth retardation and altered host immune responses are other associated features of IDA in children. Blue sclera also occasionally observed in iron deficiency in children and adolescents. Iron deficiency anemia is associated with impaired performance on a range of mental and physical functions including physical coordination and capacity, mental development, cognitive abilities, social and emotional development. Iron deficiency leads to impaired growth, compromises cognitive development and contributes to shortened attention span and scholastic failure (Table 11.3.2). Other health consequences include reduced immunity, increased morbidity, and increased susceptibility to heavy metal (including lead) poisoning. These changes may be related to functional changes in iron containing enzymes at cellular level. Iron deficiency anemia at a time of crucial brain growth and development may produce permanent and irreversible abnormalities in these functions.

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products is generally low. Heme iron is better absorbed than non heme iron and is not influenced by dietary factors. Breast milk in spite of low levels of iron (0.5 mg/L) has a better absorption and bioavailability as compared to cow’s milk. Good sources of iron in the diet include pulses, dals, green leafy vegetables, bajra, dates, nuts, jaggery, meat and fish. Administration of 50 mg of vitamin C daily increases iron absorption by twofold.

Iron deficiency anemia develops sequentially from the depletion of iron stores, iron deficient erythropoiesis to IDA (Table 11.3.3). Laboratory tests in IDA are required to diagnose IDA and to establish its cause. • Hemoglobin, RBC count and hematocrit are decreased in IDA along with low MCV, MCH and mean corpuscular hemoglobin concentration (MCHC) • Blood smear shows hypochromia, microcytosis, poikilocytosis and target cells (Fig. 11.3.2)

 

Table 11.3.2 Nonhematologic features of iron deficiency in children • • • • •

Koilonychias, glossitis, esophageal web Pica Reduced work capacity Reduced exercise performance Decrease attention span/cognition

 

Table 11.3.3 Summary of laboratory tests in iron deficiency anemia

 

Figure 11.3.1 Pallor in iron deficiency anemia Courtesy: Dr MR Lokeshwar

• • • • • • •

Depletion of stainable iron from BM Reduction of serum ferritin levels (< 15 ng/mL) Increased RDW (> 14.5%) Low serum iron (< 75 mg/dL) Increased TIBC (> 470 µg/dL) Low transferrin saturation (< 12% and 14% for infants and children) Increased red cell protoporphyrin concentration.

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Flow chart 11.3.1 An algorithm for child with microcytic hypochromic anemia

 

Figure 11.3.2 Hypochromia and microcytosis in iron deficiency anemia

•

used for tablet preparations. Iron salts of carbonate, citrate, choline citrate and pyrophosphates are not efficiently absorbed. Hemoglobin containing preparations do not offer additional advantage over simple ferrous salts. Many new iron preparations are now available that are not affected by the dietary factors, and have less gastrointestinal side effects. These are iron polymaltose complex, iron amino acid chelates and carbonyl iron. Newer iron preparations such as ferrous ascorbate and ferrous bisglycinate have a high bioavailability and are less affected by dietary factors and have fewer gastrointestinal side effects. The recommended dosage of elemental iron is 3 mg/ kg/day as higher doses are unnecessary. Higher doses may increase side effects and reduce patient compliance. Single daily doses are as effective, but 2–3 divided doses are better tolerated by children. It is recommended that 20 mg of elemental iron along with 100 µg of folic acid be used for prophylaxis in children between 6 months and 36 months in National Nutritional Anemia Control Program. Adolescents require 60 mg of elemental iron per day in case of mild anemia and 120 mg/day (60 × 2) for moderate and severe anemia. Iron therapy needs to be continued for 3 months after the blood values have returned to normal to replenish the iron stores. Suboptimal response to iron therapy may be due to poor compliance, inadequate dosage, associated infections, occult blood loss or other causes of microcytic hypochromic anemia. Knowing the elemental iron content

Management

ral ron Therapy I

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The basic principle of management of IDA is the correction of anemia and the eradication of underlying cause.

It is an effective, safe and economical mode for the treatment of IDA. Bivalent iron salts like ferrous sulfate, fumarate, gluconate, succinate and lactate are preferred over ferric preparations as these are 4–10 times better absorbed than ferric compounds. The bioavailability of 680 iron from ferric salts is 3–4 times less than that of ferrous sulfate. Ferrous sulfate (20% elemental iron) is commonly





An algorithm for diagnosis of microcytic hypochromic anemia in a child is shown in Flow chart 11.3.1. Differential diagnosis of microcytic hypochromic anemia includes the following: • IDA • Anemia of chronic infection • Thalassemias • Lead poisoning • Sideroblastic anemia.



iagnosis



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Reticulocyte count is usually normal unless the child has an acute or recent blood loss or has received hematinics. However, in mild iron deficiency, RBC morphology and indices are not altered • Low serum iron, increased total iron binding capacity (TIBC) (> 470 µg/dL) and low transferrin saturation • Serum ferritin levels may be normal if there is an associated illness as ferritin is an acute phase reactant • A low MCV with an elevated RDW is strongly suggestive of IDA. Red cell distribution width is highly sensitive (> 90%) but low in specificity (50–70%) in detecting IDA • Soluble transferrin receptor measures the severity of IDA and values more than 9 mg/L are considered abnormal • Depletion of stainable iron from bone marrow (BM) (Routinely BM examination not required).

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Megaloblastic anemia is caused by the deficiency of either folate or Vitamin B12 or both. The recommended dietary allowance for vitamin B12 is 0.3–0.5 µg/day and 1–1.5 µg/ day for infants and children respectively. These deficiencies are due to:

Reticulocytosis, peaking at 5–7 days

1–3 months

Repletion of stores

ecreased ntake

Vitamin B12 deficiency is observed with strict vegetarian diets, malnutrition and in breast fed infants of mothers with low serum B12 levels. Folate content of goat’s milk is extremely low and cooking of vegetables for long time in boiling water also reduces the folate content of the item. -

48–72 hours

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Initial bone marrow response, erythroid hyperplasia

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36–48 hours

Protection and promotion of breastfeeding with timely introduction of complementary feeding at 6 months Low-birth weight infants need iron supplementation from the age of 2 months Dietary modification and consumption of habitual foods increases consumption by 5–30% Process like germination (sprouting of green grams) and intake of green leafy vegetables are also helpful in prevention of IDA Periodic deworming should be considered in endemic areas Administration of one pediatric (small) tablet containing 20 mg of iron and 100 µg of folic acid daily for 100 days every year has been recommended by National Nutritional Anemia Control Program Food and salt fortification would be most effective strategy to control IDA. Salt fortification gives an iron content of 1 mg/g of salt in preparation. Common salt fortified with iron orthophosphate and sodium hydrogen sulfate with ascorbic acid has been found stable and effective in field trials in India Microencapsulated iron sprinkles are a novel approach and this can be sprinkled on any complementary food at the table and does not change the color or the taste of the food Various contact points like measles (9 months) and DPT booster (16–18 months) in ICDS scheme should be utilized for the distribution of iron.

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Replacement of iron enzymes, subjective improvement, decreased irritability, increased appetite

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Appropriate nutritional strategies are important factors in the prevention of IDA. These include:

Table 11.3.4 Response to iron therapy in iron deficiency anemia 12–24 hours

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Prevention of ron eficiency

Indications • Intolerance to oral iron • Persistent noncompliance • Gastrointestinal bleed aggravated by oral iron therapy. There are four commercially available IV iron products: 1. Iron dextran 2. Iron sucrose 3. Iron ferric gluconate 4. Ferric carboxymaltose injection. Iron dextran is a complex of ferric hydrochloride and high molecular weight dextran. This needs to be given by intravenous route either by infusion or bolus (single total) dose. The dosage is calculated as: Iron (mg) = Weight in kg × Hb deficit (g/dL) × 4 Life threatening anaphylactic reactions may occur and hence parenteral iron should be given in hospital setting only. Other side effects may include fever, abdominal cramps, pain, skin rash, arthralgia and serum sickness like illness. The use of iron dextran has decreased because of the risk of anaphylaxis. Ferric carboxymaltose injection has a better safety and tolerability profile than existing products and has little toxicity. High doses can be administered with good local tolerance. Table 11.3.4 shows the response to iron therapy in iron deficiency anemia with iron therapy.

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Parenteral ron Therapy



Blood transfusion may be needed in most severe cases of IDA when the Hb level is below 3–4 g/dL or when superimposed infection may interfere with optimal therapeutic response. Packed red cells may be slowly given preferably 2–3 mL/kg at one time.



of the preparation is very important to ensure the adequate intake of therapeutic dose of iron and get an optimal response. Assessment of response to treatment is made by reticulocyte count which rises 2–4 days of therapy (Table 11.3.4). Approximately 2 months are required to achieve a normal Hb level. Once weekly or twice weekly therapies are also effective as human intestine have mucosal turnover between 5 days and 6 days and greater iron absorption may be achieved by iron administration to new gut cells. Twice weekly dose is considered cost effective with a need of lesser number of doses, with fewer side effects and better compliance. Twice weekly iron folic acid supplementation is found to be comparable to daily IFA.

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Failure to secrete intrinsic factor, intestinal diseases such as celiac disease or surgical resection leads to vitamin B12 deficiency.

efective Utilization

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Drugs, such as phenytoin and pyrimethamine, interfere with folic acid metabolism.

Preterm babies, infants recovering from PEM and chronic hemolytic anemia have an increased demand for vitamin B12 and folic acid.

linical eatures

Figure 11.3.4 Peripheral smear showing macro-ovalocytes and hypersegmented neutrophils  

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Management Treatment of folate deficiency needs 100–200 µg of folate daily; however, it is given in a daily dose of 1–5 mg for 14–21 days for therapeutic response and then needs to be continued for 1–2 months for the replenishment of the body stores. Different vitamin B12 replacement regimens are used to treat vitamin B12 deficiency in infants and children with B12 deficiency. About 500–1000 µg of vitamin B12 is given intramuscularly on alternate days for a period of 2–3 weeks. This should be followed by 100–250 µg/dose once every month given intramuscularly as a maintenance therapy to prevent recurrence. Vitamin B12 given orally is not universally effective due to poor patient compliance and an erratic absorption. Treatment with folate alone can produce hematologic response in vitamin B12 deficiency but does not correct neurological impairment caused by B12 deficiency. Anemia unresponsive to folate or B12 may be caused by certain rare metabolic diseases (homocystinuria) or antimetabolic drugs. K





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Peripheral blood smear is one of the best indicators of megaloblastic anemia with the presence of macro ovalocytes, hypersegmented neutrophils (3% with more than 5 lobes) and a raised MCV (Fig. 11.3.4). There may be evidence of leukopenia and thrombocytopenia in severely deficient cases. Macrocytosis precedes anemia and the MCV may be in the range of 110–130 fl. However, it may be

masked by the presence of IDA. Red blood cells folate level and low B12 levels more accurately reflect the folate and vitamin B12 balance respectively.



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These children appear sicker than the degree of anemia warrants. Anorexia, mental apathy and fatigability are early symptoms while glossitis and diarrhea can also occur. Hyperpigmentation of dorsum of hands and knuckles are important findings (Fig. 11.3.3). Tremors, failure to thrive and developmental regression are also observed. Vitamin B12 deficiency causes neurological manifestations such as degeneration of peripheral nerves, selected columns in spinal cord and defective cerebral function. Folate deficiency does not cause neuropathy.

Figure 11.3.3 Hyperpigmentation of dorsum of hands and knuckles

• Iron deficiency anemia is the most prevalent micronutrient deficiency and affects nearly 70% of under 5 children as per NFHS-3 survey • Iron requirements are highest in infancy during period of rapid growth and these are also increased during adolescence, menstruation, pregnancy and lactation • Iron deficiency anemia is a systemic disorder affecting multiple systems rather than being only a hematological condition • A low MCV with an elevated RDW is strongly suggestive of IDA

 

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1. Awasthi S, Verma T, Vir S. Effectiveness of biweekly versus daily iron folic acid administration on anemia status in preschool children. J Trop Pediatr. 2005;51(2):67 71.

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ibliography

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2. Choudhury P. Iron Deficiency Anemia. In: Lokeshwar MR, Shah N, Agarwal B, Sachdeva A (Eds). IAP Speciality series on Pediatric Hematology and Oncology. Indian Academy of Pediatrics, Mumbai; 2006. pp. 28 35. 3. Davis I. Iron deficiency anemia. In: Zaoutis LB, Chiang VW (Eds). Comprehensive Pediatric Hospital Medicine. Philadelphia, Mosby: Elsevier; 2007. pp. 723 24. 4. Desai M. The big fight: Conventional versus new oral preparations vs. parenteral iron therapy. Blood. 2010;116: 4754 61. 5. Nagpal J, Choudhury P. Iron formulations in pediatric practice. Indian Pediatr. 2004;41(8):807 15. 6. Naithani R, Saxena R. Hematinics in Children. Indian J Pract Pediatr. 2008;10:96 105. 7. Sen A, Kanani SJ. Impact of iron folic acid supplementation on cognitive abilities of school girls in Vadodara. Indian Pediatr. 2009;46(2):137 43. 8. WHO/UNICEF/UNU. Iron deficiency anemia: assessment, prevention and control. Geneva, WHO, 2001 (WHO/NHD/ 01.3). Available from www.who.int/nut/documents/ida_ assessment_prevention_control.pdf (Accessed November, 2009.)

iseases of lood

• Oral iron therapy is an effective, safe and economical mode for the treatment of IDA. Ferrous salts are most commonly used preparations for IDA • Newer iron compounds such as iron polymaltose complex and amino acid chelates have an improved tolerance and are not affected by dietary factors • Protection and promotion of breastfeeding with timely introduction of complementary feeding at 6 months forms an important strategy in the prevention of IDA • The megaloblastic anemia should always be treated with adequate doses of both folate and vitamin B12

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one Marrow ailure yndrome

Symptom and signs depends on cell line involved. The onset is usually insidious. • Thrombocytopenia will lead to bleeding manifestations like skin bleeds, mucosal bleeds, GI tract, hematuria, menorrhagia, and rarely intracranial hemorrhage (Fig. 11.4.1A). • Neutropenia will lead to infection and fever with or without localization of infection • Anemia appears last and if severe will lead to fatigue, breathlessness, puffiness, edema of feet and congestive cardiac failure (CCF). One should look for evidence of etiological factors like hepatitis, past history of drugs use, etc. (Fig. 11.4.2) • Presence of hepatomegaly, splenomegaly, lymphade­ nopathy, bone pains, etc. usually rules out AA and sug­ gest more sinister disease like leukemia. The differential diagnosis of pancytopenia is shown in Table 11.4.2. D

tiology

iagnosis

Diagnosis of AA is one of exclusion, and proper examination of BM is essential. Table 11.4.1 Etiology of aplastic anemia Acquired a. Idiopathic

Aplastic anemia is classified as acquired or inherited. Inherited cases may or may not be present at birth (congenital). The etiological classification of AA is shown in Table 11.4.1. There is also a genetic predispostion for the development of marrow aplasia seen in patients with human leukocyte antigens (HLA) class II antigens DR2 and DPW3 (Table 11.4.1).

linical Presentation

 

Aplastic anemia (AA) is an uncommon but potentially serious hematological disorder caused due to pancytopenia with a hypocellular BM without infiltration or fibrosis with annual incidence of about 2–6/million population. It affects all the age group, and a small peak occurs at the age of 5–6 years due to inherited causes of AA. It results in decreased production of one or more hematopoietic lineages—mature red cells, granulocytes and platelets leading to pancytopenia, i.e. AA or mono or bicytopenia (e.g. agranulocytosis, red cell aplasia) and is characterized by hypocellular (or fatty) marrow. Aplastic anemia is defined as presence of any two peripheral blood criteria [absolute neutrophil count (ANC) less than 1,500/mm, platelet count less than 40,000/cumm, reticulocyte count less than 40,000/ cumm] in presence of BM hypocellularity on BM biopsy. Severe AA is characterized by presence of any two of the peripheral blood criteria (ANC < 500/mm, platelet count < 20,000/cumm, corrected reticulocyte count < 1%) along with the presence of either of the marrow criteria [severe hypocellularity (< 25%), moderate cellularity with less than 30% of hematopoietic cells]. All nonsevere AA cases are defined as moderate AA. If left untreated, 80–90% of patients with severe AA will die within a year.

environment or stromal support (a soil or microenviron­ ment deficiency) leads to AA. Success of BM transplant favors seed theory whereas success of immunotherapy proves that in some patients it is the soil which is at fault. Probably there are different mechanisms of damage in different patients. C

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b. Secondary

cquired plastic nemia

• Chemicals, e.g. benzene, sniffing glue, insecticides, dyes

Hematopoietic stem cell has tremendous proliferative capacity and has potential, not only to differentiate into various cell lineage but also has property of self renewal. It has been observed that primitive progenitor cell number is significantly reduced in all patients with severe AA. Seed theory contemplates that AA is caused due to lack of pluripotent stem cells/progenitor cells or a qualitative defect of common stem cell population.

•

684 Soil Therapy Survival and proliferation of hematopoietic cells are dependent on stroma cells. Lack of surrounding micro­

Radiation

• Viruses, e.g. Hepatitis, Epstein-Barr virus, Parvovirus •

Pregnancy

•

Paroxysmal nocturnal hemoglobinuria

•

Miscellaneous: Hypogammaglobulinemia, Thymoma, Esinophilic fasciitis, Preleukemic Syndromes, etc. 

A

Seed Theory

A

• Drugs, e.g. sulfa, anticancer drugs, antiepileptics, chloramphenicol, gold, carbamazepine,indomethacin, phenylbutazone, etc.

A

Pathophysiology

Inherited (a) Fanconi’s anemia, (b) Dyskeratosis congenita, (c) Reticular dysgenesis (d) Shwachman-Diamond syndrome Miscellaneous: Familial aplastic anemia, Monosomy 7, Down syndrome, Amegakaryocytic thrombocytopenia, etc.

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Table 11.4.2 Differential diagnosis of pancytopenia in children • Artifact: Clot in sample • Genuine: Central (Bone marrow involved) • Replacement like in leukemia, and other malignancies • Infections like Kala-azar, severe malaria

B

• Myelosclerosis, osteopetrosis, myelofibrosis, hemophagocytic lymphohistiocytosis (HLH), severe megaloblastic anemia • Peripheral • Sequestration, hypersplenism (portal hypertension). Destruction of mature elements like infection most commonly viral, immune like systemic lupus erythematosus (SLE), complement mediated like paroxysmal nocturnal hemoglobinuria (PNH) • Mechanism obscure like organic acidemias a

B

Peripheral lood Anemia with normal RDW, normocytic normochromic RBCs, occasional macrocytosis with low corrected retic count Leukopenia with decreased ANC Thrombocytopenia: Decreased platelet count with normal MPV Stress erythropoiesis: Raised fetal hemoglobin (HbF) and i antigen in some patients Coagulation parameters are generally normal -

• • •

-

• •

Pancytopenia without blasts in the blood is most likely due to marrow aplasia, but diagnosis requires aspirate and trephine biopsy of BM. Iron study may show iron overload

one Marrow and Trephine iopsy B

B



The first sign of recovery after successful therapy is a rise in reticulocyte count followed by increase in Hb levels, then neutrophils, while platelets slowest to recover if at all.

Figures 11.4.1A and B Trephine biopsy in aplastic anemia Courtesy: Dr MR Lokeshwar and Dr Nitin Shah

Supportive Therapy Supportive care provides the back bone of any therapy. It includes use of appropriate antimicrobial therapy and occasional use of colony stimulating factors for control of infections, use of blood components to tackle anemia and thrombocytopenia, and management of iron overload.

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It is mandatory to do BM trephine biopsy as well as an aspiration to diagnose AA. It will show hypocellular marrow with empty spicules, increased fats spaces, hypoplasia, may be patchy, especially early in the disease. Marrow consists of little more than fat, stromal cells, lymphocytes and plasma cells; mast cells may be prominent. Because of diminution in the erythron, storage iron and sideroblasts may be increased; ring sideroblasts are not seen, except in rare specific syndromes (Fig. 11.4.1B). • tress cytogenetics: It should always be done to rule out Fanconi’s anemia (FA) which will show increased spontaneous and clastogen induced chromosomal breaks. • thers: This includes tests to find out etiological factors like LFT, etc.

B  

•

Treatment Curative Therapy Figure 11.4.2 Aplastic anemia. Sick looking child, anemia, ecchymosis, petechiae, purpura, bleeding tendency, no hepatosplenomegaly, or bony tenderness. Courtesy: Dr MR Lokeshwar and Dr Nitin Shah  

Curative therapy for AA involves use of stem cell transplant (SCT), immunomodulating therapy, and rarely other modalities of treatment.

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It is usually started on day 21 after steroids are stopped to avoid overlapping toxicities like hypertension. It is used in doses of 5–10 mg/kg/day to keep a trough level of 100–150 ng/m and continued for up to 6 months. Nephrotoxicity can be dose limiting. All patients on CsA must receive pneumocystis carinii prophylaxis. Side effects like electrolyte disturbance, renal toxicity, liver toxicity, hirsutism, gingival hypertrophy, etc. can occur. Response to immunosuppressive therapy (ATG plus CsA): It should be assessed after 3–4 months of treatment. Response is divided as follows: •

omplete response: Defined as response to therapy where patient is free from transfusion support, Hb is maintained at normal level for age and gender, ANC is maintained greater than 1.5 x 109/ and platelets greater than 150 × 109/ on repeated counts 4 weeks apart Partial response: Defined as response to therapy where patient is transfusion independent for RBC and/ or platelets but does not have complete recovery of counts and does not any more meet criteria for severe AA No response: Patient continues to fulfill criteria for severe aplastic anemia. Overall long term survival after immunomodulatory therapy is comparable to SCT in Western world for moderate AA. However, late clonal hematological diseases like PNH, myelodysplastic syndromes (MDS), etc. can occur after apparent recovery from aplasia. The success rate is 60–70% ndrogenic steroids: They stimulate erythropoiesis. Nandrolone enanthate is used in a dose of 2–5 mg/kg/ day as injectable form once in 10 days and continued till response is evident. Some response is seen in 20–30% of patients of moderate AA. Side effects are many, especially masculinization, stunted growth, hepatotoxicity, liver carcinoma, etc. Androgens have a mixed reputation. Probably dose makes the difference. One can use nandrolone decanoate at 5 mg/kg/week IM for at least 3 months. The advantage of this preparation is freedom from hepatotoxicity orticosteroids: Steroids stimulate erythropoiesis. It also stabilizes capillary membrane and decrease bleeding. They are useful to counteract side effects of androgenic steroids on growing epiphysis and the serum sickness of immunotherapy. Oral prednisolone is used in the dose of 0.5–1 mg/kg/ day and tapered to a minimum effective dose. Pulsed IV methylprednisolone in doses of 30 mg/kg have been used by some with limited success. l

l





Standard protocols of febrile neutropenia should be followed in patients with AA who develops fever. One can use 5–10 days of G CSF in 5 mg/kg/day SC to tide over crisis in a sick severely neutropenic child with fever. Asepsis precautions like sterile diet, chlorhexidine mouthwashes, betadine bath, clean drinking water, and hand sanitization go a long way in preventing infections in neutropenic patients.

Cyclosporin A



nfections

Antithymocyte globulin/Antilymphocyte globulin can lead to anaphylaxis but fortunately it is rare. One should run the infusion slowly initially to look for hypersensitivity. Premedication with antihistamines will help reduce other minor sensitivity reactions like fever, chills and urticaria. Serum sickness after about 10 days of therapy is also common. 1 mg/kg of prednisolone is started on day 5 till 15 days and taper over next 7 days to counter these side effects.

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nemia: Leukodepleted packed cell transfusion should be given to maintain Hb above 7–8 g% avoiding use of relative donor for the fear of HLA sensitization and graft versus host disease (GVHD). Iron chelation is started when serum ferritin level is more than 500–1,000 ng/m . • leeding: Platelet transfusion is given when the patient has acute mucosal bleeds or severe internal bleeding. Isolated skin bleeds do not merit use of platelets, howsoever, grotesque and frequent they may be. Prophylactic platelets may be used when the platelet count falls below less than 5,000/cmm. However, misuse of platelets for minor or skin bleeds my lead to refractoriness. General measures like local pressure, use of epsilon aminocaproic acid (EACA) or tranexamic acid, dental care, avoiding use of NSAIDS, also help prevent bleeding.

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•

•

-

 

ntithymocyte Globulin/ ntilymphocyte Globulin

•

A

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It involves use of drugs like cyclosporine A (CsA), antithymocyte globulin (ATG), antilymphocyte globulin (ALG), and steroids used in combination. One can use these agents alone if the patient cannot afford all the drugs; however, the response is not as well as when used in combination.

They are used in doses of 10–40 mg/kg/day given for 5–10 days (follow the manufacturer’s recommendations).

 

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mmunomodulatory Therapy

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•

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-

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-

Stem cell transplant has become treatment of choice for patients with severe AA who are young and have HLA matched sibling donor. However, problem of SCT include nonavailability of HLA matched donor with small family size, nonaffordability of procedure, higher complications, especially in greater than 40 years old patients and poor response in previously heavily transfused patients and high mortality in patients who are sick with uncontrollable infection at time of transplant. Cure rates in young patients with HLA matched donor are over 80%. Complications of procedure include acute and chronic GVHD, interstitial pneumonia, other infections, veno occlusive disease. Other long term problems secondary to SCT are those due to chemotherapy and radiation. These include poor pulmonary function, endocrine dysfunction including infertility, cognitive disorders, leukoencephalopathy and occurrence of second malignancy.

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Stem Cell Transplant

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It is achieved stress cytogenetic study on peripheral blood induced by clastogen, which will show increased chromosomal breaks. Homozygotes will show 8–9 breaks per cell compared to 0.06 in non FA persons.

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Side effects include hypertension, fluid electrolyte imbalance, infections, suppression of neuroendocrine axis, psychosis, avascular necrosis of femur, etc. • olony stimulating factors: Hematopoietic growth factors like G CSF and GM CSF have been used to counter neutropenia in patients with severe AA especially neutropenia following SCT. It helps control infections when added to antibiotics and are helpful in management of infected neutropenic patients. They may also be useful as a part of immunosuppressive regimen as they promote hematopoietic regeneration.

aroxysmal Nocturnal Hemoglobinuria

-



It is rare cause of acquired AA in childhood. A variety of cells are abnormally sensitive to lysis by complement, due to a defect in the glycosylphosphatidylinositol anchor, which binds proteins to the cell membrane (including those which protect against complement). Diagnosis might be considered for hemolysis of obscure origin. Chronic hemolysis is more common than sleep induced hemoglobinuria, and hemosiderinuria is constant. Diagnosis is achieved by molecular testing for CD56.

Inherited Bone Marrow Failure Syndrome

a

-

This includes various inherited causes of mono/bi/tri cy­ topenia like FA, dyskeratosis congenital (DK), congenital amegakaryocytic thrombocytopenia, Schaumann’s syn­ drome and Diamond Blackfan syndrome, etc.

Fanconi’s Anemia

-

B

linical eatures F

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Fanconi’s anemia is inherited autosomal recessively, is the most common cause of constitutional AA caused by defect in DNA repairs leading to spontaneous or induced breaks in chromosomes. Mean age at diagnosis is 7–8 years with 4% cases less than 1 year old and 10% cases greater than 16-year-old in age. Male to female ratio is 1.06:1.0.

-

C Figures 11.4.3A to C (A) Fanconi’s anemia; (B) Ectopic kidney; (C) Trephine biopsy-hypocellular marrow. Courtesy: Dr MR Lokeshwar and Dr Nitin Shah  



-



-

Characteristic physical anomalies seen include generalized or perioral hyperpigmentation, cafe lait spots, short stature, microcephaly, mental retardation, skeletal anomalies like absent or hypoplastic thumb, bifid or triphalangeal thumb, absent radius, hypogonadism, spinal anomalies, renal anomalies like ectopic kidney, eye anomalies, deafness, ear malformations, GI anomalies, cardiopulmonary anomalies, etc. Around 15–30% of patients with FA are physically normal or have only short stature and/or skin changes (Figs 11.4.3A to C). Thrombocytopenia is usually the first sign, and may be misdiagnosed as immune mediated thrombocytopenia (ITP) if the association with somatic anomalies is not recognized; granulocytopenia and then anemia follow, evolving over months to years. Macrocytosis and increased HbF levels are common, even before onset of anemia. There is a risk (about 20%) of malignancy, especially AML M4 and squamous cell carcinoma.

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Without therapy 80% FA patients die at mean age of 16 years or 2 years following onset of aplasia and most by 4 years following aplasia. About 25% survive beyond 3rd decade.

Therapy Androgens are helpful ion FA patients with mean age of survival being 17 years or 7 years following onset of aplasia, which is little better than no therapy. Around 50–75% of FA patients respond to androgens and it may take 6–12 months for peak response to occur.

Stem Cell Transplantation However, mainstay therapy is SCT which gives the only hope of long term survival. Due to inherent chromosomal instability, these patients are sensitive to radiation and chemotherapy used for conditioning. Accordingly low doses of cyclophosphamide should be used for better outcome. The success of bone marrow transplantation (BMT) is 78% with modified conditioning regime. One must screen the sibling donor to rule out occult FA.

Figure 11.4.4 Dyskeratosis congenital Courtesy: Dr MR Lokeshwar and Dr Nitin Shah

Complications Fanconi’s anemia patients are prone to develop malignancies 20% chances of leukemia mainly AML and liver cancers mainly due to androgens. Rare cancers include preleukemia, gynecological tumors, Wilms tumor, medulloblastoma, etc.

and is responsive to administration of G CSF. About 50% of patients have anemia, 70% have thrombocytopenia, and 10% have pancytopenia. Inheritance is thought to be autosomal recessive. There is a risk of about 5% for development of leukemia.

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ongenital megakaryocytic Thrombocytopenia

hwachman’s yndrome S

S

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A rare disorder with severe diminution in megakaryocytes in marrow, attributed to stem cell defect, occurs without associated physical defects or abnormal chromosome fragility. About 80% evolve, at a median age of about 3 years, into a plastic anemia.

Diamond Blackfan syndrome or constitutional chronic pure red cell aplasia is characterized by isolated erythroid hypoplasia occurring in early childhood, inherited as autosomal dominant or recessive condition. A variety of congenital abnormalities may be associated such as strabismus, webbed neck, deformed thumb, bony abnormalities of finger and ribs, double ureter with hydronephrosis, etc. Investigations suggest normochromic, macrocytic anemia with marked reticulocytopenia (Figs 11.4.5 and 11.4.6). Marrow aspiration characteristically discloses cellular marrow with profound erythroid hypoplasia with markedly increased M:E ratio. Fetal Hb is elevated in most cases as also I antigen on the red cell surface. Mainstay of treatment is transfusion therapy and corticosteroid. Hemosiderosis is unavoidable complication and may also eventually lead to portal hypertension and hyper­ splenism and hence chelation therapy and splenectomy may be required. Dose of steroid is 1–2 mg/kg of Predniso­ lone for 4–6 weeks and if unsuccessful, then may be discon­ tinued. Steroid therapy may have to be maintained to the minimal required dose for years. Successful SCT have been reported in patients’ refractory to above therapy and hav­ ing HLA identical sibling. Intravenous gammaglobulin have been found to be useful. In most of the patients carefully adjusted steroid therapy has been found successful. -

It is characterized by ectodermal dysplasia with changes in skin, nails, teeth and hair. Leukoplakia of squamous surfaces may produce stricture of hollow viscera (e.g. esophagus) and there is a risk of about 10% for malignancy. Growth retardation is common. Most cases are X linked recessive but some are autosomal recessive or dominant (Fig. 11.4.4). C

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Prognosis

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It is characterized by pancreatic insufficiency (fatty replacement), neutropenia, metaphyseal dyschondroplasia and growth retardation.

Neutropenia 688 It is intermittent rather than constant may be cyclic, though not with the same predictability as true cyclic neutropenia. The neutrophil count may rise with infection,

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1. Bhatnagar SK, Chandra J, Narayan S, et al. Pancytopenia in children: etiological profile. J Trop Pediatr. 2005;51(4):236-9. 2. Chandra J, Naithani R, Ravi R, et al. Antithymocyte globulin plus cyclosporin in children less than 12 years with acquired aplastic anemia. Br J Haematol. 2006;133 (suppl 1):118. 3. Davies JK, Guinan EC. An update on the management of severe aplastic anaemia in children. Br J Haematol. 2007;136(4):549-64. 4. Frickhofen N, Heimpel H, Kaltwasser JP, et al. Antithymocyte globulin with or without cyclosporin A: 11-year follow-up of a randomized trial comparing treatments of aplastic anemia. Blood. 2003;101(4):1236-42. 5. George B, Mathews V, Viswabandya A, et al. Fludarabine and cyclophosphamide based reduced intensity conditioning (RIC) regimens reduce rejection and improve outcome in Indian patients undergoing allogeneic stem cell transplantation for severe aplastic anemia. Bone Marrow Transplant. 2007;40(1):13-8. 6. Kutler DI, Singh B, Satagopan J, et al. A 20 year perspective on the International Fanconi Anemia Registry (IFAR). Blood. 2003;101(4):1249-56. 7. Marsh JC, Ball SE, Darbyshire P, et al. Guidelines for the diagnosis and management of acquired aplastic anaemia. Br J Haematol. 2003;123(5):782-801. 8. Marwaha RK, Bansal D, Trehan A, et al. Androgens in childhood acquired aplastic anemia in Chandigarh, India. Trop Doct. 2004;34(3):149-52. 9. Young NS, Calado RT, Scheinberg P. Current concepts in the pathophysiology and treatment of aplastic anemia. Blood. 2006;108(8):2509-19.

 

 

Figure 11.4.6 Diamond-Blackfan syndrome cellular marrow with profound erythroid hypoplasia. Courtesy: Dr MR Lokeshwar and Dr Nitin Shah

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Figure 11.4.5 Diamond-Blackfan syndrome Courtesy: Dr MR Lokeshwar and Dr Nitin Shah

ibliography

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Thalassemia yndromes

I

MR Lokeshwar the globin chain. It is characterized by decreased synthesis of one of the polypeptide chains (α or non-α) which form Hb molecule. The α gene is present on chromosome 16 and β gene represented on chromosome 11. Thalassemia is classified depending on the deficiency of type of globin chain of Hb. In α-thalassemia, α chain synthesis is affected. They are classified into four different categories depending upon the number of genes affected (Table 11.5.1). In β-thalassemia, β chain is involved. If β chain is absent, it is termed as β0 thalassemia, if partially produced then β+ thalassemia (Table 11.5.2).

ntroduction



The hemoglobin consists of two pairs of amino acid chains: a pair of a chains and non-a chains. Adult hemoglobin (HbA) consists of two pairs of a chains and two pairs of β chains (α2β2). Fetal Hb is constituted by of two pairs of a chains and two pairs of γ chains (α2γ2). HbA2 is constituted by two pairs of a chains and two pairs of δ chains (α2δ2). Deficiency or abnormalities in any of the Hb chains leads to thalassemia syndromes or abnormal hemoglobinopathies. They encompass a group of autosomal recessive inherited heterogeneous group of single gene disorders affecting Hb chain synthesis.



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Historical eview

Thalassemia is inherited as an autosomal recessive disease. There is 25% chance that children born in each pregnancy will develop thalassemia major. However, it is not unusual to see consecutive children being born with thalassemia major, emphasizing 25% chance in each pregnancy (Figs 11.5.1A and B). E

The disease was first described by Thomas B Cooley and Pearl Lee in 1925; hence was known as “Cooley’s anemia”. Whipple and Bradford first used the term “Thalassemia” in 1932, “thalassa” in Greek meaning “sea” and “-emia”, meaning anemia around the sea. It was also known as “Mediterranean anemia” as it was described around Mediterranean countries. In India the first case of thalassemia was described by Dr M Mukherji from Kolkata. C

nheritance

pidemiology

Recent data indicate that about 7% of the world population is carrier of Hb disorders. Around 300,000–500,000 children are born each year with severe homozygous state of these diseases. Thalassemia belt stretches across African continent,

lassification

Thalassemia is caused by a defect/reduction in Hb chain synthesis due to various mutations of genes which code for

 

Table 11.5.1 Classification of α-thalassemia syndromes Clinical features

Hemoglobin pattern

Number of α globin genes affected

Silent carrier

No anemia, normal red cells

1–2% Hb Bart’s (4g) at birth

1



Syndrome

α-thalassemia trait

Mild anemia, hypochromic microcytic red cells

5–10% Hb Bart’s (4g) at birth

2

Hemoglobin H (HbH) disease

Moderate hypochromic, microcytic anemia

5–30% HbH (4b) red cells

3

Hydrops fetalis

Death in utero caused by severe anemia

Mainly Hb Bart’s, small amount of HbH

4

 

Table 11.5.2 Classification of ß-thalassemia

690

Syndrome

Clinical features

Hemoglobin pattern

ß globin genes affected

Silent carrier

Asymptomatic, no anemia, normal

Normal, diagnosed by chain synthesis

Heterozygous state

Thalassemia trait

Mild anemia, hypochromic microcytic red cells

Elevated HbA2 > 3.4%

Heterozygous state

Thalassemia intermedia

Moderate; not dependent on blood transfusion for their survival. May require some transfusion

HbF elevated

Homozygous state

Thalassemia major

Dependent on blood transfusion for their survival. Requires regular transfusion

HbF markedly elevated

Homozygous state

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Figures 11.5.1A and B Inheritance of thalassemia major: 25% inheritance means 25% in each pregnancy. All the above three children are thalassemia major Courtesy: Anupam Sachdeva, MR Lokeshwar and Mamta Manglani

Pathophysiology of ß-Thalassemia



Excess a chains that have no complementary non-a chains with which to pair form insoluble inclusions that precipitate on red cell membrane and damage it leading to premature destruction of RBC in BM and peripheral circulation particularly reticuloendothelial system of spleen (ineffective erythropoiesis) resulting in persistent progressive anemia (Flow chart 11.5.1). Due to reduced production of adult Hb in postnatal life, the normal switch mechanism leading to reduction in

 

Flow chart 11.5.1 Pathophysiology of thalassemia





Mediterranean regions, Middle East, Indian subcontinent, Southeast Asia, Southern China and Melanesia (Fig. 11.5.2). The prevalence of thalassemia and falciparum malaria was similar, suggesting that nature developed genetic mutation to overcome mortality and morbidity of malaria. However, population migration has not restricted the gene frequency to above tropical areas, and hence seen all over the world. In India, prevalence of the b gene varies from 1% to 17%. It is estimated that 8,000–10,000 children are born with thalassemia major every year in India. There are around 65,000–67,000 thalassemia patients in our country, at any given time. Thalassemia incidence varies in various communities, religions and ethnic groups in India. A higher frequency is noted in certain communities such as in Sindhis and Punjabis, Khatris, Kukreja’s in North India, Bhanushalis, Kutchis, Lohanas in Gujarat, Mahars, Chamars, Buddhas, Navabudhas, Kolies, Agris, Kunbies from Maharashtra, Reddies, Gowdas, Lingayats, Kurgs from South India, and Goud Saraswats from Goa.

691  

Figure 11.5.2 Thalassemia belt

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For detection of hemoglobinopathies and thalassemia, it is advisable to correlate clinical profile and ethnicity of the individuals, with the blood count and blood film, and do further investigations to confirm the diagnosis. C

omplete lood ounts

This includes red cell indices, PBF examination and reticulocyte count. Complete blood count is frequently sufficient to postulate the diagnosis of thalassemia.

a

B

Figures 11.5.4A and B Characteristic features of thalassemia major. (A) Occipital bossing; (B) Malar prominence and malocclusion of teeth. Courtesy: Dr MR Lokeshwar and Dr Mamta Manglani  

a

Figures 11.5.3A and B Hepatosplenomegaly in thalassemia intermedia Courtesy: Dr MR Lokeshwar and Dr Mamta Manglani  

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B



Severe b thalassemia usually manifests in the 1st year of life when the fetal Hb declines. In India many children born with thalassemia major die undiagnosed, due to lack of investigation facilities and treatment. The spectrum of clinical manifestation of β thalassemia varies widely. One end of the spectrum is the serious homozygous form (thalassemia major) that presents in early infancy (6– 18 months) with gradually increasing pallor, poor feeding, failure to thrive, irritability, fatigability, intercurrent infections and develops hepatosplenomegaly (Figs 11.5.3A and B). Affected children initially grow well for initial few months (2–4 months). No anemia is observed during newborn period. If undiagnosed and untreated, more than 90% do not survive beyond 3–4 years of age without transfusions. Untreated or irregularly treated children develop significant hemolytic facies including fronto-parietal bossing with a hot-crossbun appearance of the skull (caput quadratum), depressed bridge of nose, malar prominence and malocclusion of teeth with protrusion of maxillary teeth (Figs 11.5.4A and B). These

D

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linical Manifestation and iagnosis of Thalassemia

changes can be observed on X-rays of skull as “hairs on end” appearance and osteopenia and osteoporosis of the long bones (Figs 11.5.5A to C). Siderosis iron overload follows in various endocrine glands—pituitary, thyroid, parathyroids—as well as pancreas and heart. As a result the child develops various secondary endocrine problems (growth retardation, delayed or absent puberty), diabetes mellitus and cardiac complications (congestive failure, intractable arrhythmias). In older children liver and spleen may be enlarged due to extramedullary erythropoiesis and hemosiderosis and may develop hypersplenism). Unless supported by regular transfusions, severe and progressive anemia and retardation of growth and development are the rule. Other end of the spectrum is the heterozygous form (thalassemia minor) where children can lead relatively normal life except for mild persistent anemia not responding to hematinics, and have normal life span. They can pass on their genes to their siblings. Occasionally some of them may not even have elevated HbA2 and are termed as silent gene carriers. In between these two extremes, there are forms with varying degree of clinical manifestations of anemia, hepatosplenomegaly, and bone changes. They also maintain their life fairly comfortably and are not dependent on blood transfusions for their survival and are called as thalassemia intermedia and are homozygous.

C



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γ chain synthesis does not occur. In β thalassemia, γ chain synthesis persists after fetal life. This leads to higher HbF in postnatal life. Higher fetal Hb has high affinity for oxygen which leads to tissue hypoxia. This in turn stimulates production of erythropoietin leading to both medullary and extramedullary erythropoiesis resulting in expansion of BM spaces producing characteristic hemolytic facies—frontalparietal and occipital bossing, malar prominence and malocclusion of teeth—along with distortion and osteoporosis of ribs, vertebrae, pathological fracture of long bones, splenomegaly with its complications (hypersplenism), hepatomegaly, gallstones and chronic leg ulcers. More than 200 mutations have been described in patients with b thalassemia. The common mutations responsible for more than 90% of thalassemia mutations in our country include 619 bp deletion, IVS 1-5 (G-C), IVS11(G-T), FS8/9(+G), and FS 41/42 (-CTTT).

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Figures 11.5.5A to C Thalassemia major: Skull X-ray showing “hairs on end” appearance and osteopenia and osteoporosis of the bone. Courtesy: Dr MR Lokeshwar and Dr Mamta Manglani

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is the objective documentation of subjective anisocytosis (Normal range 11.5–14.5%). It is normal in thalassemia trait and anemia of chronic infection, and increased in IDA.

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ther nvestigations that Help in iagnosis of Thalassemia I

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In thalassemia minor, high red cell count relative to Hb concentration and hematocrit are seen. In IDA there is marked fall in RBC count, MCV and mean cell Hb. RDW is normal in thalassemia minor, increased in IDA.

Naked Eye Single Tube Red Cell Osmotic Fragility Test









Peripheral blood film (ps) examination is diagnostic and has a characteristic bizarre picture with microcytic, hypochromic red cells with striking numbers of normoblasts. Additionally, there may be target cells, macrocytosis, poikilocytosis, polychromasia, moderate basophilic stippling, cabot rings and fragmented erythrocytes (Figs 11.5.6A to C). Reticulocyte count ranges from 2% to 4%. It is characteristically low (often < 1%) in thalassemia major due to severe significant ineffective erythropoiesis in the BM, whereas in thalassemia intermedia, it may be elevated to 3–6% due to less severe ineffective erythropoiesis. Normoblasts are increased on peripheral smear. Mean corpuscular volume is reduced in both IDA as well as thalassemia minor. Red cell distribution width is the coefficient of variation of red cell volume distribution. Red cell distribution width

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Figures 11.5.6A to C Peripheral blood smears: bizarre picture with microcytic, hypochromic red cells, reticulocytosis with striking numbers of normoblasts

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ellulous acetate electrophoresis: Quantitation of HbA2 is the gold standard for the diagnosis of thalassemia trait and confirmatory investigation for the diagnosis of thalassemia syndrome. Hemoglobin electrophoresis in non-transfused patients with thalassemia major shows HbF 20–100% and 2–7% of HbA2 and HbA 0–80% depending upon genotype. Thalassemia minor is characterized by elevated HbA2 more than 3.4% (Figs 11.5.7A and B) • ther methods: Isoelectric focusing, microcolumnchromatography, automated high performance liquid chromatography (HPLC) and Biorad variant machine.

 

Figures 11.5.7A and B Elevated HbA2. (A) Paper electrophoresis; (B) Cellulose acetate electrophoresis. Courtesy: Dr MR Lokeshwar and Dr Ajit C Gorakshakar

It is not only necessary to suspect thalassemia and confirm the diagnosis, but also important to anticipate complications due to iron overload/blood transfusion involving various organs.

Principles of Therapy

Transfusion Therapy in Thalassemia Packed Red Cell Transfusions • • • •

To obviate anemia Reduces hepatosplenomegaly by reducing ineffective erythropoiesis Reduces hemolytic facies Improves tissue oxygenation and improves growth.

Types of Transfusion •

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Management of thalassemia major should be preferably done at a comprehensive thalassemia care center with outdoor transfusion facilities. A team approach includes pediatric hematologist, pediatrician, blood transfusion specialist, endocrinologist, psychologist and social worker. Management of thalassemia major should include: • Correction of anemia—packed red cell transfusions • Management of complications of blood transfusions • Management of transfusion transmitted diseases— Hepatitis B, hepatitis C, HIV, malaria, CMV, Yersinia • Removal of excess iron—Chelation therapy • Management of endocrine and cardiac complications: – Curative treatment—BMT/SCT – Hypersplenism—role of splenectomy – Management of other complications—gall stones/ anemia/hypoxia/leg ulcers – Pharmacological methods to increase gamma chain synthesis • Future treatment—Gene replacement therapy intra­ uterine BMT 694 • Prevention of disease by antenatal diagnosis and genetic counseling.

orrection of nemia

Palliative transfusion: Aimed at maintaining the Hb at 8.5 g/dL. This leads to improved survival, but the chronic illness, bone disease and cardiomyopathy persist Hypertransfusion: Maintaining the Hb above a minimum of 10 g/dL Normotransfusion: Promotes normal growth and development, prevents the onset of severe hepatos plenomegaly and hemolytic facies, lowers the absorption of gastrointestinal iron and reduces the anemia/ cardiomyopathy changes upertransfusion: Maintain pretransfusion Hb of above 12 g/dL. However this is not significantly superior to hypertransfusion and given up Moderate transfusion: In Europe, a newer regimen has been adopted and recommended by the Thalassemia International Federation. In this regimen, pretransfusion Hb is maintained between 9 g/dL and 10.5 g/dL. ­

Management of Thalassemia Major

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Measurement of HbA2



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erum iron and transferrin saturation: Decreased in IDA; increased/normal in thalassemia depending upon iron overload erum total iron binding capacity: Increased in IDA and normal in thalassemia and anemia of chronic infection erum ferritin: Decreased in IDA whereas increased in thalassemia and is proportionate to iron overload and increased in infection smotic fragility: Reduced fragility ther methods of iron estimation: Liver iron concentration (keep level below 7 mg/g of liver; levels above 15 mg/g is associated with cardiac problems), SQUID, MRI and urine iron content one marrow examination: This is not required for diagnosis. It shows normoblastic erythroid hyperplasia and iron staining of BM shows increased store of iron in the form of hemosiderin in thalassemia. B

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Iron overload is due to: • Treatment with multiple transfusions—a bottle of blood transfusion given adds 200–250 mg of iron to the body store • Ineffective erythropoiesis leading to excessive dietary absorption of iron from gut • Lack of physiologic excretory mechanisms for the removal of excess iron from the body. Iron overload leads to damage of various organs as shown below: • Liver damage starting at 2 years; fibrosis of liver at 10 years and earlier. If hepatitis B and C infection are present • Cardiac damage at about 10 years’ age and overt failure at about 15 years • Delayed pubertal development due to iron deposition in pituitary • Diabetes mellitus • Damage to thyroid and parathyroid glands. C

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Approximately 180 m /kg of red cells are required to be transfused per year in non-splenectomized, non-sensitized patients to maintain the Hb above 10 g/dL, whereas splenectomized patients require 133 m /kg/year. Even without hypersplenism, the requirement is 30% higher in non-splenectomized patients. The red cells should be transfused at the rate of 3–4 ml/ kg/hour, every 2–4 weeks to maintain the Hb above 10 g/ dL. Patients with cardiac decompensation should be given red cells at the rate of not more than 1–2 m /kg/hour.

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It is ideal to use leukodepletion filters at bedside. It is not affordable to most patients. The best alternative is use of triple saline washed red cells. The red cells should be fresh, not more than 4–5 days old. Various other methods of leukodepletion include use of frozen red cells, filtration in the blood bank or at bed side, and use of apheresis (Fig. 11.5.8).

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Leukodepletion Filters at Bedside

The advantages include: • Transfusions are given on an OPD basis and hence no hospitalization is required • Children are more comfortable with the familiar staff members • There is less school absenteeism and parents lose fewer workdays • When the patient is hospitalized and transfused in the ward of the hospital, the average expenditure is about Rs 790/patient/day compared to Rs 180/patient/day when treated on an outdoor basis • There is threat of contacting infections from other patients in the wards • Parents and children are happy to be with other children and parents who share the same feelings.





The diagnosis of thalassemia intermedia can be ascertained by observing the rate of fall of Hb without transfusions. If the Hb drops to below 7 g/dL without transfusion, in the absence of any concurrent illness, it is imperative to put the child on a regular transfusion program. It is important to know the compete genotype of the red cells to prevent red cell alloimmunization. The alternative to this is Coomb’s crossmatch for each transfusion to prevent alloimmunization. The most ideal way to transfuse thalassemics is by using group and type specific packed red cells that are compatible by direct antiglobulin test (DAT).

utdoor Transfusion enter

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Initiation of Transfusion Therapy

helation Therapy



The goal is to reduce the iron store and maintain at low ferritin level (< 2,500 ng/mL). The optimal time to start chelation therapy: • Serum ferritin level 1–2,000 ng/mL or above • Receiving more than 15–20 transfusions • Hepatic iron concentration greater than 3.2 mg/g dry weight.

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Though several hundred compounds have been developed and tried, desferrioxamine (DFO) is the gold standard therapy. It is the most effective and safe iron chelator.

 

Figure 11.5.8 Leukocyte filter

esferrioxamine

This is a hexadentate chelator. About 1 g will bind 93 mg of iron. It cannot easily mobilize iron from intracellular

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Deferiprone is a water soluble bidentate chelator. It mobilizes iron from transferrin, ferritin and hemosiderin. Results show that it is 70–100% as effective as DFO and is less expensive. • ose: 75–100 mg/kg /day in 2–3 divided doses • Toxicity: No evidence of ear or eye toxicity. Kidney and liver parameters do not show any alteration. A few children develop GI symptoms like nausea, vomiting, pain in abdomen and diarrhea. Around 20–30% children had arthropathy, which is reversible after reducing the dose or on stopping deferiprone. Antinuclear antibody, double stranded DNA antihistone antibodies may be positive in a few cases. Absolute neutropenia and thrombocytopenia also have been reported in occasional cases • aution: Physical examination particularly of the joints and complete blood count including platelet count must be done regularly. E

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Deferasirox is a new-class tridentate chelator with a high specificity for iron and is an orally active chelating agent. It is twice as effective as subcutaneous DFO. • ction: It mobilizes iron from both the hepatocellular and reticuloendothelial source. It prevents myocardial cell iron uptake and removes iron directly from myocardial cells. In liver, it removes iron from the intracellular labile iron pool, and from the surface of reticuloendothelial cells at the location where iron is handed over to transferrin A

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ocal reactions: Local pain, redness, indurations, erythema may appear at the site of injection and hence it is important to rotate the site of injection Visual abnormalities: Decreased acuity of vision, peripheral field vision defects, defective dark adaptation and cataracts Hearing: High frequency sensory-neural hearing loss Growth retardation and slowed growth: Delayed linear growth, may be seen in children less than 3 years of age treated with DFO and may be accompanied by L

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mild skeletal abnormalities such as short trunk, sternal protrusion and genu valgum aution: As the auditory and visual toxicity is reversible, regular slit-lamp eye examination and audiometric evaluation (Brain evoked response audiometry) is recommended annually. ontinuous intravenous infusion: Continuous intra venous infusion significantly enhances iron excretion, presumably due to exchange between DFO and tissue iron pools. ndications: Children with very high levels of ferritin, cardiac complications, during pregnancy, prior to BMT, and persistent local reaction at injection site ose: For intravenous DFO is 50–100 mg/kg body weight. Given for severe iron load with cardiac involvement and for IV therapy: ral chelating compounds: Though DFO is a gold standard in the management of iron overload in thalassemia major; it has not become popular particularly in the developing countries. The high cost of DFO and the need for continuous subcutaneous injection over 6–8 hours, poor compliance, particularly in the adolescent group has prompted the need for simpler oral chelators. O

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compartment due to its high molecular weight. Other disadvantages include: • Desferrioxamine cannot be given orally. Given for severe iron load and cardiac involvement DFO slowly binds iron to form ferrioxamine. • Desferrioxamine does not bind with iron from trans­ ferrin. • It has a short half life of 5–10 minutes • For routine use DFO has to be given as a continuous subcutaneous infusion with the help of a pump in a dose of 20–40 mg/kg/day (not to exceed more than 100 mg/kg) over 8–10 hours for 5–6 nights a week (Figs 11.5.9A and B) • Giving DFO only during transfusion is not recommended and it should never be added directly to the blood unit. Vitamin C helps convert Fe+++ to Fe++ which is chelatable and thus increases the iron excretion. It is recommended in a dose not more than 2–3 mg/kg/day; 50 mg for children less than 10 years; and 100 mg greater than 10 years. Do not increase greater than 200 mg. • Toxicity of desferrioxamine: Desferrioxamine has minimal side effects. When given parenterally, there may be liberation of histamine leading to bradycardia, hypo/hypertension, rigors, headache, photophobia, feeling cold and hot, etc.

B Figures 11.5.9A and B Desferal subcutaneous pump  

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erum ferritin: It is prudent to maintain values of less than 2,000 ng/mL. However, serum level of ferritin can be affected by various factors like inflammation, ascorbate status and hepatitis. Liver iron concentration of less than 7 mg/g dry weight of liver is associated with reduced cardiac or liver complications. MRI and SQUID can also measure liver iron concentration noninvasively. But these technologies are less widely available.

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Splenectomy should be considered when: • Annual blood requirement exceeds 1.5 times the basal requirement for a patient maintaining pretransfusion Hb about 10 g/dL (Transfusion requirement increases to more than 200–220 m /kg/year of packed red cells) • Massive spleen enlargement posing a risk of splenic rupture or when splenic enlargement is associated with left upper quadrant pain or early satiety • Presence of leukopenia or thrombocytopenia • Splenectomy should be delayed till the patient is 5 years of age as there is a risk of overwhelming sepsis below this age. Prophylaxis: All patients undergoing splenectomy should receive immunization to protect against capsulated organisms. These include pneumococcal, Hib, mening ococcal vaccines, Salmonella typhi, which should be given at least 4 weeks before surgery. Lifelong post-splenectomy penicillin prophylaxis 125 mg twice a day for children up to 2 years and 250 mg twice a day for children 2 years and above is recommended. Chemoprophylaxis is recommended for at least 2 years while some advocate this for whole life. In the presence of early signs of infection treatment should be started immediately with broad-spectrum antibiotics without waiting for the result of laboratory tests. Post-splenectomy, there may be transient or persistent thrombocytosis. Aspirin 50–100 mg/day is recommended for patients whose platelet count exceeds 800,000/mm3. C

ardiac omplications

Iron overload causes deposition of iron in the ventricular walls, mainly in the left, relatively sparing the atria and the conduction system. Cardiac failure and ventricular arrhythmias are the main cause of death in patients with ß-thalassemia major. Other complications include decrease in left ventricular ejection fraction, overt cardiomyopathy left atrial dilatation and aortic root dilatation. Early detection of cardiac involvement is done by evaluation of ferritin level regularly along with cardiac function tests such as ECG, 2D echocardiogram, stress test and Holter monitoring. T2 cardiac MRI is the only method of accessing accurately the severity of cardiac iron overloading. Deferiprone/L1 has better protective effect on myo cardial tissue. Continuous subcutaneous/intravenous high dose DFO can reverse the ventricular dysfunction and can improve progressive heart failure and complicated arrhythmias. ­

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The huttle hypothesis: Combination therapy have been tried to bring down the cost, improve the compliance, increase the efficacy of the chelation therapy and to reduce the side effects. Combination of deferasirox and DFO has additive and synergistic effect. Deferasirox acts as intracellular chelator and DFO acts as powerful extracellular chelator. A bidentate (L1) or a tridentate ligand with access to a variety of tissues acts as a “shuttle” to mobilize the iron from tissue compartments to the bloodstream, where most exchanges with a larger hexadentate (DFO) “sink”. The sink binds this iron irreversibly, promoting its excretion. Combination therapy is more effective with HBED and L1; ICL670A and DFO also have been successfully tried. Oral deferiprone 75 mg/kg/day for 4–5 days during weekdays and DFO 40–50 mg/kg/day subcutaneously on weekends (2 days) is a good acceptable regimen. olic acid: Folic acid (1 mg/day) should be given to nontransfused or low-transfused patients because they have increased folate consumption and may develop folic acid deficiency.

Splenectomy



Combination Therapy

Hypersplenism may occur due to inadequate transfusions, alloimmunization and rarely autoimmune hemolysis complicating thalassemia major and chronic liver disease.

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Various other drugs under trial include desferrithiocin, hydroxybenzyl-ethylenediamine-diacetic acid (HBED), NaHBED, and pyridoxal isonicotinoyl hydrazone.

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Management of omplications



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Metabolism: The plasma half-life (11–19 hours) supports the once daily oral dosing regimen. Excretion is mainly via feces and is dose-dependent ose and administration: It is available as dispersible tablets containing 125, 250 and 500 mg. Dose are 20–80 mg/kg. Oral bioavailability is as high as 100% in 10 mg/ kg dose. It is to be taken on empty stomach at least 30 minutes before food, preferably at the same time each day. The tablets are to be dispersed in water, orange juice or apple juice prior to administration ide effects: It is neither mutagenic (teratogenic), nor carcinogenic. Side effects include skin rashes and pigmentation, gastrointestinal disturbances (abdominal pain, diarrhea, nausea, vomiting, and constipation), hearing loss, nephropathy and transient asymptomatic increase of liver enzymes.

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Osteopenia and osteoporosis are major causes of morbidity in aging thalassemic population more in women. Osteoporosis as defined by WHO is a “progressive systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with consequent increase in bone fragility and susceptibility to fracture”. This can be diagnosed by DEXA scan for bone density and biochemical studies of serum calcium, inorganic phosphate, alkaline phosphatase, urinary calcium/creatinine ratio (> 0.2) and urinary phosphorus/creatinine ratio (> 0.6).

Treatment of Osteopenia and Osteoporosis

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Leg ulcers are more common in thalassemia intermedia and thalassemia minor. Bed rest, regular transfusions and wound care are adequate. Local infiltration of growth factors such as G-CSF has been found useful.

Gall tones S

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Pharmacologic Manipulation of etal Hemoglobin Drugs like hydroxyurea, butyrate, 5-azacytidine and erythropoietin have been tried to induce HbF production with varying success. Hydroxyurea has been found to be useful particularly in thalassemia intermedia, double heterozygotes and sickle cell disease.

Gene Therapy Gene therapy is an exciting prospect for thalassemic children. Aim of therapy is addition of a normal copy of the human beta-gene along with key regulatory sequences into lentivirus vectors, a group of retroviruses. These are still experimental and hopefully will become available in near future.

Prevention of Thalassemia

Gall stones are more commonly seen in children receiving irregular treatment as well as in thalassemia minor. In

Not even 5–10% of thalassemic children born in India receive optimal treatment. Cost of treatment of a 4-year-old thalassemic child is around Rs 100,000 annually. Bone marrow transplantation as a curative treatment is out of reach for majority of children which costs around ` 10,00,000 (1 million). The birth of thalassemic child places considerable strain not only on affected child and family but on society at large. Therefore there is emphasis for shift from treatment to prevention of birth of such children in future.

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Hormone replacement therapy Calcitonin inhibitor of osteoclasts Hydroxyurea, bisphosphonates and IV Pamidronate— other modalities. Moderate and high impact activities—walking, ballet dancing, aerobics jogging, etc. Diet, rich in Calcium and Vitamin D Hormone replacement therapy for endocrine abnormalities.

uture Perspectives

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tem ell Transplantation

This is only the curative therapy available today for thalassemia major. The sources for stem cells include BM, cord blood, peripheral blood and fetal liver. Though expensive, it is cost effective as compared to yearly cost of regular packed red cell transfusions. Stem cell transplantation costs around ` 8–10 lakhs. Umbilical cord stem cells have good results in most centers. Lower GVHD and longer engraftment have been reported. However, some have found higher early morbidity. Bone marrow transplantation in utero at 16–18 weeks of gestation is under research at present. It is believed that there would be no rejection with this procedure as the immune system would not have developed at that time. Mother’s purified stem cells can be used.

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urative Treatment

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Hepatic ysfunction

asymptomatic cases no active treatment is required. However they may be removed along with splenectomy (if splenectomy is indicated).

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The commonly affected endocrine glands include pituitary, pancreas, thyroid, parathyroid glands and gonads. Clinically, they may remain latent. Hence investigations should be done in all thalassemic children from time to time to detect these disorders and treat them appropriately. • Short stature is commonly noted at 10–11 years of age • Diabetes may be seen as early as 5 years of age and particularly seen in adolescent children • Dysfunction of thyroid and parathyroid glands may be subclinical initially. Glucose tolerance test, thyroid functions particularly T4 and TSH, serum calcium, phosphorus and alkaline phosphatase should be done frequently if possible every year, beginning at the age of 5 years. Height, weight, growth, velocity, cardiac workup, endocrine study and bone studies evaluation are required from 10 years of age onward. This helps in early detection and better management.

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The various strategies for career screening include the following: • Population education • Mass screening—Screening of target population • Genetic counseling of “minor” couples • Prenatal diagnosis of thalassemia.

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ibliography

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Most thalassemic children and their families expect to reach the age of puberty, with normal growth and development. Growth failure and pubertal delay and fertility represent major obstacles to the fulfillment of these hopes. They also expect same attainment as those of their healthy peers— in education, employment and a well-adjusted social and sexual life. Until last few decades thalassemia was regarded as uniformly fatal disease and death was expected during the 2nd decade of life before adulthood. However, progress in the understanding and management of the disease has brought brighter prospects of survival extending into 3rd and 4th decades of life provided they receive the latest treatment with good compliance. This has opened a new chapter in the management of thalassemia beyond blood transfusion and chelation therapy. The advent of advanced technology, with better management modalities and facilities, have metamor



uture Prospects

1. Agarwal MB. ICL 670: a new oral chelator: a major breakthrough in treatment of Thalassemia. Indian J Hematol Blood Transfusion. 2003;31:26-8. 2. Anderson LJ, Wonke B, Prescott E, et al. Comparison of effects of oral deferiprone and subcutaneous desferrioxamine on myocardial iron concentrations and ventricular function in beta-thalassemia. Lancet. 2002;360(9332):516-20. 3. Colah RB, Mohanty D. Beta-thalassemia: expression, molecular mechanisms and mutations in Indians. Indian J Pediatr. 1998;65(6):815-23. 4. Giardina PJ, Grady RW. Chelation therapy in b-thalassemia: an optimistic update. Semin Hematol. 2001;38(4):360-6. 5. Lokeshwar MR, Shah N, Kanika S, Manglani M. IAP textbook of paediatrics, 3rd edition. New Delhi: Jaypee Publishers; 2006. 622-30. 6. Manglani M, Lokeshwar MR, Vani VG, et al. ‘T’: an effective screening test for b-Thalassemia trait. Indian Pediatr. 1997;34(8):703-8. 7. Orkin SH, Nathan DG. Thalassemia in Nathan and Oski’s hematology of infancy and childhood. In: Nathan DG, Orkin Sh, Ginsburg D, Look AT, 6th edition. Philadelphia: WB sunders Co; 2003. pp. 842-919. 8. Vaz FE, Thakur CB, Banerjee MK, et al. Distribution of betathalassemia mutations in the Indian population referred to a diagnostic center. Hemoglobin. 2000;24(3):181-94. 9. Weatherall DJ, Clegg JB. The Thalassemia Syndromes. 4th edition. Oxford: Blackwell Scientific Publications; 2001. 10. Wonke B. Clinical Management of b-thalassemia major. Semin Hematol. 2001;38(4):350-9.

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The incidence of misdiagnosis in prenatal testing is less than 1%. The reasons for failure include technical failure to amplify target DNA fragment, doubtful paternity, maternal contamination of samples and sample exchange. Both preimplantation diagnosis and preconception diagnosis are available especially for couples who do not wish to undergo MTP. However, the procedures are technically demanding, difficult to organize and involve enormous cost.



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Prenatal iagnosis of Thalassemia

phosed thalassemia major from a fatal to a preventable, manageable as well as a curable disease.

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Methods used for screening include measurement of RBC indices, Naked eye single tube red cell osmotic fragility test, HPLC analysis of Hb and genetic counseling.

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ickle ell isease

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Sickle cell disease (SCD) is a term used for a group of genetic disorders characterized by production of Hb “S”. Sickle cell hemoglobinopathy occurs due to mutation of beta-globin gene situated on short arm of chromosome 11, where adenine is replaced by thymine in base of DNA coding for the amino acid in the sixth position in beta-globin chain. This leads to an amino acid change in beta chain of Hb molecule, from glutamic acid to valine. The result is profound change in the molecular stability and solubility of Hb “S”. Minor variations in noncoding nucleotide sequences of gene are also seen. These polymorphic variations are called haplotypes, responsible for variability in presentation of SCD in different parts of world (Fig. 11.6.1). Four such haplotypes have been found. Arab-Indian haplotype is found in Eastern Saudi Arabia and Indian subcontinent. Benin haplotype, Bantu haplotype is prevalent in Africa, Mediterranean countries, Northern and Southern American countries. Senegal haplotype is prevalent in Africa. Sickle cell disease includes several distinct genotypes more commonly seen. I

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Homozygous sickle cell disease (SS) Sickle cell anemia, heterozygous form (AS) Sickle-beta thalassemia (SB0).

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Prevalence of ickle ell isease in ndia

Less commonly seen forms are: • SD Punjab disease, SO Arab disease • Sickle E syndrome • Sickle α-thalassemia

The “sol” (soluble) form of Hb changes to “gel” form, when Hb “S” is deoxygenated. In gel form the Hb crystallizes to small, rigid, boat-shaped objects known as ‘’tactoids’’. These tactoids polymerize forming insoluble structure, deforming the RBC to sickle shape. The RBC membrane becomes more fragile. The polymerization is facilitated by increased concentration of Hb “S”, acidic pH, low oxygen saturation, stasis of blood flow, decreased levels of Hb”F” Upon reoxygenation the sickle cell initially resumes normal configuration, but with repeated cycles of sickling and unsickling, fixation of membrane occurs in sickled configuration, leading to irreversible sickle cell formation, and hemolysis. This hemolysis is responsible for anemia In SCD the red cells have increased adherence to endothelium The red cells assume sickle shape after deoxygenation and damage the endothelial cells leading to subendothelial infiltration and narrowing of the vessels Platelets aggregate over the adherent red cells and damaged endothelium, causing blockage of microvasculature and ischemia of the tissue.

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Figure 11.6.1 Gene frequency of sickle disease in various parts of India

Occurs due to obstruction to microvascular circulation. Obstruction of capillaries of BM causes ischemic necrosis and death of BM, and initiates inflammatory response, increasing intramedullary pressure Clinically there is swelling over the affected bones with severe pain and tenderness In younger children, this process is most marked in small bones of hands and feet, causing “Hand-foot syndrome” or dactylitis (Fig. 11.6.2). Hand-foot syndrome disappears coincidently with physiological regression of active BM from the small bones of hands and feet in children above 5 years the pain distribution reflects articular areas of long bones.

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Figure 11.6.2 Hand-foot syndrome or dactylitis

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Stroke occurs in 6–17% patients in Benin and Bantu haplotypes. In our series we have found it to be 2.5%. This could be due to high Hb”F” levels in our Arab-Asian haplotype. Common age group is 3–10 years. Around 70–90% patients experience repeated episode of stroke within 36 months unless they are on transfusion regimen maintaining Hb”S” level below 30%.

Avascular Necrosis Avascular necrosis of bone occur secondary to vasoocclusion of nutrient artery. Femoral head, humerus, upper-third of tibia can be affected, but weight bearing makes femoral head necrosis more likely to cause severe disability.

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Priapism is persistent painful penile erection (Figs 11.6.4 and 11.6.5). Recurrent acute episodic attacks last from few minutes to several hours. It usually subsides spontaneously. Impotency may be a sequel. Blood transfusion is indicated if pain, engorgement persists for 24–48 hours.

Painful Abdominal Crisis Painful abdominal crisis occurs due to localized areas of bowel dysfunction due to vaso-occlusion (Fig. 11.6.3). There is severe abdominal pain and signs of peritoneal irritation. Persistence of bowel sound differentiates its acute abdomen from requiring surgical exploration. It usually resolves in a period of 3–5 days. The management consists of bowel rest, maintenance of hydration by intravenous fluids.

Acute Chest Syndrome It occurs due to vaso-occlusion of pulmonary vessels leading to infarction and pulmonary sequestration. Superadded infection complicates the issue.

 

Figure 11.6.4 Priapism. Courtesy: MR Lokeshwar and Vibhawari Dani

 

Figure 11.6.5 Deformed sickle shaped red cells in peripheral smear

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Figure 11.6.3 Painful abdominal crisis due to vaso-occlusion

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Treatment of Painful risis C

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The event is characterized by sudden trapping of large amount of blood in spleen or less commonly in liver. These patients present with profound anemia and shock. Enormously enlarged spleen fills the abdomen. Dramatic regression of splenomegaly and increase in Hb level occurs with prompt correction of hypovolemia and blood transfusion. Splenic dysfunction occurs due to obstruction of sinusoidal blood flow, causing diversion of blood through intrasplenic shunts, bypassing phagocytic reticuloendothelial element of the spleen. Children with palpable spleen at 6 months of age are at high risk of pneumococcal septicemia.

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Gallstones—only symptomatic gallstones should be subjected to surgery enal involvement: Hyposthenuria is common. Hema turia occurs due to ischemia of renal medulla and necrosis of papillary tip. Nephrotic syndrome is known complication Somatic and sexual growth is delayed in SCD. Age of menarche is delayed by 2.5 years. Zinc deficiency has been suggested as a cause for poor growth. In our study, we have observed that zinc supplementation augments sexual growth but does not affect somatic growth. R

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It occurs due to sudden arrest of erythropoiesis due to folate depletion. Chronic erythroid hyperplasia drains the folate reserve and folate deficiency occurs. The Hb level can drop to 2–3 g/d . Treatment is by oral folate supplementation.

Prevention •

Exposure to hypoxia, dehydration, extreme cold, extreme heat, change in altitude, infections are precipitating factors for crisis • Dehydration and loss of electrolytes may lead to red cell dehydration precipitating sickling process. Fluid requirement is usually increased by 50% of the usual requirement • Parent’s education for recognizing specific complication at the earliest, should be done • Immunization with: Newer pneumococcal vaccine at age of 6 weeks, 10 weeks, 14 weeks, booster at 18 months. Influenzae (Hib) vaccine 6 weeks, 10 weeks, 14 weeks, booster at 18 months. Hepatitis B vaccine at birth, 6 weeks, 6 months, booster every 5 years • Hemoglobin levels should be maintained at 10–12 g/d . • Folate supplementation should be given, as there is rapid turnover of BM • Genetic counseling and mass education of high-risk communities should be done to avoid marriages between homozygous or heterozygous persons, to reduce prevalence. l

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plastic risis

The causative organism is Parvovirus B19, leading to destruction of erythroid precursors in BM. The child presents with acute anemia, without reticulocytosis. The condition is always self-limiting with duration of 7–10 days. Blood transfusions during this period prevent mortality.

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Antenatal diagnosis can be done at 8–10 weeks of gestation, with chorionic villus biopsy, or amniocentesis Diagnosis of a neonatal screening of high-risk population should be done for SCD. Newborn with SCD should be given oral penicillin 125 mg, twice a day, up to the age of 3 years. Oral penicillin 250 mg, twice a day should be given to children above 3 years

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Management •

For mild pain—codeine, aspirin, ibuprofen, acetaminophen, naproxen, can be used For severe pain: meperidine, ketorolac, tolmetin, oxycodone, etc. may be useful Vasodilators like Pentoxifylline, nifedipine, and buflomedil increase microvascular circulation Blood transfusion—increases oxygen saturation thereby reversing sickling process and relieves obstruction to microvascular bed Hydroxyurea, leads to increase in Hb“F”, which ameliorates the severity of SCD Zinc supplementation of 10–15 mg of elemental zinc seems to be beneficial. It prolongs red cell life span. Zinc has membrane-modifying effect thus it reduces irreversibly sickled cells. It decreases the adherence of red cells to endothelium thereby reducing vascular obstruction. Zinc also causes maturation of gonads and may be of help in delayed sexual growth.

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Epistaxis is a frequent complaint Retinal infarcts, retinal detachment, vitreous hemorrhage may occur Nonhealing chronic leg ulcers are uncommon in children in Arab-Asian haplotype.

Screening test of older children can be done by solubility test, early and late sickling test after adding sodium metabisulfite The diagnosis can be confirmed by Hb electrophoresis, isoelectric focusing, high performance liquid chromatography, globin DNA analysis.

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Drugs like 5-azacytidine, hydroxyurea, and sodium butyrate lead to increase in Hb“F”, which ameliorate the severity of SCD Benzyl esters increase the solubility of Hb and prevent polymer formation. These drugs are still under experimental trial

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• In Indian patients spleen remains enlarged in pediatric age group • Quality of life can be much better if hemoglobin level is maintained above 10 g/d l

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Once diagnosed, a child should be under regular follow-up Maintain Hb level above 10 g/d In our country’s hot climate child should be given plenty fluids to avoid dehydration Splenectomy may be considered in case of repeated attacks of sequestration crisis. K

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ibliography

1. Atweh GF, Sutton M, Nassif I, et al. Sustained induction of fetal hemoglobin by pulse butyrate therapy in sickle cell disease. Blood. 1999;93(6):1790-7. 2. Brawley OW, Cornelius LJ, Edwards LR, et al. National Institutes of Health Consensus Development Conference statement: hydroxyurea treatment for sickle cell disease. Ann Intern Med. 2008;148(12):932-8. 3. Italia K, Jain D, Gattani S, et al. Hydroxyurea in sickle cell disease-a study of clinico-pharmacological efficacy in the Indian haplotype. Blood Cells Mol Dis. 2009;42(1):25-31. 4. Mashon RS, Dash PM, Khalkho J, et al. Higher fetal hemoglobin concentration in patients with sickle cell disease in eastern India reduces frequency of painful crisis. Eur J Haematol. 2009;83(4):383-4. 5. Saunthararajah Y, Vichinsky EP, Embury SH. Sickle cell disease. Clinical features and management. In: Hoffman R, Benz EJ, Shattil SS (Eds). Hematology: Basic Principles and Practice, 5th edition. Philadelphia, Pa: Churchill Livingston; 2008.

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Practice Points/Tips

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Bone marrow transplant has potential cure. Today it is controversial, needs expertise, and is very expensive.

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ntroduction

The erythrocyte membrane structure comprises an outer lipid bilayer of phospholipids and glycolipids, with integral proteins which penetrate or span this bilayer. These include glycoproteins and glycophorins for MNS blood group and others interacting with the inner cytoskeleton. Important among these are the band 3 proteins which are vital for anion transport in cellular respiration and contain ABO blood group antigens on their outer surface. Inner to the lipid bilayer is a separate network of proteins forming a membrane cytoskeleton, viz. spectrin, ankyrin, actin, protein 4.1, protein 4.2, actin and many others. A normal intact membrane structure is critical to red cell deformability, stability and membrane permeability. A hereditary or acquired defect in any of these structural components destabilizes the cytoskeleton, alters red cell morphology and shortens the red cell lifespan resulting in variable degrees of anemia. S

Hereditary pherocytosis This the most common of red cell membranopathies, characterized by: • Hemolysis, intermittent jaundice, splenomegaly with the spherocytes in the peripheral smear being its morphologic hallmark • It is inherited as an autosomal dominant trait in a majo­ rity of patients, although de novo sporadic mutations are also seen and rarely may be recessively inherited • Hereditary spherocytosis results from a deficiency or defect in spectrin or its anchoring proteins, ankyrin,

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band 3 protein or protein 4.2. Molecular defects causing these deficiencies are now known (Fig. 11.7.1) However, most mutations though common within a family, almost always vary between families Deficient cytoskeleton results in loss of membrane lipids and converts red cells into rigid, osmotically fragile spherocytes which get sequestered in the spleen. In the process they undergo various metabolic changes, nutrient loss, and lose other membrane components. These deformed RBCs are susceptible to destruction by splenic macrophages.

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There is marked heterogeneity of clinical presentation from the asymptomatic to a transfusion-dependent hemolytic anemia: • Most patients present during infancy or childhood with anemia, although presentation in the 4th or 5th decades are also known (Fig. 11.7.2) • Typically there is a history of mild jaundice, mild or absent anemia or intermittent anemia and jaundice • However, mild to moderate splenomegaly is always present • More severe forms may present in the newborn period with anemia and severe hyperbilirubinemia necessitating ET • As in other hemolytic anemias, they are prone to aplastic crisis following parvovirus infection, or megaloblastic crisis due to folate deficiency • Some patients may develop or rarely even present with symptomatic gallstones

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Figure 11.7.1 Molecular defects and pathogenesis in hereditary spherocytosis

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Figure 11.7.4 Osmotic fragility curve

 

Figure 11.7.2 Anemia with hepatosplenomegaly, jaundice (indirect type), hereditary spherocytosis

Rarely leg ulcers and growth retardation can also complicate the course.

aboratory eatures

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fragility when incubated with hypotonic NaCl solutions in vitro, yielding a diagnostic osmotic fragility curve (Fig. 11.7.4).

The Hb is usually mildly decreased or normal, with normal MCV, typically high MCH content • Most patients however exhibit marked reticulocytosis indicating compensatory erythroid hyperplasia • Red cell morphology is distinctive with 15–20% being hyperchromatic spherocytes lacking a central pallor (Fig. 11.7.3) There is variable polychromatophilia and even spherocytosis peripheral smear. Poikilocytosis in severe HS is due to combined spectrin ankyrin deficiency or in recessive variants. The most common diagnostic screening test used is osmotic fragility test. Red cells in HS show increased osmotic

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In a majority of cases, a definitive diagnosis of HS can be made on the basis of family history, red cell indices and morphology and a positive screening test However, quantitation of membrane proteins, especially spectrin content is possible by flow cytometric or gelelectrophoretic analysis, and also characterization of molecular lesions is done in the research setting Patients can be classified into clinical severity pheno­ types based on Hb, reticulocyte count, serum bilirubin, and spectrin content (Table 11.7.1).

Clinically HS should be differentiated from other inherited disorders presenting with episodic anemia jaundice and splenomegaly such as other red cell membranopathy, enzymopathies, unstable Hb and autoimmune hemolytic anemia.

Management

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Basic supportive care is advised to all patients in the form of: • Lifelong folate supplementation • Prevention of iron deficiency • Prompt treatment of infections • Blood transfusion may be required on a regular basis in severe phenotypes, in individuals in a steady state during episodes of acute hemolysis, or during aplastic crisis • Regular follow up is recommended to monitor growth, spleen size, Hb trend, and occurrence of gall stones

 

Table 11.7.1 Differential diagnosis of spherocytes Spherocytes are also seen in other states such as: • ABO incompatibility • Immune-mediated hemolytic anemia • Burns • Clostridium perfringens sepsis

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Figure 11.7.3 Peripheral smear showing microspherocytes

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Splenectomy prolongs RBC survival to almost 80% of normal and prevents other complications, however, is recommended only in clinically severe phenotype Because of the higher risk of post splenectomy sepsis, it should be postponed to at least 5 years of age. -

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Acquired Spherocytosis Certain acquired conditions may also cause reduction in membrane surface area with resultant spherocyte formation, such as: • Immune adherence, thermal injury • Mechanical injury (microangiopathic anemia) • Clostridial sepsis • Certain snake, bee and spider venoms.

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Treatment is rarely indicated for mild HE or its variants Daily folate supplementation is recommended in patients with significant hemolysis Acute hemolysis during viral infections or other febrile illnesses may need attention Vigilance for gallstones is required Splenectomy may be indicated in severe HE/HPP wherein it results in increase in Hb, decrease in reticulocyte counts and improved symptoms.

ed ell Permeability isorders

Hereditary stomatocytosis: It is a rare heterogeneous group of autosomal dominant hemolytic anemia charac terized by marked increase in RBC membrane permeability to sodium and an increase in red cell water content. This results in cup-shaped red cells that have a mouth like slit in place of the normal central pallor on stained blood films. Most patients have a very mild hemolytic anemia and jaundice with variable reticulocyte increase, high MCV, 10–50% red cells as stomatocytes and an increased osmotic fragility.

Hereditary pyropoikilocytosis (HPP) is a recessively inherited form of hemolytic anemia biochemically related to common HE, having a severe clinical phenotype. They typically present in the newborn period with severe anemia and neonatal jaundice (NNJ), with red cell fragmentation, poikilocytosis, elliptocytosis and microspherocytosis. South East Asian ovalocytosis is another variant of HE 706 seen in malaria-endemic regions of South East Asia, and



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Hereditary Pyropoikilocytosis

Hemoglobin may be normal or decreased and the reticulocyte count will reflect the severity of hemolysis. Other evidence of hemolysis may be present such as reduced serum haptoglobin, elevated serum lactate dehydrogenase (LDH), serum bilirubin and urinary urobilinogen levels. Osmotic fragility testing is not required although it is increased in severe HE/HPP. Red cells in HPP also show increased thermal instability as red cells undergo lysis at lower temperatures.

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is characterized by red cells with a broad oval shape and presence of stomatocytes. It is clinically a benign disorder (Fig. 11.7.5).



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Figure 11.7.5 Ovalocytes in peripheral smear

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Hereditary elliptocytosis designates a group of inherited disorders that have in common the presence of elliptical RBCs Characterized by defects in spectrin binding with other membrane proteins In most patients it is inherited as an autosomal dominant trait with a striking molecular heterogeneity, having a variable clinical spectrum ranging from the asymptomatic trait to a life-threatening hemolysis Members of the same family may exhibit different clinical courses and an individual’s frequency and severity may change with time Although mutations of alpha spectrin are responsible for most cases of dominantly inherited common HE, it is also seen due to deficiencies in protein 4.1 or glycophorin C or with defects in band 3 protein/betaspectrin impair ankyrin binding These defects in the cytoskeleton make the red cells less tolerant to shear stress during circulation. Red blood cell precursors here are round initially but become more elliptical as they age In children and adults common HE is usually asymptomatic often discovered accidentally on a peripheral smear showing 15–20% elliptocytes Others many have a mild hemolytic anemia and splenomegaly, sometimes with gallstones Common HE is asymptomatic in the neonatal period with elliptocytes appearing only by 4–6 months of age. -

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Acquired acanthocytes are seen in hypothyroidism, anorexia nervosa, postsplenectomy, severe hepatocellular disease, vitamin E deficiency especially in neonates/ preterms. Inherited neurological disorders such as abetali poproteinemia and MaCleod’s syndrome.

1. Abdullah F, Zhang Y, Camp M, Rossberg MI, et al. Splenectomy in hereditary spherocytosis: Review of 1,657 patients and application of the pediatric quality indicators. Pediatr Blood Cancer. 2009;52(7):834 7. 2. Golan DE. Hemolytic anemias: red cell membrane and metabolic disorders. In: Goldman L, Ausiello D (Eds). Cecil Medicine, 23rd edition. Philadelphia, Pa: Saunders Elsevier; 2007. 3. Hassoun H, Palek J. Hereditary spherocytosis: a review of the clinical and molecular aspects of the disease. Blood Rev. 1996;10(3):129 47. 4. Maciag M, Plochocka D, Adamowicz Salach A, et al. Novel beta-spectrin mutations in hereditary spherocytosis associated with decreased levels of mRNA. Br J Haematol. 2009;146(3):326 32. 5. Perrotta S, Della Ragione F, Rossi F, et al. A truncated beta chain responsible for dominant hereditary spherocytosis. Haematologica. 2009;94(12):1753 7. 6. Perrotta S, Gallagher PG, Mohandas N. Hereditary spherocytosis. Lancet. 2008;372(9647):1411 26. -



Red blood cell membrane lipid disorders are characterized by presence of acanthocytes, echinocytes and target cells.

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It is a rare autosomal dominantly inherited hemolytic anemia characterized by increased red cell permeability to potassium ions and thereby leakage of potassium and water out of the cell. This results in cellular dehydration and is also known as dehydrated stomatocytosis. Laboratory features are characterized by elevated MCH content, mildly elevated mean corpuscular contraindicated.

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Hereditary erocytosis

Echinocytes are seen in hemolytic anemia associated with hypophosphatemia, PK deficiency, uremia, long distance runners. Target cells are formed due to increased ratio of cell surface compared to volume and are seen in thalassemia, Hb C disease, familial lecithin cholesterol acyltransferase deficiency and obstructive liver disease.

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Splenectomy is contraindicated as these stomatocytic red cells are abnormally adherent thereby increasing the risk of thrombosis in conjunction with postsplenectomy thrombocytosis.

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ntroduction

Defects in various enzymes associated with the RBC glycolytic pathway, hexose monophosphate shunt or pentose phosphate pathway (PPP), leading to the development of hemolytic anemias of varying severity, are defined as red cell enzymopathies or erythroid enzymopathies (EEP). These anemias are mostly congenital nonspherocytic hemolytic anemias. The enzymopathies are linked to the prevention of oxidative damage or the generation of energy in the RBCs.



nheritance

NADP+ is the major rate limiting step for PPP. Nicotinamide adenine dinucleotide phosphate-oxidase is required to keep glutathione in reduced form, which prevents red cells from oxidative damage. The clinical consequences of G6PD deficiency are virtually limited to the RBCs, with occasional malfunction of the leukocytes, in some variants, as RBCs cannot generate NADPH in any other way. Majority of the mutations affect the stability of the transcribed enzyme so that the activity declines rapidly in the mature enucleate RBCs. Being an X-linked disorder, males are commonly affected and females are heterozygous carriers (Fig. 11.8.2). These heterozygous females are often susceptible to oxidative stress because of the effects of X-inactivation and marked lyonization in leaving a significant population of deficient red cells.

Glucose-6-phopsphate dehydrogenase deficiency and phosphoglycerate kinase deficiency are chromosome X-linked recessive, and the other EEPs are usually inherited in an autosomal recessive manner.

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Pentose Phosphate Pathway (Hexose Monophosphate hunt) Glucose-6-phopsphate dehydrogenase is the first enzyme involved in the PPP and controls the flux through this pathway. Figure 11.8.1 depicts the PPP and Figure 11.8.2 shows the glutathione cycle and synthetic pathways along with the various enzymes involved in different reactions.

pidemiology

Glucose-6-phosphate dehydrogenase deficiency is widely disseminated throughout Africa, the Mediterranean basin, the Middle East, South East Asia, and indigenous populations of the Indian subcontinent. In South East Asia, the prevalence varies widely in different ethnic groups—10–20% in certain Cambodian groups to 1–3% in Vietnamese population groups. Glucose-6-phosphate dehydrogenase deficiency was reported about 40 years ago from India, and varying prevalence rates of 0–27% have been reported from diverse ethnic, caste, linguistic and tribal groups. The most common variants are:

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Mediterranean variant among the caste groups Odisha variant among the Indian tribal





Glucose-6-phopsphate dehydrogenase deficiency is the commonest genetically determined enzymopathy in the world, with approximately 440 million people being affected. At least 127 enzyme variants and numerous other polymorphisms that do not affect enzyme activity have been described. The gene for G6PD is located on the X chromosome at Xq28, and comprises of 13 exons and 12 introns. It helps in the conversion of glucose-6-phosphate to 6 phosphogluconate through the reduction of NADP+ to nicotinamide adenine dinucleotide phosphate-oxidase (NADPH). 6 Phosphogluconate is also a substrate for the glycolytic pathway. Under normal conditions only 10% glucose is metabolized by the PPP, and its activity is governed by the availability of NAD+ and its feedback inhibition by adenosine triphosphate (ATP). NADP+ availability is dependent on the activity of the glutathione pathway, which is linked to the PPP through the enzyme glutathione reductase. The availability of

 

Figure 11.8.1 Pentose phosphate pathway

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Figure 11.8.2 The Glutathione cycle and synthetic pathways



A higher incidence of G6PD deficiency has been observed in north and west India (15% in Parsees to 27% in Angami Nagas), as compared to the south (1–2%), except in the tribal of Tamil Nadu and Andhra Pradesh (5–13%). D

Glucose-6-Phosphate ehydrogenase and Malaria It has been hypothesized that the distribution of G6PD deficiency equates with areas where Plasmodium falciparum malaria is common, and this is thought to be the evolutionary drive that produced such widespread polymorphisms. It has subsequently been confirmed that G6PD deficiency does indeed protect against lethal falciparum malaria, particularly in childhood. This hypothesis has been called G6PD/malaria or “malaria hypothesis”. Malarial parasite grows less well in red cells deficient in G6PD. Decreased parasitemia has been documented in these individuals in various studies.

Variants of Glucose-6-Phosphate ehydrogenase D

Kerala-Kalyan is the third most common variant seen in India.

Based upon biochemical and other characterization, 442 different variants of G6PD have been identified. Of them, 299 have been characterized with the methods recommended by WHO. About 100 biochemical variants are thought to be polymorphic in human populations. Thirteen biochemically characterized variants have been reported from India. These variants are grouped to five classes by WHO scientific working group depending upon the residual enzymatic activity and clinical presentation, as given in Table 11.8.1. •

Polymorphic variants: These variants have achieved a high frequency in some populations and represent balanced polymorphisms, e.g. G6PD Mediterranean, G6PD African and Oriental variants

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poradic variants: These are characterized by chronic nonspherocytic hemolytic anemia (CNSHA) and get exacerbated by oxidant stress. These are not limited to a particular population alone. Thirteen such variants have S

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Table 11.8.1 Variants of glucose-6-phosphate dehydrogenase seen in India Severe deficiency

(< 20%)

Congenital nonspherocytic hemolytic anemia, acute exacerbations

II

Severe deficiency

(< 10%)

Favism, AIVHA (drug induced), neonatal Jaundice

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(10–60%)

AIVHA (drug induced) Neonatal jaundice

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(60–100%)

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(> 2 Xn)



































Clinical presentation



Enzyme activity

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Glucose-6-phosphate dehydrogenase mutations in ndia: Mutations in the Indian subcontinent in the G6PD are seen in exon 6 and 7 which is in close proximity to G6PD binding site. Glucose-6-phosphate dehydrogenase Mediterranean (563 C-T) is the most common polymorphism in India and it is a severely deficient variant associated with DIHA, favism and NNJ. Glucose-6-phosphate dehydrogenase Kerala-Kalyan (949 G-A) and G6PD Odisha (131 C-G) are the other common variants in India. Glucose-6-phosphate dehydrogenase Chatham (1003 G-A) with undetectable enzyme activity and G6PD Insuli (989 G-A) with normal enzyme activity are very rare in Indian population.

reported. In an Indian series, in 12 out of 100 neonates with jaundice, G6PD deficiency was the cause, of them 10 being G6PD Mediterranean type.

Acute Intravascular Hemolysis

linical Presentation





There are four main syndromes associated with G6PD deficiency. In G6PD deficient individuals, hemolysis is aggravated by exposure to oxidative stress through infection or ingestion of oxidative foods or drugs. The four syndromes are: • Neonatal jaundice • Favism • Chronic nonspherocytic hemolytic anemia • Drug-induced hemolytic anemia. The NNJ syndrome has been described in class I, II and III variants: favism in mainly, although not exclusively, class II, CNSHA in class I and the drug-induced hemolysis mainly class III.



Neonatal Jaundice and Glucose-6-Phosphate Dehydrogenase Deficiency in Infancy

Glucose-6-phosphate dehydrogenase was first described during investigation for “primaquine sensitivity”. Since then many drugs have been incriminated to result in intravascular hemolysis in individuals with G6PD deficiency. Children with certain variants of G6PD deficiency are clinically in a steady state till they develop anemia of sudden onset under the effect of some oxidative stress. Within 24–48 hours of exposure to such stress, the child suddenly becomes pale and has cola colored or dark colored urine. Depending upon the severity of hemolysis and the resultant anemia the child may present with incipient or frank CCF. Depending upon degree of extravascular hemolysis, splenic enlargement may be noticed. Hemolysis occurs after exposure to stressor but does not continue with continued exposure. This is thought to be on account of older RBCs being damaged first as they have most severe deficiency of enzyme. Once the population of deficient RBC is hemolyzed, the juvenile RBC and reticulocytes withstand the stress as they have typically higher levels of enzyme activity. Hemoglobinemia and hemoglobinuria may result in azotemia and/or acute renal failure. Laboratory findings during intravascular hemolysis include moderate to severe anemia which is usually normocytic-normochromic. Red blood cell morphology shows anisocytosis due to increased number of juvenile red cells and contracted cells. Poikilocytosis with presence of “bite cells” may be seen. Intense reticulocytosis is present. Plasma Hb level is increased and so is unconjugated bilirubin level. Haptoglobin and other Hb binding proteins are decreased. Table 11.8.2 lists the drugs that need to be avoided in G6PD deficient individuals and the risk of hemolysis associated with these drugs. In an Indian series bacterial sepsis, malaria and hepatitis were identifiable triggers other than drugs. Alpha hydroxy acids following ingestion of soft drink containing ascorbate has also been reported from India.



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been reported from the Indian subcontinent, though all of these have not been characterized at the molecular level

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Favism Favism is the term given to the G6PD syndrome when acute intravascular hemolysis may be precipitated by exposure to the broad bean vicia faba. Pallor, jaundice and hemoglobinuria are the clinical hallmarks. Fresh, dried or frozen beans or even exposure to pollen may precipitate the crisis. The offending agent is divicine, or its aglycone isouramil, which can produce free oxygen radicals on autoxidation. The extent of hemolysis is related to the extent of exposure. In children, acute hemolysis, sometimes life-threatening, is common, but renal failure is uncommon although there may be systemic symptoms of fever and loin pain. Renal failure occurs more often in adults, possibly because of comorbidity. Favism is usual in class II variants,

Neonatal jaundice is a severe manifestation of G6PD deficiency and resultant kernicterus is the main cause of morbidity and mortality. Most common variants have been associated with NNJ, including the A- and Mediterranean variants. The jaundice probably starts in utero in the perinatal period, but the clinical problem becomes apparent only about the 2nd or 3rd day after birth. Between 10% and 50% of the deficient infants are affected. Phototherapy or ET may be required to prevent neurological sequelae. Anemia is usually absent, and it is thought that this is a manifestation of liver enzyme deficiency, along with the physiological underdevelopment of neonatal liver function or the co-inheritance of uridine diphosphate glucuronyl transferase 1 deficiency of Gilbert’s syndrome. Acute hemolytic crises may occur in G6PDdeficient infants, usually through exposure to oxidative stress, including nitrites or nitrates in water or the ingestion of fava beans by the mother which may result in severe intrauterine hemolysis and hydrops fetalis or in some cases idiopathic severe and sometimes fatal hemolysis has been

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Acetanilide Acetylphenylhydrazine (2-Phenyl Acetohydrazide) Aldesulfone sodium (sulfoxone) Aminophenazone (aminopyrine) Antazoline (antistine) Arsine Ascorbic acid Beta-naphthol (2-Naphthol) Chloramphenicol Chloroquine Ciprofloxacin Colchicine Dapsone (dia phenylsulfone) Dimercaprol Diphenhydramine (diphenhydramine) Dopamine (L-dopa) Doxorubicin Furazolidone Glibenclamide Glucosulfone (glucosulfone sodium Isobutyl nitrite Isoniazid Menadiol sodium sulfate Menadione (menaphtone) Menadione sodium bisulfite (Vitamin K3 sodium bisulfite)

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Mepacrine (Quinacrine) Mesalazine 5-aminosalicylic acid (paraminosalicylic acid) Methyltioninium Chloride (methylene blue) Nalidixic acid Naphthalene, pure (naphthalene) Niridazole Nitrofural (nitrofurazone) Nitrofurantoin Norfloxacin O-acetylsalicylic acid (acetylsalicylic acid) Oxidase, urate (urate oxidase) Phenazopyridine Phenylbutazone Phenytoin Pamaquine Para-aminobenzoic acid (4-aminobenzoic acid) Paracetamol (acetaminophen) Pentaquine Phenacetin (acetophenetidin) Phynylhydrazine Phytomenadione (Vitamin K1) Primaquine Probenecid Procainamide Proguanil (chlorguanidine)

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Pyrimethamine Quinidine Quinine Stibophen Streptomycin Sulfacetamide Sulfacytine Sulfadiazine Sulfadimidine Sulfafurazole (sulfafurazone, sulfisoxazole) Sulfaguanidine Sulfamerazine Sulfamethoxazole Sulfamethoxypyridazine Sulfanilamide (sulfanilamide) Sulfapyridine Sulfasalazine Salazosulfapyridine (salazopyrin) Thiazosulfone (thiazolesulfone) Tiaprofenic acid Tolonium chloride, tolonium chloride (toluidine blue) Trihexyphynidyl (benzhexol) Trimethoprim Trinitrotoluene (2,4,6-trinitrotoluene) Tripelennamine

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Table 11.8.2 Drugs to be avoided in patients with glucose-6phosphate dehydrogenase deficiency

for example, Mediterranean and Canton, but may occur in others, including the African A-variant. Some other chemicals and compounds like, topical henna and some of the pulses used to make up local sweetmeats can also precipitate hemolysis. Patients with favism are G6PD deficient, but not all G6PD deficient patients develop favism when they ingest fava beans.

Chronic Nonspherocytic Hemolytic Anemia

Contd...

Chronic anemia with normal/near normal red cell morphology is the most severe form of G6PD deficiency and is usually seen in infancy or childhood. Chronic nonspherocytic hemolytic anemia develops in a minority of cases with G6PD deficiency (Class I variants). Most of the mutations causing CNSHA are seen on exon 10 and affects the formation of dimers and tetramers. Clinical presentation is variable. Chronic nonspherocytic hemolytic anemia affects only male patients and these patients usually have history of neonatal jaundice (NNJ) necessitating therapeutic intervention. The patient presents later with anemia and jaundice. Splenomegaly is variable. Anemia is normocytic, normochromic, slight macrocytosis may be observed due to reticulocytosis. Unconjugated hyperbilirubinemia, increased levels of LDH and decreased levels of haptoglobin are present. Hemolysis is usually extravascular, although additional oxidant stress may precipitate intravascular 711 hemolysis. Continuous hemolysis in these patients results

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Preventive and Therapeutic trategies Preventing the development of hemolysis is of key importance in managing patients with G6PD deficiency, along with appropriate treatment of acute and chronic anemia and NNJ. WHO recommends screening all newborns for G6PD 712 deficiency population groups with prevalence rates of



ther nzymopathies of the Glutathione Pathway E

• γ-Glutamyl cysteine synthetase deficiency: It is the rate limiting enzyme in glutathione biosynthesis. Patients may present with CNSHA, oxidative hemolytic anemia, basophilic stippling and spinocerebellar degeneration in adulthood. The genetic locus is identified on chromosome 6p12. • Glutathione Peroxidase (G H-Px) deficiency: This enzyme is responsible for the elimination of hydrogen peroxide from the erythrocytes and its production depends on adequate selenium supply. Moderate deficiency may result in nonspherocytic hemolytic anemia in infants or self-limited NNJ, and Heinz bodies. Oxidizing drugs need to be avoided. The genetic locus is localized to chromosome 3p21.3. • Glutathione synthetase deficiency: Mutations in the glutathione synthetase gene lead to low levels of this enzyme in the RBCs, leading to 5-oxoprolinemia and oxoprolinuria. The classical triad of presentation is hemolysis, metabolic acidosis and mental deterioration. The affected gene is located at chromosome 20q11. Treatment is to supplement vitamin C, vitamin E, bicarbonate and avoidance of oxidative drugs. • Glutathione reductase deficiency: This enzyme is responsible for the reduction of oxidized glutathione in the presence of flavin adenine dinucleotide and its deficiency leads to increased susceptibility to druginduced hemolysis and favism. Its activity increases with dietary riboflavin supplementation in a few patients. In patients with a 2,246 base pair gene deletion in the S

The acute intravascular hemolysis raises the suspicion of G6PD deficiency. The peripheral blood smear shows red cells with contracted Hb in “ghost” membrane. Hemoglobinuria may be gross, producing almost black urine without red cells in the centrifuge deposit. Several screening tests have been devised to identify G6PD deficiency in RBCs. The most widely used tests are the brilliant Cresyl blue decolorization test, the MetHb reduction test and an ultraviolet spot test. These are good qualitative tests that can differentiate between the deficient and non-deficient cases but do not provide quantitative data. If a screening test indicates deficiency or is doubtful, the ideal follow-up test for definitive diagnosis is quantification of G6PD activity by spectrophotometric assay. The quantification is essential in case of hemolytic attack, wherein the oldest red cells (with the least G6PD activity) are destroyed selectively, and the surviving red cells have a relatively higher (but still deficient) G6PD activity. This increases further as the reticulocyte response evolves. During this time, a screening test might yield a false-normal result and, rarely, even a quantitative test might do so. In such cases, it is best to repeat the test a couple of weeks later. The oldest remaining cells can be isolated by differential centrifugation and they can be shown to have a low G6PD activity. Quantitative estimation is also important for the diagnosis of heterozygous females; the probability of clinically significant hemolysis in a heterozygote roughly correlates with the proportion of G6PD-deficient red cells in her blood. Thus, the demonstration of a normal level of G6PD activity in a heterozygote makes it unlikely that the affected individual will be at risk of G6PD-related hemolysis. In regions where G6PD has a high prevalence and the main variants are known, DNA analysis is the most effective way of identifying heterozygotes. Enzyme-linked immunosorbent assay (ELISA)-based methods have been developed for field use. A recent study reported a good sensitivity and specificity of this test and recommended for use in resource limited settings. Another test for field studies is NADPH fluorescence test on paper (NFP test). This test was compared with PCR-based G6PD genotyping also using blood samples on filter papers. There was good agreement between the NFP test results and the PCR findings. The estimate of the sensitivity of the NFP test was 98.2% (95.8–99.6%) and the specificity was 97.1% (94.2–99.2%).

3–5% or more in males. Identifying the affected newborns early, makes it easier to take due precautions for preventing the development of NNJ. Avoidance of the known oxidative stresses and drugs in G6PD-deficient individuals can help prevent the development of hemolytic anemia. Management of NNJ should be as per the standard protocols, including phototherapy and ET. Phototherapy in these neonates may be started at a lower level than otherwise recommended. A novel approach is use of heme-oxygenase inhibitor— Tin-mesoporphyrin (SnMP) which reduces bilirubin production and has shown promising results in preventing the development of significant hyperbilirubinemia in G6PD-deficient neonates. Treatment of acute episode of intravascular hemolysis includes transfusion support to correct anemia and supportive care. Adequate fluid therapy during hemolytic episodes is crucial for prevention and treatment of acute renal failure. Patients with CNSHA require meticulous monitoring. In most cases occasional exacerbation may require blood transfusion. During steady state, administration of folic acid is recommended to meet the increased demands due to increased red cell turnover. Occasional patient may need to be started on chronic transfusion therapy. Splenectomy may be required due to large size, development of hypersplenism or to decrease the transfusion requirement. O

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from red cell membrane damage due to oxidation of sulfhydryl group of Hb resulting in its precipitation.

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Pyruvate kinase enzyme catalyzes the final step of the glycolytic pathway, leading to overall net gain of ATP from this pathway. This enzyme is a tetramer with four tissue specific subunits: R (RBC), L (liver), M1-muscle and M2 platelets and leukocytes. Genetic control is separate for RL subunit and M1 M2 subunits. Deficient PK activity leads to accumulation of substrates upstream, including 2, 3 DPG, which shifts the oxygen dissociation curve to the right, indicating low oxygen affinity. Pyruvate kinase activity decreases during RBC ageing, as the enzyme is gradually denatured, and after the activity falls below a critical level, glycolytic failure and ATP depletion result. Over 150 genetic mutations are associated with PK deficiency. Most patients are compound heterozygotes for the two most common mutant forms of the enzyme. This deficiency is common in people of northern European lineage. Prevalence of PK deficiency has varied from 0.14% to 6%. PK deficiency provides some protection against malaria. Figure 11.8.3 depicts the biochemical role of PK.

F



aboratory eatures F

Pyruvate Kinase Deficiency

linical eatures

Chronic nonspherocytic hemolytic anemia with extravascular hemolysis is the hallmark of clinical presentation in PK deficiency. Around one-third of patients present with jaundice in the newborn period and one-third of these cases are severe enough to warrant packed RBC transfusions and/or ET. Severe anemia and hydrops are the usual cause of death during this period. Milder variants usually present in late childhood with nonsevere anemia, unconjugated hyperbilirubinemia and splenomegaly, which may be massive at times. Chronic leg ulcers are a complication in some individuals. Aplastic crisis due to parvovirus infection can occur. Gallstones are increasingly seen after 1st decade. The prognosis is confounded by the lack of good correlation between PK activity level and the severity of clinical hemolysis. L

E

•

glutathione reductase gene, riboflavin supplementation does not lead to its increased activity. nzymopathies of the glycolytic pathway: Pyruvate kinase deficiency is the most well-recognized enzymopathy of glycolytic pathway, and along with G6PD deficiency (Fig. 11.8.3). It is the most common cause of CNSHA. In contrast to G6PD deficiency, patients with deficiency of enzymes of glycolytic pathway usually have CNSHA with onset in neonatal period. Drug-induced hemolytic anemia is not a common problem in these patients. Table 11.8.3 lists the important features of important enzymopathies of the glycolytic pathway.

C

 

Figure 11.8.3 The reactions of pyruvate kinase and the sites affected by various mutations in pyruvate kinase deficiency

Red cell morphology is normocytic normochromic. Active regeneration of RBCs leading to macrocytosis and acanthocytosis may be observed. Reticulocyte count is increased but not proportionate to extent of hemolysis, due to selective sequestration of young RBCs and reticulocytes in the spleen. A paradoxical rise in reticulocytes after splenectomy therefore is commonly seen. Hepatic PK deficiency, leads to elevated liver enzymes. Iron overload disproportionate to transfusions is sometimes observed and has been explained on the basis of associated hemochromatosis mutations.

Treatment Treatment of PK deficiency includes transfusion support, folate supplementation, splenectomy and cholecystectomy for gallstones. Use of salicylates may lead to hyperhemolytic crisis in patients with PK deficiency. The role of splenectomy 713

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Fructose diphosphate Aldolase (ALDOA)

Triose phosphate isomerase (TPI)

Glyceraldehyde3-phosphate dehydrogenase

Phosphoglycerate kinase

2, 3-Diphosphoglycerate 7q23-q34/AR mutase (DPG mutase)

Enolase

Pyruvate kinase

4.

5.

6.

7.

8.

9.

10.

Lactate dehydrogenase

Phosphofructokinase

3.

11.

Glucose phosphate isomerase

2.

1q21-q22(PKLR)/ AR rarely AD

Xq13/X-linked

12p13/AD

12p13/AR

16q22-q24/AR

1(M) and 21(L)/ complex

19 cen-q12/ AR

10q11.2/AR

Hexokinase

1.

Genetics (chromosome/ inheritance)

Enzyme

S. no.

Neuromuscular, Cardiac

Myopathy, dysmorphism, mental retardation

Dominant myopathy

Decreased levels not associated with anemia

See text -

Spherocytosis

Shortened red cell survival not necessary, nitrofurantoin induced hemolysis

None

Reticulocytosis Erythrocytosis

CNS, myopathy, rhabdomyolysis

Polycythemia, None neonatal onset of progressive anemia described with 50% activity

CNSHA, NNJ

Nonspecific

Very high reticulocyte count

Normal red cell morphology

No lactate production in “ischemic arm test”, muscle biopsy

Erythrocytosis very high reticulocyte count, high MCV

Red cell morphology unremarkable

None directly

None directly

Hematological/other laboratory findings

Other systems affected

None/associated with other defects None like hereditary spherocytosis

Moderate to severe CNSHA, Neonatal anemia

Severe CNSHA

Erythrocytosis (Type VII Glycogen storage disease), mild hemolytic anemia

NNJ, hydrops, CNSHA, hyperhemolytic episodes

NNJ, anemia, splenomegaly, chronic nonspherocytic hemolytic anemia (CNSHA), gallstones, hyperhemolytic episodes, high O2 affinity

Clinical features

Table 11.8.3 Enzymopathies of the glycolytic pathway

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Undefined

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Rare, variable systems involved

Gene syntenic with TPI, membrane protein band 6

Sudden death

Very few cases

Tarui’s disease, subunit genes

Most common after PK deficiency

Very rare. Occasional AD

Comments

Commonest CNSHA

Phlebotomy for Very rare symptomatic polycythemia

? Splenectomy

Nonspecific

Transfusions, folic acid, splenectomy

Undefined

Unsatisfactory

Packed RBC transfusions Folic acid splenectomy

Packed RBC transfusions Folic acid splenectomy

Treatment

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This enzyme is involved in lipoprotein metabolism and its deficiency leads to erythroid membrane defects due to excess of unesterified cholesterol. These patients may have renal disease with proteinuria and corneal opacifications, and the lipid profile shows decreased HDL levels.



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Heme-oxygenase 1 converts heme to bilirubin and is protective against oxidative stresses. Clinical presentation is in early childhood with hemolytic anemia, abnormal coagulation/fibrinolytic system, asplenia and marked growth retardation. It can present as intravascular hemolysis with RBC fragmentation in the absence of hyperbilirubinemia and decreased haptoglobin.



Heme-Oxygenase 1 Deficiency

ibliography

1. Frank JE. Diagnosis and management of G6PD deficiency. Am Fam Physician. 2005;72(7):1277-82. 2. Ip S, Chung M, Kulig J, et al. An evidence-based review of important issues concerning neonatal hyperbilirubinemia. Pediatrics. 2004;114(1):e130-e153. 3. Mohanty D, Mukherjee MB, Colah RB. Glucose-6-phosphate dehydrogenase deficiency in India. Indian J Pediatr. 2004;71(6):525-9. 4. Mohanty D, Sukumar S, Mukherjee MB, et al. G6PD deficiency and malaria in India. Am J Hematol. 2003;72(2):150-1. 5. Standardization of procedures for the study of glucose6-phosphate dehydrogenase. Report of a WHO Scientific Group. World Health Organ Tech Rep Ser. 1967;366:1-53. 6. Steiner LA, Gallagher PG. Erythrocyte disorders in perinatal period. Semin Perinatol. 2007;31(4):254-61. 7. Sukumar S, Mukherjee MB, Colah RB, et al. Molecular basis of G6PD deficiency in India. Blood Cells Mols Dis. 2004;33(2): 141-5. 8. www.g6pd.org/favism/english/index.mvc?pgid=avoid 9. www.hembase:niddk.nih.gov/ 10. Zanella A, Fermo E, Bianchi P, et al. Red cell pyruvate kinase deficiency: molecular and clinical aspects. Br J Haematol. 2005;130(1):11-25.

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ther nzymopathies ssociated with Hemolysis E

O

Adenosine deaminase (ADA) is a purine catabolic enzyme that leads to conversion of adenosine to inosine. Its deficiency leads to severe combined immunodeficiency, while its excess due to increased amplification of the ADA mRNA, produces hemolytic anemia.

B

Adenosine Deaminase Excess



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It is probably the third most common erythroid enzymo pathy, probably equal to glucose phosphate isomerase deficiency. P5NI deficiency is inherited in an autosomal recessive manner, and the gene is located on chromosome 7p15-14. The accumulation of pyrimidine nucleotides in high concentration leads to marked basophilic stippling in the RBCs. Diagnosis is confirmed by a decrease in the nucleotide OD260:OD280 ratio and decreased enzymatic activity. Patients present with hemolysis of varying severity and its sequelae. Splenectomy is usually of little value, though some cases have reported benefit.



Pyrimidine 5’ Nucleotidase (Uridine 5’ Monophosphate Hydrolase) Deficiency

The diagnosis of enzymopathy should be suspected in all cases with chronic hemolysis and unexplained unconjugated hyperbilirubinemia particularly if red cell morphology is unremarkable. Intense reticulocytosis supports the diagnosis of various enzymopathies. In cases presenting with acute intravascular hemolysis, history of exposure to trigger drugs helps in the diagnosis. Family history of jaundice, anemia, splenectomy and cholelithiasis may also point toward such a disease. In absence of such history, the diagnosis may be difficult. The diagnosis can be confirmed by appropriate enzyme assays or by the demonstration of, accumulation of proximal or depletion of distal intermediary compounds of the glycolytic pathway. The diagnostic tests need to be made available more widely and a high index of suspicion is needed to suspect these conditions.



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nzymopathies of the Nucleotide Metabolism

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as a therapeutic measure is not well-established and variable response rates are reported.

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utoimmune Hemolytic nemia

•

•

•

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•

•

Primary AIHA is not uncommon in children and is next to ITP in its occurrence as immune hematological disorder 4.

 

Table 11.9.1 Classification of autoimmune hemolytic anemia Primary autoimmune hemolytic anemia: • Cold agglutinin disease (mainly IgM and complements)

•

• Paroxysmal cold hemoglobinuria (mainly IgG and complements) Secondary AIHA: • Underlying autoimmune disorders, e.g. systemic lupus erythematosus, Evan’s syndrome

716

• Immunodeficiency, e.g. HIV, Primary immunodeficiency • Specific infections, e.g. mycoplasma infection • Malignancies, e.g. lymphomas, leukemia

•

R

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A

old eactive utoimmune Hemolytic nemia

• Drug induced, e.g. penicillin

Caused by autoantibody of IgG class that binds the red cell antigens at 37°C, sometimes fixes complements and leads to extravascular hemolysis Autoantibody IgG molecule binds firmly to red cell antigens which may or may not fix complements. The RE system recognizes the Fc segment of the bound IgG through its interaction with the Fc receptor present on the surface of the RE cells. The sensitized red cell if engulfed completely is removed from circulation leading to extravascular hemolysis. However, if only a part of the red cell membrane is bitten off, it will form a spherocyte which will return to circulation Warm-reactive IgG antibody-sensitized red cells are preferentially removed in spleen12. If IgG antibody also fixes and activated complements, it will be recognized by the macrophages with receptor to C3b, mainly in the liver. A

• Warm-reactive antibody (mainly IgG)

A

A

R

Warm eactive utoantibody

A

Primary utoimmune Hemolytic nemia

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linical orms of utoimmune Hemolytic nemia

Autoimmune hemolytic anemia can be classified in various ways depending on the type of autoantibody, site of hemolysis or the precipitating illness. However, the most practical classification of AIHA is whether it is primary or secondary as shown in Table 11.9.1. A

Secondary AIHA occurs as a part of some systemic illness or wider baseline immune disease. • It occurs more common in adolescents and young adults and is more common in females, as are other immune disorders • Cold agglutinin disease have abrupt onset of symptoms, short history, need aggressive short-term treatment and ultimately recover. Paroxysmal cold hemoglobinuria area caused by auto antibody of IgG class that binds red cell antigen at below 37°C efficiently fixes complements and leads to intravascular hemolysis.

C

lassification

A

econdary utoimmune Hemolytic nemia

A

In children, hemolytic anemia is usually caused by intrinsic red cell defect leading to hemolysis and anemia as seen typically in membranopathy or red cell enzymopathy; and most of these are inherited in nature. At times hemolytic anemia can result due to factors extrinsic to red cell and most of these causes are acquired in nature. Autoimmune hemolytic anemia (AIHA) is one such cause resulting from interaction of red cell with the immune system. It is characterized by shortened red cell life, hemolysis and anemia. It is caused by autoantibody to red cell antigens. Keen clinical observation led to the concept of AIHA as a disease different from the congenital causes like HS. Invention of Coomb’s reagent and testing led to detection of the “incomplete” autoantibodies seen in AIHA. Detection of complement components on red cell membrane in AIHA further expanded the understanding of the pathophysiology. Improved understanding of the spleen and its functions help understand the mechanism of red cell clearance in AIHA. Focus for current research, as in any autoimmune disorder, is on the role of T-cell and B-cell in AIHA, reasons of failure of self-tolerance and uncontrolled production of autoantibodies, and possible therapeutic options based on molecular pathophysiology.

Primary AIHA occurs without any baseline immune disorder or obvious precipitating factors, though many of the primary AIHA cases occur following nonspecific viral infections and cold agglutinin disease in children usually follows specifically mycoplasma infection In west it is more common than hypoplastic anemia but in our country hypoplastic anemia is more common due to rampant misuse of drugs and highly prevalent viral infections These are seen at any age and have slight predominance in males. A

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Caused by autoantibody of IgM class that binds red cell antigen at below 37°C efficiently fixes complements and leads to intravascular hemolysis and rarely IgG [in paroxysmal cold hemoglobinuria (PCH)]

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Peripheral mear Peripheral smear (PS) will show presence of macrocytosis, polychromasia, anisocytosis, presence of nucleated red cells and microspherocytes. In extreme cases there may be presence of autoagglutination. Features of microangiopathy like schistocytes and helmet cells will be absent differentiating it from other causes of hemolytic anemia (Microangiopathic hemolytic anemia). Presence of significant target cells would suggest hemoglobinopathy. Others: There will be other markers of hemolysis like high serum LDH levels and increased serum bilirubin with high indirect component. Intravascular hemolysis will lead to hemoglobinuria with presence of Hb in urine without red cells, hemoglobinemia, low hemalbumin and low hemopexin levels and in long run hemosiderinuria. • Bone marrow is not indicated in the clinical set-up of suspected hemolytic anemia. However, if BM study is done it will show erythroid hyperplasia • Presence of utoantibody: The direct evidence of AIHA is to detect presence of autoantibody and or complement component C3 on red cell. This is done by DAT also known as Combs’ test (Fig. 11.9.1) A

•

Patients with AIHA usually have typical history and physical findings. The patient will present with anemia, acholuric jaundice, and organomegaly. There may be presence of fever in some patients History suggestive of nonspecific viral infection in recent past. Being an acquired disorder the family history is usually not contributory Anemia will present with fatigue, lassitude, and giddiness Acholuric jaundice due to indirect hyperbilirubinemia following hemolysis (icterus in eyes without dark urine). Presence of dark urine is usually due to intravascular hemolysis (cola-colored urine with presence of Hb without presence of red cells on urinalysis) Organomegaly in form of enlarged liver and spleen which occur due to hyperplasia of RE system, the site of extravascular hemolysis. Marked hepatosplenomegaly should arouse suspicion of some other disease like leukemia. Always look for secondary cause like SLE, malignancy, HIV, recent ingestion of certain drugs, etc.

Evan’s syndrome the platelet count as well as Hb may be low due to autoimmune pancytopenia • The red cell indices: The red cell indices like MCV and MCHC will be normal as the large reticulocytes are balanced by presence of microspherocytes; however, the RDW will be high due to presence of marked anisocytosis. High MCHC should arouse suspicion of HS. • eticulocyte count: Reticulocyte count will be high indicating presence of hemolysis with normal marrow response. It will be seen as polychromasia on PS stained with Wright’s stain. Very high reticulocyte count with presence of nucleated red cells on smear may suggest more severe disease with propensity to chronicity • Reticulocyte count may be low due to autoantibody also affecting the red cell precursors in BM or due to associated parvovirus B19 infection.



•

linical valuation E

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It reacts with the red cell antigen at 40°C and fixes complements, however at body temperature the antibody dissociates and there is hardly any antibody attached to red cells. However, the complement activation continues. If the complement activation is complete, the red cell will lyse and lead to intravascular hemolysis. If the complement activation stops at C3b, it will be recognized by the receptor to C3b present on the surface of the macrophages of the RE system, preferentially in liver • Often have chronic illness with intermittent relapses and remissions, need long-term therapy and develop treatment-associated complications. However, overall mortality in children with AIHA is usually less than 10%. Children between 2 years and 12 years seem to have best prognosis. Paroxysmal cold hemoglobinuria caused by auto antibody of IgG class that binds red cell antigen at below 37°C efficiently fixes complements and leads to intravascular hemolysis.

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aboratory Workup

C

Hemoglobin may fall as low as 3–5 gm% without many symptoms or cardiac failure as there is adequate cardiovascular compensation—white blood cell count and platelet count—should be normal as low platelet count may suggest microangiopathic anemia and presence of low WBC counts and platelet counts will suggest other cause like AA; though in rare cases of

717 Figure 11.9.1 Positive direct antiglobulin test  

•

omplete lood ount B

C

Investigations are targeted to look for: • Presence of hemolysis • Presence of autoantibody • Presence of secondary cause if any.

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ifferential iagnosis

A

Warm-reactive IgG autoantibody has thermal reactivity at 37°C, which means that is shows activity at body temperature. Cold-reactive IgG autoantibodies of PCH show thermal reactivity at 4°C. They bind the red cell antigen at 4°C and bind complements. At body temperature the IgG antibody dissociates and cannot be detected by DAT at 37°C, but the complement cascade gets amplified leading to hemolysis. Hence this antibody is demonstrated by a special biphasic test. IgM autoantibody seen in cold agglutinin disease has thermal activity below 37°C and is best at 4°C. The clinical

­

Presence of anemia, acholuric jaundice, splenohepatomegaly, reticulocytosis, PS showing changes of hemolysis with positive DAT clinches diagnosis of AIHA. • Hereditary spherocytosis: Presence of microsphe rocytes may lead to confusion with HS. Clinical settings are totally different in these conditions. Microspherocytes are not the prominent feature in AIHA and DAT is negative in HS. Besides, MCHC will be high in HS. Microspherocytes may also be seen in other conditions • Microangiopathy may be confused with AIHA; however, platelets will be low and DAT negative in microangiopathic hemolytic anemia • Secondary cause of AIHA should be looked for like SLE, malignancies, immunodeficiency syndromes especially HIV, and incriminating drugs. Autoimmune hemolytic anemia with low reticulocyte count should be investigated for Parvovirus B19 infection.

Thermal mplitude A

•

thermal range, capacity to fix complements, binding affinity and antigenic specificity • ntibody isotype: In most cases of AIHA, the antibody is of IgG class. Most of the IgG autoantibodies are warmreactive, though some may be cold-reactive as seen in PCH or rarely cold agglutinin disease. In others the autoantibody is of IgM type as seen classically in cold agglutinin diseases following mycoplasma infections seen in children. Rarely the autoantibody is of IgA class which is not detectable by standard DAT test. The essential characteristics of these different autoantibody isotypes seen in the three clinical forms of primary AIHA are shown in Table 11.9.2. In 70% of the cases with IgG autoantibody, IgG1 is the only subtype, in 20% it is IgG1 plus some other subtype. In rest subtypes other than IgG1 are involved. IgG1 and IgG3 are better capable to bind complement than IgG3 or IgG411.



•

While IgM antibody coating red cell membrane can be detected by saline agglutination tests, IgG antibody is an incomplete antibody not detectable easily. In DAT polyspecific sera containing antihuman IgG and anticomplement rabbit globulin is added. This helps “bridge” the autoantibodies present on the red cell and leads to agglutination. Once DAT is positive, one can characterize presence of autoantibody or complement C3 or both by using monospecific test. This will also help characterize cold agglutinin disease where the IgM may no more be attached to red cell at 37°C or presence of Donath-Landsteiner antibody Direct antiglobulin test is usually reported on a scale of 1 to 4 depending on the strength of reaction. One can estimate titers of the autoantibody involved. Direct antiglobulin test may be false negative if the steps of the tests are not followed properly In 10% of patients of AIHA, DAT may be truly negative either due to scanty number of autoantibodies or due to presence of IgA antibody Direct antiglobulin test may also be false positive in some otherwise normal patients who never progress to develop AIHA. It can also be positive following recent blood transfusion. However, in both these cases it is weakly positive. D

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Cold agglutinin

Isotype

IgG

IgG

IgM

Temperature

37°C

4°C

4°C

Complement fixation

Variable

Yes

Yes

Antigen specificity

Rh

P

I/i

Site of destruction of RBC

Extravascular

Intravascular

Intravascular/ Liver

At 37°C

IgG±C3

C3

C3

At 4°C

No need

IgG±C3

C3

Titers of antibody

Low

Moderate

High

Treatment

Avoid cold Steroids/ Steroid Intravenous Immunoglobulin Splenectomy

Avoid cold Avoid cold

Plasmapheresis outcome

Chronic

Short term













PCH



Warm-reactive







DAT



Both primary and secondary AIHA are caused by presence of autoantibodies that bind the red cell antigens. This leads to intravascular hemolysis (as in cold agglutinin disease or PCH) or extravascular clearance of the sensitized red cells in spleen or liver (as in warm-reactive antibody). Hence it is important to understand the role of the autoantibody and the RE system in AIHA. • utoantibody: It is important to understand the 718 characteristics of the autoantibody including its isotype,

Characteristic



Pathophysiology

Table 11.9.2 Essential characteristics of difference autoantibody isotypes seen in autoimmune hemolytic anemia

Short term

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Patients with mild disease who are otherwise comfortable are better observed alone without much therapy • Most patients are usually very sick looking in first few days. They may go into severe intravascular hemolysis with renal involvement • It is important to maintain good urine output • As there is rapid turnover of red cells, folic acid should be replaced in therapeutic doses • Packed RBC transfusion (PRBC): – Packed RBCs can be life saving in patients with severe AIHA and should never be withheld with fear of hemolytic reactions • Hemoglobin levels should be maintained at 6–8 gm%. If the Hb is allowed to drop lower than that, it can lead to cardiovascular decompensation. There may occur two problems with transfusion in patients with AIHA: • First, there is usually a problem with crossmatching the unit • Second, there are chances of hemolysis following transfusion. As most of the warm-reactive antibodies are against Rh system, they are pan-reactive and will react with all the units of PRBC. One can use the pack that is found to be “least incompatible” on crossmatching and start the transfusion at very slow rate initially to see for hemolytic reaction. Always watch for hemolysis which will be evident with fever, restlessness, loin pain, hemoglobinuria (dark urine) and check for hemoglobinemia in plasma and hemoglobinuria in urine tests.

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I

Intravenous immunoglobulin (IVIg) in high doses of 2–5 g/ kg has only limited response, and is exorbitantly expensive and has potential side effects. It has shown benefit only in 30–50% of AIHA treated with IVIg. It is not the standard of care as the first-line therapy in AIHA. • Exchange transfusion: Exchange transfusion is bene ficial as it removes the antibody, complements and the sensitized red cells. However, it is labor intensive and hazardous. • Plasma exchange: Plasma exchange is found to be very successful in IgM antibody-induced AIHA. IgM being a large molecule stays in the circulation and does not leak into the tissues. As IgM does not bind to red cells at body temperature, it is likely to be free in plasma available for exchange especially in warm atmosphere.







•

ntravenous mmunoglobulin

­

General Management

Corticosteroids are the first line and the mainstay in the definitive therapy of AIHA. It is indicated for moderate-tosevere disease. They are effective in 80% of warm-reactive antibodies and occasionally even in cold agglutinin disease. For initial few days one can use IV methylprednisolone in the dose of 1–2 mg/kg 6–8 hourly. Once the patient is stable, one can switch over to high dose oral prednisolone in the dose of 2 mg/kg/day for 2–4 weeks followed by gradual tapering over 3 months based on the symptoms, Hb levels, evidence of hemolysis, serum LDH levels, reticulocyte count and DAT grade. While tapering one may switch over to daily or alternate single dose of steroids. Steroids work by blocking the Fc receptor as well as suppressing the antibody production. Hence the effect is usually seen in few days of therapy. One should regularly monitor for common side effects, especially blood pressure, blood sugar and weight (Fig. 11.9.2). I



Management

teroids

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disease also depends on the antigenic specificity and the complement binding capacity. Complement binding capacity, red cell antigen specificity and antibody binding affinity: Bound immunoglobulin binds complement C1q via its Fc portion. This leads to further cascade effect up to formation of C3b. At this juncture, either the red cell is cleared by the RE system that recognizes the C3b via specific-surface receptor leading to extravascular hemolysis, or the complement cascade activation continues till the red cell is destroyed leading to intravascular hemolysis. As IgG autoantibody has specificity to Rh system which has sparse distribution on red cell surface, and as two molecules of IgG antibodies are needed nearby to bind C1q, the complement capacity binding of IgG autoantibody is inefficient leading to extravascular hemolysis. Whereas, IgM autoantibody being a pentamer binds complement efficiently leading to intravascular hemolysis. IgM antibody has antigen specificity against I/i antigen. Similarly as the cold-reactive IgG autoantibody has specificity against P antigen, which is densely present on the red cell membrane; it binds the complements efficiently leading to intravascular hemolysis. IgG antibody binds the red cell antigen with high affinity as compared to IgM antibody.

 

Figure 11.9.2 Autoimmune hemolytic anemia on steroid therapy Courtesy: Dr MR Lokeshwar and Dr Bharat Agarwal

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Autoimmune hemolytic anemia can occur as a part of underlying autoimmune disease or as a result of a specific precipitating cause, which must be looked for in every case. Secondary AIHA can occur in patients with underlying autoimmune disease like SLE, scleroderma, Sjogren’s syndrome, dermatomyositis, etc. It can occur as a part of autoimmune cytopenias—Evan’s syndrome where one sees antibody to platelets and at times to neutrophils. Evan’s syndrome is potentially severe and fatal and hence needs aggressive management.

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econdary utoimmune Hemolytic nemia

ibliography



1. Collins PW, Newland AC. Treatment modalities of autoimmune blood disorders. Semin Hematol. 1992;29(1):64-74. 2. Engelfriet CP, Overbeeke MAM, von dem Borne AE. Autoimmune hemolytic anemia. Semin Hematol. 1992;29(1):3-12. 3. Heidemann SM, Sarnaik SA, Sarnaik AP. Exchange transfusion for severe autoimmune hemolytic anemia. Am J Pediatr Hematol Oncol. 1987;9(4):302-4. 4. Hilgartner MW, Bussel J. Use of intravenous gamma globulin for the treatment of autoimmune neutropenia of childhood and autoimmune hemolytic anemia. Am J Med. 1987;83(4A):25-9. 5. Kowal-Vern A, Jacobson P, Okuno T, et al. Negative direct antiglobulin test in autoimmune hemolytic anemia. Am J Pediatr Hematol Oncol. 1986;8(4):349-51. 6. Salama A, Berghofer H, Mueller-Eckhardt C. Red blood cell transfusion in warm-type autoimmune haemolytic anaemia. Lancet. 1992;340(8834-8835):1515-7. 7. Salama A, Mueller-Eckhardt C. Autoimmune haemolytic anemia in childhood associated with non-compliment binding IgM autoantibodies. Br J Haematol. 1987;65(1):67-71. 8. Ware RE. Autoimmune hemolytic anemia. In: Nathan DG, Ginsburg D, Orkin SH, Look AT (Eds). Hematology of Infancy and Childhood. Pennsylvania: Saunders; 2003. pp. 521-59.

High dose dexamethasone Cytotoxic drugs like vincristine, cyclophosphamide, azathioprine Immunomodulators like danazol, cyclosporine, etc. Rituximab, the monoclonal anti-CD20 antibody, has been used as off label in many autoimmune disorders including AIHA with anecdotal reports of success. There is limited experience to use these drugs in children with AIHA. They also have limited success and are toxic in children.



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• •

ther Modalities Tried

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• •

It can also occur in malignancies like acute leukemia and lymphoma. The main problem in such patients is of course the malignancy and not AIHA. Also seen in patients with immunodeficiency including HIV as a result of immune dysregulation. Cold agglutinin disease in children usually occurs following mycoplasma infection. Bacterial sepsis can lead to exposure of the cryptic T antigen and immune hemolysis. Drugs like penicillin including cephalosporins can induce AIHA. Secondary AIHA needs twofold therapy, treatment of AIHA and treatment of the baseline disease. Attention should be paid to remove the offending drugs. Steroids are equally useful in secondary AIHA as in primary AIHA, and can be used without fear even in cases of immunodeficiency.



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Warm-reactive AIHA is likely to be chronic in spite of steroids and IVIg use. Many such patients who are perpetually sick and need repeated admission and packed red cell transfusions with its own therapy-related complications, and splenectomy is the ultimate therapy of choice and works better in patients with IgG-induced AIHA than IgM-induced AIHA. Nearly 60% respond very well and another 20% have satisfactory response. All the precautions like immunization against capsulated organisms before splenectomy, and penicillin prophylaxis for life after splenectomy have to be followed. Splenectomy is avoided as far as possible till the age of 5 years. O

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Coagulation Disorders and Hemophilia





Diseases of Bloo

11.10

Diagnostic pproach in Bleeding Disorder Child A

ntroduction

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History Clinical evaluation of bleeding patients begins with taking a careful history, taking into account the child’s age, sex, clinical presentation, past history and family history while a bleeding history is being elicited; attention should be directed to the type of bleeding present as given in Table 11.10.1.

ge and ex of the Patient S



Coagulation disorders are disruptions in the body’s ability to control blood clotting, an essential function of the body designed to prevent blood loss. Coagulation disorders are usually discovered when an injury or surgery initiates bleeding and bleeding does not stop spontaneously. Coagulation is a complex process (called coagulation cascade) that involves 12 coagulation factors found in blood plasma and several other blood components. A deficiency in clotting factors or a disorder that affect one of the many steps in the entire process can disrupt clotting and severely complicate blood loss from injury, surgery or spontaneously (Figs11.10.1A to C).

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Inherited bleeding disorders should be strongly considered when the onset of bleeding manifestations occurs in

B

C

 

Figures 11.10.1A to C Coagulation disorders. Courtesy: Dr MR Lokeshwar and Dr Sunil Gomber

 

Table 11.10.1 Clinical presentation past history and family history of bleeding patients Clinical finding

Coagulation disorders

Purpuric disorders (disorder of platelets and blood vessels)

Skin-petechiae

Not usually seen

Characteristics

Ecchymosis

Common-large one or more

Characteristic: Small or many scattered

Soft-tissue hematoma

Characteristics

Rare

Joint hemorrhages

Characteristics: Hallmark of disease

Not usually seen

Delayed bleeding

Common

Rare

Bleeding from superficial skin abrasion

Uncommon

Common and persistent

F/H of bleeding

Common

Rare

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Hemophilia A (FVIII def.) and hemophilia B (FIX def.) are the most common and serious congenital coagulation factor deficiencies. The clinical findings in hemophilia A and hemophilia B are virtually identical. Hemophilia A is more common than Hemophilia B. Diagnosis of hemophilia: Hemophilia should be suspected in patients presenting with a history of: • •

Easy bruising in early childhood Spontaneous bleeding (particularly into joints and soft tissue) Excessive bleeding following trauma or surgery.

•

The severity of bleeding manifestation in hemophilia is generally corrected with the clotting factor level as shown in Table 11.10.2. Bleeding manifestation in hemophilia











Site of bleeding Serious Life-threatening Joint CNS * Muscle/soft tissue GIT * Mouth/gum/nose Neck/throat * Hematuria Incidence of different sites of bleeding: • Hemarthrosis: 70–80% • Muscle/soft tissue: 10–20% • Other major bleed: 5–10% • CNS bleed: < 5% Chronic complications of hemophilia: • • • • • • • • •

Musculoskeletal complications Chronic hemophilic arthropathy Chronic synovitis Deforming arthropathy Contractures Pseudotumor formation (soft tissue or bone) Fracture Inhibitors against F VIII/F IX Transfusion-related infection.





and Hemophilia B

 



Table 11.10.2 Clotting factor level Severity

Clotting factor Bleeding episodes level (% activity)

Mild

5–40

Severe bleeding with major trauma or surgery

Moderate

1–5

Occ. spontaneously bleeding, severe bleeding with trauma, surgery

Severe

<1

Spontaneous bleeding predominantly in joints and muscles















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The usual initial screening tests in a bleeding child include quantitation of platelets, examination of peripheral blood smear and coagulation tests. Routine test of blood coagulation, such as prothrombin time (PT), activated partial thromboplastin time (aPTT), and thrombin time (TT) are frequently ordered to assess clotting function in patients. • Prothrombin time: The patient is used to assess the extrinsic pathology of clotting, which consists of tissue factor (TF) and factor vii and coagulation factor in the common pathway (factors ii, v, x and fibrinogen) • ctivated partial thromboplastin time: This is used to assess the integrity of the intrinsic coagulation pathway (prekallikrein, high-molecular weight kininogen, factors xii, xi, ix, viii) and final common pathway • Thrombin time: The thrombin time measures the final step of the clotting pathway, the conversion of fibrinogen to fibrin • eptilase time: Reptilase, a thrombin like enzyme obtained from snake venom, differs from thrombin by generating fibrinopeptide A but not fibrinopeptide B from fibrinogen and by resisting inhibitor by heparin via antithrombin III • Mixing studies: After an abnormality in a clotting test (PT or aPTT) has been detected, it is important between a clotting factor deficiency and an inhibitor against clotting factors. This is accomplished by performing a mixing study, in which the patients plasma is mixed in a 1:1 ratio with normal serum (NS) or aluminum hydroxide adsorbed plasma (Ads) and the abnormal tests are repeated. Normal serum contains F IX, X, XI, XII and Ads contains FV, VIII, XI, XII. Mixing studies (Prolonged activated partial thromboplastin time) NS (corrected) NS (not corrected) NS (not corrected) Ads (not corrected) Ads (corrected) Ads (not corrected) ↓ ↓ ↓ Diagnosis: FIX def. FVIII def. Factor XI, XII def. Vwd (↓ BT) Factor Assay

Hemophilia



aboratory Testing

Clot solubility in urea: Fibrin is cross-linked through the action of factor XIII, making the final fibrin clot insoluble in 5 molar urea. The ability of urea to solubilize the mature clot reflects a deficiency of factor XIII.

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infancy or early childhood and is associated with a positive family history. However, a negative family history does not exclude an inherited coagulation disorder, as up to onethird of patients with hemophilia have a negative family history.

Diagnostic Test

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ibrin D-dimer: Plasmin cleaves fibrin at multiple sites and release fibrin degradation products (FDPs). One of the major FDPs is D-dimer. An elevated plasma concentration of D-dimer indicates recent or ongoing intravascular blood coagulation F

•

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Diseases of Bloo

Type of hemorrhage

Hemophilia A

 

Hemarthrosis

40 IU/kg FVIII conc. on D1, then 20 IU/kg on D2, 3, 5 until joint functions normal or back to baseline

60–80 IU/kg FIX conc. on D1, then 40 IU/kg on D2, 4

Muscle or subcutaneous hematoma

20 IU/kg FVIII conc., may need every other day treatment until resolved

40 IU/kg FIX conc ,may need treatment every 2–3 days until resolved

Mouth and tooth extraction

20 IU/kg FVIII conc., antifibrinolytic therapy

40 IU/kg FIX conc., antifibrinolytic therapy

Iliopsoas hemorrhage

50 IU/kg FVIII conc. then 25 IU/kg every 12 hours until asymptomatic then 20 IU/kg every other day for a total of 10–14 days

120 IU/kg FIX conc. then 50–60 IU/kg every 12–24 hours until asymptomatic then 40–50 IU/kg every other day for a total of 10–14 days

Principles of Care Prevention of bleeding should be the goal: – Acute bleeds should be treated early (within 2 hours if possible) – Home therapy should be used to manage only uncomplicated, mild or moderate bleeding episodes – All severe bleeds should be managed in the hospital settings – Patients should avoid trauma by adjusting their life style – IM injection and arterial puncture must be avoided – Regular exercise should be encouraged to promote strong muscle. Management of bleeding: When mild-to-moderate bleeding occurs, levels of factor VIII or factor IX must be raised to hemostatic levels in the 35–50% range. For lifethreatening or major hemorrhages, the dose should aim to achieve levels of 100% activity. Calculation of the dose of FVIII and FIX is as follows: Dose of FVIII (IU) = % desired (rise in FVIII) × body weight × 0.5 Dose of FIX (IU) = % desired (rise in FIX) × body weight × 1.0 Treatment of some common type of hemorrhage in patients with hemophilia has been listed in Table 11.10.3.

•

•





•

in addition to increasing factor level with clotting factor conc. or desmopressin in mild hemophilia A. • Antifibrinolytic drugs (e.g. tranexamic acid, EACA) for 5–10 days are effective as adjunctive treatment for mucosal bleed and are used to decrease the use of coagulation product in dental extractors Prophylaxis: Prophylaxis is the administration of clotting factors at regular interval to prevent bleeding and must be the goal of all hemophilic care programs until a cure is available



Management of Hemophilia

Desmopressin

A

It is synthetic analog of antidiuretic hormone. It boosts the plasma levels of FVIII after administration and useful in treatment of person with mild hemophilia. This is not effective in treatment of moderate or severe hemophilia and hemophilia B.

•

djunctive Management Rest, ice, compression and elevation is an important adjunctive management for bleeding in muscle or joints

d

 

Table 11.10.3 Treatment of some common type of hemorrhage in patients with hemophilia

•

Primary prophylaxis: Usually such programs are initiated with the first joint hemorrhage. Such programs, although expensive, are highly effective in preventing or greatly limiting the degree of joint pathology. Treatment is usually provided every 2–3 days to maintain a measurable plasma level of clotting factor (1–2%) when assayed just before the next infusion. Currently the most commonly suggested protocol for prophylaxis is the infusion of 25–40 IU/kg of clotting factor conc. Three times a week and twice a week for those with hemophilia A and hemophilia B respectively Second prophylaxis: In patients with repeated bleeding particularly into specific joints (target joints), shortterm secondary prophylaxis for 4–8 weeks can be used to interrupt the bleeding cycle. This may be combined with intensive physiotherapy or synoviorthesis Comprehensive care: Today patients with hemophilia are best managed through comprehensive hemophilia care centers. Such centers are dedicated to patients and family education as well as to the prevention and/or treatment of the complications of hemophilia, including chronic joint disease and inhibitor development as well as infection, such as hepatitis C and HIV. Such centers involve a team of physicians, nurse, orthopedists, physical therapists and psychosocial workers, among others.

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Platelet and Vascular isorders

Primary defects predominantly present with superficial bleed whereas secondary defects often lead to deep visceral bleed. Primary platelet disorders

ntroduction

• •

Quantitative platelet disorders • •

Neonatal Postneonatal. As discussed before, there are many causes of neonatal thrombocytopenia but the most common cause of significance includes alloimmune and autoimmune platelet disorders.

Neonatal lloimmune Thrombocytopenia • • • • •

• •

 

Table 11.11.1 Neonatal Autoimmune/Alloimmune

Antenatal

Pre-eclampsia/eclampsia Abruptio placentae Dead twin fetus Congenital infections

Natal

Breech delivery

Postnatal

Infections/Respiratory distress syndrome Hypoxia Indwelling catheters

Drugs

Prolonged antibiotics Thiazides in mother

•

Bone marrow disorders

Fanconi’s syndrome/Osteopetrosis Congenital leukemia

•

Inborn error of metabolism Isovaleric acidemia/Propionic acidemia Isolated megakaryocytic hypoplasia

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Immune disorder

•

Most common cause of severe thrombocytopenia Occurs in 10–20% babies with neonatal thrombocytopenia Commonest antigen responsible: HPA1-a (PLA-1) The severity of disease increases with subsequent pregnancies Pathogenesis: Maternal sensitization to the paternallyderived antigens expressed on fetal platelets; occurs during early gestation—production of IgG antibodies— crosses placenta and attach to fetal platelets leading to platelet destruction Any systemic disease in baby and mother should be ruled out Typically, healthy infants present with petechiae, purpurae and ecchymosis and bleeding; 10–15% may present with intracranial bleed Ninety percent have a platelet count of less than 50,000/ mm3 Mainstay of treatment includes PLA negative platelet transfusion, IVIg and steroids. Recovery of platelet count occurs in 2–3 weeks. A

Neonatal utoimmune Thrombocytopenia • •

• •

Passive transfer of antibodies from the mother to baby Noted in maternal conditions including SLE, hypo thyroidism, lymphoproliferative states and ITP Autoimmune thrombocytopenia is less severe than autoimmune thrombocytopenia Gestational thrombocytopenia does not lead to neonatal thrombocytopenia Antibody formed against an antigen present on maternal platelet as well as fetal platelet Commonest antigens: Gp 2b/3a, Gp1b/9 ­

•

Primary: Qualitative/quantitative defect in platelet number and function, and vascular disorders econdary: Clotting factor defect. S

•

Quantitative Qualitative.

A



Platelets play a pivotal role in vascular hemostasis. They are present in blood in a concentration of 1.5–4 lakh/mm3. Any derangement in platelet number or function leads to loss of vascular hemostasis. Platelet plug formation occurs after a sequence of events starting from vascular wall injury resulting in exposure to collagen and endothelial protein. Initial platelet adhesion is mediated via von Willebrand factor (VWF) and collagen binding to Gp1b/9 and Gp2b/3a, fibrinogen and calcium. Platelet adhesion results in intracellular signaling and platelet activation resulting in degranulation, activation of gp2b/3a complex, exposure of anionic phospholipids and generation of procoagulant microvesicles. The release of various granules and proteins leads to collagen binding to Gp 6 resulting in cellular activation and firm adhesion. This leads to further platelet aggregation. Exposure of anionic phospholipids results in thrombin generation and fibrin production leading to hemostatic plug stabilization. The actin-myosin complexes within the platelet shorten leading to clot retraction. TXA2 generation induces further platelet aggregation, blood vessel contraction and vasoconstriction (Table 11.11.1). Disorders of vascular hemostasis can be broadly classified as:



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Decreased platelet production

Platelet pooling

Idiopathic (immune)

Drugs: Chlorothiazide, tolbutamide

Hypersplenism

Infections

Megaloblastic anemia

Hypothermia

Drug induced

IEM

Autoimmune

Aplastic anemia: diopathic/acquired

Hemolytic uremic syndrome, thrombocytopenic purpura

Marrow infiltration

DIC

Infections: Rubella

Hemophagocytic syndrome

Constitutional

D

i

Increased platelet destruction

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Table 11.11.2 Neonatal autoimmune thrombocytopenia

 

Figure 11.11.1 Bone marrow examination in immune-mediated thrombocytopenia. Courtesy: Dr MR Lokeshwar and Professor Sunil Gomber

Kasabach–Merritt syndrome Lymphoreticular malignancy

• •

Mainstay of treatment includes platelet transfusion, IVIg and steroids Recovery occurs in nearly 3 weeks (Table 11.11.2).



As idiopathic thrombocytopenic purpura (TTP) is the most common cause of thrombocytopenia in healthy children, we have discussed the same in detail (Figs 11.11.1 to 11.11.3).





Most common cause of thrombocytopenia in children Peak age of occurrence: 2–5 years Mechanisms: Antibody-mediated destruction directed against Gp2b/3a, Gp1b/9 and Gp1a/2a Impaired megakaryopoiesis mediated by immune cell derived. Cytokines and antibody and cellular cytotoxicity.

Figure 11.11.2 Idiopathic thrombocytopenic purpura Courtesy: Dr MR Lokeshwar and Professor Sunil Gomber  

• • •

Clinical Presentation • • •

Commonly presents 1–3 weeks after a viral infection; implicated virus: HIV, rubella, hepatitis C, CMV, chickenpox, live viral vaccines Predominantly presents with petechiae, purpurae and ecchymosis. May present with bleeding. Intracerebral hemorrhage is noted in 0.2–0.8% A typical presentation includes isolated thrombocytopenia, with normal counts in otherwise healthy child without any hepatosplenomegaly, lymphadenopathy and bony tenderness and may be preceded by a viral infection 1–3 weeks earlier.

Investigations Complete blood count to be done in all cases BM examination shows normal or increased megakaryocytes with normal or erythroid and myeloid maturation. In a typical case, BM examination is unnecessary.

Figure 11.11.3 Glanzmann’s thrombasthenia Courtesy: Dr MR Lokeshwar and Professor Sunil Gomber

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Qualitative Platelet isorders D

Majority (80%) remit within 6 months. Only reassurance and danger signs is to be explained if platelet count greater than 20,000/mm3 with no bleed. Platelet transfusion to be given if count less than 10,000/ mm3 irrespective of bleed. The working party of British Committee for standards in hematology considered: • Treat mild cases with supportive advice and a 24-hour contact program • Intervention reserved only for children with organ or life-threatening bleeding irrespective of the platelet count. Any serious bleed should be managed with platelet support. Prednisolone (oral): 4 mg/kg/day for 4 days f/b 2 mg/kg/ day for 10 days f/b tapering over next 10 days. In a randomized controlled study group receiving oral prednisolone (60 mg/m2/day for 21 days) had a significantly faster platelet rise than the group receiving a placebo. Around 90% children achieved a platelet count of 30 x 109/ with in first 10 days. Methyl prednisolone (i ): 30 mg/kg/day for 3–5 days. It seems wise to use high-dose corticosteroids regimens for

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Management

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as short a time as necessary to achieve a meaningful endpoint. ntravenous immunoglobulin: 1 g/kg x 2 days. High dose IVIg block the Fc receptors on macrophages in the RE system especially spleen, causing dramatic increase in platelets. Randomized controlled trial by Blanchette et al. showed IVIg equivalent to oral steroids in early rise of platelet count to greater than 20 x 109/ and superior to oral steroids in rise of platelet count to greater than 50 x 109/ . nti- globulins ( V h g): A single dose of 75 µg/kg of anti D can be recommended as standard dosing for treatment of children with acute ITP who are rhesus (D) positive. Beneficial effect is due to competitive inhibition of RE function by preferential sequestration of immunoglobulin coated autologous RBCs. Randomized clinical trial in 101 children by Tarantino et al. IV anti-D 75 µg/kg superior to IV anti-D 50 µg/kg and equivalent to IVIg (0.8 g/kg) with respect to platelet count greater than 20x109/ at 24 hour after therapy (Table 11.11.3).

As qualitative platelet defects are not common, we have enlisted the disorders in Table 11.11.4.

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Indications for bone marrow examination: • Presentation suggestive of leukemia/AA • Sick child • Persistent thrombocytopenia beyond 6 months • Presence of generalized lymphadenopathy/bony tenderness • Anemia disproportionate to the severity of bleeding • Presence of weight loss • Before starting corticosteroids.

 

 

Table 11.11.4 Qualitative platelet disorders Adhesion defects Primary aggregation defects Bernard-Soulier Glanzmann’s thrombasthenia syndrome

Table 11.11.3 Other modalities of treatment ? Some benefit in chronic immune Nonsteroidal immunosuppressive therapy mediated thrombocytopenia (vincristine, cyclosporine, rituximab) Plasmapheresis ? Some benefit as emergency measure Splenectomy Acute immune-mediated thrombocytopenia with uncontrolled bleed chronic immune-mediated thrombocytopenia persisting at least 12–24 months

Arachidonic acid pathway defect Cyclo-oxygenase deficiency

Others Platelet factor 3 deficiency

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Platelet secretion disorders Storage pool disease -Hermansky- udlak -Chediak- igashi -Gray platelet syndrome

Von Willebrand’s disease

Congenital afibrinogenemia

Thromboxane synthetase deficiency

Afibrinogemia

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valuation of a Child with Thrombosis

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Diseases of Bloo

11.12

E

E

The process of hemostasis is easily conceptualized by dividing it into cellular and fluid phases. The former involves platelets and the vascular wall, while the latter involves plasma proteins. The physiology of hemostasis is complex and involves a fine balance between flow of blood (i.e. fluid) and local responses to vascular injury (i.e. clotting). The fluid phase is divided into three processes:

Thrombosis can cause significant morbidity and even mortality in newborns and children. Excessive coagulation or abnormal hemostasis leading to the formation of a thrombus, potentially obstructing blood flow, it may be venous or arterial. This is a relatively uncommon emergency in pediatrics. However, it is important to ensure early diagnosis and proper management to reduce permanent sequelae (Figs 11.12.1A and B).

•

pidemiology

Children who are critically ill may have thrombosis which is due to inflammation, infection, DIC, impaired liver function, central venous or arterial catheters • Sick newborns are at higher risk as children till 6 months of age have lower levels of the vitamin K-dependent coagulation factors II, IX, and X, compared to adults • Levels of thrombin inhibitors, such as antithrombin and heparin cofactor II, and protein C and S are lower at birth. Protein S levels reach adult levels by 1 year of age, but protein C levels remain low throughout childhood • Furthermore, plasminogen levels are low in newborns and infants. Thrombin generation is decreased (probably because of low-prothrombin levels) and delayed in newborns compared with adults. The incidence of thrombosis peaks in infants younger than 1 year and again during adolescence.

•

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• • •

The multiple-step zymogen pathway that leads to thrombin generation Thrombin-induced formation of fibrin clot Complex fibrinolytic mechanisms which limit clot propagation Current evidence suggests there is overlap between the previously described intrinsic and extrinsic pathways and an important interaction between cells directly involved in hemostasis (i.e. TF-bearing cells and platelets) and the coagulation factors (Hoffman 2007). This model more accurately represents the interaction between cellular activity and coagulation proteins that leads to blood clot formation. Tissue factor-VIIa complex from the extrinsic pathway activates factors in both extrinsic and intrinsic systems. The important role of platelets, has led to a cell-based model of coagulation. The cell-based model identifies the membranes of TF-bearing cells and platelets as the site of activation of specific coagulation factors. In this model there is a three-phase process:

B

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Figures 11.12.1A and B Children with thrombosis. Courtesy: Dr MR Lokeshwar and Dr Tulika Seth

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Symptoms of thrombosis vary with the site and type— whether venous or arterial In deep vein thrombosis (DVT) there may be pain and swelling of the limb. Pulmonary embolism may present with anxiety, breathlessness, pleuritic chest pain, fever and cough and a high index of suspicion is required









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Table 11.12.1 Risk factors for thrombosis in children • Time-limited risk factors – Indwelling catheters – Infections – Surgery – Disseminated intravascular coagulation – Postinfectious transient antiphospholipid antibodies – Surgically correctable congenital heart disease (risk decrease once corrected) - Ongoing risk factors - Inherited thrombophilias – Factor V Leiden – Deficient antithrombin, protein C, protein S – Elevated homocysteine level – Elevations in lipoprotein (a) – Other less common genetic disorders of coagulation regulation or fibrinolysis • Acquired thrombophilias and prothrombotic states – Primary antiphospholipid antibody – Acquired decrease in coagulation regulatory proteins (nephrotic syndrome, protein-losing enteropathy, etc.) – Indwelling catheters – Leukemia, solid tumors and chemotherapy (e.g. L. asparaginase, etc.) – Inflammatory diseases (e.g. SLE, inflammatory bowel disease, etc.) – Prosthetic cardiac valves – Sickle cell anemia – Thalassemia intermedia – Diabetes mellitus

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to identify this early. Symptoms of CNS thrombosis include vomiting, lethargy, seizures, or weakness in an extremity. • Strokes may occur in utero, the newborns will present with seizures and lethargy. In older children the presentation is with headaches and acute onset of weakness in an extremity/hemiplegia; with a preceding episode of infection, dehydration or trauma. Patients with renal vein thrombosis may present with flank pain and hematuria • Signs such as limb edema, erythema and tenderness on dorsiflexion of the foot (Positive Homan’s sign) are present in DVT, but difficult to elicit in young children • Thrombosis of the inferior vena cava (IVC) and/or renal vein can cause flank tenderness • Signs of pulmonary embolism are nonspecific and include diaphoresis, tachycardia and tachypnea • Signs of arterial thrombosis include diminished or absent peripheral pulses and a coolness of extremity skin, with ischemic changes if not diagnosed early. Some important sites and their clinical features and risk factors are described below: • Cerebral sinovenous thrombosis: The cerebral sinovenous system in children may develop thrombosis, this system is comprised of the superficial cortical veins, superior sagittal sinus, lateral sinuses and deep, straight sinus, vein of Galen, internal cerebral and Jugular vein. The important risk factors for thrombosis in children are infection of the head and neck region, trauma to the head and neck, dehydration. Other factors implicated are perinatal complications in newborn infants (hypoxia, placental abruption, etc. ) bacterial sepsis, connective tissue disorder, hematologic disorders (e.g. sickle cell disease, leukemia, pediatric myelodysplasia and PNH), solid tumors, cardiac disease, indwelling vascular catheter, prothrombotic states (antiphospholipid antibodies or lupus anticoagulant; Factor V Leiden or prothrombin G20210A; acquired deficiency of protein S, protein C or antithrombin III), procoagulant drugs (e.g. L-asparaginase). A small percentage of patients (2%) will not have any identifiable risk factor. • enal vein thrombosis: Neonates may develop thrombosis of a renal vein, risk factors are polycythemia, dehydration, gestational diabetes (as it is associated with polycythemia and respiratory distress), asphyxia, sepsis and hypercoagulable state (protein-C deficiency, antithrombin III deficiency). The newborn presents with flank mass, hematuria, hypertension, thrombocytopenia and oliguria. A high clinical suspicion must be kept and appropriate diagnostic testing performed, e.g. ultrasonography. The infant should be evaluated for a hypercoagulable state if no other causative factor is identified • Protein C deficiency: This will usually present in early infancy or childhood. There may be a history of consanguinity in the family. The parents are heterozygous for the protein C defect. The patient

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– Initiation – Amplification – Thrombin production and action. This initiation occurs after a vascular injury, that results in binding of cells that bear tissue and these bind to and activate Factor VII. This step leads to the production of a small amount of thrombin, which activates platelets and cofactors in the amplification phase. The prothrombinase complex (factor Xa + cofactors bound to activated platelets) is responsible for burst of thrombin production, which then leads to the third phase of clot formation. The coagulation cascade is triggered after injury to a blood vessel allowing exposure to TF-bearing cells. The factor Xa and activated factor V (Va) as a cofactor, propagates coagulation by converting prothrombin (Factor II) to thrombin (Factor IIa). Factor Xa central to the amplification of this process. This process may be triggered due to inherited prothrombotic factors (Table 11.12.1), but are more commonly due to inflammation, vasculitis, infection, malignancy, etc.

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• • •

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Many clotting factors are consumed in the clot formation and some tests are hindered by concomitant

 

Table 11.12.2 Initial workup for thrombosis to evaluate for hypercoagulable state • Complete hemogram (Hb/TLC/platelet count, DLC) • PT/aPTT • Radiology as indicated by symptoms • Activated protein C resistance and/or factor V Leiden mutation • Antithrombin (Fig. 11.12.2) • Lupus anticoagulant (which may be screened by using the dilute Russell viper venom test) 

•

Greater than or equal to one vascular thrombosis in any artery, vein or small vessel confirmed by an objective criterion and in the absence of vasculitis Greater than or equal to three unexplained consecutive abortions before 10th week of gestation with normal maternal and paternal cytogenetics and normal maternal anatomy Greater than or equal to one unexplained fetal death after 10th week of gestation with normal fetal morphology Greater than or equal to one premature birth before 34th week of gestation because of eclampsia or severe pre-eclampsia Greater than or equal to one premature birth before 34th week of gestation with placental insufficiency.

If venous thrombosis is present, look for fever, recent surgery, trauma, central venous catheter use, nephrotic syndrome, varicella and other infections Elicit a history of any previous thrombosis. Obtain a thorough family history to suggest inherited thrombo philia states (Table 11.12.2) Inquire for a history or symptoms suggestive of congenital heart disease and/or recent cardiac catheterization, which are the most common causes of arterial thrombosis in children.

• Anticardiolipin antibodies • Lipoprotein (a) level

Laboratory Criteria

• Plasma homocysteine values

•

• Prothrombin gene 20210A mutation (infrequent in India)

• •

• Protein C (usually decreased in acute thrombosis) • Free and total protein S (usually decreased in acute thrombosis) • Warfarin therapy affects protein C, protein S and antithrombin assay 

• Heparin therapy (both unfractionated and low-molecular weight) affects antithrombin, protein C, protein S and APC resistance assays • Neither drug affects results of anticardiolipin antibodies, factor V Leiden, the prothrombin mutation, lipoprotein (a) or homocysteine levels 

•

Lupus anticoagulant on greater than or equal to two occasions greater than or equal to 12 weeks apart IgG and/or IgM anticardiolipin antibody at moderate to high titers (> 40 GPL or MPL units) on greater than or equal to two occasions greater than or equal to 12 weeks apart IgG and/or IgM anti-beta-2-glycoprotein antibody on greater than or equal to two occasions greater than or equal to 12 weeks apart Mixed (more than one of the above).

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Clinical Criteria •

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Modalities of Diagnosis

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In children portal vein thrombosis is rare, it may occur if certain risk factors are present. These may involve the liver, the portal vein or the intra-abdominal structures drained by the portal vein. Known risk factors are intra-abdominal infection or inflammation, decreased blood flow due to cirrhosis with portal hypertension, fibrosis, etc. mass lesion interfering with blood flow including congenital anomalies; hyper coagulable states—protein S or C deficiency, antithrombin III deficiency or factor V Leiden; vascular injury from blunt abdominal trauma, catheterization infusion of drugs or hyperosmolar glucose into the umbilical vein and ET via umbilical vein.



A

Portal Vein Thrombosis

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will have a marked deficiency of protein C (< 1% of normal), usually associated with a homozygous or double heterozygous deficiency. The patient will have recurrent episodes of purpura fulminans and/or DVT unless anticoagulation therapy is given. This requires early identification, but may be difficult to differentiate from DIC in a newborn • ctivated protein C resistance ratio: Activated protein C (APC) normally has an anticoagulant effect. Some patients with recurrent venous thrombosis do not show the expected anticoagulant effect when APC is added to clotting tests, and these persons were termed “resistant” to the anticoagulant effect of APC. This is usually due to an autosomal dominant inherited mutation in factor V (Factor V Leiden) which resists proteolysis by APC when activated to factor Va • ntiphospholipid syndrome: If either lupus anti coagulants or increased anticardiolipin antibodies levels are present, then the antiphospholipid syndrome should be considered. The diagnosis of antiphospholipid antibody should not be made on a single abnormal test. It is important to demonstrate that the antibody is persistent in a patient with appropriate clinical findings, with at least two positive values at least 6 weeks apart. Criteria for the diagnosis of the antiphospholipid syndrome (Sydney Criteria): At least: (1) clinical criterion and (2) one of the four laboratory criteria.

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evaluation of subsegmental pulmonary arteries is limited to 80% visualization Ventilation-perfusion (V/Q) scanning is the procedure of choice in children with suspected PE. As an alternative, if D-dimer levels are elevated and if the V/Q scan indicates intermediate probability, spiral CT may be useful.

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Figure 11.12.2 Picture of disseminated intravascular coagulation (DIC). This picture shows decreased platelets, spherocytes and fragmented red cells

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use of heparin or warfarin, and the reported low protein C, S level may be the result of the existing thrombosis. Hence tests need to take account of the current status and type of antithrombotic medications being given The child should be evaluated to rule out DIC, complete blood count with peripheral blood smear, PT, aPTT and fibrinogen level.

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Imaging studies are difficult as the child requires sedation, and the small size of blood vessels makes the imaging even more complex. Imaging is not required if there is a very high index of suspicion with corresponding evidence from other tests and no contraindication to anticoagulation. • Color Doppler imaging is performed in vessels with thrombosis. The Doppler signals are absent and the lumen cannot be compressed with direct pressure in a thrombosed vessel. However, this may not be sufficiently sensitive to detect thrombosis in certain vessels such as subclavian veins, superior vena cava or brachiocephalic veins • Echocardiography is of great utility in detecting vena caval and proximal subclavian vein thrombosis • A head CT with intravenous contrast material is useful for detecting venous sinus thrombosis. However both MRI and magnetic resonance angiography (MRA) are better at detecting early arterial ischemic strokes • MRI and MRA of the head are the modalities of choice for evaluating a child with suspected CNS thrombosis • Chest radiography can show classic findings of PE include small pleural effusions with a wedge-shaped pleural-based opacity of pulmonary infarction, but frequently the X-ray chest may be normal • Multi-row detector computed tomography pulmonary angiography, pulmonary computed tomography angio graphy studies are successful in visualizing arteries 730 to the level of segmental pulmonary arteries, but the

Once a diagnosis of thrombosis is made the child needs urgent management to decrease mortality and late sequelae. If sick then stabilization is required, if respiratory distress or neurological problems exist then management in an intensive care unit is required. Screening tests for hypercoagulable state should be sent prior to initiating anticoagulation therapy if possible. Initial therapy requires heparin [unfractionated heparin (UH) or low-molecular weight heparin (LMWH)] followed by oral warfarin therapy (Table 11.12.3). Close monitoring is required to prevent over dosage and risk of bleeding. Under dosing will hamper resolution of the thrombus, most early recurrent thrombosis is due to inadequate therapy. The decision for long-term thrombosis depends on the risk of recurrence; this can be assessed by testing for thrombophilia status usually best done after 3 months of event and after stopping anticoagulants. The international normalized ratio (INR); which is PT of patient/to standard is the most useful test for monitoring oral anticoagulation. The INR therapeutic range is 2–3. Because the effects of LMWH on thrombin are minimal so the aPTT prolongation by LMWH is also correspondingly small. Hence aPTT can be used for monitoring of UH only, and for LMWHs, the anti-Xa assay may be needed if presence of renal compromise or extreme obesity. Newer guidelines recommend UH also be monitored by anti-Xa activity; however this is available in only few hospitals in India. Thrombolytic agents can be administered systemically or locally. The most relevant monitoring during thrombolytic therapy is clot lysis as determined by objective imaging. Clots should be imaged prior to and at the conclusion of thrombolytic therapy. Some children may need special care in selection of anticoagulant medication or may need alternative therapy due to a contraindications to anticoagulation, these children may benefit from placement of a temporary IVC filter (Table 11.12.4). Antithrombin activity is necessary to mediate the anticoagulant effect of heparin, this is decreased physiologically in well-term infants, more so in sick preterm infants and low in children with extensive thromboses, nephrotic syndrome or on Lasparaginase chemotherapy. A baseline aPTT within the normal range for age, can be used to monitor UH with a target aiming for a prolongation to 2–3 times the baseline value. Recurrent thrombosis is of justifiable concern, though in children with no adverse genetic factors the risk is low 4.8% recurrence rate (RR). Children with a single genetic risk factor 17.6% RR and those with two or more risk factors have an almost 50% RR. Recurrent thrombosis can be due to inadequate anticoagulation therapy.

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Oral warfarin Dose

Monitoring

Infants younger than a year

up to 0.5 mg/kg/d

Other children

0.1–0.15 mg/kg/d

The international normalized ratio (INR) is first measured after 3–5 days of therapy Warfarin should be overlapped with heparin. Heparin should not be discontinued until the INR is in therapeutic range for two consecutive readings INR between 2 and 3 is therapeutic range

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Table 11.12.3 Dosing for antithrombotic therapy in children

Unfractionated heparin by continuous intravenously (Loading dose, U/kg initial maintenance dose) Age

Loading (maintenance dose)

Monitoring

Neonates 28–37 weeks of gestation Infants at least 37 weeks of gestation Infants and children older than 1 month

50 U/kg (15 U/kg/h) 100 U/kg (28 U/kg/h) 75 U/kg (20 U/kg/h)

Baseline activated partial thromboplastin time is prolonged in neonates and infants, may be difficult to monitor Therapeutic range activated partial thromboplastin time is 2 x of normal

Age

Dose

Monitoring (if needed)

Newborns less than 1-month-old Infants between 1 month and 1 year of age Children 1–5 years of age Children 6–18 years of age

1.625 mg/kg 1.5 mg/kg 1.375 mg/kg 1.25 mg/kg

Anti-Xa activity 0.5–1.0 U/m

after DVT and is difficult to treat. This may cause significant stress and impairment in quality of life.

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Table 11.12.4 Contraindications to antithrombotic treatment in infants and children



• • •

Presence of residual thrombosis at 3 or 6 months after onset Recurrent thromboembolism within 2 years in a previously unaffected venous system Development of post-thrombotic syndrome.

Hence children with elevation of factor VIII and/or D-dimer at presentation with thrombosis or with a persistent elevation of factor VIII and/or D-dimer 3–6 months after standard duration anticoagulant therapy need close followup and therapy.

ecent dvances A

The sequelae can be devastating and permanent; they will depend on the site, extent and duration of thrombosis. • In utero CNS thrombosis or placental thrombosis may lead to severe, irreversible neurologic damage • Superior sagittal vein thrombosis if managed early may have only slight residual weakness which may resolve • Arterial thrombosis may lead to vascular compromise and even loss of limb • Post phlebitic syndrome characterized by persistent swelling, skin discoloration and pain is very common

Predictors of a poor outcome in a child with thrombosis were evaluated by Goldenberg et al. They used Factor VIII and D-dimer levels to identify children who may have poorer outcomes. They evaluated (a) Initial factor VIII level, (b) initial D-dimer level at presentation, (c) levels of factor VIII after standard duration anticoagulant therapy, (d) levels of D-dimer after standard duration anticoagulant therapy, at 3, 6, 12 months from episode and annually. The factors found to co-relate with a poor thrombotic outcome were:



Complications

Prognosis

R

For unfractionated heparin Known allergy to heparin History of heparin-induced thrombocytopenia For low-molecular weight heparin Known allergy to low-molecular weight preparation History of heparin-induced thrombocytopenia Plan to perform an invasive procedure within 24 hours Thrombolysis by interventional radiology Limitations due to small size of involved vessels Known allergy Systemic tissue plasminogen activator Active bleeding Central nervous system ischemia/hemorrhage/surgery (includes birth asphyxia) in last 7–10 days Seizures within the last 48 hours Had an invasive procedure within the last 3 days Known allergy

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Factor Xa activates clotting over a wider concentration range than thrombin, in both in vitro and in vivo systems. Direct 731 Factor Xa inhibitors in development have many properties of an ideal anticoagulant, including oral administration,

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and red cell counts and glucose and a protein level of 262 g/dL. An MRI showed thrombosis of the straight sinus and internal cerebral veins, hemorrhage in the posterior limb of the left internal capsule. The patient was started on continuous UH infusion. Increased intracranial pressure was treated with dexamethasone and mannitol. A partial workup for hypercoagulable disease per formed factor V Leiden, anticardiolipin antibodies, beta2 glycoprotein, and serum homocysteine serum levels were all within normal. The patient was discharged on warfarin, with regular monitoring of INR from the outpatient department. On follow-up after 6 months of oral anticoagulation his complete thrombophilia workup was performed including protein C, protein S and antithrombin and were found to be normal. Repeat MRI showed resolution and anticoagulation was stopped. On followup at 4 years of age, the child had a normal neurologic examination, except for a slight terminal tremor in the right upper extremities.









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rapid onset of action, and predictable pharmacokinetics and pharmacodynamics; with reduced need for monitoring. A number of new orally administered direct Factor Xa inhibitors are currently in development. These include rivaroxaban, apixaban, betrixaban and a group of as yet unnamed clinical entities (LY517717, YM150 and DU-176b). Rivaroxaban has been approved in Europe for the prevention of venous thromboembolism (VTE) in adult patients. Thrombin has a central role in the coagulation cascade. Produced in small amounts in the initiation phase and large amounts in the propagation phase, thrombin is essential for the amplification of coagulation and fibrin formation. Parenteral direct thrombin inhibitors currently available for clinical use—lepirudin, bivalirudin, and argatroban— are generally reserved for the treatment of patients with heparin-induced thrombocytopenia. These medications are administered parenterally and require individual dosing based on laboratory monitoring. Platelet adhesion to the injured endothelium depends on the interaction between subendothelial proteins and glycoprotein receptors on the platelet surface. This preliminary step in coagulation theoretically could be inhibited by blocking the platelet receptors for collagen and VWF. Like hirudin, an anticoagulant first isolated from leech saliva, a different type of anticoagulant protein has been isolated from mosquito saliva. This protein inhibits thrombosis by blocking platelet adhesion. Anopheline antiplatelet protein interferes with the link between collagen and the platelet glycoprotein VI receptor. Adenosine diphosphate (ADP) is the ligand for both P2Y1 and P2Y12 receptors. Stimulation of P2Y1 receptors initiates platelet activation and aggregation. Activation of P2Y12 amplifies the process. The P2Y12 receptor is the target for the thienopyridines group of drugs-clopidogrel and ticlopidine. Prasugrel, a new thienopyridine binds P2Y12 more avidly than clopidogrel. A different approach to platelet inhibition involves the hydrolysis of ADP into inactive adenosine monophosphate, thereby removing this potent stimulant from the platelet’s microenvironment. CD39, found on epithelial surfaces, has a hydrolytic function that confers both anti-inflammatory and antithrombotic properties. Recombinant human CD39 has been shown to inhibit platelet aggregation in vivo.

Practice Guidelines Early initiation of treatment is required for good outcome, standard dosing and monitoring is required. Lifelong anticoagulation is not needed in all children. Consultation with a hematologist for severe thrombosis and to get the appropriate thrombophilia tests performed is required, as this may be a life-threatening condition. The baseline aPTT is prolonged in neonates and infants. Unfractionated Heparin does not result in a linear further prolongation of the aPTT and regular monitoring is essential.

Practice Points/Tips Inadequate dosing results in recurrent thrombosis and frequent boluses may put the child at risk for hemorrhage. Unfractionated heparin and LMWH have similar results, the clinical scenario will dictate which will be used and the need for monitoring will depend on the underlying disease and risk for bleeding in the individual case. Due to fear of bleeding complications associated with anticoagulation, clinicians are reluctant to treat neonates and children with thrombosis aggressively despite a high prevalence of shortand long-term sequelae in this age group.

A 15-month-old boy presented with lethargy and seizures after 3–4 days low-grade fever, vomiting and diarrhea. Initial examination showed responsiveness only to painful stimuli, extensor posturing, and hyper-reflexia of the lower extremities (left greater than right) with bilateral clonus. Hemoglobin was 12.9 g/dL, TLC 5000 and platelet count was 325,000/L. Cerebrospinal fluid showed normal white

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ey Messages

• • • •

Thrombosis needs treatment Investigate to find the underlying cause Treat other comorbid factors Initial thrombophilia workup prior to anticoagulation (if possible) • Repeat thrombophilia workup after 3–6 months

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1. Biswas A, Ranjan R, Meena A, et al. Homocystine levels, polymorphisms and the risk of ischemic stroke in young Asian Indians. J Stroke and Cerebrovasc Dis. 2009;18(2):103-10. 2. deVeber G, Andrew M, Adams C, et al. Cerebral sinovenous thrombosis in children. N Engl J Med. 2001;345(6):417-23. 3. Ghosh K, Ghosh K. Advances in haematological pharmacotherapy in 21st Century. Indian J Hematol Blood Transfus. 2010;26(2):30-40. 4. Goldenberg NA, Knapp-Clevenger R, Manco-Johnson MJ, et al. Elevated plasma factor VIII and d-dimer levels as predictors

of poor outcome of thrombosis in children. N Engl J Med. 2004;351(11):1081-8. 5. Hoffman M, Monroe DM. Coagulation 2006: a modern view of hemostasis. Hematol Oncol Clin North Am. 2007;21(1):1-11. 6. Manco-Johnson MJ. How I treat venous thrombosis in children. Blood. 2006;107(1):21-9. 7. Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4(6):295-306. 8. Tormene D, Gavasso S, Rossetto V, et al. Thrombosis and thrombophilia in children: a systematic review. Semin Thromb Hemost. 2006;32(7):724-8.

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Bibliography

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isseminated ntravascular oagulation

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ntroduction

Disseminated intravascular coagulation is a syndrome characterized by massive activation of coagulation that occurs inside the blood vessels, leading to widespread deposition of fibrin in the small vessels, thus compromising blood supply to major organ systems. At the same time, the ongoing coagulation consumes platelets and coagulation factors, leading to severe bleeding. Disseminated intravascular coagulation is never a disease per se; it is always secondary to an underlying disorder that causes activation of coagulation in vivo.

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11.13

• •

•

tiology Disseminated intravascular coagulation has been seen in 0.4–1% of hospitalized children. In children, 95% of the cases are due to underlying infections Disseminated intravascular coagulation is a clinical diagnosis, based on deranged laboratory values in a patient with an underlying disease that is known to be associated with disseminated intravascular coagulation (DIC). It is usually a rare complication of many of the diseases listed below: Conditions associated with DIC (Table 11.13.1)

 

Table 11.13.1 Conditions associated with disseminated intravascular coagulation Infections • Bacterial sepsis (especially caused by Gram-negative organisms, e.g. meningococcemia) • Viruses (HIV, cytomegalovirus,Varicella, herpes, rubella, Acute-hepatitis, Reye syndrome) Fungal (Histoplasma, Aspergillosis) Protozoal (Malaria, Kala-azar) Rickettsial

Tissue injury/organ failure • Polytrauma, massive head injury, crush injury • Hypoxia/hypoperfusion, Shock • Cardiac arrest, Hypothermia, • Heat stroke • Extensive surgical intervention • Fat embolism • Extracorporeal circulation • Severe pancreatitis • Liver cell failure

Immunological conditions • Systemic lupus erythematosus • Autoimmune hemolytic anemia • Crohn’s disease/ulcerative colitis • Transfusion reactions • (ABO incompatibility) • Transplant rejections, Graft versus host disease

Vascular abnormalities • Kasabach-Merritt syndrome • Large vascular aneurysms • Coarctation of aorta • Large prosthetic arterial grafts

Cancer • Acute promyelocytic leukemia • Acute monoblastic leukemia • Lymphoproliferative disorders • Hemophagocytic lymphohistiocytosis • Solid tumors (neuroblastoma)

Gastrointestinal • Fulminant hepatitis • Severe inflammatory bowel disease

Neonatal • Maternal toxemia • Maternal infections • Dead twin • Abruptio placentae • Amniotic fluid embolism • Necrotizing enterocolitis • Perinatal hypoxia • Congenital infections • Respiratory distress syndrome • Erythroblastosis fetalis

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Thrombotic disorders • Homozygous Protein C def • Antithrombin III deficiency • Heparin-induced thrombosis

Miscellaneous • Snake bites • Insect bites • Recreational drugs • Poisoning: acute iron toxicity • Massive transfusions • Infusion of activated prothrombin complex concentrates

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In Gram-negative infections, endothelial injury occurs due to circulating endotoxins, resulting in collagen exposure, activation of platelets and activation of TF. Any factor that increases the propagation of sepsis, like immunosuppression can foster DIC. There is no difference in the incidence of DIC in patients with Gramnegative or Gram-positive sepsis • In diseases like cancers, tissue injury, etc. there is release of procoagulant tissue extracts into the circulation which then results in TF activation and generation of thrombin • Promyelocytes in acute promyelocytic leukemia (APML) express annexin II that results in increased plasmin production and increased fibrinolytic activity. Leukemic blasts also release TF containing vesicles into the circulation • In obstetric complications like placental abruption, release of decidual fragments results in a similar process • In giant hemangiomas as in Kasabach Merritt syndrome, there are large gaps in the endothelium that expose the subendothelial collagen which initiates the coagulation process • Disseminated intravascular coagulation is commonly observed with venomous snakebites worldwide. Hematological toxicity is observed commonly in viper envenomation. These venoms contain proteinases that activate the coagulation process; phospholipases that cause hemolysis of red cells and polypeptides that disrupt the endothelial lining. These result in consumption of coagulation factors, fibrinolysis and DIC • Further for activation of coagulation is the release of cytokines like endotoxins, IL-1, IL-6, IL-8, platelet activating factor and tumor necrosis factor.

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linical eatures leeding

Typically seen in acute DIC, it is often abrupt, massive and occurring from multiple sites. Bleeding occurring from intravascular access sites, venipuncture sites, surgical wounds are early indications of DIC. Mucocutaneous bleeding in the form of petechiae, purpurae, gum bleeding and epistaxis may be noticed. Bleeding may be also noticed from tracheal tubes while suctioning. In advanced disease gastrointestinal bleeding, hematuria leading to hemodynamic compromise and intracranial bleeding leading to increased intracranial pressure; herniation of brain leading to respiratory compromise has been observed. Bleeding is often severe enough to lead to hypovolemia and hypoperfusion (Figs 11.13.1A to D). Flow chart 11.13.1 Pathophysiology clinical features in disseminated intravascular coagulation  

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What nitiates isseminated ntravascular oagulation?

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Once initiated, there is accelerated turnover of platelets and coagulation factors. Natural anticoagulants like antithrom bin and protein C are also diminished in DIC. Impaired protein C pathway contributes to the procoagulant manifestation seen in this disease. The end result of coagulation pathway activation is the formation of strands of fibrin in the small blood vessels. Circulating RBCs get injured while passing through microvasculature with intravascular fibrin strands, thus forming schistocytes. Fibrin deposition on endothelial surfaces activates the process of fibrinolysis thus resulting in the formation of FDPs (Flow chart 11.13.1). • hronic disseminated intravascular coagulation: Otherwise known as compensated DIC, it occurs when the trigger is either a weak stimulus or is intermittent. Chronic DIC has been observed in giant hemangiomas, various vasculitis, aneurysms and some forms of cancers. In such conditions, the destruction and coagulation of clotting factors are balanced. C

The various stimuli that initiate DIC act on the normal processes that activate coagulation, viz. platelet adhesion and aggregation and activation of coagulation process either by contact factor activation (intrinsic pathway) or TF activation (extrinsic pathway). However, unlike in normal coagulation, these activating stimuli drive the coagulation process unchecked, thus preventing the normal compensatory processes. As a result, thrombin gets generated persistently, and fibrin strands are generated in the small blood vessels. Fibrinolytic pathways also get activated, thus leading to the formation of FDPs, which per se impair the hemostatic function. Bleeding occurs as a result of consumption of coagulation factors and platelets whereas microvascular occlusion due to fibrin generation leads to organ dysfunction. This process perpetuates as a vicious cycle and ultimately the interplay between various compensatory mechanisms (e.g. fibrin generation vs fibrinolysis, coagulation factor consumption vs repletion) dictates the clinical manifestation and course of the disease.

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nitiating isseminated ntravascular oagulation D

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Propagation of isseminated ntravascular oagulation

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Figures 11.13.1A to D Clinical features of disseminated intravascular coagulation. (A) Disseminated intravascular coagulation in a child; (B) Disseminated intravascular coagulation in a newborn with hematuria; (C) Gangrene following microvascular thrombosis; (D) Purpura fulminans. Courtesy: MR Lokeshwar and Sachdeva A



Generalized microvascular thrombosis leads to the development of purpura fulminans, peripheral acrocyanosis and gangrenous changes in digits, genitalia, nose and ears. Sharply demarcated ecchymotic areas can occur due to thrombotic occlusion of dermal vessels. In advanced disease, microvascular occlusion leads to multiorgan failure (Table 11.13.2). In a recent study of the profile of DIC in over 5,000 hospitalized children, it was observed in 1.12% of the patients. The underlying etiology was infection in over

 

Table 11.13.2 Clinical manifestations Hemorrhagic

Thrombotic

Peripheral acrocyanosis, purpura fulminans gangrenous changes in digits, nose, genitalia

Multiorgan dysfunction in disseminated intravascular coagulation

Derranged hepatic, renal and cardiac function jaundice, arrhythmias, oliguria, respiratory distress, gastrointestinal ulcerations, adrenal insufficiency, CNS abnormalities



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Skin and mucous membrane bleeding, hemorrhage from surgical incisions, drains, intravascular catheters, venipuncture sites

95% and major trauma in around 5% of the patients. Bleeding and thrombosis were observed in 48% and 4.8% respectively. Multiorgan dysfunction was observed in 85% of these patients with DIC. I

Thrombosis

nvestigations

There is no single laboratory test that can either confirm or rule out the diagnosis of DIC. Hence it is of utmost importance to consider both the clinical background and the various laboratory variables while coming to a decision. Laboratory investigations are aimed at: • • •

Identifying the underlying etiology Demonstrating evidence of consumption coagulopathy and increased activation of fibrinolytic cascade Disseminated intravascular coagulation is a dynamic process. Laboratory values change rapidly, and hence frequent monitoring is necessary to guide therapeutic decisions. The International Society for Thrombosis and Hemostasis Scientific Standardization, Subcommittee on DIC, proposed a scoring system based on four laboratory values: prothrombin time, platelet count, fibrin-related markers and fibrinogen level.

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The ISTH Sub-Committee of the Scientific and Standardization Committee has proposed a scoring system for the diagnosis and monitoring of DIC in 2001.

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ifferential iagnosis

• •

Thrombotic thrombocytopenic purpura Patients present with thrombocytopenia, microangiopathic hemolysis and multiorgan dysfunction. Differentiating features are rarity of petechiae, purpurae and normal coagulation functions (PT, aPTT, TT and FDP) in TTP. Fulminant hepatic failure. Decreased synthesis of coagu lation factors along with thrombocytopenia due to portal hypertension with hypersplenism leads to laboratory values that suggest DIC. Also FDP may be elevated due to reduced clearance in liver disease. However the generalized bleeding tendency is less in liver disease compared to DIC. Bleeding is often due to varices, gastritis or GI ulcers. ­

•

Management The most important aspect of managing a patient with DIC is to identify the underlying disorder and control it. In few situations, resolution of the underlying condition leads to complete resolution of DIC by itself. Usually supportive

 

Table 11.13.3 Scoring system for disseminated intravascular coagulation Risk assessment: Does the patients have an underlying disorder known to be associated with overt DIC? • If yes: Proceed • If no: Do not use this algorithm

1. Scoring system













• Platelet count – > 100 ×109/l = 0 – < 100 × 109/l = 1 – < 50 × 109/l = 2 2. Elevated fibrin marker (D-dimer, Fibrin degradation products)

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Thrombocytopenia: Suggests thrombin-induced platelet aggregation leading to consumption of platelets. Platelets counts are usually in the range of 50,000– 100,000/µL. Platelet count of less than 50,000/µL is noticed in around 50% of the cases. A single normal platelet count does not rule out DIC. A persistent downward trend in platelet count is a sensitive indicator of DIC • Peripheral smear shows fragmented RBC or schistocytes. The percentage of schistocytes, however, does not correlate to clinical severity. Schistocytes are neither sensitive nor specific for the diagnosis of DIC. It may be seen in other cases of microangiopathy like thrombotic TTP • Prothrombin time and activated partial thrombo­ plastin time and thrombin time: Prolonged in around 50% of the cases of DIC due to consumption of coagulation proteins. The other factors that lead to similar prolongation are liver disease, vitamin K deficiency and massive bleeding per se. In some cases, PT and aPTT may be shortened or be normal, due to the presence of circulating activated coagulation factors like thrombin. Hence normal PT and aPTT do not rule out DIC. Thrombin time is prolonged in greater than 50% of cases due to low serum fibrinogen and high levels of circulating FDPs. Thrombin time per se again does not have a role in diagnosis of DIC, but is helpful along with reptilase test to rule out heparin contamination • ibrin degradation products/ dimer: Fibrinolytic activity, measured as FDPs is increased in DIC. D-dimer assay, which measures cross-linked FDPs, is a sensitive test for detection of DIC. Semiquantitative assays are used now. However, increased D-dimer levels are not specific for DIC and may be observed in trauma, recent surgery and in VTE. Hence elevated levels should always be interpreted in the light of the clinical scenario and associated changes in platelet count and coagulation profile. Also, D-dimer helps in differentiating DIC from liver disease which is also associated with low platelet counts and altered coagulation profile, but is associated with normal D-dimer levels • erum fibrinogen: Although being used as a marker for evidence of DIC, the levels of serum fibrinogen remain normal for a long period of time, as it is an acute phase reactant. Inflammatory conditions lead to elevation of serum fibrinogen. Hence a drop in fibrinogen to normal values in DIC may be interpreted as normal, unless monitored serially • ther investigations: Thrombin antithrombin comp lexes, plasmin antiplasmin complexes are often elevated in sepsis-associated DIC. Abnormal light transmission of aPTT is a recent investigation that has been shown to be a simple and rapid indicator of DIC. •

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A five step diagnostic algorithm has been proposed that utilizes common investigations available in most hospitals. It is found to be useful in both acute and chronic DIC. The clinical setting for DIC is a must to use this algorithm. Score of greater than or equal to 5 has 91% sensitivity and 97% specificity for the diagnosis of DIC. For each point increase in DIC score, the odds ratio for mortality increase by 1.29 (Table 11.13.3).

• No increase = 0 • Moderate increase = 2 • Strong increase = 3 3. • • •



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Prolonged PT < 3 seconds = 0 3 seconds but < 6 seconds = 1 > 6 seconds = 2

Fibrinogen level • > 1 g/l = 0 • < 1 g/l = 1 Cumulative score • 5: compatible with overt DIC. Advised to repeat score daily • < 5: suggestive for non-overt DIC. Advised to repeat every 1–2 days

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Abbreviation: DIC, Disseminated intravascular coagulation

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Anticoagulation with heparin is a rational approach to inhibit the activation of intravascular coagulation in DIC. Treatment with heparin should be considered in cases where the thrombotic manifestations predominate such as venous or arterial thromboembolism, peripheral ischemia, purpura fulminans, etc. beneficial in chronic DIC • In patients at high risk for bleeding UH is preferred due to its short half-life and rapid reversibility. Small doses of 10 µg/kg/hour may be used without targeting aPTT 738 prolongation. It would be difficult to monitor heparin anyway due to the underlying coagulopathy

onclusion ­

Disseminated intravascular coagulation results from conti nuous activation of hemostasis leading to pathological circulation of thrombin and fibrin. Clinical manifestations of DIC include bleeding or thrombosis or both. Successful therapy of DIC hinges on identifying the triggering factor and switching off the activation of coagulation pathways. Valuable time should not be wasted trying to correct the abnormal laboratory values without attempting to correct the underlying disorder. B

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ntifibrinolytic gents

Antifibrinolytic agents that are used commonly in other bleeding diathesis like tranexamic acid have limited benefit in patients with bleeding. As formation of fibrin predominates in the pathogenesis of consumptive coagulopathy, the use of fibrinolysis inhibitors have been debated. In some conditions where there is a component of hypofibrinolysis (as in APML) to the DIC, it may be used. However, recent studies have failed to show any benefit in APML-associated DIC. Moreover severe thrombosis may be observed when tranexamic acid is used along with differentiating agents like all transretinoic acid used in APML.

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Rational therapy in patients who are bleeding or are at risk of bleeding is to attempt restoring the consumed platelets and coagulation factors. • This is ensured by platelet transfusions and restoring coagulation factor by transfusing fresh frozen plasma, cryoprecipitate and fibrinogen. Fears in the past of “feeding the fire” and worsening thrombosis by transfusing platelets and coagulation factors in patients with active DIC is no longer considered true • The decision for transfusion should be always based on the clinical condition and should not be based on the laboratory values alone • Platelet transfusion: A threshold of less than 50 × 109/ is used for platelet transfusion in patients with bleeding. In non-bleeding patients, a lower cut off of 10–20 × 109/ may be used. However, in patients at high-risk of bleeding, it is prudent to use a higher cut off. • Plasma transfusion: Fresh frozen plasma (FFP) may be administered at a dose of 15 m /kg. The main aim of replacement therapy should be to replenish the fibrinogen. This can be achieved by administering cryoprecipitate (1 unit = 250 mg fibrinogen), FFP or purified fibrinogen concentrates when available • There are few case reports of the successful use of recombinant factor VIIa in the management of lifethreatening hemorrhage in DIC • Therapy should never be instituted on the basis of laboratory results alone and should always be guided by the clinical indication. So also, response should be monitored by both improvements in the clinical condition as well as normalization of laboratory variables.

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eplacement Therapy

Again anticoagulants are indicated for the prophylaxis of VTE in paints with DIC who are not bleeding • Use of heparin has been established in cases of chronic DIC where recurrent thrombosis ensues • Anticoagulant factor concentrates like antithrombin concentrates and APC concentrates have been evaluated in DIC. There are no randomized trials to prove the efficacy of antithrombin supplementation. Activated protein C concentrates have been found to be beneficial in patients with DIC due to sepsis. However there is a high risk of major bleeding including intracranial hemorrhage. A

Although replacement of coagulation factors and platelets help in controlling DIC, identification and treatment of the underlying trigger for DIC is of utmost importance. In few situations treatment of the underlying disorder itself will help reverse DIC.

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Treatment of Underlying isorder

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measures are required to control DIC until the underlying condition is resolved.

ibliography

1. Franchini M, Lippi G, Manzato F. Recent acquisitions in the pathophysiology, diagnosis and treatment of disseminated intravascular coagulation. Thromb J. 2006;4:4. 2. Labelle CA, Kitchens CS. Disseminated intravascular coagulation: treat the cause, not the lab values. Cleve Clin J Med. 2005;72(5):377-8. 3. Levi M, Opal SM. Coagulation abnormalities in critically ill patients. Crit Care. 2006;10(4):222. 4. Levi M, Toh CH, Thachil J, et al. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology. Br J Haematol. 2009;145(1):24-33. 5. Oren H, Cingöz I, Duman M, et al. Disseminated intravascular coagulation in pediatric patients: clinical and laboratory features and prognostic factors influencing the survival. Pediatr Hematol Oncol. 2005;22(8):679-88. 6. Rodgers GM. Acquired coagulation disorders. In: Pine JW (Ed). Wintrobe’s Clinical Hematology, 12th edition. Philadelphia: Lippincott Williams and Wilkins; 2009.

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Transfusion Medicine and Component Therapy

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Deepak Bansal

ntroduction

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Blood is a precious commodity. The demand for this lifesustaining product invariably exceeds the amount collected. In spite of this, majority of the country’s annual collection is wasted as single unit whole blood transfusions (Table 11.14.1). Advances in transfusion therapy have improved blood preservation technique and enabled separation of whole blood into its component. It has thus become possible to transfuse specific components selectively, depending on the actual need of an individual patient.

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11.14

S

Blood Component and eparation Techniques  

Figure 11.14.1 Cell separator for collection of specific components from whole blood or for plasmapheresis Table 11.14.1 Country India Korea Sri Lanka Nepal Thailand

Blood components used in various countries Whole blood % used as Components % used as 80 20 1 99 5 95 30 70 20 80

 



Whole blood is made up of cellular elements (RBCs, leukocytes, platelets) and plasma. Whole blood can be separated into its components by centrifugation techniques, as illustrated in Flow chart 11.14.1. Apheresis is a specialized procedure wherein whole blood is removed from the donor and is then separated into its component parts by centrifugation in a cell separator (Fig. 11.14.1). The desired components (e.g. platelets) are harvested, and the remainder returned to the donor. The procedure allows selective collection of platelets or granulocytes in sufficient amounts from a single matched, ABO compatible donor. Valume, storage temperature and shelf life are listed in Table 11.14.2.

Table 11.14.2 Volume, storage temperature and shelf life of blood and components  

Whole Blood There are very few indications for the use of whole blood. The major indication would be in some cases of cardiac surgery

Volume (ml)

 

Flow chart 11.14.1 Separation of components from blood

Storage temperature°C

Shelf life

2–6

35 days

Whole blood

400–500

Packed RBC

150–200

Platelet concentrates

50

20–24

3–5 days

Fresh frozen plasma

250

< -20

1 year

Cryoprecipitate

15

< -20

1 year

F

or massive hemorrhage. It may be the only choice for lifethreatening hemorrhage when red blood cell component therapy is not available. For ET in neonates, whole blood or reconstituted whole blood may be used.

resh Whole Blood

It is a myth that whole blood collected within 24 hours is the best. It is often requisitioned in bleeding disorders in the erroneous belief that it provides platelets and clotting factors. Almost 90% of platelets and 40% of activity of factor VIII are lost within 24 hours of storage at 4°C. In addition, time is required for mandatory screening for infections. This age old practice, therefore, has no role in modern times. Specific 739 blood component therapy should be requested depending

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In severe (Hb < 5 g/dL) chronic anemia, child should receive 2–3 aliquots of 3–5 m /kg over 2–3 hours, separated by a few hours A partial ET may be considered in those presenting with overt features of CHF. This corrects the anemia rapidly and isovolumetrically. l

Packed ed Blood Cells R

•

The usual dose for packed RBCs is 10–15 mL/kg, but varies greatly on the clinical indication (Tables 11.14.3 and 11.14.4).

Platelet Transfusion Table 11.14.3 Indications for packed red blood cell transfusion in neonates  

• PCV < 36% and requiring

– > 35% supplemental oxygen



– Mean airway pressure ≥ 6–8 cm H2O by CPAP/IMV

The process of obtaining platelet rich plasma and platelet concentrate is outlined in Flow chart 11.14.1. The alternative approach involves the collection of single donor platelets by apheresis using a cell separator (Fig. 11.14.1). A single unit obtained from apheresis equals 5–6 random donor platelets. The yield is higher with single donor platelets and the donor exposure is reduced. Platelets are stored at 20–24°C, under constant agitation to avoid aggregation. Storage is recommended only for 3–5 days because of risk of bacterial contamination. The dose of random donor platelets is 1 unit per 10 kg of body weight or 5–10 m /kg for newborns. Indications include DIC with bleed (50 × 109/L), major surgery (50–100 × 109/L), leukemia, AA (10 × 109/L; the units may have own policy, lower threshold if concomitant fever or sepsis) and platelet function defects with severe bleeding. Indications in neonates are listed in Table 11.14.5.

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on the etiology of bleeding. For neonatal ET, blood up to 7–10 days old is good enough to prevent hyperkalemia.

• PCV < 31% and – Requiring < 35% supplemental oxygen or MAP < 6 cm H2O by CPAP/IMV



– > 9 episodes of apnea and bradycardia in 12 hours or 2 episodes in 24 hours, requiring bag and mask ventilation while on methylxanthine

l







– Heart rate > 180/min or RR > 80/min, persisting for > 24 hours



– Weight gain < 10 g/day for 4 days, while on 100 cal/k/day



– Undergoing surgery



Packed cell volume < 21% and – Asymptomatic with reticulocytes < 2%

resh rozen Plasma

F

•

• Hypovolemic shock associated with acute blood loss

Indications

Abbreviations: CPAP, Continuous positive airway pressure; IMV, Intermittent mandatory ventilation; MAP, Mean airway pressure.

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Cryoprecipitate The contents include fibrinogen, Von Willebrand factor, factor VIII and XIII. The corresponding indications are fibrinogen less than 1.0 g/L (e.g. DIC with bleeding),

 

Table 11.14.5 Indications of platelet transfusion in neonates < 50 x 109/L • Preterm infant (< 33 weeks): 1st week of life • Clinically unstable term infants: 1st week of life • Invasive procedure (e.g. ventricular tap) To be started on ibuprofen or indomethacin

–

Recent onset grade 3 or 4 IVH

 

–

 

 

• Preterm neonate

 

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Table 11.14.4 Indications for packed rad blood cell transfusion children ≥4 months of age 1. In deficiency anemia, with features of overt congestive heart failure. Often children with iron deficiency anemia are treated with oral iron alone, even with Hb < 5 g/d 2. Thalassemia major: Attempt should be made to maintain a pretransfusion Hb > 9 g/dL 3. Aplastic anemia: Children often do well with Hb > 6–7 g/d . Leukocyte filters (Fig. 11.14.2) should be used to prevent alloimmunization and increased chances of graft rejection, if a BMT is planned 4. Malignancies: Hb < 8 g/d . Factors influencing decision include intensity of chemotherapy and timing (counts expected to rise or fall) 5. Significant preoperative anemia: Individual approach is necessary; most children who do not have cardiorespiratory disease do not require Hb > 8 g/d 6. Postoperative Hb < 8 g/dL with symptoms/signs of anemia. Most children can quickly restore Hb with oral iron. There should be a compelling reason to administer a postoperative red-cell transfusion 7. Pediatric ICU: Restrictive strategy is gaining favor in the PICU. It has been demonstrated that in stable, critically ill children, an Hb of 7 is as good as 9.5 g/dL (Children with severe hypoxia, hemodynamic instability and cyanotic heart disease were excluded in the study). Blood is immunosuppressive. Cytokines released following the transfusion may contribute to enhanced inflammatory response and increased morbidity

• • •

Coagulopathy with bleeding (e.g. hemorrhagic disease of newborn, liver disease) Hemophilia A/B (if factors cannot be afforded) Deficiency of antithrombin III, Protein C/S Massive transfusion. The use of FFP is not justified for hypovolemia (use crystalloids), prolonged INR in absence of bleeding and for hypoalbuminemia (use albumin). The dose is 10–20 m /kg for infants/children and 5–10 m /kg for newborns. l



F

• PCV < 40% and

< 20 × 109/L • Stable infants beyond 1st week of life without active bleeding

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hemophilia A (Note: it does not contain factor IX), Von Willebrand’s disease and Factor XIII deficiency. The average dose is 1 unit for 5–10 kg body weight.

rradiated Blood Products

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eukoreduction







utologous Blood

It is the collection and reinfusion of the patient’s own blood. It is possible for some children who have to undergo elective surgery for which transfusion is anticipated. Advantage is reduction in the risk of transfusion-transmitted viral diseases. Blood, proportionate to the size of the child is collected 4–5 weeks prior to surgery. The Hb should be greater than 11 g/dL before collection of blood. Oral iron is supplemented. All risks are not avoided: the stored unit could still be contaminated with bacteria or a wrong unit could be inadvertently transfused.

Hazards of Blood Transfusion Adverse reactions to blood transfusion can be subdivided according to whether they are immediate or delayed and whether they are immunologically mediated (Table 11.14.8). Acute hemolytic reaction is the dreaded complication of blood transfusion, one of the common causes being clerical errors of mislabeling or misidentification, resulting in the infusion of the wrong patient’s blood. Signs and symptoms include fever, chills, back/chest pain, flushing, nausea and hemoglobinuria. These can progress to shock with acute renal failure. Management is outlined in Table 11.14.9. Two common, but less known adverse effects are detailed below.





 

Table 11.14.6 When to ask for irradiated blood products? • Donations from relatives • Intrauterine transfusion • Exchange transfusion – If there is previous intrauterine transfusion – Related donor – Routine cases: Only if it does not unduly delay the procedure • Immunocompromised patients: SCID, bone marrow transplantation, Hodgkins Abbreviation: SCID, Severe combined immunodeficiency.

Figure 11.14.2 A bed-side leukocyte filter  

It refers to the removal of white cells from a blood product. Deleterious effects caused by leukocytes include: • Febrile-nonhemolytic reactions • HLA alloimmunization • Platelet refractoriness • Transmission of CMV • Possibly organ dysfunction • Increased mortality. White cells can be removed soon after collecting blood (prestorage) or at bed-side. Prestorage leukoreduction is better as inflammatory cytokine accumulation from WBC during storage is avoided. It is likely that leukoreduction will prevent GVHD, but is not certain. In Indian circumstances, bed-side leukocyte filters (Fig. 11.14.2) should be considered for patients receiving multiple transfusions, e.g. thalassemia major.

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Under normal circumstances, T lymphocytes in donor blood are destroyed by the recipient. They can survive and proliferate if they are not recognized as foreign (e.g. related donor) or if recipient is immunocompromised. The proliferating T-cells cause GVHD. It is a rare but frequently fatal complication that occurs 3–30 days following blood transfusion. As there is no effective treatment, aim is to recognize high-risk patients and to use blood products with T cells that have been rendered ineffective (Tables 11.14.6 and 11.14.7). This is done by exposing blood bag to ionizing radiation. Facilities for irradiating blood are gradually increasing at various centers in India.

 

Table 11.14.7 Conditions where irradiated blood is not required Newborns for top up transfusion HIV, AIDS Acute leukemia Autoimmune diseases

Bacterial Contamination of Blood Products This is a relatively common, however poorly recognized complication. The source of contamination could be the donor (skin commensals or unrecognized bacteremia), environment or improper handling of product. Clinical profile often resembles an acute hemolytic reaction. Platelets are most commonly implicated as they are stored at room temperature. Broad-spectrum antibiotics should be initiated at the earliest suspicion.

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Hemolysis

Red cell incompatibility

Anaphylaxis

Antibody to IgA in donor plasma

Febrile, nonhemolytic

Antibody to donor leukocyte antigen

Urticaria

Antibody to donor plasma proteins

Transfusion related acute lung injury

Donor antibody to leukocyte of patient

•

Case cenarios and requently sked Questions F

Usual cause

Immunological

There is no role of steroids or diuretics Mortality is 5–10% Antibodies (HLA or WBC) from donor are implicated in causing pulmonary capillary leak Prevention is by deferral of donors who are commonly multiparous females. S

Nonimmunological

Q. Ans.

Volume overload

Fever with shock

Bacterial contamination

Hypothermia

Rapid infusion of cold blood

Air embolus

Air infusion in line

Hyperkalemia

Rapid infusion of multiple units of stored blood

Hypocalcemia

Massive transfusion of citrated blood

Disease transmission

HIV, Hepatitis B, C, CMV, malaria, syphilis

Iron overload

Multiple transfusions in chronically anemic patients without blood loss



Congestive heart failure

1.5 kg preterm, 5 days old, Hb: 9 g/dL, on ventilator. Has to be given packed red cells: 25 m . What should one do with the remaining bag? The best option is to request the blood bank to issue blood in a pediatric bag. One red cell unit can be divided into several pediatric bags to be used for a single neonate/infant, over an extended period of time (Figs 11.14.3A and B). This reduces donor exposure and prevents wastage. Remaining unit should never to be stored in refrigerator (Fig. 11.14.4). l

Adverse effect

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Graft versus host disease Functional lymphocytes in blood

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Table 11.14.8 Adverse effects of transfusion

 

Table 11.14.9 Management of acute hemolytic transfusion reaction

• Discontinue blood transfusion, however maintain IV access • Alert blood bank and send back unit of blood Draw clotted and anticoagulated blood specimens from a vein other than the one being used for transfusion. Requisition the following tests: Direct Coombs’ test, plasma Hb, blood counts, urea, creatinine, bilirubin 

•

B Figures 11.14.3A and B The use of blood can be optimized in neonates and infants by the use of pediatric bags  

• Collect urine sample for urinary Hb

a

• Investigate for DIC; blood culture if fever is a prominent feature • Monitor urine output 

• Treatment is largely supportive: infusion of normal saline to maintain adequate urine output, furosemide and dopamine to enhance renal cortical perfusion. Dialysis may be required if acute tubular necrosis develops

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It is currently the most common cause of transfusion-related death reported in western literature: • The incidence is 1/1,200–5,000 plasma containing transfusions (RBCs, platelets, FFP) • Typically occurs during or within 6 hours of completion of transfusion • It is characterized by acute onset hypoxemia in absence of circulatory overload • Cxy shows bilateral lung infiltration • It usually resolves in 24–72 hours 742 • Management is supportive. Mechanical ventilation may be required

Figure 11.14.4 Blood is never to be stored in the fridge  

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Table 11.14.10 Requirement of ABO and Rh compatibility for transfusing blood components  

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Sepsis, fever, ITP, DIC, splenomegaly, amphotericin and alloimmunization. Remedial measures include ordering ABO compatible product, single donor platelets, increasing the number of units transfused and requesting HLA or cross-matched platelets. I ordered platelets at 9 PM, but subsequently decided to transfuse them next morning. In which compartment of the fridge should I store them until the next day? Platelets are stored under continuous agitation to prevent clumping, at 20–24°C. A child has A+ve blood group. Can he be transfused B+ve platelets? Same blood group is preferred. Alternate group can be transfused, if the plasma volume is limited. B+ve platelets are transfused to a B-ve patient inadvertently. The patient is asymptomatic. Does anything need to be done? Rh-Immunoglobulin should be administered, especially to females of child-bearing age to prevent Rh-alloimmunization from the transfused red cells (Table 11.14.10). How should FFP be thawed? Ideally by a plasma thawing bath. As it may not be available in majority of units, the bag may be thawed by placing over a clean surface. If using water, ensure that the ports are above the water level. Blankets, body surface (e.g. arm pits) or heaters should not be used. I diagnosed a 7-month-infant with thalassemia major. Is there anything that should be requested from the blood bank prior to the 1st transfusion? Extended red cell phenotyping (Rh, K, Kidd, Duffy) should ideally be performed. Attempt should be made to match minor blood group antigens in patients who receive multiple transfusions. A child develops urticarial lesions while blood is running. Should I hold or discontinue the transfusion. The algorithm is illustrated in Flow chart 11.14.3. A child with thalassemia major has frequent “reactions” to blood. What can be done? Prophylactic antihistaminic and paracetamol can be given. Leukocyte filter should be used, if affordable. Request blood matched for C, E and Kell antigens. Washed red cells may be required (saline washing removes plasma proteins).

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Flow chart 11.14.2 Algorithm for management of fever while a blood transfusion is running  

Q.





Q.

Ans.





Ans.

Q.





Q.

Ans.





Ans.

Q.



Ans. Q.



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Ans.

I requested blood for an anticipated use; however the unit was not administered. Can the blood be returned to the blood bank? Every blood bank should have a policy for unused products. Ideal policy is that the blood components that have been outside of a temperature-controlled environment for greater than 30 minutes must be discarded. Red cell transfusion is on flow for a child. He develops fever of 39°C after 30 minutes. What should be done? The algorithm is illustrated in Flow chart 11.14.2. How late can one wait to start a blood transfusion after obtaining the bag from the blood bank? If transfusion is not initiated within 30 minutes of removal from blood bank or an approved temperature-controlled blood product refrigerator, the unit should be returned immediately to prevent waste. There is an 11-year-old boy with Thalassemia major. He receives 3–4 weekly blood transfusions. Hb is 8 g/dL on a visit for transfusion to the hospital. How slowly should one transfuse a unit of packed red cells? It is appropriate to transfuse over a period of 2–3 hours. No diuretic is required, unless the Hb is very low for a longer duration. No transfusion should take greater than 4 hours, because of risk of bacterial proliferation at room temperature. Platelets were transfused to a patient; however the post-transfusion count did not increase significantly. What are the common causes and remedial measures?

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ABO compatibility

Rh compatibility

Red cells

Must

Must

Platelets

Preferred

Preferred

Plasma

Must

Cryoprecipitate

Preferred, but not required

No

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Flow chart 11.14.3 Algorithm for management of allergic reaction while a blood transfusion is running

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Q. Ans.

is 2 x 109/L. Decision is taken to administer Anti-D. Should platelets be transfused? No. It is a common error to transfuse platelets for ITP. Transfused platelets are rapidly destroyed due to circulating antibodies. Platelet transfusion is rarely indicated for life-threatening situations (e.g. intracranial bleed) along with steroids/IVIg. How can I improve transfusion practice in my unit? Cordial and regular communication with blood bank personnel is the key. Avoid blame game. Accept limitations and frame guidelines after mutual discussion.

ummary

Blood and blood products should be transfused only when there are clear and specific therapeutic indications. The risk of transfusion reactions and transfusion related infections deserve careful consideration. Specific blood component therapy suited to the requirements of an individual patient must he recommended, whenever possible.

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Bibliography



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1. Bansal D, Marwaha RK. Transfusion reactions. Indian J Pediatr. 2001;68(2):133-9. 2. Carless PA, Henry DA, Carson JL, et al. Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion. Cochrane Database Syst Rev. 2010;(10):CD002042. 3. Gupta A, Bansal D, Dass R, et al. Transfusion associated graft versus host disease. Indian Pediatr. 2004;41(12):1260-4. 4. Lacroix J, Hébert PC, Hutchison JS, et al. Transfusion strategies for patients in pediatric intensive care units. N Engl J Med. 2007;356(16):1609-19. 5. Marwaha N. Whole blood and component use in resource poor settings. Biologicals. 2010;38(1):68-71. 6. Sloan SR, Friedman DF, Kao G, Kaufman RM, Silberstein L. Transfusion medicine. In: Orkin SH, Nathan DG, Ginsburg D (Eds). Nathan and Oski’s Hematology of Infancy and Childhood, 7th edition. Philadelphia: Saunders Elsevier; 2009. pp. 1623-62. 7. Treleaven J, Gennery A, Marsh J, et al. Guidelines on the use of irradiated blood components prepared by the British Committee for Standards in Haematology blood transfusion task force. Br J Haematol. 2011;152(1):35-51.

Ans.

A child needs blood transfusion. Father is an engineer. Fearing risk of transmission of HIV, the concerned father offers to donate blood for his baby. Should such a directed donation be encouraged? No. There is a risk of transfusion-associated GVHD from products obtained from close relatives. Such transfusions, if given, must be irradiated. What are the tests mandatory for infection screening of blood in India? HIV 1 and 2, Hepatitis B and C, syphilis and malaria. What are the additional tests performed in the developed world? Nucleic acid testing for HIV and HCV, Human T-cell lymphotropic virus, CMV, West Nile virus, etc. A child develops dyspnea during transfusion. What are the possible causes? Transfusion-related acute lung injury, circulatory overload and anaphylaxis. A 3-year-old child is diagnosed with ITP. He has widespread skin bleeds and epistaxis. Platelet count





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Section

12 Pediatric Malignancies

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Introduction: Malignancies in children: Purna A Kurkure Leukemia: Anupama Borker Lymphomas in hildren: Brijesh Arora Wilms Tumor: Purna A Kurkure Neuroblastoma: ATK Rau Retinoblastoma: Amita Trehan Soft Tissue Sarcoma: Gauri Kapoor Pediatric Bone Marrow Transplantation: Satya Prakash Yadav

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12.1. 12.2. 12.3. 12.4. 12.5. 12.6. 12.7. 12.8.

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Introduction: Malignancies in hildren Purna A Kurkure



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First chance is the best chance and giving optimum treatment at outset is the most important factor in deciding the outcome. Any advances in health care are only as valuable as it is available and accessible to those who need it. It has been well documented that organized and coordinated treatment programs carried out by experienced pediatric oncologists in well-staffed and well-equipped pediatric cancer units are effective. But, at the same time, early referral for prompt diagnosis and for ensuring efficient follow-up, the community pediatrician’s role is crucial. The “National Training Project in Practical Pediatric Oncology” has been initiated under the auspices of Pediatric Hematology Oncology chapter of Indian Academy of Pediatrics (IAP) in collaboration with the International Society of Pediatric Oncology (SIOP) since 1998 with an aim to train, educate and encourage pediatricians to participate in shared care of childhood cancer patients. Advances in the treatment of childhood cancers have dramatically increased survival rates to around 70% in developed countries. It has been estimated that by the year 2010, approximately 1 in 250 young adults will be survivors of childhood cancer in USA. Although this constitutes a remarkable medical achievement, the late morbidity in this growing survivor population has become an area for concern. The need to predict the future impact of current therapeutic strategies is a major challenge for the pediatric oncologist. A balance of reassurance to the survivor and vigilance in monitoring for relapse, second malignancies and other sequelae is required. Recent concept of a truly “cured child” in pediatric oncology envisages not only a biological cure of the disease but also a child on par with peers in growth and development physically and in achievements and aspirations, both mentally and emotionally.

The recent understanding and advances in the total management of pediatric cancers forms one of the most exciting chapters in the entire field of oncology. With increasing control of infectious diseases, eradication of malnutrition and the rapid strides of the pediatric surgeons in correcting benign surgical problems, more children are now going to be affected by cancer. In USA, cancer is second to accidents as a cause of mortality in children beyond 1st year of life. There is paucity of accurate vital statistics in our country. Children constitute approximately 40% of India’s population, which is more than 1 billion. Annual incidence rates of cancer are about 75 and 80 per 105 men and women, respectively or around 800,000 new cancers per year. Approximately 5% of these are in pediatric age group as estimated by population-based cancer registries. Thus, 40,000 new pediatric cancers are estimated to be diagnosed annually. Leukemias and lymphomas comprise nearly half of pediatric cancers followed by tumors of the central nervous system (CNS), sympathetic nervous system, soft tissues, kidney, bone, eye, liver and germ cells. “Child is not a miniature adult.” The types of childhood cancers and response to therapy totally differ from those in adults. The hallmark of success in pediatric oncology is the multidisciplinary approach executed through carefully orchestrated combined modality team comprising of a pediatric oncologist, a pediatric surgeon, a radiation oncologist, various diagnostic specialists (pathologist, hematopathologist, molecular pathologist and radiologist) and supportive care services. Burchenal succinctly characterized the basic tenet of multidisciplinary approach by stating that “the pride of discipline must be put aside”. All the experts should work together, keeping well-being of the child as the central issue.

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12.2

the basis of chromosomal aberrations that are known to influence outcomes (Table 12.2.2). Similarly, the morphologic classification of AML has given way to the World Health Organization (WHO) classification based on morphology, cytogenetic features, etiology and preceding myelodysplasia (Table 12.2.3).

ntroduction

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Leukemias are malignant neoplasms arising from the uncontrolled proliferation and loss of differentiation of hematopoietic stem cells. Depending on the lineage of the progenitor stem cell involved, they are classified as lymphoid or myeloid. Depending on the natural history of the leukemia, they are classified as acute or chronic. Acute leukemias account for about 40% of childhood cancers. Acute lymphoblastic leukemia (ALL) comprises about 70–80% and acute myeloid leukemia (AML) about 10–15% of childhood leukemias. The remaining subset consists of the uncommon childhood leukemias, viz. chronic myeloid leukemia and juvenile myelomonocytic leukemia.

CD10 , CD19 , CD20+, CD21+, HLA DR+

The most common subtype with good prognosis

CD19+, CD20+, CD21+, sIg+

Burkitt’s leukemia (L3), good prognosis with short duration intensive chemotherapy

CD3+, CD5+, CD7+

Common in older boys, associated with high WBC counts, mediastinal mass and CNS involvement

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Abbreviations: ALL, cute lymphoblastic leukemia; CD, luster of differentiation; HLA, uman leukocyte antigen; WBC, hite blood cell; CNS, entral nervous system a

Table 12.2.2 Common chromosomal abnormalities in acute lymphoblastic leukemia Chromosomal abnormality

Fusion protein

Clinical significance

t(9;22)

BCR/ABL

Considered very high risk. Therapy with imatinib along with chemotherapy has improved survival.

t(4;11)

MLL

Common in infantile leukemia, asso­ ciated with high tumor burden, intrinsically drug resistant. Connotes poor prognosis

t(1;19)

PBX1/E2A

Associated with higher rates of CNS relapse

t(12;21)

TEL/AML1

Good prognosis, needs minimal therapy

t(8;14)

MYC/IgL

Burkitt’s leukemia, needs short duration intensive chemotherapy

lassification of eukemia L

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Abbreviations: BCR, B cell receptor; MLL, ixed lineage leukemia; PBX1, Pre B cell leukemia transcription factor 1; AML1, cute myeloid leukemia 1; IgL, Immunoglobulin L; CNS, entral nervous system -

Acute leukemias in children are classified according to their lineage as ALL and acute myeloblastic leukemia. The further subclassification of ALL and AML keeps evolving as does our understanding of the characteristics of leukemia cells at the cytogenetic and molecular level. Beginning from the morphologic classification as L1, L2 and L3, authors now classify ALL on the basis of the surface markers as those derived from B or T cell precursors (Table 12.2.1). Cytogenetic analysis further characterizes leukemia on

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ALL subtype Pre B cell

The exact etiology of acute leukemia is unknown. Several genetic conditions are known to predispose to leukemia. These include Down’s syndrome (Trisomy 21), Fanconi’s syndrome, Bloom’s syndrome, Schwachman’s syndrome, Klinefelter’s syndrome, Turner’s syndrome (45,XO), neuro­ fibromatosis, ataxia telangiectasia, severe combined immunodeficiency and Li Fraumeni’s syndrome (p53 deletion). Exposure to ionizing radiation, benzene and certain drugs like alkylating agents, nitrosoureas and epipodophyllotoxins have been clearly associated with the development of leukemia. Certain environmental factors, viral infections and immunodeficiency states may also predispose to leukemia. Leukemia arises following certain carcinogenic stimuli that lead to the malignant transformation of hematopoietic cells rendering them capable of unregulated proliferation (self renewal) coupled with loss of differentiation and loss of apoptosis (programmed cell death). The uncontrolled proliferation of these malignant cells leads to expansion of the marrow cavity with resultant suppression of normal cell lines.

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Table 12.2.1 Classification of acute lymphoblastic leukemia (ALL)

 

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The common age group for acute leukemia is 2–5 years, and males are affected slightly more often than females. Fever is the most common presenting feature of acute leukemia.

tiopathogenesis



linical Features

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French-American-British (FAB) classification Minimal differentiation

M1

Myeloblastic leukemia without maturation

M2

Myeloblastic leukemia with maturation

M3

Promyelocytic leukemia

M4

Myelomonocytic leukemia

M5

Monocytic leukemia

M6

Erythroleukemia

M7

Megakaryocytic leukemia



M0

mostly occurs in T cell ALL. The resultant obstruction of the superior vena cava and the airway can present as medical emergencies. Children and adolescents with the superior vena cava syndrome present with edema and suffusion of the face and upper extremities, headache and dilated neck veins. The superior mediastinal syndrome resulting from compression of the trachea leads to cough, breathlessness and air hunger; and untreated may progress to hypoxia with cyanosis, altered sensorium and seizures. Children with large tumor burden may sometimes develop spontaneous tumor lysis syndrome leading to acute renal failure, secondary to uric acid nephropathy. Less common presenting features include bone and joint pains with tenderness, and rash or eruption, which may be due to cutaneous involvement. About 5–10% patients have CNS involvement at diagnosis, and may present with cranial nerve palsies or seizures. Signs of raised intracranial pressure like headache and papilledema may be present. Painless testicular enlargement suggestive of testicular involvement is extremely rare at diagnosis. Gum hypertrophy is rather a common presentation of AML, especially M4 subtype. Extramedullary myeloid cell tumors or chloromas can occur at a variety of locations and may sometimes precede the development of marrow involvement in AML. Disseminated intravascular coagulation is more common in AML especially in M3 subtype or acute promyelocytic leukemia (APML).

World Health Organization classification



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Acute myeloid leukemia with multilineage dysplasia: •  With prior MDS •  Without prior MDS

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Abbreviations: AML 1, cute myeloid leukemia-1; CBF-α, ore binding factor alpha; PML, romyelocytic leukemia; RAR-α, etinoic acid receptor alpha; CBF-β, ore binding factor beta; MLL, ixed lineage leukemia; MDS, yelodysplastic syndrome

The other features usually reflect the suppression of one or more hematopoietic cell lines. Anemia may present with progressive pallor, weakness, fatigue, lethargy, refusal to feed or shortness of breath. Thrombocytopenia leading to petechiae, ecchymosis or gum bleeds is common. Neutropenia with resultant infections may present with fever, pneumonia, otitis, skin, soft tissue and perianal infections. Mucositis with oral ulcers and thrush is a common finding in neutropenic patients. Hepatosplenomegaly and lymphadenopathy, secondary to leukemic infiltration, is common. The lymphadenopathy can be generalized 748 and sometimes massive. Mediastinal lymphadenopathy

The differential diagnosis of acute leukemia includes several benign and malignant conditions. Viral infection induced cytopenias are the most common conditions, which mimic leukemia. Infectious mononucleosis, cytomegalovirus infection and a host of other viral infections may present with fever and lymphadenopathy along with anemia, thrombocytopenia and/or neutropenia with atypical lymphocytosis. Immune thrombocytopenia presents with sudden onset of thrombocytopenia with petechiae, purpura and ecchymosis, in an otherwise well child. The presence of atypical features like fever, lymphadenopathy or anemia may warrant a bone marrow examination to rule out leukemia. Drug induced cytopenias can be suspected by a detailed history and withdrawal of the offending drug usually leads to recovery of the concerned cell lines. Bone marrow failure syndromes, myelodysplastic syndromes and hypoplastic/aplastic anemia usually have a long standing history and need a bone marrow biopsy for confirmation. Some collagen vascular disorders like rheumatoid arthritis and systemic lupus erythematosus can present with symptoms of leukemia. Langerhans cell histiocytosis with or without marrow involvement is another common differential. Malignant conditions that mimic acute leukemia include metastases from solid tumors like neuroblastoma and rhabdomyosarcoma and marrow involvement in non Hodgkin lymphoma (NHL). -

Acute myeloid leukemia minimally differentiated Acute myeloid leukemia without maturation Acute myeloid leukemia with maturation Acute myelomonocytic leukemia Acute monocytic leukemia Acute erythroid leukemia Acute megakaryocytic leukemia Acute basophilic leukemia Acute panmyelosis with myelofibrosis

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•  •  •  •  •  •  •  •  • 

ifferential iagnosis

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Acute myeloid leukemia, otherwise categorized:



•  Alkylating agent related •  Epipodophyllotoxin related •  Other types

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Acute myeloid leukemia with myelodysplastic syndrome, therapy related:

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•  Acute myeloid leukemia with t(8;21)(q22;q22) AML-1/CBF-α/ETO •  Acute promyelocytic leukemia: Acute myeloid leukemia with t(15;17) (q22;q12) and variants PML/RAR-α •  Acute myeloid leukemia with abnormal bone marrow eosinophils and inv(16)(p13;q22) and t(16;16)(p13;q22) CBF-β/MYH-1 •  Acute myeloid leukemia with 11q23 MLL abnormalities

-

Acute myeloid leukemia with recurrent chromosomal translocations:

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Table 12.2.3 Classification of acute myeloid leukemia (AML)

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The treatment of acute leukemia involves specific antileukemic therapy and supportive care. Specific antileukemic therapy depends upon the subtype of the leukemia. At diagnosis, the leukemic tumor burden approximates to 1012 cells. Chemotherapy given in phases reduces the leukemia cells exponentially with each cycle.

•  Serum lactate dehydrogenase

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•  Serum electrolytes: serum sodium, potassium, chloride, calcium, phosphorus, magnesium •  Liver function tests

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-

•  Cerebrospinal fluid examination: to look for presence of blasts

•  Renal function tests

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•

•

•  Serum uric acid

•  Blood grouping •  Quantitative serum immunoglobulin •  Chest X-ray •  Ultrasound of abdomen Abbreviations: FISH, Fluorescence in situ hybridization; PCR, Polymerase chain reaction; HIV, Human immunodeficiency virus; HBsAg, Hepatitis B surface antigen; HBsAb, Hepatitis B surface antibody; HCV, Hepatitis C virus

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•  Serology for HIV, HBsAg, Anti-HBsAb, Anti-HCV

A

-

•  Coagulation profile: prothrombin time, activated partial thromboplastin time, fibrinogen, D dimer

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•

•  Bone marrow aspiration: Morphology, immunophenotyping, cytogenetic analysis, FISH or PCR for specific translocations •  Bone marrow biopsy, if dry tap

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•  Complete blood counts with peripheral smear

Induction chemotherapy refers to the first 4–6 weeks of chemotherapy designed to induce a clinical and morphological remission in the marrow. It typically uses three to four drugs including a steroid (prednisone or dexamethasone), vincristine and daunorubicin or L asparaginase along with weekly doses of intrathecal methotrexate. About 90–95% patients achieve a remission at the end of induction chemotherapy. Consolidation chemotherapy has 16–20 weeks of intensive chemotherapy administered to further decrease the leukemic cell burden in the body. It uses combinations of drugs including cyclophosphamide, cytosine arabinoside, methotrexate, vincristine and daunorubicin. Central nervous system directed therapy is aimed at eliminating the leukemic cells from within the CNS, which are usually shielded by the blood brain barrier. The components of CNS directed therapy include cranial irradiation, intrathecal chemotherapy and high dose systemic chemotherapy. Although an effective means of CNS therapy, cranial irradiation is associated with serious long term toxicity including neurocognitive dysfunction and secondary malignancies. Newer protocols have documented equivalent results with prolonged intrathecal chemotherapy and high dose systemic chemotherapy thus eliminating the use of radiotherapy (RT). Maintenance chemotherapy is low dose oral chemo­ therapy administered for 24–30 months after completion of intensive chemotherapy, and is necessary to clear the marrow of residual leukemic cells. Methotrexate and 6-mercaptopurine are used for maintenance therapy.

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Table 12.2.4 Investigations recommended for the diagnosis of acute leukemia

cute ymphoblastic eukemia

In ALL, antileukemic therapy is given in phases with specific aims.



The complete blood count may reveal anemia and/ or thrombocytopenia. The white cell count may be increased or decreased; in either case, it is characterized by neutropenia. Hyperleukocytosis [white blood cell (WBC) count > 100,000/cumm] is seen more commonly in ALL than AML. The peripheral blood smear may or may not reveal blasts. Often, they may be reported as atypical lymphocytes or immature cells. Coagulopathy may be present with elevated prothrombin time (PT), partial thromboplastin time (PTT) and fibrinogen degradation products. The diagnosis of leukemia is established by a bone marrow aspiration. The presence of 25% blasts confirms the diagnosis of ALL (20% in case of AML). Rarely in case of dry tap, bone marrow biopsy needed. In patients with high white cell counts, there may be elevation of uric acid and lactate dehydrogenase (LDH). Tumor lysis syndrome is characterized by elevated potassium, phosphorus, uric acid and depressed calcium. In severe cases, renal function may be compromised with elevation of blood urea nitrogen and creatinine. Elevated transaminases and hyperbilirubinemia may occasionally, be present in cases of extensive liver involvement. Chest X ray may reveal a mediastinal mass, more often, in T cell ALL. Hepatosplenomegaly and occasionally nephromegaly may be documented by a sonography. Table 12.2.4 gives the investigations needed at the diagnosis of acute leukemia.

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Management

Pediatric Malignancies

aboratory Features and iagnosis

In AML, induction chemotherapy uses two or three drugs— daunorubicin, cytosine arabinoside with or without etoposide. The remission rate is approximately 70% and then followed by two to four cycles of consolidation chemo­ therapy usually with cytosine arabinoside. Intrathecal chemotherapy with methotrexate or cytosine arabinoside is used for CNS therapy. There is no established role of 749 maintenance chemotherapy in AML.

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upportive are

Supportive care involves management of emergencies that the patient may present with at diagnosis and of complications during therapy. Emergencies at diagnosis include obstructive conditions like the superior vena cava syndrome and the superior mediastinal syndrome, metabolic conditions like tumor lysis syndrome and hematological conditions like severe anemia and bleeding. Children with superior vena cava and superior mediastinal syndrome need prompt care in the intensive care unit with close monitoring. Patients should be kept in the propped up position to prevent the mediastinal mass from further compressing the airway and the great vessels. If patient has high white cell count with circulating blasts, definitive diagnosis can be established by morphology and immunophenotyping of the peripheral blood, thereby obviating the need for a marrow examination. If there is associated pleural effusion, thoracocentesis can be diagnostic as well as therapeutic as flow cytometry of pleural fluid can clinch the diagnosis. If bone marrow study is mandatory, it should be performed with the patient in the propped up position without sedation or general anesthesia to prevent hypoxia as these patients are difficult candidates for endotracheal intubation. Intravenous hydration should be started using a leg vein to avoid aggravating the congestive symptoms in the upper body. Once a diagnostic specimen has been obtained, the patient can be started on steroids, which give rapid relief by shrinking the mass.

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cute Promyelocytic eukemia

Acute promyelocytic leukemia is a type of AML with a distinct cytogenetic abnormality t(15;17) with the promyelocytic leukemia (PML)/retinoic acid receptor alpha (RAR α) fusion. It is characterized by the proliferation of promyelocytes rich in granules that result in disseminated intravascular coagulation. Treatment with all transretinoic acid (ATRA) results in differentiation of the promyelocytes into mature neutrophils leading to resolution of the coagulopathy and to remission.

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Patients with hyperleukocytosis (WBC count > 100,000/ cumm) may present with symptoms of thrombosis or with tumor lysis syndrome with hyperkalemia, hyperuricemia, hyperphosphatemia and hypocalcemia. Untreated this condition can rapidly progress to azotemia and acute renal shutdown. Tumor lysis syndrome occurs usually within 7 days of starting cytotoxic therapy but can occur due to spontaneous cell lysis even before starting the treatment. Patients with hyperleukocytosis need rigorous monitoring with electrocardiogram (ECG) and electrolytes to prevent complications like arrhythmias and acute renal failure. Intravenous hydration with twice maintenance potassium free fluids is recommended. The urine pH should be maintained between 7 and 8 to prevent precipitation of uric acid and phosphate crystals. Allopurinol, a xanthine oxidase inhibitor, helps to prevent the formation of uric acid. Rasburicase, a urate oxidase helps in degrading uric acid converting it into the water soluble allantoin, which is easily excreted by the kidneys. Supportive care during therapy includes blood component therapy and aggressive management of infectious complications. Packed red blood cell (RBC) transfusions are indicated to maintain hemoglobin over 8 g/dL in well children and over 10 g/dL in patients with fever and infection. Platelet transfusions are indicated, if platelet count is less than 10,000/cumm or in the case of overt bleeding, especially in patients with fever and infection. Every episode of febrile neutropenia should be treated aggressively with broad spectrum antibiotics after drawing blood cultures. All patients should receive prophylaxis for Pneumocystis carinii pneumonia with cotrimoxazole and for oral candidiasis with clotrimazole lozenges. Maintenance of oral and perianal hygiene reduces the risk of infections to a significant extent. The use of hematopoietic growth factors [granulocyte colony stimulating factor (G CSF) and granulocyte macrophage colony stimulating factor (GM CSF)] reduces the period of neutropenia, but they are expensive and do not improve the overall outcome of the patients. In ALL, bone marrow transplantation (BMT) is indicated for very high risk patients, those who fail induction therapy and those who have early relapse while still on therapy. In AML, BMT is indicated for patients with unfavorable cytogenetic features and those who relapse.

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Acute lymphoblastic leukemia with t(9;22), also known as Philadelphia chromosome positive ALL, was conventionally considered very high risk in ALL due to its chemoresistant nature, and needed bone marrow transplantation for cure. Since the advent of the targeted drug imatinib, its prognosis has vastly improved. Imatinib is a tyrosine kinase inhibitor that binds the adenosine triphosphate (ATP) binding site of the tyrosine kinase molecule and disrupts its downstream enzymatic activity, thereby inhibiting cell division. Given in combination with chemotherapy, it induces lasting remissions in patients. -

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cute ymphoblastic eukemia with t(9;22)

Acute lymphoblastic leukemia is a heterogeneous disease and treatment outcomes depend on several factors. These factors are divided as those pertaining to the patient like age, sex, ethnicity and underlying immunodeficiency; those pertaining to the disease like presenting white cell count and tumor burden, CNS involvement, lineage, subtype, chromosomal abnormality and ploidy; and those pertaining to therapy like chemotherapy regimens and their intensity. The early response to treatment as judged by the clearance

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Features

Low risk

Age 1–9 years, WBC count < 50,000/cumm, Pre B ALL, Trisomy 4 and 10, hyperdiploidy, t(12;21)

Standard risk

Age 1–9 years, WBC count < 50,000/cumm, Pre B ALL, normal cytogenetics

High risk

Age < 1 years and > 9 years, WBC count > 50,000/ cumm, T cell ALL, CNS involvement, hypodiploidy

Very high risk

t(9;22), t(4;11), induction failure

-

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Risk stratification

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Practice uidelines •

Abbreviations: WBC, White blood cell; ALL, Acute lymphoblastic leukemia; CNS, Central nervous system

•

of blasts from the peripheral blood by day 7 of therapy and from the marrow by day 14 of therapy is one of the best predictors of outcomes. Risk stratification based on the above features helps to tailor therapy to ensure the best results with the least toxicity. Table 12.2.5 shows risk stratification of ALL.

• •

Always establish a complete and accurate diagnosis before committing a patient to therapy. Treat the patient according to published protocols without undue deviations to ensure the best outcomes. Promptly initiate broad-spectrum antibiotics during febrile neutropenia treating it as a medical emergency. Follow up of leukemia survivors lifelong for late effects and secondary malignancies.

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Table 12.2.6 The Multicenter protocol (MCP) 841 Cycle*

Chemotherapy

Dose and schedule

Induction 1 (I1)

Prednisone Vincristine Methotrexate† L asparaginase Daunorubicin

40 mg/m2 PO days 1–28 1.4 mg/m2 IV days 1, 8, 15 and 22 12 mg IT, days 1, 8, 15 and 22 6000 u/m2 IM on alternate days × 10 doses, days 2–20 30 mg/m2 IV days 8, 15 and 29

Induction 2 (I2)

Mercaptopurine Cyclophosphamide Methotrexate† Cranial radiation

75 mg/m2 PO daily days 1–7 and days 15–21 750 mg/m2 IV days 1 and 15 12 mg/m2 IT days 1, 8, 15 and 22 180 cGy daily × 10 days (total 1800 cGy)

Same as I1

Doses and schedule as per I1

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Repeat induction (RI1) Consolidation (C)

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Cyclophosphamide Vincristine Mercaptopurine Cytarabine Daunorubicin Prednisone Vincristine Daunorubicin L asparaginase Methotrexate -

Maintenance (M, six cycles)

Pediatric Malignancies

Presently, the cure rates in ALL in developed countries are as high as 79–86% using intensive protocols. Few studies published from tertiary institutes in India have reported cure rates of 40–60%. The multicenter protocol (MCP) 841 is an indigenous protocol in use in various centers for the last 20 years with manageable toxicity (Table 12.2.6). Cure rates for AML are about 60% in developed countries and around 30–40% in developing countries.

Table 12.2.5 Risk stratification of acute lymphoblastic leukemia (ALL)

Mercaptopurine

750 mg/m2 IV day 1 1.4 mg/m2 IV days 1 and day 15 75 mg/m2 PO daily days 1–7 and days 15–21 100 mg/m2 SC every 12 hours × 6 doses on days 1–3 and days 15–17 30 mg/m2 IV days 15 40 mg/m2 PO days 1–7 1.4 mg/m2 IV on day 1 30 mg/m2 IV on day 1 6000 u/m2 IM days 1, 3, 5 and 7 15 mg/m2 PO once a week; missing every 4th for a total of 12 weeks. Begin on day 15 75 mg/m2 PO daily, 3 weeks out of every 4 for total of 12 weeks. Begin on day 15 s

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Abbreviations: PO, er os; IV, ntravenous; IT, ntrathecal; IM, ntramuscular; cGy, entigray; SC, ubcutaneous Keys: *Each cycle subsequent to I1, begins as soon as the neutrophil count is >/= 1000/m3 and the platelet count is >/= 100,000/mm3 † Dose for patient >/=3 years: patients aged 2–3 years 10 mg; patients aged 1–2 years received 8 mg and patients less than 1 year received 6 mg.

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ibliography

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1. Bajel A, George B, Mathews V, et al. Treatment of children with acute lymphoblastic leukemia in India using a BFM protocol. Pediatr Blood Cancer. 2008;51(5):621-5. 2. Davies SM, Mehta PA. Pediatric acute lymphoblastic leukemia: is there still a role for transplant? Hematology Am Soc Hematol Educ Program. 2010;2010:363-7. 3. Hunger SP, Raetz EA, Loh ML, et al. Improving outcomes for high risk ALL: translating new discoveries into clinical







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6.

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5.

care. Pediatr Blood Cancer. 2011;56(6):984-93. doi: 10.1002/ pbc.22996. Epub 2011. Kulkarni KP, Marwaha RK, Trehan A, et al. Survival outcome in childhood ALL: experience from a tertiary care center in North India. Pediatr Blood Cancer. 2009;53(2):168-73. Magrath I, Shanta V, Advani S, et al. Treatment of acute lymp hoblastic leukemia in countries with limited resources; lessons from use of a single protocol in India over a twenty year period [corrected]. Eur J Cancer. 2005;41(11):1570 83. Epub 2005. Margolin JF. Molecular diagnosis and risk-adjusted therapy in pediatric hematologic malignancies: a primer for pediatricians. Eur J Pediatr. 2011;170(4):419 25. Epub 2011. Pui CH, Campana D, Pei D, et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Eng J Med. 2009;360(26):2730-41. Pui CH, Carroll WL, Meshinchi S, et al. Biology, risk stratification, and therapy of pediatric acute leukemias: an update. J Clin Oncol. 2011;29(5):551-65. Epub 2011. Schultz KR, Prestidge T, Camitta B. Philadelphia chromosome positive acute lymphoblastic leukemia in children: new and emerging treatment options. Expert Rev Hematol. 2010;3(6):731-42. Urayama KY, Ma X, Selvin S, et al. Early life exposure to infections and risk of childhood acute lymphoblastic leukemia. Int J Cancer. 2011;128(7):1632-43. doi: 10.1002/ ijc.25752. Epub 2010. -

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• The incidence of leukemia is high enough for all pediatricians to maintain a high index of suspicion in children with unusual symptoms. • Refer a suspected case of leukemia early to a tertiary center, as early diagnosis can make a significant difference in the outcome of this curable disease. • Be wary of administering steroids to a patient suspected of having leukemia. It can precipitate tumor lysis syndrome, and sometimes, mask the diagnosis. • If a patient is severely anemic, packed RBC transfusion can be given before transfer to a tertiary center as it can be life saving.





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ymphomas in hildren

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Pediatric Malignancies

12.3

infection, familial clustering of cases and higher incidence in twins may be some of the other contributing factors.

ntroduction

Lymphomas are the third most common group of cancers in children and adolescents after leukemias and brain tumors, accounting for 10–15% of newly diagnosed cancers in this age group. They are neoplasms of lymphocytes or their precursors, which arise as a consequence of genetic aberrations that influence their proliferation, differentiation and ability to undergo apoptosis (or cell death). They usually present with distinct clinical syndromes reflecting the histological subtype. Sixty percent of all childhood lymphomas have been classified as NHLs representing 3% of all childhood malignancies for children younger than 5 years and 8–9% in children and adolescents between 5 years and 19 years of age. Hodgkin lymphoma comprises 6% of childhood cancers. Both of these major lymphoma subtypes have distinct origins, clinical presentations, biology, treatment approaches and outcome (Table 12.3.1), and hence, they are discussed separately in the following sections.

T

All cases of Hodgkin lymphoma arise from germinal center B-cells that cannot synthesize immunoglobulin and are characterized by a variable number of characteristic multinucleated giant cells [Reed-Sternberg (R-S) cells] or large mononuclear cell variants [lymphocytic and histiocytic (L&H) cells] in an inflammatory background of small lymphocytes, histiocytes, neutrophils, eosinophils, plasma cells, and fibroblasts in different proportions depending on the histologic subtype. It has been conclusively shown that R-S cells and/or L&H cells represent a clonal population. Also, EBV genetic material can be detected in R-S cells from some patients with Hodgkin lymphoma. Hodgkin lymphoma can be divided into two broad pathologic classes: 1. Nodular lymphocyte-predominant Hodgkin lymphoma and 2. Classical Hodgkin lymphoma.

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Hodgkin disease (HD) occurs in 5–7 per 100,000 population. The incidence is highest in late childhood and early adulthood (15–35 years). It is very uncommon under 5 years of age and almost never seen under 2 years of age. In Asian population, HD is common even at younger ages. The sex ratio varies from male preponderance of 10:1 under the age of 7 years falling to 1:1 after the age of 12 years.

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Nodular Lymphocyte-Predominant Hodgkin Lymphoma This pathologic class of Hodgkin lymphoma is characterized by large cells with multilobed nuclei, referred to as Table 12.3.2 Histopathologic classification of classical Hodgkin disease  

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Hodgkin isease

Pathobiology ( able 12.3.2)



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Distinctive features

Relative frequency (%)

Variation in the incidence of HD in different ethnic groups and association with HLA suggest that inherited susceptibility plays an important role in the pathogenesis. Environmental factors such as Epstein-Barr virus (EBV)

Lymphocyte rich (LR)

Benign appearing lymphocytes with or without histiocytes. Few Reed-Sternberg (R-S) cells. No fibrosis

10–15

Table 12.3.1 Comparative clinical features of Hodgkin and nonHodgkin lymphoma

Nodular sclerosis (NS)

Thickened capsule with proliferation of orderly collagenous bands that divide lymphoid tissue in nodules: Lacunar variant of R-S cells.

20–50

Mixed cellularity* (MC)

5–15 R-S cells/high power field. Fine fibrosis in interstitium. Focal necrosis may be present.

20–40

Lymphocyte depletion (LD)

Abnormal cells with relative paucity of lymphocytes. Fibrosis and necrosis common but diffuse.

5–16

 

Clinical feature

Hodgkin disease

Non-Hodgkin lymphoma

Nodal spread

Continuous

Discontinuous

Localized

Yes

Rare

Extranodal disease

Rare

Common

CNS disease

Rare

Common

Bone marrow

Rare

Common

B-symptoms

Common

Uncommon

Abdominal disease

Uncommon

Common

Subtype-based therapy

Not important

Crucial

Cure rates

85–95%

70–80%

Abbreviation: CNS, entral nervous system c

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REAL subgroups

tiology

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Abbreviation: REAL, Revised European-American lymphoma *Most common in developing countries and in children.

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Classical Hodgkin Lymphoma

S

The hallmark of classical Hodgkin lymphoma is the R-S cell that is often characterized by a bilobed nucleus, with two large nucleoli, giving an owl’s eye appearance to the cells. The classical subtypes are defined according to the number of R-S cells, characteristics of the inflammatory milieu, and the presence or absence of fibrosis. A striking characteristic is the rarity (about 1%) of the malignant R-S cells in specimens and the abundant reactive cellular infiltrate. The histologic features and clinical symptoms of Hodgkin lymphoma have been attributed to the numerous cytokines secreted by the R-S cells, which include interleukin-1, interleukin-6 and tumor necrosis factor. Classical HD is divided into four subtypes as detailed in the Table 12.3.2.

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popcorn cells. Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is most common in males younger than 10 years of age. Patients with NLPHL generally present with localized, nonbulky disease usually in the mediastinum. Almost all patients are asymptomatic.

Hodgkin disease has an insidious onset. The most frequent presentation in up to 80% of patients is painless cervical or supraclavicular lymphadenopathy, of which 60% have asymptomatic involvement of the mediastinum. Enlarged nodes are generally firm and have a rubbery texture. Constitutional or class “B” symptoms such as fever, night sweats and weight loss are more common with advanced disease (stage I-5%, stage IV-81%) and are associated with a poorer outcome. Approximately 20% of patients have bulky adenopathy (maximum mediastinal diameter greater than one-third of the chest diameter and/or a node or nodal aggregate larger than 10 cm). Fifteen to twenty percent of patients have noncontiguous extranodal involvement (stage IV) of lung, liver, bones and bone marrow. A reduced cell-mediated immunity results in an increase susceptibility to infections.

Evaluation of a Patient • • • • •

Table 12.3.3 Modified Ann Arbor classification of Hodgkin disease

•

 

Current Hodgkin lymphoma staging is based on Cotswold’s modification of Ann Arbor staging proposed in 1998, which is detailed in Table 12.3.3.

Description

I

Involvement of single lymph node region (I) or of a single extralymphatic organ or site (IE) by direct extension

II

Involvement of two or more lymph node regions on the same side of diaphragm or localized involvement of an extralymphatic organ or site and of one or more lymph node regions on the same side of the diaphragm (IIE)

III1

Involvement of lymph node regions on both sides of the diaphragm Abdominal disease is limited to the upper abdomen (i.e. spleen, splenic hilar nodes, celiac nodes, porta hepatitis nodes)

III2

Involvement of lymph node regions on both sides of the diaphragm Abdominal disease includes para-aortic, mesenteric and iliac involvement with or without disease in the upper abdomen

IV

Disseminated involvement of one or more extralymphatic organs or tissues with or without associated lymph node disease

A

No symptoms

B

Fever, night sweats or weight loss of more than 10% of bodyweight in the previous 6 months

X

Bulky disease (> 10 cm in maximum dimension; > 1/3rd of the internal transverse diameter of the thorax at the level T5/T6)

E

Limited involvement of a single extranodal site

CS

Clinical stage: When based solely on physical examination and imaging technique

PS

Pathologic stage: When based on biopsies

•

History and physical examination Complete blood counts Liver and renal function tests, serum LDH and serum albumin Lymph node biopsy Bone marrow aspiration and biopsy: This is done in patients with advanced disease (stage III/IV), B-symptoms and bony involvement or abnormal counts. Radiological studies: Chest X-ray; computed tomography (CT) scan of neck, chest, abdomen and pelvis; imaging of other sites as and when indicated. Positron emission tomography scan of the whole body: Positron emission tomography (PET) scanning may identify more sites of initial disease than conventional imaging and is more accurate in detecting viable Hodgkin lymphoma in post-therapy residual masses. Rapid early response documented by significant reduction in disease volume and PET negativity at an early stage (after one or two cycles of chemotherapy) is associated with a favorable outcome. PET scanning should be performed at baseline and a minimum of 3 weeks postchemotherapy completion and 8–12 weeks postradiation.

Prognostic actors F

Stage

linical Presentation

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Several factors influence the success and choice of therapy. Pretreatment factors associated with an adverse outcome include advanced stage of disease, presence of symptoms, bulky disease, extranodal extension, male sex and elevated erythrocyte sedimentation rate. These factors are interrelated in the sense that disease stage, bulk and biologic aggressiveness are frequently codependent. There is some controversy as to whether histology is an important prognostic factor. The rapidity of response to initial cycles of chemotherapy based on PET is also prognostically important and is being used to determine subsequent therapy in current trials.

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All children generally receive combination chemotherapy as initial treatment. While regimens containing alkylating agents are associated with an increased risk for infertility and therapy-related leukemia; in non-alkylator-containing regimens, doxorubicin (DOX) is associated with cardiac damage and bleomycin can produce pulmonary fibrosis. Common regimens currently utilized for treatment include non-alkylator-containing regimens such as adriamycin (DOX), bleomycin, vinblastine and dacarbazine (ABVD) or hybrid regimens with lower total cumulative doses of alkylators, DOX, and bleomycin such as cyclophosphamide,

 

Table 12.3.4 Treatment modalities and results in Hodgkin disease Risk group

Treatment modality

Overall survival (%)

Low risk (Stage I, IIA, no bulk, no B-symptoms)

VAMP/ABVE/ABVD 2–4 cycles + Low-dose (15–25 Gy) IFRT

96–98

High risk (IIB, III, IV, bulky disease)

COPP-ABV/ABVE-PC/ ABVD/BEACOPP 6 cycles + LD (15–25 Gy) IFRT

85–90

Nodular Lymphocyte-Predominant Hodgkin Lymphoma Children with nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) have a favorable outcome, particularly when the disease is in early stage. Thus, treatment for NLPHL focuses on reducing initial therapy to reduce longterm treatment-related morbidity and mortality. Although, current standard therapy for children with NLPHL is chemotherapy plus LD-IFRT; patients have also been successfully treated with either chemotherapy alone or complete resection of isolated nodal disease. Anti-CD-20 monoclonal antibody, rituximab is increasingly being used as a single agent or in combination with chemotherapy in relapsed NLPHL and is being evaluated as a frontline therapy in clinical trials.

a

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ate ffects

Survivors of Hodgkin lymphoma are at risk for numerous late complications of treatment. Alkylating agents and VP16 have been associated with AML and myelodysplastic syndromes. Doxorubicin can lead to cardiomyopathy and bleomycin can cause pulmonary fibrosis. Steroid use can produce avascular necrosis. Radiation therapy can lead to thyroid dysfunction, increased risk for myocardial atherosclerotic heart disease and is associated with solid tumor development in radiation fields. All these potential complications mandate a close long-term follow-up after completion of therapy. C

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Abbreviations: IFRT, nvolved field radiotherapy; VAMP, Vincristine, adriamycin, methotrexate and prednisone; ABVE, driamycin, bleomycin, vincristine and VP16; ABVD, driamycin, bleomycin, vincristine and dacarbazine; COPP, yclophosphamide, oncovin (vincristine), procarbazine and prednisone; ABV, driamycin, bleomycin and vincristine; BEACOPP, leomycin, VP16, Adriamycin, cyclophosphamide, oncovin (vincristine), prednisone and procarbazine

Most newly diagnosed children are treated with riskadapted chemotherapy alone or in combination with LDIFRT. Low-dose involved-field radiation therapy involves the use of meticulous and judiciously designed fields to achieve local control of disease and to minimize damage to normal tissue. The low-dose radiation therapy (LDRT) treatment volume includes the initially involved lymph node region(s). In general, doses of 15–25 Gy are used, with modifications based on patient’s age, the presence of bulk or residual (postchemotherapy) disease and normal tissue concerns. Transposition of ovaries to midline and midline pelvic block to protect ovarian function and testicular shield or sperm banking in male children is routinely considered.

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Principles of Chemotherapy

Principles of Radiotherapy

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Treatment of HD in pediatric population is different in certain respects from adults. Devising the ideal therapeutic approach for children with HD is complicated by their increased risk for late adverse effects. In particular, radiation therapy can cause profound musculoskeletal growth retardation and increase the risk for cardiovascular disease and secondary solid malignancies in children. Further complicating the treatment of children are genderspecific differences in chemotherapy-induced gonadal injury. The desire to cure young children with minimal side effects has stimulated attempts to reduce the intensity of chemotherapy (particularly alkylating agents) and radiation dose or volume. In general, the use of combined chemotherapy with radiation broadens the spectrum of potential toxicities, while reducing the severity of indivi dual drug-related or radiation-related toxicities. Current approaches use chemotherapy alone with or without low-dose (15–25 Gy) involved-field radiation therapy (LDIFRT). The volume of radiation and the intensity/duration of chemotherapy are determined by risk grouping based on prognostic factors at presentation, including presence of constitutional symptoms, disease stage and bulk. The current therapeutic strategy and outcome for children with HD is outlined in Table 12.3.4.

oncovin [vincristine (VCR)], procarbazine and prednisone (COPP)/adriamycin, bleomycin and vinblastine (ABV), adriamycin, bleomycin, VCR and etoposide (VP16) (ABVE), bleomycin, VP16, adriamycin, cyclophosphamide, oncovin (VCR), prednisone, and procarbazine (BEACOPP) and VCR, adriamycin, methotrexate and prednisone (VAMP).

Pediatric Malignancies

Management

onclusion

Hodgkin disease is one of the most curable cancers in children. Current use of appropriate staging techniques and risk-adapted treatment, protocols have resulted in an excellent overall survival. The formidable challenge is to 755 maintain high cures and ameliorate treatment sequelae.

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1. Hudson M, Constine LS. Hodgkin’s disease. In: Halperin EC, Constine LS, Tarbell NJ (Eds). Pediatric Radiation Oncology, 4th edition. Philadelphia, Pa: Lippincott Williams & Wilkins. 2004.pp.223-60. 2. Hudson MM, Donaldson SS. Hodgkin’s disease. In: Pizzo PA, Poplack DG (Eds). Principles and Practice of Pediatric Oncology, 5th edition. Philadelphia, Pa: Lippincott Williams & Wilkins. 2006.p.695. 3. Re D, Thomas RK, Behringer K, et al. From Hodgkin disease to Hodgkin lymphoma: biologic insights and therapeutic potential. Blood. 2005;105(12):4553-60. Epub 2005. 4. Schwartz CL. The management of Hodgkin disease in the young child. Curr Opin Pediatr. 2003;15(1):10-6. 5. Thomson AB, Wallace WH. Treatment of paediatric Hodgkin’s disease. a balance of risks. Eur J Cancer. 2002;38(4):468-77.

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lassification and linical Presentation ( able 12.3.5) In children, NHL is distinct from the more common forms of lymphoma observed in adults. While lymphomas in adults are more commonly low or intermediate grade, are dominantly nodal, have variable growth fraction and poor long-term outcome; almost all NHL that occurs in children is high grade, extranodal, has higher growth fraction and good outcome. Non-Hodgkin lymphoma of childhood currently falls into three therapeutically relevant categories: (1) B-cell NHL [Burkitt lymphoma/leukemia (BLL) and diffuse large B-cell lymphoma (DLBL)]; (2) lymphoblastic lymphoma (LL; primarily precursor T-cell lymphoma, and less frequently, precursor B-cell lymphoma); and (3) ALCL (T-cell or null-cell lymphomas). Each type of childhood NHL is associated with distinctive clinical presentation, immunophenotype and molecular biological characteristics. Distribution of NHL subtypes among children and adolescents in India differs from the rest of the world, namely a higher prevalence of DLBL and LL and a lower frequency of BLL. C

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• Hodgkin lymphoma comprises 6% of childhood cancers and 40% of all childhood lymphomas. • It is of two distinct pathologic subtypes: Nodular lymphocyte dependent and classical Hodgkin lymphoma with presence of hallmark malignant R-S cells. • It usually presents with painless cervical lymphadenopathy with contiguous spread and B-symptoms in advanced stages. • It is diagnosed on lymph node biopsy and staged based on modified Ann Arbor’s staging system. • Risk-stratified treatment based on use of multiagent chemotherapy with LD-IFRT achieves cure in 80–90% children. • The current focus is on maintaining high cure rates with minimal chemoradiotherapy and minimization of long-term late effects.

estimated to occur annually in India. It occurs most commonly in the second decade of life, and occurs less frequently in children younger than 3 years of age. Immunodeficiency, both congenital (e.g. Ataxia-telangiectasia, Wiskott-Aldrich syndrome) and acquired [human immunodeficiency virus (HIV) infection or post-transplant], increases the risk of NHL. Indeed, NHL is the most frequent malignancy in children with acquired immunodeficiency syndrome (AIDS). With current treatments, about 80% of children and adolescents with NHL will survive at least 5 years.



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Non-Hodgkin lymphoma is neoplasm of a wide range of cell types that comprise the immune system. It is generalized disease from the outset and has patterns of spread that mimic the migration patterns of their normal cellular counterparts. It accounts for approximately 7% of cancers in children less than 20 years of age. Approximately 2,500 cases of childhood NHL are

Burkitt lymphoma accounts for about 50% of childhood NHL and exhibits consistent, aggressive clinical behavior. The malignant cells show a mature B-cell phenotype, and tumor has “starry sky” appearance. Burkitt lymphoma expresses a characteristic chromosomal translocation, usually t(8;14) and more rarely t(8;22) or t(2;8). Each

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Pediatric on-Hodgkin ymphoma

 

Table 12.3.5 Major histopathological categories of pediatric NHL as per World Health Organization (WHO) classification Immunophenotype

Clinical presentation

Chromosome translocation

Burkitt and Burkitt-like lymphomas

Mature B-cell (CD10, CD19, CD20) and kappa and lambda light chains

Intra-abdominal (sporadic), head and neck (non-jaw, sporadic), jaw (endemic)

t(8;14)(q24;q32), t(2;8) (p11;q24), t(8;22) (q24;q11)

Diffuse large B-cell lymphoma

Mature B-cell (CD19, CD20, CD22, CD38 and CD79a)

Nodal, abdomen, bone, primary CNS, mediastinal

No consistent cytogenetic abnormality identified

Lymphoblastic lymphoma (precursor T cell or precursor B-cell)

Pre-T cell

Mediastinal, bone marrow

t(1;14)(p34;q11), t(11;14) (p13;q11)

Pre-B cell

Skin, bone

Anaplastic large cell lymphoma (systemic)

CD30, Alk, EMA+

Lymph node, skin, bones, visceral, soft tissues

T cell or null cell

t(2;5)(p23;q35)

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Abbreviations: NHL, on-Hodgkin lymphoma; CD, luster of differentiation; CNS, entral nervous system n

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Lymphoblastic Lymphoma



Lymphoblastic lymphoma makes up approximately 20% of childhood NHL. More than 75% of lymphoblastic lymphomas have a T-cell immunophenotype and the remainder has a precursor B-cell phenotype. Nearly 75% of patients with LL present with anterior mediastinal mass, and symptoms of dyspnea, wheezing, stridor, dysphagia, or swelling of the head and neck suggestive of superior vena cava syndrome (SVCS). Pleural effusions may be present and the involvement of lymph nodes, usually above the diaphragm, may be a prominent feature. There may also be involvement of bone, skin, bone marrow, CNS, abdominal organs (but rarely bowel), and occasionally, other sites such as lymphoid tissue of Waldeyer’s ring and testes. Patients with more than 25% marrow blasts are considered to have leukemia, and those with fewer than 25% marrow blasts are considered to have lymphoma.

Anaplastic Large Cell Lymphoma ­

Anaplastic large cell lymphoma accounts for approximately 10% of childhood NHL. While the predominant immuno phenotype of ALCL is mature T-cell; null-cell disease [i.e. no T-cell, B-cell or natural killer (NK)-cell surface antigen expression] does occur. More than 90% of ALCL cases have the translocation t(2;5)(p23;q35) leading to the expression of the fusion protein nucleophosmin (NPM)/anaplastic

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taging, Prognostication and isk tratification

The modified Ann Arbor staging classification does not adequately reflect prognosis in childhood NHL. The most widely used staging scheme for childhood NHL is that of the St. Jude Children’s Research Hospital (Murphy’s staging), which is outlined in Table 12.3.7. In general, treatment for childhood NHL depends on localized versus disseminated disease. Localized disease is usually defined as stage I or II disease, while stage III or IV disease is generally considered disseminated. Currently, B-cell non-Hodgkin lymphoma (B-NHL) is risk stratified further for treatment planning, which incorporates stage, LDH, extent of surgical resection and extent of bone marrow or CNS involvement. Similarly, ALCL is classified further

Table 12.3.6 Evaluation of patient with non-Hodgkin lymphoma  

Diffuse large B-cell lymphoma (DLBCL) is a mature B-cell neoplasm that represents 10–20% of pediatric NHL. Diffuse large B-cell lymphoma occurs more frequently during the second decade of life than during the first. Pediatric DLBCL may present clinically similar to Burkitt, though it is more often localized and less often involves the bone marrow or CNS. Outcomes for children with DLBCL are more favorable than those observed in adults, with overall 5-year event-free survival (EFS) rates of approximately 90% at 5 years. About 20% of pediatric DLBCL present as primary mediastinal disease [primary mediastinal B-cell lymphoma (PMBCL)]. This presentation is more common in older children and adolescents, and is associated with an inferior outcome compared with other pediatric DLBCL.

valuation of hildren with on-Hodgkin ymphoma

Pediatric NHL is a high grade and a very rapidly growing tumor; hence, rapid diagnosis is imperative to prevent complications. Table 12.3.6 lists the diagnostic tests required in the evaluation of NHL. Determination of the histologic subtype and immunophenotype on lymphnode/ tissue guides therapy. Patients with large mediastinal masses and SVCS are at risk of cardiac or respiratory arrest during general anesthesia or heavy sedation. Due to these risks, the least invasive available procedure to establish the diagnosis of lymphoma such as bone marrow examination, thoracocentesis, a lymph node biopsy under local anesthesia or a CT–guided core needle biopsy should be contemplated. S

Diffuse Large B-Cell Lymphoma

lymphoma kinase (ALK). Clinically, ALCL has a broad range of presentations, including involvement of lymph nodes and a variety of extranodal sites, particularly skin, bone, gastrointestinal tract, lung, pleura and muscle. Involvement of the CNS and bone marrow is uncommon. Anaplastic large cell lymphoma is often associated with systemic symptoms (e.g. fever, weight loss) and a prolonged waxing and waning course, making diagnosis difficult and often delayed.

Pediatric Malignancies

of these translocations juxtaposes the c-myc gene to immunoglobulin locus regulatory elements, resulting in the inappropriate expression of c-myc, the gene involved in cellular proliferation. The two most common primary sites of disease are: (1) abdomen and (2) headneck region. In India, these patients usually present with abdominal pain, vomiting, abdominal distension, palpable mass, intussusception, ascites, obstructive jaundice or hepatosplenomegaly (sporadic presentation). Endemic Burkitt lymphoma is common in Africa, presents as jaw mass in majority of cases and is usually associated with EBV infection. Other sites of involvement include testes, bone, peripheral lymph nodes, skin, bone marrow and CNS.

• History and physical examination • Complete blood count with peripheral smear for blasts • Biochemistry: Blood urea, uric acid, creatinine, liver function tests, serum electrolytes, serum lactate dehydrogenase, calcium, phosphorous • Imaging: X-rays, ultrasound, CT scan or MRI of primary site and for staging, PET Scan(optional) • Adequate surgical biopsy for immunophenotyping, cytogenetics/ molecular studies • Bone marrow aspiration and biopsy • CSF for cytology Abbreviations: CT, Computed tomography; MRI, Magnetic resonance imaging; PET, Positron emission tomography; CSF, Cerebrospinal fluid

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Table 12.3.7 St Jude’s staging system for childhood non-Hodgkin lymphoma Stage Definition • Single tumor (extranodal) • Single anatomic area (nodal) excluding mediastinum or abdomen • Single tumor (extranodal) with regional node involvement • Primary gastrointestinal tumor with or without involvement of mesenteric node or • On same side of diaphragm: – Two or more nodal areas – Two single extranodal tumors with or without regional node involvement

III

• • •

All primary intrathoracic tumors All extensive primary intra-abdominal disease Two or more nodal or extranodal areas on both sides of diaphragm

IV

•

Any of the above with CNS or bone marrow involvement

   

       

T

 

 

 

 

 

Low Risk (Localized)

II

High Risk (Advanced)

 

 

I

Abbreviation: CNS, Central nervous system

based on visceral, skin and mediastinal involvement (Table 12.3.8).

Management Childhood NHL is an extremely chemosensitive disease. Surgery plays a very limited role, mainly for arriving at a diagnosis or for emergency management of obstruction or perforation. Radiation of primary sites is used very rarely in emergency situations. Hence, multiagent chemotherapy directed to the histologic subtype and stage of the disease remains the cornerstone of therapy.

Emergency Management Pediatric NHL has very high growth fraction and short doubling time, sometimes as short as 24 hours seen with Burkitt’s lymphoma. Life-threatening complications may develop as a result of physical compression of tumor

masses on vital structures or because of high cell turnover in a large tumor with resultant biochemical disturbances. The following complications can occur and which must be anticipated early and addressed immediately: • Superior vena cava obstruction and esophageal compression from mediastinal masses seen with LL • Tumor lysis syndrome due to metabolic disturbances seen with LL and BLL • Airway obstruction from pharyngeal or intrathoracic masses • Respiratory or cardiac compromise from massive serous effusions related to involvement of pleura/peritoneum or pericardium • Paraplegia from epidural tumor or raised intracranial pressure and neurological deficits from intracranial lymphoma/CNS involvement • Obstructive jaundice and pancreatitis from compression of bile/pancreatic ducts

 

Table 12.3.8 Pediatric non-Hodgkin lymphoma (NHL): New risk grouping Protocol

Group

Definition

Five year EFS

B-NHL (FAB)

A B C

Completely resected stage-I and abdominal stage-II Unresected stage-I, non-abdominal stage-II All stages III and IV B-ALL < 70%, Blast CNS –ve B-ALL > 70%, Blast CNS +ve

98% 92% 84%

B-NHL (German group)

R1 R2 R3 R4

Stage-I/II initial complete resection Stage-I/II unresected, stage-III with LDH < 500 U/L Stage III with LDH >500–999 U/L, BM +ve and LDH < 1000 U/L LDH > 1000 U/L and/or CNS +ve

94% 94% 85% 81%

ALCL

Low risk Standard risk High risk

Stage-I completely excised No skin, mediastinal, liver, spleen, lung involvement Biopsy proven skin, mediastinal, liver, spleen, lung involvement.

90% 90% 60%

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Abbreviations: EFS, vent-free survival; B-ALL, B-cell acute lymphoblastic leukemia; CNS, entral nervous system; LDH, actate dehydrogenase; B-NHL, B-cell non-Hodgkin lymphoma; FAB, French-American-British; ALCL, naplastic large cell lymphoma

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Localized (low-risk) non-Hodgkin lymphoma in children: Stage I and II patients with grossly-resected (> 90%) disease regardless of histology have low-risk disease and an excellent prognosis, with 90% or better disease-free survival (DFS). For localized B-NHL (Burkitt or DLBL), use of short, intensive, pulsed chemotherapy for 2–3 months with aggressive CNS-directed chemotherapy without cranial radiation is standard. Common drugs used are dexamethasone, cyclophosphamide, methotrexate, cytarabine, prednisolone, intrathecal (IT) methotrexate, ifosfamide (IFOS), VP16 and DOX. For localized LL (grossly resected, i.e. > 90% stage I/II disease), a leukemia like approach with induction, consolidation, CNS-directed therapy and maintenance for a total of 18–24 months leads to more than 90% DFS. For localized ALCL, pulsed chemotherapy similar to B-NHL therapy is preferred.

Disseminated Childhood B-cell Non-Hodgkin Lymphoma Patients with disseminated B-lineage NHL (Burkitt or DLBCL) have an 80–90% long-term survival through the use of short, intensive, pulsed chemotherapy using above mentioned drugs for 5–6 months with aggressive CNS-directed intrathecal chemotherapy without cranial radiation. The use of high-dose methotrexate (> 5 g/m2), cytarabine and VP16 have appeared to be helpful in addition to the drugs mentioned above. Patients with Burkitt leukemia should be treated with protocols designed for Burkitt lymphoma. Multiagent chemotherapy protocols associated with excellent outcome include continuous Children’s Hospital of Philadelphia (CHOP)/Childhood Obesity Prevention Mission Project (COMP) (American protocol), FrenchAmerican-British lymphoma malignancy B (FAB-LMB-96) protocol, Berlin-Frankfurt-Munster (BFM) protocols (German multicentric protocol) and MCP-842 (Indian protocol). Rituximab is a mouse/human chimeric monoclonal antibody targeting the CD-20 antigen and is routinely used against DLBCL in adults. In children, rituximab in combination with the intensive chemotherapy regimen is being evaluated.

Patients with disseminated LL have long-term survival rates higher than 80%. As opposed to other pediatric NHL, LL responds much better to ALL like therapy with induction, consolidation, CNS-directed therapy (intrathecal drugs), reinduction and maintenance for a total of 2 years than with shorter, intensive, pulsed chemotherapy regimens used for B-NHL. Common drugs used are prednisone, dexamethasone, VCR, daunorubicin, DOX, L-asparaginase, cyclophosphamide, cytarabine, methotrexate, 6-mercaptopurine and 6-thioguanine. Cranial radiation is currently used only for patients with CNS disease at diagnosis. Commonly used protocols include BFM (German multicentric protocol) and LSA2L2 (American protocol).

Disseminated Childhood Anaplastic Large Cell Lymphoma Children and adolescents with disseminated ALCL have a DFS of approximately 60–75%. Both short pulse-intensive as well as lymphoblastic lymphoma like strategies are effective for the treatment of disseminated ALCL. However, B-NHL like short pulse-intensive regimens incorporating vinblastine is being preferentially used. Role of hematopoietic stem cell transplantation: Hematopoietic stem cell transplantation (HSCT) is currently considered for children with recurrent or refractory NHL. Among relapsed patients with B-NHL and LL, despite current salvage chemotherapy and autologous HSCT, only about 10–30% patients survive long term. However, in ALCL, with salvage chemotherapy and/or autologous or allogenic HSCT, more than half of children become longterm survivors.

Definitive Therapy of Pediatric Non-Hodgkin Lymphoma

Disseminated Childhood Lymphoblastic Lymphoma

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Gastrointestinal bleeding, obstruction of bowel and rarely perforation from intestinal involvement In patients with SVCS at risk of cardiac or respiratory arrest, least invasive available procedure to establish the diagnosis of lymphoma should be used and treatment started immediately in intensive care unit as discussed earlier. Tumor lysis syndrome results from the rapid breakdown of malignant cells resulting in a number of metabolic abnormalities, most notably hyperuricemia, hyperkalemia and hyperphosphatemia. Hyperhydration and allopurinol or rasburicase (urate oxidase) are essential components of therapy.

Pediatric Malignancies

•

onclusion

Non-Hodgkin lymphoma presents with distinct clinical syndromes reflecting the histological subtype. The prognosis for childhood NHL has improved significantly over the past two decades. The management includes supportive care to prevent tumor lysis syndrome, anticipation and management of oncologic emergencies and multiagent chemotherapy. Intensive combination chemotherapy regimens with optimal supportive care have been shown to be feasible and curative for most children with NHL. The current focus is now on risk-stratified therapy to reduce chemotherapy and associated complications for low-risk disease and intensifying treatment for highrisk NHL for optimum long-term survival. Management of relapses continues to be a challenge and warrants highdose chemotherapy with stem cell rescue in selected cases.

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1. Gore L, Trippett TM. Emerging non-transplant-based strategies in treating pediatric non-Hodgkin’s lymphoma. Curr Hematol Malig Rep. 2010;5(4):177-84. 2. Gross TG, Termuhlen AM. Pediatric non-Hodgkin’s lymphoma. Curr Oncol Rep. 2007;9(6):459-65. 3. Magrath IT. Malignant non-Hodgkin’s lymphomas in children. In: Pizzo PA, Poplack DG (Eds). Principles and Practice of Pediatric Oncology, 4th edition. Philadelphia, Pa: Lippincott Williams & Wilkins; 2002.pp.661-705. 4. Pinkerton R. Continuing challenges in childhood nonHodgkin’s lymphoma. Br J Haematol. 2005;130(4):480-8. 5. Shukla NN, Trippett TM. Non-Hodgkin’s lymphoma in children and adolescents. Curr Oncol Rep. 2006;8(5):387-94.



ibliography





• Non-Hodgkin lymphoma is the third most common cancer in children. • Childhood NHL is high-grade and aggressive requiring rapid confirmation of diagnosis, staging and prompt initiation of therapy. • Prevention and appropriate management of oncologic emergencies is a must. • Multiagent combination chemotherapy direct to histologic subtype is the mainstay of treatment and has improved the cure rate of childhood NHL to more than 75%. • Children with LBL are treated with protocols designed for ALL, which provide EFS rates up to 80%. • Children with B-NHL are treated with a strategy of short, rapidly repeated, pulse-intense regimens, which leads to EFS rates of up to 90%.



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• In patients with ALCL, comparable results are achieved with either strategy. Although, ALCL has the highest relapse rate but many relapses can be salvaged with vinblastine-based regimens with or without HSCT.

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Wilms umor





Pediatric Malignancies

12.4

The median age at presentation is 4 years for unilateral tumors and 2.5 years for bilateral tumors. About 1.5% cases of WT are familial. It constitutes 6% of all childhood cancers. Wilms tumor has been reported to be associated with various anomalies. Genitourinary anomalies are the most common and account for incidence of 4–8%. These include fused kidney, renal dysplasia, cryptorchidism, hypospadias, duplication of the collecting system and WT, aniridia,

The classic triphasic WT [favorable histology (FH)], is made up of varying proportions of three cell types: (1) blastemal, (2) stromal and (3) epithelial. Unfavorable histology (UH) is characterized by qualitative variation from the classical type. Presence of focal or diffuse anaplasia, clear cell sarcoma and rhabdoid tumor (RT) are considered to be unfavorable histologic features. Most WTs are unicentric, 11% are multicentric but unilateral and 7% are bilateral. The SIOP trials recognized three prognostic groups of renal tumors of childhood: (1) low risk, (2) intermediate risk and (3) high-risk tumors (Table 12.4.1).

pidemiology

Pathology

 

Table 12.4.1 International Society of Pediatric Oncology working classification of renal tumors of childhood (2001) Low-risk tumors

 

I.

Primary nephrectomy cases Low-risk tumors

I.

 

Pretreated cases

•  Mesoblastic nephroma •  Cystic partially differentiated nephroblastoma

•  Mesoblastic nephroma •  Cystic partially differentiated nephroblastoma •  Completely necrotic nephroblastoma  

II. Intermediate-risk tumors •  •  •  •  • 

Intermediate-risk tumors

II.

 

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Wilms tumor (WT) is the most common renal tumor encountered in childhood. It develops as a result of abnormalities in the development of metanephric blastema. It is the paradigm for multidisciplinary treatment of pediatric malignant solid tumors. Large randomized controlled trials by various collaborative groups, including the National Wilms Tumor Study Group (NWTSG), SIOP and the United Kingdom Children’s Cancer Study Group (UKCCSG) have facilitated WT treatment to be customized to minimize morbidity for low-risk disease and to maximize the prognosis for high-stage, high-risk patients. Consequently, the outcome for patients with WT has improved remarkably in the past few decades.

genitourinary abnormalities and mental retardation (WAGR) syndrome. Wilms tumor is also featured in many disorders of overgrowth including Beckwith-Wiedemann syndrome (BWS), Perlman syndrome and isolated hemihypertrophy. Although, most patients with WT are karyotypically normal, genomic studies have led to the localization and subsequent cloning of WT genes in two regions: (1) 11p13 and (2) 11p15. The former is WT1 gene and is associated with WAGR syndrome and the latter is WT2 gene, which is associated with BWS.



ntroduction

•  Non-anaplastic nephroblastoma and its variants •  Nephroblastoma—focal anaplasia

Nephroblastoma—epithelial type Nephroblastoma—stromal type Nephroblastoma—mixed type Nephroblastoma—regressive type Nephroblastoma—focal anaplasia

 

III. High-risk tumors •  Nephroblastoma—blastemal type •  Nephroblastoma—diffuse anaplasia •  Clear cell sarcoma of the kidney (CCSK) •  Rhabdoid tumor of the kidney Abbreviation: RT, Rhabdoid tumor

III.

 

I

Purna A Kurkure

High-risk tumors •  Nephroblastoma—diffuse anaplasia •  CCSK •  Rhabdoid tumor of the kidney

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• • •

Asymptomatic flank mass Pain in abdomen Others—hematuria and hypertension.

nvestigations

inspection for local tumor extension, hilar and regional lymph nodes, liver metastases and peritoneal seedings. Prevention of tumor spillage should be of prime concern as this has a bearing in upstaging the tumor; hence, gentle handling and careful removal is mandatory. The inferior vena cava (IVC) and the renal vein should be palpated for the presence of tumor thrombus, which if present should be removed en-bloc with the kidney. Generally, WT does not infiltrate the adjoining structures; hence, a radical en-bloc resection is rarely needed. However, a wedge resection, if performed safely, may help in down staging the tumor to stage II. As regards to lymph node dissection, sampling of suspicious lymph node is recommended instead of a formal lymph node dissection. Partial nephrectomy in the routine management of WT has not gained popularity. The reasons being most WT are large or centrally located, making only less than 5% eligible for partial nephrectomy at presentation and even after preoperative chemotherapy only about 10% would be feasible for a nephronsparing surgery. These surgeries carry a risk of leaving behind nephrogenic rest in addition to other procedure-related complications. Hence, partial nephrectomy is recommended for patients with synchronous or metachronous bilateral tumors, tumors in solitary kidneys, renal insufficiency of any etiology and children with risk of multiple neoplasm’s such as in BWS.

Table 12.4.3 provides the staging system of the National Wilms Tumor Study Group (upfront surgery) and Table 12.4.4 provides the staging system of the SIOP (upfront chemotherapy).

Management

S

Overall management plan has been represented in Flow charts 12.4.1 and 12.4.2.

urgery

Table 12.4.3 Staging system of the National Wilms Tumor Study Group (upfront surgery) Stage I

 

Table 12.4.2 Investigations to be done in Wilms tumor Purpose

Abdominal ultrasonogram (USG)

Organ of origin Identify contralateral kidney Presence/absence of tumor thrombus in IVC

CT scan

Further evaluation of extent of tumor Extension into adjoining structures such as liver, spleen and colon Visualization and function of contralateral kidney Pulmonary metastasis

Bone scan and skeletal survey

Bone metastasis in clear cell sarcoma of kidney (CCSK)

Brain imaging (MRI/CT Scan)

Intracranial metastasis in rhabdoid tumor (RT) and CCSK

Fine needle aspiration cytology of mass

Cytological confirmation of diagnosis prior to prenephrectomy chemotherapy

c

Abbreviations: CT, omputed tomography; MRI, imaging; IVC, nferior vena cava

m

Chest X-ray

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Investigation

agnetic resonance

Tumor limited to the kidney and completely excised: –  The tumor was not ruptured before or during removal –  The vessels of the renal sinus are not involved beyond 2 mm –  There is no residual tumor apparent beyond the margins of excision



The timing of surgery with regards to preoperative therapy has varied between the European and the North American groups. Nevertheless, surgical resection is an important constituent in the multimodal management of WT. Debates about the exploration of contralateral kidney at surgery exists but evidence now suggests that it can be omitted. Data from NWTS 4 study showed that omission of routine exploration does not affect the outcome or management of newly diagnosed WT, if adequate preoperative CT or MRI is obtained. A transperitoneal approach is preferred to provide adequate exposure for complete staging, which includes

 

taging





These are listed in Table 12.4.2. S

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Stage II

Tumor extends beyond the kidney but is completely excised: –  No residual tumor is apparent at or beyond the margins of excision –  Tumor thrombus in vessels outside the kidney is stage II if the thrombus is removed en-bloc with the tumor Although tumor biopsy or local spillages confined to the flank were considered stage II by NWTSG in the past, such events will be considered stage III in upcoming COG studies.

Stage III

Residual tumor confined to the abdomen: –  Lymph nodes in the renal hilum, the periaortic chains or beyond are found to contain tumor –  Diffuse peritoneal contamination by the tumor –  Implants are found on the peritoneal surfaces –  Tumor extends beyond the surgical margins either microscopically or grossly –  Tumor is not completely resected because of local infiltration into vital structures

Stage IV

Presence of hematogenous metastases or metastases to distant lymph nodes

Stage V

Bilateral renal involvement at the time of initial diagnosis

Abbreviation: COG, Children’s Oncology Group

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Pediatric Malignancies

 

Table 12.4.4 Staging system of International Society of Pediatric Oncology (SIOP) (upfront chemotherapy) Stage I

Tumor is limited to kidney or surrounded with fibrous pseudocapsule if outside of the normal contours of the kidney, the renalcapsule or pseudocapsule may be infiltrated with the tumor, but it does not reach the outer surface, and is completely resected (resection margins “clear”): –  The tumor may be protruding into the pelvic system and “dipping” into the ureter (but it is not infiltrating their walls) –  The vessels of the renal sinus are not involved –  Intrarenal vessel involvement may be present Fine-needle aspiration cytology (FNAC) or core needle biopsy does not upstage the tumor. The presence of necrotic tumor or chemotherapyinduced changes in the renal/sinus fat and/or outside of the kidney should not be regarded as reason for upstaging a tumor.

Stage II

Tumor extends beyond the kidney but is completely excised or penetrates through the renal capsule and/or fibrous pseudocapsule into perirenal fat but is completely resected (resection margins “clear”): –  The tumor infiltrates the renal sinus and/or invades blood and lymphatic vessels outside the renal parenchyma but is completely resected –  The tumor infiltrates adjacent organs or vena cava but is completely resected

Stage III

–  Incomplete excision of the tumor, which extends beyond resection margins (gross or microscopical tumor remains postoperatively) –  Any abdominal lymph nodes are involved –  Tumor rupture before or intraoperatively (irrespective of other criteria for staging) –  The tumor has penetrated through the peritoneal surface –  Tumor implants are found on the peritoneal surface –  The tumor thrombi present at resection margins of vessels or ureter, transected or removed piecemeal by surgeon –  The tumor has been surgically biopsied (wedge biopsy) prior to preoperative chemotherapy or surgery

C

The presence of necrotic tumor or chemotherapy-induced changes in a lymph node or at the resection margins should be regarded as stage III. Stage IV

Hematogenous metastases (lung, liver, bone, brain, etc.) or lymph node metastases outside the abdomen-pelvic region.

Stage V

Bilateral renal tumors at diagnosis. Each side should be substaged according to the above criteria.

hemotherapy

 

Flow chart 12.4.2 International Society of Pediatric Oncology management plan

The current first-line drugs for WT are vincristine (VCR), dactinomycin (DAM) and doxorubicin (DOX). The secondline drugs for high risk, relapse disease are ifosfamide (IFOS), etoposide, carboplatin (Carbo) and cyclophosphamide. Large cooperative groups have different chronology for

 

Flow chart 12.4.1 National Wilms Tumor Study Group (NWTS) management plan

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Abbreviations: SIOP, International Society of Pediatric Oncology; Carbo, arboplatin; CPM, yclophosphamide; DAM, dactinomycin; DOX, doxoru bicin; EPI, epirubicin; IFOS, fosfamide; VCR, incristine; RT, adiotherapy c

Abbreviations: NWTS, National Wilms Tumor Study Group; FH, favorable histology; UH, unfavorable histology; wk, eek; PI, pulse intensive; DAM, Dactinomycin; VCR, incristine; DOX, doxorubicin; RT, adiotherapy; CPM, yclophosphamide

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Table 12.4.5 National Wilms Tumor Study (NWTS) V treatment results (favorable histology) Stage

4 year EFS (%)

4 year OS (%)

I

92.4

98.3

II

81.4

97.6

III

88.7

94.8

IV

74.6

86.3

Abbreviations: EFS, event-free survival; OS, overall survival

Absolute Indications for Prenephrectomy Chemotherapy • • • •

Large tumor technically is difficult to deliver at surgery Presence of major tumor thrombus in the IVC Bilateral WT Wilms tumor in a solitary kidney or horse shoe kidney Bilateral tumors and tumors considered inoperable at first should receive 4–6 weeks of chemotherapy followed by second-look surgery. In case of bilateral tumors, effort should be made to preserve as much of each kidney as possible. In such cases, chemotherapy may have to be given for a longer period to enable partial nephrectomy to be done.

Table 12.4.6 National Wilms Tumor Study (NWTS) V treatment results (unfavorable histology)  

extbook of Pediatrics

Stage

4 year EFS (%)

4 year OS (%)

I

69.5

82.6

II

82.6

81.2

III

64.7

66.7

IV

33.3

33.3

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K

Since WT is one of the most curable malignancies of childhood, special emphasis needs to be laid on the need for surveillance for late effects of therapy in terms of cardiotoxicity, musculoskeletal development, fertility and second malignant neoplasm.









1. Dome JS, Cotton CA, Perlman EJ, et al. Treatment of anaplastic histology Wilms’ tumor: results from the fifth National Wilms’ Tumor Study. J Clin Oncol. 2006;24(15):2352-8. 2. Graf N, van Tinteren H, Bergeron C, et al. Characteristics and outcome of stage II and III non-anaplastic Wilms’ tumour treated according to the SIOP trial and study 93-01. Eur J Cancer, 2012. 3. Pritchard-Jones K, Moroz V, Vujanic G, et al. Treatment and outcome of Wilms’ tumour patients: an analysis of all cases registered in the UKW3 trial. Ann Oncol. 2012;23(9):2457-63. Epub 2012. 4. Tongaonkar HB, Qureshi SS, Kurkure PA, et al. Wilms’ tumor: An update. Indian J Urol. 2007;23(4):458-66.

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Radiotherapy should be planned starting within 10 days of surgery • No change of RT dose for FH and UH • Target volume: Volume should encompass tumor bed and site of excised kidney with 2–3 cm margin • Entire vertebral body to be encompassed to avoid disproportionate growth. The results of FH WT are given in the Table 12.4.5. The 764 results of UH WT are given in the Table 12.4.6.



Principles of Radiation Therapy •

ey Messages

• The survival of patients with WT has dramatically improved from 30% several decades ago to almost 90%. • A long standing difference of opinion about the timing of nephrectomy in management of children with unilateral WT remains unresolved. • Upfront versus delayed nephrectomy results in similar tumor control rates but a different overall burden of treatment. • The improved survival has brought into focus important late sequelae of treatment; therefore, the emphasis is now shifting from successful treatment to reducing burden of treatment.



As a result of the NWTSG and SIOP studies, the role of surgery has been customized though not eliminated. Radiation was an important treatment modality in preoperative and adjuvant settings in the earlier studies. With subsequent refinement in therapy with an aim in maximizing cure and reducing morbidity, there are now precise indications for adjuvant radiotherapy (RT). The current standard of care includes flank/abdominal irradiation (10•8 Gy in six fractions) for stage III FH tumors and stage II–III diffuse anaplastic WT. The role of lung irradiation in metastatic disease is unresolved with difference among the groups. The National Wilms Tumor Study Group continues to administer whole lung irradiation (12 Gy in eight fractions) in patients with pulmonary metastases, while the SIOP group advocates omission of RT for patients whose lung metastases disappear completely after 6 weeks of prenephrectomy chemotherapy with VCR, DAM and DOX. The role of pulmonary irradiation in children with pulmonary metastases visible on CT but not chest radiograph is further mystified.

onclusion



adiotherapy

Abbreviations: EFS, event-free survival; OS, overall survival



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deliverance of chemotherapy, drug combination and duration, which have been refined over successive trials to optimize survival rates while minimizing acute and long-term toxicities. Despite these differences, the survival results amongst all group is similar. The SIOP and UKCCSG group has favored the use of preoperative chemotherapy in an attempt to down stage the tumor, whereas the NWTSG advocates upfront nephrectomy without preoperative therapy in order to precisely identify the tumor stage.

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euroblastoma

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Pediatric Malignancies

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–

The etiology of the tumor is as yet unknown. However, there are reports of a 40 times higher than expected incidence of neuroblastic precursor cells in the autopsies of infants less than 3 months of age who have died of other causes, implying that though the presence of neuroblastic cells is common in the first few months of life, all of them do not go on to become malignant. Other reports have suggested an association between alcohol and drugs in pregnancy, parental occupation and viral infections. Familial occurrence, as well as association with other diseases such as neurofibromatosis, Hirschsprung disease and heterochromia iridis have been reported.

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tiopathogenesis

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Neuroblastomas constitute 8% of all neoplasia in childhood and are the most solid frequent malignant tumors in infancy. The mean age at diagnosis in various studies has been estimated as between 2 years and 3 years, while the cumulative age distribution has been noted as follows: • Less than 1 year – 35% • Less than 2 years – 50% • Less than 4 years – 75% • Less than 10 years – 90% The tumor occurs with equal incidence in girls and boys and is rarely observed in adolescents and adults.





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Sites: The tumor can occur in any area where sympathetic tissue exists. However, some sites are more often involved than others which in order of frequency are as given below. • Abdomen – 65% • Adrenal medulla – 46% • Posterior mediastinum – 25% • Pelvis – 4% • Head and neck – 3% • Others – 3% Symptomatology: It can be broadly divided under four headings: 1. Those due to tumor: Pallor, lassitude, weight loss, fever, abdominal pain, irritability and bone pains. 2. Those due to increased catecholamine secretion: Paroxysmal attacks of sweating, pallor, flushing, headache, palpitations and hypertension. 3. Paraneoplastic features, which may manifest as the opsoclonus-myoclonus syndrome or the vasoactive intestinal peptide (VIP) syndrome associated with diarrhea and hypokalemia or persistent anemia and thrombocytopenia due to bone marrow infiltration. 4. Localized symptoms pertaining to various organ systems as follows: • Eyes – Periorbital edema and ecchymoses (Fig. 12.5.1)— the so-called “raccoon eyes” – Proptosis, exophthalmos, strabismus – Retinal hemorrhage, optic atrophy

Neuroblastomas are malignant embryonal tumors of precursor cells of the sympathetic ganglia and adrenal medulla. These are essentially tumors of infancy, at which age if detected early, are associated with excellent prognosis. However, these tumors are also seen in later childhood when, due to various reasons, not the least being due to different tumor biology, the outcome is poor.

linical Features



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Molecular haracteristics

Figure 12.5.1 The typical “raccoon eyes” of neuroblastoma

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MYCN amplification, expression of neurotropic receptors, the deoxyribonucleic acid (DNA) index and chromosomal abnormalities are commonly observed in these children and help in prognostication. MYCN amplification seen usually in older children, suggests a uniformly poor survival rate, while hyperdiploidy, common in infants, indicates excellent survival (95%). Increased expression of tyrosine kinase (TRK) 1, a neurotropic receptor, indicates increased susceptibility to chemotherapy and improves chances of survival.

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•

–

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Neck – Cervical lymphadenopathy – Horner’s syndrome – Supraclavicular mass Chest, mediastinum and vertebra – Superior mediastinal and vena caval syndromes (SMS/SVC) – Infiltration into the intervertebral spaces—the “dumb-bell” tumor – Nerve compression: Gait disturbances, paresthesia, and bowel and bladder dysfunction Abdomen – Abdominal mass, usually detected by an enthusiastic clinician during routine immunization. Frequently crossing the midline, this characteristic differentiates it from a WT, which is also a tumor seen predominantly in this age group. – Hepatomegaly—“pepper liver” Skin – Subcutaneous nodules, which rapidly change color from an initial blue to bright-red color as it becomes more vascular. These nodules are seen mainly in neonates and younger infants with disseminated neuroblastoma. Bone and bone marrow –

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Figure 12.5.2 Typical morphology of neuroblastoma showing the Homer-Wright pseudorosettes

 

–

Table 12.5.1 Immunohistochemistry in pediatric “round blue cell” tumors Tumor

IHC markers

Neuroblastoma

Neuron-specific enolase, chromogranin, synaptophysin, TRK A, ganglioside GD2

Rhabdomyosarcoma

Myogenin, desmin, muscle-specific actin, dystrophin, vimentin, MyoD1

Ewing sarcoma/ primitive neuroectodermal tumors (PNET)

CD99, β2–microglobulin, synaptophysin, vimentin

Synovial sarcoma

Epithelial membrane antigen (EMA), cytokeratin, Bcl-2, TLE 1

Desmoplastic small round cell tumors

Desmin, cytokeratin, WT-1, EMA, CD57

Lymphoma

CD34, CD45, CD3, CD5, CD7, CD19, CD20, Sig, HLA-DR

Wilms tumor

WT-1, EMA, cytokeratin

–

•

Lytic lesions on X-ray of skull and long bones Marrow infiltration, which occurs in about 50% of patients and may be the only organ involved other than the primary tumor, which is then designated as stage IV-S. Metastatic spread: The tumor spreads through the lymphatics and blood. Metastasis at diagnosis is present in 40–50% of children below 1 year of age and in 70% of older children. Sites of metastasis include the bone, bone marrow, liver, skin, brain, spinal cord and lungs. –

–

– –

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valuation

The laboratory tests for diagnosis include elevated levels of vanillylmandelic acid (VMA), homovanillic acid (HVA) and 3-methoxy-4-hydroxy-phenylglycol (MHP) seen in over 90% of patients. These tests are also useful as follow-up tumor markers. The bone marrow biopsy analysis confirms primary or metastatic involvement and is essential for staging the disease.

­

Gross: These tumors are pale gray and soft with varying amounts of necrosis and calcification within. Most are noted to be highly adherent to the underlying structures. Microscopy: One of the so-called “round blue cell tumor”, these tumors vary widely in differentiation ranging from the undifferentiated neuroblastoma to the moderately-differentiated ganglioneuroblastoma to the well-differentiated ganglioneuroma. The characteristic histopathological feature is the psuedorosette also called the “Homer-Wright” psuedorosettes as seen in Figure 12.5.2. However, in many instances, it becomes very difficult to distinguish the tumor from other members of the round blue cell tumor family and requires immunohistochemistry (IHC) to confirm the diagnosis. Table 12.5.1 denotes the various differential diagnoses and their characteristic 766 reactions to IHC.

t

Abbreviations: IHC, mmunohistochemistry; TRK A, yrosine kinase A; MyoD1, yogenic differentiation 1; CD 99, luster of differentiation; TLE 1, ransducin-like enhancer of split 1

Pathological Features

c

•

Imaging •

Conventional radiography often reveals mediastinal widening or calcification in an abdominal tumor

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D

 

Figure 12.5.5 Methylisobenzoyl guanidinium (MIBG) scan of an infant with neuroblastoma showing increased uptake by the tumor tissue

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As mentioned earlier, all malignant tumors that have the characteristic “round blue cell” morphology have to be differentiated from neuroblastoma and these include lymphoma, primitive neuroectodermal tumors (PNET), undifferentiated rhabdomyosarcoma (RMS), Ewing sarcomas and retinoblastomas. Nonmalignant differentials include osteomyelitis, rheumatoid arthritis, cerebellar ataxia and other causes of pyrexia of unknown origin.

Figure 12.5.3 Typical plain X-ray abdomen showing left-sided paraspinal calcification

taging

Accurate staging is one of the keys to tailoring therapy in these children. Faulty understaging results in inadequate therapy and subsequent relapse while faulty up staging results in unacceptable toxicity of therapy. The International Neuroblastoma Staging System (INSS) is presently used (Table 12.5.2) in all tertiary centers around the world in those cases where surgery is performed upfront and histopathology details are available. This system of staging is highly accurate and useful for prognosis. In those children in whom surgery is not feasible at the beginning of therapy, the older but simpler Evan’s clinical staging [Children’s Cancer Study Group (CCSG)] system (Table 12.5.3) is used to stage the disease and start therapy accordingly.

Figure 12.5.4 Computed tomography film of a left-sided abdominal mass with calcification—typical of neuroblastoma

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isk tratification and herapy S

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•

 

•

Pediatric Malignancies

•

(Fig. 12.5.3). A complete body bone scan is useful in detecting bone metastasis and is an inescapable requirement for staging. Ultrasound scan, CT (Fig. 12.5.4) and MRI all help to delineate the primary tumor and detect metastasis. The methylisobenzoyl guanidinium (MIBG) scintigraphy scan (Fig. 12.5.5) is a radiolabeled, specific and very sensitive method for evaluation and follow-up of primary and metastatic disease. Recent reports also suggest its very useful therapeutic role in the treatment of advanced and relapsed disease. Myelography is of utmost importance in the evaluation of primary or metastatic spinal disease and performed early can diagnose the exact location and site of lesions causing impending motor weakness of the limbs. However, of late, safer modes of investigations (e.g. MRI) are preferred.

Neuroblastomas are classified as low-risk, intermediate risk and high-risk, based on 13 prognostic factors including age, stage, histology, MYCN status, DNA ploidy and others. Low risk: Surgery alone is the treatment of choice in a majority of patients in this group but in some symptomatic patients 767 6–12 weeks of chemotherapy with Cyclophosphamide

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I

Localized tumor with complete gross excision, with or without microscopic residual disease with ipsilateral representative lymph nodes (IRLs) negative for tumor microscopically (nodes attached to the tumor itself may be positive.)

IIA

Localized tumor with incomplete gross excision; IRL negative microscopically.

IIB

Localized tumor with or without complete gross excision. Ipsilateral representative lymph nodes are positive for tumor. Representative contralateral nodes are negative for disease.

III

Unresectable unilateral tumor infiltrating across the midline with or without regional lymphnode involvement; or localized unilateral tumor with contralateral node involved or midline tumor with bilateral extension or lymphnode involvement.

IV

Primary tumor with distant metastasis to bone, bone marrow, liver, skin or other organs (except stage IV-S disease as given below.)

IV-S

Localized primary tumor (stage I, IIA or IIB) with dissemination to bone marrow, liver or skin (restricted to infants < 1 year of age.)

Monoclonal antibodies, Cis-RA and its newer synthetic analogs as well as MIBG in a therapeutic role have all shown promise. These are at present undergoing trials and are awaiting approval before being introduced into newer protocols. Autologous stem cell transplants (SCTs) with high-dose MIBG administration has shown promise (40% increase in survival) in the management of high-risk/ relapsed disease.

 

Table 12.5.3 Evan’s clinical staging system Stage Description I

Tumor limited to organ or structure of origin

II

Tumor with regional spread not crossing the midline

III

Tumor crossing the midline; bilateral nodes involved

IV

Distant metastasis

IV-S

Localized primary tumor with disseminated disease to liver; skin and/or bone marrow (in infants < 1 year of age)

ewer herapies T

 

Stage Description

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Intermediate risk: Patients with intermediate risk are treated with surgery and 12–24 weeks of chemotherapy using the same drugs as in low-risk cases. High risk: High-risk patients are aggressively treated with a combination of high-dose chemotherapy with cisplatin (Cis), Ifosphamide (IFOS), VP16, DOX and CTx. After preliminary chemotherapy (neoadjuvant chemotherapy), “second look” surgery is performed after which consolidation with near myeloablative chemotherapy is instituted. Radiation, with or after chemotherapy, is offered in some cases. Maintenance chemotherapy thereafter with 13-cis-retinoic acid (cis-RA) improves chances of survival in these children. Table 12.5.4 delineates risk stratification and therapy recommended for each category. Relapse: Newer drugs like topotecan, paclitaxel, irinotecan and MIBG have been used with varying success in relapsed cases.

Table 12.5.2 International Neuroblastoma Staging System (INSS)

Prognosis • •

C

(CTx), Doxorubicin (DOX), Etoposide (VP16) a nd Carboplatin (carbo) may be added. These include cases with spinal cord compression, respiratory distress due to hepatic infiltration and infants with large stage IV-S disease. Selected cases of low-risk neuroblastomas (small tumors incidentally detected in neonates and infants with low VMA and HVA levels and without spinal cord or great vessel involvement) may safely be observed without either obtaining a definitive histological diagnosis or subjecting the child to surgery thus, avoiding potential complications of therapy.

Low risk: 90% long-term EFS Intermediate and high risk: 60–70% respond to initial therapy with partial or complete remission but a large number relapse with conventional chemotherapy. However, if consolidation includes very high-dose chemotherapy with autologous stem cell rescue, the chances of survival in this group is about 50–60%.

onclusion

Neuroblastomas are basically, tumors of infants and young children in whom prognosis after adequate therapy is excellent. However, in older children, with the tumor biology

 

Table 12.5.4 Risk stratification Stage

Age (months) MYCN

Therapy

Survival

Low

I IIA/IIB IV-S

Any Any < 1 year

Non-amp Non-amp Non-amp

Surgery Surgery + LDCT Observation/CT or RT

> 90% > 80%

Intermediate III IV IV-S

< 18 months Any Any

Non-amp Non-amp Non-amp

CT (CTx + Cis + VP16 + DOX) > 75% RT to tumor bed if residual disease + /second look surgery

High

> 12 months

Amp

Multiagent CT + Autologous SCT + maintenance Cis RA

II/III/IV/IV-S

50%

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Abbreviations: LDCT, ow-dose chemotherapy; CT, hemotherapy; RT, adiotherapy; CTx, yclophosphamide; Cis, isplatin; VP16, toposide; DOX, oxorubicin; SCT, tem cell transplant; Cis RA, 13-cisretinoic acid c

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1. Arceci RJ. Proceedings of the 42nd Congress of the SIOP, Boston. J Pediatr Blood Cancer. 2010;55(5). 2. Coppes MJ, Fry TJ, Mackall CL. Hematopoietic Stem Cell Transplantation. Pediatr Clin North Am. 2010;57(1): 1-352. 3. Pizzo PA, Poplack DG (Eds). Principles and Practice of Pediatric Oncology, 6th edition, Philadelphia, Pa: Lippincott Williams & Wilkins, 2011.





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• Recent advances in therapy promises a great deal in the treatment of advanced and relapsed neuroblastomas, especially in older children. • Early diagnosis and adequate therapy is still the cornerstone to successful outcome.

ey Messages

• Neuroblastomas are primitive blastemal tumors that are usually seen in infants and young children. • Infants and young children with the disease have excellent prognosis while older children do not do so well despite adequate therapy.

Pediatric Malignancies

and molecular properties being different, the prognosis in these children is guarded. As with all pediatric solid tumors, the first chance at therapy is the best, and thus, it is essential that the tumor is diagnosed early, staged accurately and treated adequately to obtain optimal results. Newer therapeutic intervention in the form of targeted molecular therapies will certainly bring tremendous improvements in survival and are the hopes of the future.

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etinoblastoma

The incidence of sporadic Rb is 1 in 15,000–20,000 live births, with no gender or racial predilection. It typically presents in the first 2–3 years of life, the median age being 12 months in heritable cases and around 24 months in sporadic cases. Presentation after 6 years of age is rare.

Genetics

I

The tumor arises from primitive cells of the developing retina with loss of function of the Rb tumor suppressor gene (Ch13q14). There are two copies (alleles) of the Rb gene in every cell in the body. At least one functioning allele is required to prevent the development of Rb in a retinal cell. Loss of both alleles results in Rb tumors.

nheritance

I

pidemiology

nvestigations

The diagnosis is essentially clinical, with support from imaging. • undoscopic examination: This is generally performed under anesthesia. This includes assessment of intraocular pressure. • -scan ultrasonography: This confirms the presence of masses in the posterior segment of the eye. Calcification is characteristic of this tumor. • omputed tomography/ magnetic resonance imaging scan: Imaging is done for visualization of the globe, orbit, CNS and the pineal region (to look for pinealoblastoma, trilateral Rb). Magnetic resonance F

Retinoblastoma (Rb) is the most common primary intraocular malignancy of childhood affecting around 8,000 children annually and accounting for 1% of tumors in infancy. When the disease is diagnosed in its early intraocular stages, as is usual in developed countries, the probability of diseasefree survival is around 90%. In developing countries, the diagnosis of Rb is frequently made at later stages of the disease when extraocular dissemination has occurred resulting in poor survival, estimated to be 60% and 30% in low-middle and low-income countries.

lymphadenopathy is frequently seen at presentation in developing countries (including India) because of late presentation (Fig. 12.6.1). Metastases occur by spread of the tumor along the optic nerve to involve the CNS, or through the choroid resulting in hematogenous spread to bones, lungs and abdominal solid organs. The important differential diagnosis includes: • Coats’ disease • Persistent fetal vasculature • Toxocariasis • Cellulitis • Metastasis • Cataract • Coloboma • Retinopathy of prematurity • Retinal detachment.

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ntroduction

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linical eatures F

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Retinoblastoma may be inherited or occur sporadically. Sixty percent are nonhereditary and unilateral; 15% are hereditary and unilateral, and 25% are hereditary and bilateral. The inherited form is autosomal dominant with incomplete penetrance. Over 90% of children carrying the Rb gene defect will develop Rb.



The most frequent presenting symptom is leukocoria, a white pupil, noted by family members or the child’s pediatrician. Other clinical features include redness and pain, secondary to tumor deposits and increased intraocular pressure. Bilateral cases often present with poor vision, and nystagmus or searching eye movements as a result of tumor involving the central part of the retina (macula) in both eyes. Massive proptosis or a fungating mass with

 

Figure 12.6.1 Large mass is the presenting feature in developing countries

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Group A

No tumor greater than 3 mm in dimension; away from fovea and optic nerve

Group B

Any eye not in Group A with no vitreous seeding, subretinal fluid is less than 5 mm from the base of the tumor

Group C

Tumors with focal fine vitreous seeding or subretinal fluid (less than one quadrant)

Group D

Massive or diffuse vitreous seeding, extensive subretinal masses

Group E

Unsalvageable eyes; neovascular glaucoma, tumor touching the lens, anterior segment tumor, phthisis diffuse infiltrating retinoblastoma

t

Laser therapy is the primary treatment in smaller tumors. It is also used after chemoreduction. Laser treatment is not effective for vitreous seeds. Cryotherapy: A special probe is applied through the sclera to produce temperatures as low as −60°C to −80°C resulting in cryonecrosis of the tumors. This is suitable for larger, peripheral tumors or localized vitreous disease close to the retina. Radiotherapy: This could be in the form of external beam RT; plaque RT or intensity-modulated radiation therapy. Proton beam therapy is an emerging technique. Chemotherapy: Its main role is to shrink the tumors to a size where local treatment can be effective. It is effective against vitreous and subretinal disease. Cure in extraocular involvement and metastases rely on high-dose chemotherapy. Enucleation: It is the treatment for advanced uniocular disease with no hope for vision or the worse eye of bilateral cases. The eye is removed with a long segment of optic nerve.

Newer modalities: • • •

•

Periocular injections of carboplatin/other agents to increase levels of the drug and enhance efficacy. Direct injection of drugs into the vitreous cavity has been attempted. However, this technique has the fear of producing extraocular spread of the tumor. Intra-arterial chemotherapy with interventional radiology: This allows delivery of a high dose of chemotherapeutic agents (e.g. melphalan) into the ophthalmic artery. Gene therapy: “Suicide gene therapy” has been tried in early clinical trials in children with advanced intraocular disease (Fig. 12.6.2).

 

Table 12.6.2 Staging: International staging system for retinoblastoma

Treatment

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Table 12.6.1 International classification of intraocular retinoblastoma

Pedia ric Mali nancies

imaging is preferred, as there is limited radiation exposure and improved visualization of the periorbital structures and orbital portion of the optic nerve. • umbar puncture: This is indicated in extraocular disease/CNS disease or in the presence of choroidal involvement on histopathology. • one marrow: This is performed in patients with extraocular disease (stage II and above) and/or those with altered complete blood counts. • iopsy or fine-needle aspiration cytology: This is not indicated unless the diagnosis is in doubt in select circumstances. • Mutation testing: This can be performed on peripheral blood and tumor tissue if available. This helps distinguish between germline and somatic cases. The International Classification of Intraocular Retinoblastoma is given in Table 12.6.1. The details of staging are given in Table 12.6.2.

Patients treated conservatively

Stage I

Eye enucleated, completely resected histologically

Stage II

Eye enucleated, microscopic residual tumor

Stage III

Regional extension – Overt orbital disease – Preauricular or cervical node extension

Stage IV

Metastatic disease

 

 

Stage 0

Figure 12.6.2 White eye reflex of intraocular retinoblastoma  

 

 

 

 

 

•  Hematogenous metastasis [without central nervous system (CNS) involvement] – Single lesion – Multiple lesions •  Central nervous system extension (with or without any other site of regional or metastatic disease) – Prechiasmatic lesion – Central nervous system mass – Leptomeningeal and cerebrospinal fluid (CSF) disease

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1. Chantada GL, Dunkel IJ. Treatment of extraocular and metastatic retinoblastoma. In: Rodriguez-Galindo C, Wilson MW (Eds). Retinoblastoma, 1st edition. New York: Springer; 2010.pp.103-14.













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• Retinoblastoma has a good prognosis when diagnosed intraocularly. • It is diagnosed late in developing countries. • Essentially, it is a clinical diagnosis. • Small tumors need focal therapy. • Chemotherapy helps shrink tumors. • 40% tumors are inherited.

2. Chevz-Barrios P, Gimbos DS. Clinical features, diagnosis, pathology. In: Rodriguez-Galindo C, Wilson MW (Eds). Retinoblastoma, 1st edition. New York: Springer; 2010.pp.2540. 3. Hurwitz R, Shields CL, Shields JA, et al. Retinoblastoma. In: Pizzo PA, Poplock DG (Eds). Principles and Practice of Pediatric Oncology, 6th edition. Philadelphia: Lippincott Williams & Wilkins; 2011. pp. 809-37. 4. Parulekar MV. Retinoblastoma—current treatment and future direction. Early Hum Dev. 2010;86(10):619-25. 5. Rodriguez-Galindo C. Chemotherapy in the treatment of retinoblastoma. In: Rodriguez-Galindo C, Wilson MW (Eds). Retinoblastoma, 1st edition. New York: Springer; 2010.pp.6790. 6. Wilson MW. Treatment of intraocular retinoblastoma. In: Rodriguez-Galindo C, Wilson MW (Eds). Retinoblastoma, 1st edition. New York: Springer; 2010.pp.91-101.

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About 3% of all childhood cancers are rhabdomyos­ arcoma (RMS). About 350 new cases of RMS occur each year in the USA. The number of new cases has not changed much over the past few decades. Most RMS cases are diagnosed in children and teenagers. About 6 out of 10 of these tumors are diagnosed in children under the age of 10 years. These tumors are usually embryonal RMS and occur in the head and neck area or in the genital and urinary tracts. Adolescents and adults are more likely than younger children to have alveolar RMS, which are found more often in the arms, legs or trunk. This disease is slightly more common in boys than in girls. There is no particular geographic location or ethnic group that has an unusually high rate of RMS.

tiopathogenesis

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No known environmental factors are known to cause RMS in children. Some genetic and environmental factors have been associated with the development of NRSTS: Li Fraumeni’s syndrome and neurofibromatosis type 1 (NF1). Members of the Li Fraumeni families have an increased risk of developing soft tissue tumors, bone sarcomas, breast cancers, brain tumors and acute leukemias and have heritable mutations in the p53 tumor suppressor gene. Approximately 4% of patients with NF1 develop malignant

The most common sign of childhood STS is a painless lump or swelling, which may occur anywhere in the body. There may be no other symptoms at first; however, as the sarcoma grows, it may manifest with pressure symptoms on adjacent organs, nerves, muscles or blood vessels, leading to pain or weakness, etc. Systemic symptoms (e.g. fever, weight loss and night sweats) are rare. Hypoglycemia and hypophosphatemic rickets have been reported in cases of hemangiopericytoma, whereas hyperglycemia has been noted in patients with fibrosarcoma of the lung. • Rhabdomyosarcomas may originate in different sites of the body depending upon the age of the child. Most head and neck tumors occur in children under the age of 8 years, while those of the extremity are most commonly found in adolescents. Less common primary sites for this cancer are the genitourinary tract, including the bladder and prostate in the male and the vagina in the female. • The NRSTS arise most commonly in the trunk and extremities. These neoplasms can present initially as an asymptomatic solid mass, or they may be symptomatic because of local invasion of adjacent anatomical structures. Synovial sarcomas, the most common NRSTS, reported in children most commonly occur in the lower extremity followed by upper extremity, trunk, abdomen, and head and neck. Approximately 30% of patients with synovial sarcoma are younger than 20 years. The most common site of metastasis is the lung.

iagnosis

The first step is to establish a confirmed histological diagnosis. Often an imaging, a CT scan or MRI, of the tumor is done followed by fine needle aspiration cytology (FNAC) prior to planning a biopsy. These results determine type of biopsy—Tru Cut needle biopsy, incisional biopsy or excisional biopsy. Rhabdomyosarcoma is a malignant round cell tumor, and can appear very similar to other childhood cancers at the microscopic level, and immunohistochemistry (IHC) and molecular genetic tests may be required to establish a firm diagnosis. Hence, obtaining adequate tissue for histology and IHC is very important. -

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pidemiology

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Pediatric soft tissue sarcomas (STS) are a group of malignant tumors that originate from primitive mesenchymal tissues and account for 7% of all childhood tumors. Rhabdomyosarcomas are the most common of these and constitute about half of all cases of STS in children. The remaining nonrhabdomyosarcomatous soft tissue sarcomas (NRSTS) account for approximately 3% of all childhood tumors. The latter constitute a heterogeneous group of tumors and are rare in children. They include fibrosarcoma, neurofibrosarcoma, leiomyosarcoma, liposarcoma, synovial sarcoma, hema­ ngiopericytoma, alveolar soft part sarcoma, and malignant fibrous histiocytoma; of which the synovial sarcomas, fibrosarcomas and malignant peripheral nerve sheath tumors predominate in pediatric patients.

peripheral nerve sheath tumors. Patients with familial adenomatous polyposis are at increased risk for developing desmoid tumors. The malignant fibrous histiocytoma can develop within a previously irradiated site; others (e.g. leiomyosarcoma) have been linked to EBV infection in patients with AIDS. C

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The treatment outcome for pediatric RMS depends on anatomic site, patient age, stage and histology, on the basis of which they are risk stratified. The various unfavorable prognostic factors include older age, metastatic disease, large tumor, alveolar histology and primary tumor in trunk or pelvis. Low risk, intermediate risk and high risk patients have a 3 years failure free survival rate of 88%, 55–75% and less than 30%, respectively (Table 12.7.4).

Management

-

Radiotherapy Radiotherapy is an important local control measure for all children with RMS except those with completely resected stage I and II disease. Total radiation dose ranges from 4,000 to 5,500 cGy over a period of 4–6 weeks. It is usually planned approximately 9 weeks after chemotherapy has begun and earlier for those with parameningeal disease. With the use of both surgery and radiation therapy, local control of the primary tumor can be achieved in more than 80% of patients.

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The treatment for childhood STS requires a multidisciplinary oncology team comprising of pediatric oncologists, surgeons and radiotherapists.

All children diagnosed with RMS also require surgery, either to remove all or part of the primary tumor, or to perform an incisional/needle biopsy to reach a definitive diagnosis. Only about 10% of newly diagnosed children have tumors that can be completely removed. Every attempt should be made to resect the primary tumor with negative margins before or after chemotherapy (second look surgery) and while causing minimum cosmetic and functional impairment.

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habdomyosarcoma

Chemotherapy Rhabdomyosarcoma is a chemosensitive disease, and micrometastatic disease is believed to be present from its

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Once histological diagnosis is confirmed, further tests are done to determine the stage of the disease. Clinical staging has an important role in predicting the clinical outcome and determining the most effective therapy for pediatric STS. In RMS, bone marrow aspiration and biopsy, CT chest and bone scan are done to look for metastatic disease at these sites while for NRSTS, only CT chest is usually required. Whole body PET scan may also be done as a single imaging to look for metastatic disease. The staging systems used are the Intergroup RMS Study (IRSG) and tumor, node, metastases (TNM) for RMS and the Children’s Oncology Group (COG) staging system for children with NRSTS (Tables 12.7.1 to 12.7.3).

onset. Hence, all children with RMS receive chemotherapy, which forms the backbone of treatment, and the dose and duration depend on various risk factors. The most effective drugs include cyclophosphamide vincristine, dactinomycin, doxorubicin, ifosphamide and etoposide. The total duration of treatment ranges from 6 months to 12 months.

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For NRSTS, surgery is the cornerstone of treatment. Ideally, the surgeon will attempt to completely remove the mass with wide margins (portions of the surrounding tissue)

 

Table 12.7.1 Classification of soft tissue sarcomas (STS) according to histological type with corresponding chromosomal aberration Group

Histological type

Chromosomal aberration

Rhabdomyosarcomas (RMS)

Pleomorphic RMS Embryonal RMS Alveolar RMS

LOH of 11q15 t(2;13)(q35;q14), t(1;13)(p36;q14)

Nonrhabdomyosarcomas soft tissue sarcomas

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Fibrosarcoma Neurofibrosarcoma Infantile fibrosarcoma Malignant fibrous histiocytoma Dermatofibrosarcoma protuberans Kaposi’s sarcoma Hemangioendothelioma Leiomyosarcoma Liposarcoma Angiosarcoma Synovial sarcoma Alveolar soft part sarcoma Epithelioid sarcoma

Deletion 17q11.2 t(12;15)(p13;q25) (qp+, ring chromosome) t(17;22)(q22;q13)

t(12;14)

t(x;18)(p11.2;q11.2) t(x;17)(p11.2;q25)

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Table 12.7.2 Children’s oncology group-soft tissue sarcomas (COG-STS) pretreatment staging system for rhabdomyosarcoma (RMS) T stage

Tumor size

Regional lymph nodes

Distant metastasis

I

Favorable sites Orbit Head and neck Genitourinary

T1 or T2 T1 or T2 T1 or T2 T1 or T2

Any size

N0 or N1 or NX

M0

II

Unfavorable sites Bladder/prostate Extremity Cranial arameningeal

T1 or T2 T1 or T2 T1 or T2 T1 or T2 T1 or T2

a, ≤ 5 cm

N0 or NX

M0

III

Other Unfavorable sites Bladder/prostate Extremity Cranial arameningeal

T1 or T2 T1 or T2 T1 or T2 T1 or T2 T1 or T2

a, ≤ 5 cm

N1

M0

Other Any site All

T1 or T2 T1 or T2

Any size

b, > 5 cm N0 or N1 or NX

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Stage Sites of primary tumor

IV

N0 or N1 or NX

M1

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Abbreviations: M0, bsence of metastatic spread; M1, resence of metastatic spread beyond the primary site; N0, bsence of nodal spread; N1, resence of nodal spread beyond the primary site; NX, nknown N status

 

Table 12.7.3 Children’s oncology group-soft tissue sarcomas (COG-STS) Surgicopathologic group system for rhabdomyosarcoma (RMS) Group

Definition

I (Approximately 13% of all patients are in this group)

A localized tumor that is completely removed with pathologically clear margins and no regional lymph node involvement

II (Approximately 20% of all patients are in this group)

A localized tumor that is grossly removed with: •  Microscopic disease at the margin •  Involve, grossly removed regional lymph nodes •  Both (a) and (b)

III (Approximately 48% of all patients are in this group)

A localized tumor with gross residual disease after incomplete removal or biopsy only

Group

Low risk Excellent (70–≥ 85%)

Embryonal

1

I, II, III

Embryonal

2, 3

I, II

Intermediate risk Good (50–70%)

Embryonal

2, 3

III

Alveolar

1, 2, 3

I, II, III

High risk Poor (≤ 30%)

Embryonal or Alveolar 4

Radiation therapy is indicated for patients with inadequate surgical margins and for larger, high grade tumors. This is particularly important in high grade tumors with tumor margins less than 1 cm. Brachytherapy and intraoperative radiation may be applicable in select situations. -

Stage

to ensure that no microscopic disease remains. The most important prognostic factor is the ability to completely remove the primary tumor.

hemotherapy

Chemotherapy is sometimes used to shrink large tumors to make them operable. The role of adjuvant (postoperative) chemotherapy remains controversial for NRSTS.

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Table 12.7.4 Children’s oncology group-soft tissue sarcomas (COG-STS) rhabdomyosarcoma risk group classification

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IV (Approximately 18% of all patients are in this group) Distant metastases are present at diagnosis

Improved outcomes with multimodality therapy in children with STS have caused increasing concern about

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1. Available from www.cancer.org/ Cancer/ Rhabdomyosar­ coma/ DetailedGuide/ rhabdomyosarcoma key statistics. 2. National Cancer Institute. Childhood rhabdomyosarcoma treatment (PDQ®). [online] Available from www.cancer.gov/ cancertopics/pdq/treatment/childRMS/HealthProfessional. [Accessed October, 2012]. 3. National Cancer Institute. Soft tissue sarcoma. [online] Available from www.cancer.gov/cancertopics/types/soft tissue sarcoma. [Accessed October, 2012]. 4. Okcu MF, Pappo AS, Hicks J, et al. The nonrhabdomyosarcoma soft tissue sarcoma. In: Pizzo PA, Poplack DG (Eds). Principles and Practice of Pediatric Oncology. 6th edition. Philadelphia, Pa: Lippincott Williams & Wilkins; 2010. pp.953 86. 5. Wexler LH, Meyer WH, Helman LJ. Rhabdomyosarcoma. In: Pizzo PA, Poplack DG (Eds). Principles and Practice of Pediatric Oncology, 6th edition. Philadelphia, Pa: Lippincott Williams & Wilkins; 2011. pp.923 53. -





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• Soft-tissue sarcomas comprise the fifth most common type of childhood solid tumor, of which RMS is the most common. • It can arise at any site and in any tissue in the body except bone, hence may present as a mass or lump. • Confirmation of histology and staging work-up are essential prior to starting therapy. • The treatment for childhood STS is a coordinated multidisciplinary team effort comprising of pediatric oncologists, surgeons and radiotherapists. • Chemotherapy is an essential component of therapy for RMS along with surgery and/or RT for local control. Survival depends on risk group.

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the potential long term side effects of therapy, especially when considering the expected longer life span of children. Late effects including consequences on growth and development, cardiac function, second malignancy, etc. all need to be considered when planning treatment.

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Pediatric Bone Marrow ransplantation

History

Bone Marrow From the earliest efforts to offer HSCT to humans until about 1993, all donations were collected from the bone marrow. Bone marrow is harvested from the patient (for autologous SCT) or the donor (for allogeneic SCT) under general anesthesia by aspiration from the pelvic bones (iliac crests) (Fig. 12.8.1).

Peripheral Blood tem ells Since 1993, transplanters have been increasingly using peripheral blood for harvesting stem cells. Hematopoietic stem cell (HSC) may be mobilized from the peripheral blood following administration of granulocyte colonystimulating factor (G-CSF) and harvested using cell separators (Fig. 12.8.2). C

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The molecules encoded by class I and II major histocompatibility complex are called HLA, and these constitute a major component of the immunological barriers. The currently known class I genes are HLA-A, HLA-B and HLA-C, and are found on virtually all nucleated cells and they are for recognition of self. Class II genes are expressed only on lymphocytes and a few other cells and the most important genes are HLA-DR, HLA-DQ and HLA-DP; these are necessary for cross talk between immunological cells and self antigens.

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An allogeneic stem cell transplant (SCT) is a transplant between two individuals, a donor and a recipient. When individuals are identical twins, the transplant is known as syngeneic; when the donor and recipient are not related, the transplant is known as matched unrelated donor (MUD) and when donor and recipient are HLA matched siblings, then it is called matched sibling donor (MSD). An autologous SCT is a transplant by which patient’s own stem cells are harvested (collected), stored and later returned intravenously.

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Indications for allogeneic HSCT are given in Table 12.8.1. Indications for autologous HSCT are described in Table 12.8.2.

ypes of Hematopoietic tem ell ransplant

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In 1956, George Mathe treated four physicists exposed to high-dose radiation, following an accident at nuclear plant at Vinca (then Yugoslavia), with intravenous infusions of allogeneic bone marrow cells harvested from family donors. In 1977, Donnall (Don) Thomas and his colleagues reported the results of human leukocyte antigen (HLA)— identical sibling transplants in 100 patients with “endstage” leukemia. Thomas was awarded the Nobel Prize in medicine in 1990 for his substantial contributions to this research. The past two decades have seen a rapid development in HSCT, as the procedure has become safer and more widely used.

The best donors are HLA-identical sibling donors because they are not only phenotypically matched for HLA antigens, but have genotypic identity also. The chances of finding a MSD are about 30%. Most current studies suggest that a “perfect” donor is one who is fully molecularly matched for HLA-A, B, C, DRB1 and DRQB1. Such a donor is referred to as 10/10 match. In general, mismatches of two or more HLA subtypes are associated with a considerably poorer outcome. Matched unrelated donor SCT is offered to those who do not have a MSD available. National Marrow Donor Program has a facility for searching a worldwide donor register consisting of over 13 million HLA-typed volunteers. This pool is currently able to provide suitable donors for about 80% of recipients for a Caucasian; the corresponding figures for patients from ethnic minorities drop to below 30%. Other sources when MUD is not available are unrelated cord blood (CB) units from many public cord banks worldwide.

Hematopoietic stem cell transplant (HSCT), a term that covers bone marrow transplant (BMT), peripheral blood stem cell transplant (PBSCT) and cord blood transplant (CBT), is a well-recognized therapy for diverse malignancies, both blood cancers and some solid tumors, in addition to selected nonmalignant diseases.

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Table 12.8.1 Indications for allogeneic hematopoietic stem cell transplantation for pediatric diseases •  Acute lymphoblastic leukemia (ALL) in CR1 for patients with very high-risk ALL (prednisone poor response on day 7 with T-immunophenotype or total leukocyte count more than 100,000/ µl; t(9;22); not in remission at the end of induction phase) and CR2 or later complete remission •  Acute myeloid leukemia in CR1 except those with presence of t(15;17), t(8;21) and inv16 or those who are relapsed cases •  Chronic myeloid leukemia •  Myelodysplastic syndromes •  Relapsed or refractory Hodgkin and non-Hodgkin lymphoma •  Severe acquired aplastic anemia •  Inherited bone marrow failure syndromes (Fanconi anemia, dyskeratosis congenita, Diamond Blackfan anemia) •  Hemoglobinopathies (thalassemia major, sickle-cell disease) Figure 12.8.1 Bone marrow harvest from bilateral iliac crests from a donor under general anesthesia  

•  Congenital immunodeficiency syndromes (severe combined immunodeficiency, Wiskott-Aldrich syndrome, Hyperimmunoglobulin M (IgM) syndrome, leucocyte adhesion defects, Chediak-Hegashi’s syndrome, Kostmann’s syndrome, chronic granulomatous disease and other neutrophil defects) •  X-linked lymphoproliferative disorder (Duncan syndrome) •  Familial hemophagocytic lymphohistiocytosis •  Infantile malignant osteopetrosis •  Selected types of mucopolysaccharidosis (Hurler) or other liposomal/ peroxisomal disorders (X-linked adrenoleukodystrophy) •  Selected severe variants of platelet function disorders (BernardSoulier’s syndrome and Glanzmann’s thrombasthenia) c

Abbreviation: CR, omplete remission

 

Table 12.8.2 Indications for autologous hematopoietic stem cell transplantation for pediatric diseases •  Acute myeloid leukemia in CR1 or CR2 •  Acute lymphoblastic leukemia after an isolated extramedullary relapse •  High-risk, relapsed or resistant brain tumors

Figure 12.8.2 Peripheral blood stem cell harvest by leukapheresis  

•  Relapsed Hodgkin or non-Hodgkin lymphoma •  High-risk neuroblastoma •  Relapsed/refractory rhabdomyosarcoma •  Relapsed/refractory Ewing sarcoma •  Life-threatening autoimmune diseases resistant to conventional treatments (systemic lupus erythematosus, juvenile rheumatoid arthritis) c

Abbreviation: CR, omplete remission

Figure 12.8.3 Umbilical cord blood unit after thawing  

leading to delayed engraftment. The major advantages are the abundant supply of CB units with no risk to mother or infant and immaturity of immune cells reduces the risks of HLA mismatch (even 4/6 and 5/6 matches are acceptable) 778 and subsequent graft-versus-host disease (GVHD) incidence is low.

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Table 12.8.3 Glucksberg’s criteria for staging and grading of acute graft-versus-host disease  

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Most conditioning treatment regimens comprise of chemo therapy, immunotherapy and sometimes radiotherapy. The principal function of this treatment is to kill all cancer cells that might still be present at the time of SCT, reduce disease to a minimal level and make “space” in the bone marrow “niches” for the donor stem cells and to suppress the host immune system so that the donor cells (graft) are unlikely to be rejected.

Organ

Stage

Extent of organ involvement

Skin

1 2 3

< 25% 25–50% Generalized erythema Desquamation, bullous 2–3 mg/dL 3.1–6 mg/dL 6.1–15 mg/dL > 15 mg/dL 10–15 mL stool/kg/ day 16–20 mL stool/kg/ day 21–25 mL stool/kg/ day > 25 mL stool/kg/day; severe pain with or without ileus

4 Liver bilirubin

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omplications

1 2 3 4 1 2 3 4

Overall clinical grade

Organ system

Clinical stage

I (mild)

Skin Liver Gastrointestinal Skin Liver Gastrointestinal

1–2 0 0 1–3 1 1

III (severe)

Skin Liver Gastrointestinal

2–3 2–3 2–3

IV (life threatening)*

Skin Liver Gastrointestinal

2–4 2–4 2–4

II (moderate)

*With severe constitutional symptoms

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Graft-versus-host disease, infection and interstitial pneu monia are the major complications of HSCT.

Gastrointestinal

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Conditioning is administered over a period of 7–10 days. On day 0, stem cells are infused to the recipient from donor. A rising neutrophil count followed by rising platelet counts over the next 15–45 days is evidence of engraftment. Donor engraftment can be confirmed by polymerase chain reaction (PCR) based chimerism studies, fluorescence in situ hybridization (FISH) for XX/XY in sex mismatch SCT or change of blood group of recipient to donor group in ABO mismatched SCT. The patient is transferred out of the BMT unit when his neutrophil count is over 500/cumm and discharged when there are no intravenous (IV) medications to be administered. Following HSCT for a patient who has no GVHD, cyclosporine is given as prophylaxis at full doses for 6 months after which it is tapered and stopped 1 year post-transplant.

This is one of the most devastating complications of HSCT and is termed as acute (Table 12.8.3) if it occurs in the first 100 days following transplantation and chronic (Table 12.8.4) if it continues or develops after this period. C

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Short-term and long-term complications of HSCT are described in detail in Table 12.8.5.

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Hematopoietic tem ell ransplant in ndia In September 2005, data from six transplant centers in India were collected and a total of 1,540 transplants have been performed in a country of over 1 billion population. At the center in Vellore, a total of 626 transplants have been performed in 595 patients. At Sir Ganga Ram Hospital

Table 12.8.4 Staging of chronic graft-versus-host disease Limited chronic GVHD •  Localized skin involvement •  Hepatic dysfunction secondary to chronic GVHD Extensive chronic GVHD •  Generalized skin involvement or •  Localized skin involvement or hepatic dysfunction (or both) as a result of chronic GHVD plus –  Liver histology showing chronic aggressive hepatitis, bridging necrosis, cirrhosis, or –  Eye involvement: Schirmer’s test (< 5 mm wetting), or –  Involvement of minor salivary glands or oral mucosa demonstrated by buccal biopsy, or –  Involvement of any other target organ Abbreviation: GHVD, Graft-versus-host disease

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• Pediatric BMT is feasible in India and should be offered early.



1. Chandy M. Stem cell transplantation in India. Bone Marrow Transplant. 2008;42(Suppl 1):S81-4. 2. Haining WN, Duncan C, Lehmann LE. Principles of bone marrow and stem cell transplantation. In: Orkin SH, Nathan DF, Ginsburg D, Look AT, Fisher DE, Lux SE (Eds). Nathan and Oski’s Hematology of Infancy and Childhood, 7th edition. Philadelphia: Saunders. 2009. pp.397-452. 3. Yadav SP, Kalra M, Sachdeva A, et al. The experience of hematopoietic stem cell transplantation from an emerging center in North India. Blood (ASH Annual Meeting Abstracts). 2009;114:4317.



Bibliography



•  Late graft failure •  Chronic graft-versus-host disease and its sequelae 9, e.g. bronchilotis obliterans) •  Pulmonary disorders •  Infection •  Altered intellectual and growth development in children •  Endocrine dysfunction –  Hypothyroidism –  Growth retardation –  Pubertal delay, gonadal failure –  Sexual dysfunction •  Complications secondary to radiation therapy (e.g. cataracts, radiation nephritis) •  Complications secondary to immunosuppressive therapy (e.g. aspectic necrosis of bone) •  Dental problems •  Psychosocial problems •  Increased risk for second malignancies

Practice ips



Table 12.8.5 Short-term and long-term complications of hematopoietic stem cell transplant Short term •  Graft rejection •  Infection •  Bleeding •  Acute graft-versus-host disease •  Veno-occlusive disease of the liver •  Idiopathic pneumonitis •  Side effects of radiation therapy, chemotherapy, and immunosuppressive therapy (e.g. pancytopenia, mucositis) Long term

ecent dvances

There are key developments happening in the field of haploidentical SCT, natural killer cell immunotherapy, infusing T-regulatory cells to control GVHD and gene therapy for severe combined immunodeficiency and thalassemia, etc.



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from January 2006–August 2009, authors have performed 39 transplants (16 allogeneic and 23 autologous) in 34 patients.

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13 Endocrinology



13.1 13.2 13.3 13.4 13.5 13.6 13.7 13.8 13.9 13.10























Section Editor : PSN Menon

Disorders of Growth: PSN Menon Disorders of Pituitary: PSN Menon Obesity: Anju Virmani Disorders of Puberty: Prisca Colaco Disorders of Thyroid Gland: Meena P Desai Disorders of Bone and Mineral Homeostasis: Vijayalakshmi Bhatia Disorders of Adrenal Glands: Preeti Dabadghao Disorders of Adrenocortical Biosynthesis: P Raghupathy Disorders of Sexual Development: P Raghupathy Diabetes Mellitus: Vijayalakshmi Bhatia

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Short Stature A child is diagnosed to have short stature when his or her height is below the third percentile or below 2 SD of the mean height for that age and gender. Even when the actual height measurements are within normal ranges, the child should be regarded as short, if the height velocity is less than the 25th percentile for age over 6–12 months of observation or the child is very short for midparental or target height. Children with very slow growth rate resulting in crossing of two major percentile lines between the age of 2 years and puberty also need to be evaluated even if the height is in the normal range.

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Measurement of Growth



Supine length is measured by an infantometer in infants and children less than 2 years and standing height by a stadiometer in older children. The techniques for measuring height are detailed in Chapters 3.1 and 3.2. In addition to height, measurements of weight, midarm circumference, skin fold thickness and head circumference are often helpful in diagnosis. The height and weight can be expressed as standard deviation scores (SDS or Z score). Z score is calculated using the formula: (The child’s height–mean height for age from a reference chart) 1 SD of height for that age in the reference data.

Height Velocity Estimation of height velocity is essential for optimal decision-making. On an average most infants measure 50 cm in length at birth, and gain approximately 25 cm in the first year of life, 12.5 cm in the second year, 6–7 cm each in the third and fourth years, and subsequently 5 cm every year until pubertal growth spurt. The peak height velocity during adolescence is about 9–11 cm/year for boys and about 7–9 cm/year for girls. Retardation of height is very significant if height velocity is low or decreasing. On the other hand, if the child has a normal height velocity and is growing along his/her percentiles, the parents can be reassured. Height velocity can also be expressed in Z scores.

Growth Charts The growth pattern of child should be recorded both numerically as well as graphically using appropriate growth charts.

Predicting Adult Height A crude way to assess the genetic potential is to plot the height of the parents on the adult equivalent (e.g. at 18– 20 years) on a standard growth chart. The target height or midparental height is calculated by the formula—for boys: average of father’s height and mother’s height + 6.5 cm; for girls: average of mother’s and father’s height –6.5 cm. Midparental height should be plotted on the adult equivalent on the growth chart. It provides the target height for the child and the percentile he/she is likely to follow (Fig. 13.1.1).

Body Proportions The body proportions employed in clinical decisionmaking are upper:lower segment ratio (US:LS ratio) and arm span:height ratio. They vary with age. The US:LS ratio is approximately 1.7 at birth, 1.3 at 3 years, 1.1 by 6 years and 1 by 10 years. Arm span is less than length at birth by 2.5 cm and equals height at about 11 years and thereafter it is greater than height. An abnormal US:LS ratio or arm span:height ratio indicates disproportionate short stature. Children with achondroplasia have a normal sized trunk with short limbs, while spondyloepiphyseal dysplasia gives rise to short trunk and normal limbs.

Pubertal Assessment Pubertal assessment has an important role in the diagnosis and prognosis of short stature. Onset of puberty is associated with the height spurt seen during adolescence. Delayed or precocious puberty thus has an important role in stature. The stage of puberty is assessed by the Tanner’s method of sexual maturity rating detailed in Chapter 3.4. Testicular volume is measured by comparing testis with an orchidometer.

Bone Age Assessment An essential investigative tool for evaluating short stature is bone age measurement. This is conventionally done from X-ray of wrist and elbow. The bone age is computed from the appearance of epiphyseal centers and fusion of epiphysis with metaphysis using Greulich-Pyle atlas or Tanner-Whitehouse method. A child with delayed bone age has a better prognosis for future height gain than those with appropriate or advanced bone age. Children with familial genetic short stature have bone age appropriate for chronological age, whereas those with an endocrine cause for such as growth hormone deficiency (GHD) or

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Figure 13.1.1 Growth chart showing how to record a child’s height. The actual height of a 9-year-old girl is recorded as 120 cm as “measured height”. The father’s height, mother’s height and the target or midparental height is recorded at 20 years on the growth chart. She is expected to follow the 25th percentile according to the target height but is short for her target height for age. The mean height for the age is recorded at the 50th percentile. Bone age, recorded as a triangle is further behind her chronological age, but equal to her “height age”, the point where the actual height crosses the 50th percentile

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An algorithmic approach to diagnosis of short stature is given in (Flow chart 13.1.1).

Clinical History The time of onset of short stature has great relevance in the differential diagnosis. Hence, antenatal and birth history (including maternal illness during pregnancy, birth weight, length, gestational age, signs of congenital anomalies),

 

Table 13.1.1 Differential diagnosis of short stature



















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A. Normal variants 1. Familial genetic short stature 2. Constitutional delay in growth and puberty B. Disproportionate short stature 1. Skeletal dysplasia: Achondroplasia, hypochondroplasia, spondyloepiphyseal dysplasia 2. Rickets: Nutritional, metabolic 3. Untreated hypothyroidism C. Proportionate short stature of prenatal onset 1. Intrauterine growth retardation • Placental insufficiency disorders: Maternal toxemia, diabetes mellitus • Intrauterine infections: TORCH complex • Teratogens: Alcohol, nicotine, drugs 2. Dysmorphic syndromes: Russell-Silver syndrome, Seckel syndrome 3. Chromosomal anomalies: Down syndrome, Turner syndrome, Prader-Willi syndrome D. Proportionate short stature of postnatal onset 1. Nutritional disorders: malnutrition 2. Chronic infections: tuberculosis 3. Gastrointestinal disorders: Celiac disease, chronic diarrhea, malabsorption syndromes, chronic liver disease 4. Hematological disorders: Hemolytic anemia 5. Renal disorders: Chronic renal failure, tubular disorders 6. Cardiac disorders: Congenital cyanotic heart disease, chronic congestive failure 7. Pulmonary disorders: Cystic fibrosis, chronic asthma 8. Endocrine disorders: Hypothyroidism, growth hormone deficiency and insensitivity, Cushing syndrome, hypogonadism, pseudohypoparathyroidism, diabetes mellitus 9. Psychosocial short stature

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linical and aboratory Evaluation

development, puberty, psychosocial behavior and nutrition are essential. Details of consanguinity, family history of short stature and pubertal development are indispensable. • Short stature with normal height velocity with growth curve following a line parallel to third percentile and positive family history suggest familial short stature (FSS). • Children with constitutional delay in growth and puberty (CDGP) have growth failure from the age of 2–3 years with delayed onset of puberty, positive family history in parents or siblings. • When the growth failure is noted postnatally, environ mental causes such as malnutrition, chronic infections, and emotional disturbances in family should be probed • Social history is important to detect psychosocial short stature. • All systems including endocrine, renal and gastro intestinal, should be reviewed carefully to identify the likely cause for deceleration of growth. ­

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Short stature may be due to a variety of disorders (Table 13.1.1). Common endocrine causes include hypothyroidism, hypopituitarism, diabetes mellitus, Cushing syndrome, pseu dohypoparathyroidism and hypogonadism. A significant number of children who turn-up for evaluation of short stature have no pathological cause and have a physiological cause for their short stature. ­

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Etiology of Short Stature

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hypothyroidism have delayed bone age. Adult height can be predicted by computing chronological age and bone age using the Bayley-Pinneau charts.

Physical Examination The presence of characteristic physical signs of an endocrine disease or dysmorphic syndrome greatly facilitates the diagnostic work-up. Children with endocrine disorders generally have a weight percentile better than that of height, whereas those with systemic disorders usually lose weight first and are thin by the time they are short. Disproportions of body are seen in skeletal dysplasia, rickets, hypothyroidism and some dysmorphic syndromes. Pallor and signs of vitamin deficiencies are frequent in many nutritional disorders, malabsorption, chronic anemia, hypothyroidism and renal failure. It is also important to evaluate the genitalia and grade the pubertal development. • Constitutional delay in growth and puberty is defined as a delay of growth and puberty in an otherwise healthy child, usually an adolescent, with a standing height below the expected for chronological age, but not for his bone age. It tends to affect more boys than girls. It should be a diagnosis of exclusion. The final adult height will be within the normal range. These children are short from around 2–3 years of age. Growth is just below but parallel to third percentile initially with a further deviation as the adolescent pubertal spurt is delayed. Bone age is delayed. There is a familial tendency for short stature and delayed catch-up. The spine length may be relatively short compared to limb length. • Children with FSS are short with a height appropriate for the parent’s height with normal height velocity. The growth curve is below but parallel to the third percentile. Body proportions are normal and pubertal development is appropriate for age. Bone age is appropriate for his/ her age. Again this is a diagnosis of exclusion. • Children with congenital GHD are short with a cherubic appearance, doll-like face and microphallus. Presence of midline anomalies, such as cleft lip, cleft palate or single central incisor tooth, suggests the possibility of

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Flow chart 13.1.1 An algorithmic approach to diagnosis of short stature

Abbreviations: LFT, Liver function tests; RFT, Renal function tests

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•

•

•

Pseudohypoparathyroidism manifests with short stature, round facies, central obesity, short fourth metacarpals and mental subnormality, hypocalcemic tetany or seizures, cataract and calcification in the basal ganglia. Turner syndrome may present in girls with short stature alone. It is characterized by the presence of short webbed neck, shield chest, widely placed nipples, lymphedema with characteristic cardiac, renal and skeletal defects. Down syndrome, a common cause of mental retar dation, has short stature with characteristic facies with mongoloid slant of eyes. ­

•

hypopituitarism. Visual field defects, optic atrophy, optic nerve hypoplasia and papilledema are often associated with septo-optic dysplasia and tumors of the pituitaryhypothalamic region. Acquired hypothyroidism often manifests as short stature. Coarse facies, myxedema, dry rough skin, macroglossia and developmental retardation with delayed relaxation of deep tendon reflexes characterize hypothyroidism. Growth retardation may sometimes be the only presenting feature of Cushing syndrome in childhood.

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Russell-Silver syndrome is characterized by intrauterine growth restriction (IUGR), small triangular facies, hemihypertrophy, clinodactyly, occasionally a large penis and precocious puberty, and sometimes growth hormone (GH) deficiency.

• •

Investigations If the clinical work-up suggests a cause for short stature, the appropriate confirmatory test should be performed. Many a time children with short stature present with no other abnormality on history and examination. Thus in all cases of significant short stature with a low growth velocity and/ or delayed bone age, it is advisable to perform screening investigations to diagnose some of the important causes (Table 13.1.2). Estimation of bone age is the first vital step in the diagnosis of short stature. Most children with CDGP, nutritional disorders, chronic diseases have mild delay and endocrinopathies such as GH deficiency and hypothyroidism have significantly delayed bone age. Cushing syndrome and precocious puberty cause an advancement of bone age. Metacarpal shortening may be present in Turner syndrome and pseudohypoparathyroidism. Madelung deformity (dorsal and radial bowing of the radius) may be present in some cases of SHOX and SHOXY gene mutations, Turner syndrome and Leri-Weill syndrome. • If the screening tests are normal, tests to exclude relatively silent causes of short stature should be performed. These include tests to exclude hypothyroidism, GH deficiency, renal tubular acidosis (RTA), Turner syndrome, and celiac disease • Celiac disease and RTA are two commonly missed causes of short stature on routine diagnostic evaluation • It is a policy in some pediatric endocrine centers to do thyroid function in all children and chromosome studies (for Turner syndrome) in all girls referred for short stature. Elevated gonadotropins, especially FSH, also point toward the diagnosis of Turner syndrome.

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After the initial visit, the family should be advised regarding the need for a balanced diet with adequate calories and proteins, coupled with regular physical exercises. Supplemental hematinics may be prescribed if indicated. Height and weight should be recorded and height gain assessed regularly. Counseling of the child and the family is essential in conditions such as FSS, CDGP, skeletal dysplasia and IUGR. The importance of regular follow-up and monitoring of therapy should be stressed. Treatment of short stature essentially depends on the cause. There is no specific treatment for FSS and most cases of IUGR. Constitutional delay in growth and puberty can cause enormous anxiety, and peer-group pressure may lead to psychological distress. They may benefit from a short course of low-dose testosterone (50 mg testosterone intramuscularly every 3–4 weeks) or estrogen (2.5 µg of ethinyl estradiol daily) given for 3–6 months. This will trigger the secondary sexual characteristics and the pubertal growth spurt. Hypothyroidism should be managed with replacement by levothyroxine. Low-dose estrogens are useful in girls with Turner syndrome and delayed puberty. Anabolic steroids (oxandrolone) have been tried with some success in Turner syndrome and a few children with CDGP. They act by increasing GH secretion. A low-dose daily regimen will induce growth spurt, which continues even after the steroids are stopped. Specific therapy for chronic systemic disorders, e.g. RTA and celiac disease is associated with good catch-up growth. For most skeletal dysplasias, there is no medical treatment, even though GH has been shown to benefit some selected groups. Limb lengthening surgery is an option for some skeletal dysplasias. Growth hormone is indicated in children with GH deficiency. The recombinant GH is given in a dose of 0.23–0.3 mg/kg/week (1 mg = 3 IU) divided in 6–7 doses subcutaneously, preferably at night, till adult height is reached. There are very few side effects reported in children who have received GH for GH deficiency. Contrary to earlier

Radiology: X-ray for bone age; for deformities, sella • Hematological tests: Hemoglobin, hematocrit, total and differential leukocyte counts, blood cell morphology, ESR • Urinalysis: pH, specific gravity, osmolality, microscopy, protein, glucose estimations • Stool examination: Microscopy for parasitic infections, fat for malabsorption, glucose • Blood chemistry: fasting blood sugar, urea, creatinine, sodium, potassium, calcium, phosphate, alkaline phosphatase, cholesterol, albumin and transaminases, venous CO2 • Special tests: Tuberculin test and chest X-ray, thyroid hormones (T4 and TSH), tests for celiac disease (anti-endomysial and transglutaminase antibodies), FSH and karyotype (Turner syndrome) • Tests for hypothalamic-pituitary axis: IGF-I, IGFBP-3 and GH stimulation tests, X-ray skull for suprasellar calcification, MRI brain

•

Management



 

Table 13.1.2 Laboratory evaluation for short stature

Those with disproportionate short stature require skeletal survey, and evaluation for hypothyroidism and RTA. Low bicarbonate levels suggest RTA. A measurement of insulin like growth factor-I (IGF-I) is useful when the cause of short stature is uncertain. In some centers IGF binding protein, IGFBP-3 is also estimated as a screening tool. Low levels (below 2 SD of the mean) of IGF1 and IGFBP-3 suggest the probability of GHD. Measurement of GH in a random blood sample is not a reliable test for GHD, as GH levels are usually low during day and spontaneous peaks are brief and unpredictable. The most practical method is a pharmacological GH stimulation test using clonidine, insulin or other agents. A GH level less than 10 µg/mL following stimulation indicates impaired pituitary secretion. Details of GH deficiency and insufficiency are given in Chapter 13.2.

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Constitutional tall stature Exogenous obesity Precocious puberty Hyperthyroidism Growth hormone excess—Gigantism Sotos syndrome Marfan syndrome Homocystinuria Beckwith–Wiedemann syndrome Klinefelter syndrome Fragile X-syndrome



Table 13.1.3 Etiology of tall stature in children • • • • • • • • • • •

1. Allen DB. Growth hormone therapy for short stature: is the benefit worth the burden? Pediatrics. 2006;118(1):343-8. 2. Bajpai A, Sharma J, Menon PSN. Practical Pediatric Endocrinology, 1st edition. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2003. 3. Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adole scence: summary statement of the GH Research Society. GH Research Society. J Clin Endocrinol Metab. 2000;85(11):3990-3. 4. Desai MP, Menon PSN, Bhatia V. Pediatric Endocrine Disorders, 2nd edition. Hyderabad: Universities Press; 2008.pp.60-179. 5. Drop SL, Greggio N, Cappa M, et al. Current concepts in tall stature and overgrowth syndromes. J Pediatr Endocrinol Metab. 2001;14 Suppl 2:975-84. 6. Farber RS, Kerrigan JR. The multiple indications for growth hormone treatment of pediatric patients. Pediatr Ann. 2006;35(12):926-32. 7. Menon PSN. Use of growth hormone (GH) in non-GH deficient short stature. Indian J Pediatr. 2008;75(Suppl):S14-9. 8. Ranke MB, Lindberg A, Chatelain P, et al. Prediction of long-term response to recombinant human growth hormone in Turner syndrome: development and validation of mathematical models. KIGS International Board. Kabi International Growth Study. J Clin Endocrinol Metab. 2000;85(11):4212-8. 9. Rosenthal S, Cohen P, Clayton P, et al. Treatment perspectives in idiopathic short stature with a focus on IGF-I deficiency. Pediatr Endocrinol Rev. 2007;4(Suppl 2):252-71.



Bibliography



Compared to short stature, referrals for tall stature are rather uncommon. A list of common causes for tall stature is given in (Table 13.1.3). • Some children have constitutional tall stature with tall parents. Tall stature is usually evident early in childhood. They have a high growth velocity and often a slightly advanced bone age. If the tall stature is a matter of psychological concern, sex steroids appropriate for sex may be given at the onset of puberty to achieve early epiphyseal fusion. • Many children with exogenous obesity appear tall, but the adult height is normal. • Children with precocious puberty appear to be taller than peers due to the growth enhancing action of

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gonadal steroids. However, early epiphyseal fusion makes them short as adults, unless treated early. Gigantism is due to excessive production of GH by an acidophil adenoma of the pituitary gland. It is characterized by tall stature with prognathism, increased soft tissue of hands and feet, broad root of nose, increased sweating, hypertension and glucose intolerance. The diagnosis is confirmed by detection of raised IGF–I levels and lack of suppression of GH (levels < 1 µg/ml) following administration of oral glucose, 1.75 gm/kg. Treatment is by transsphenoidal pituitary surgery. Recurrence can be managed by octreotide, a somatostatin analog. Sotos syndrome (cerebral gigantism) is characterized by increased birth weight and length, macrocephaly and dolichocephaly, hypertelorism and mental retardation. Marfan syndrome is characterized by tall stature, arachnodactyly (long thin fingers) and long thin limbs with an abnormally long lower segment resulting in arm span more than height. In addition there may be hypotonia, hyperextensible joints, scoliosis, flexion contractures, dislocation of the lens, and cardiac anomalies. Klinefelter syndrome is associated with tall stature, abnormally long legs, gynecomastia, mental retardation and behavioral abnormalities with a karyotype of 47, XXY.

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suggestions, there is no report of increased susceptibility to tumors or leukemia in treated children. Children gain on an average 10–12 cm in the first year of therapy and 6–8 cm/year thereafter every year. However, the high cost of therapy has limited its use in the subcontinent. Growth hormone has been used to increase height in a number of other disorders with limited success. These include Turner syndrome, end-stage chronic renal failure, and a group of children with IUGR with poor catch-up growth. It is also used in children with Russell-Silver syndrome. It has been shown to be effective in some groups of children with constitutional delay and idiopathic short stature. The dose used is higher than that used in GH deficiency. In Turner syndrome, a combination of GH with low-dose estrogen and/ or oxandrolone has been shown to produce excellent height gain. The chances for development of side effects are higher in these children. Hence, regular monitoring of therapy with recording of height is essential to obtain good results. Recently aromatase inhibitors such as anastrozole and letrozole have been tried with some success in adolescent boys with short stature. These aromatase inhibitors delay the tempo of bone age acceleration by estrogen blockade.

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isorders of Pituitary PSN Menon

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tiology

The spectrum of GHD varies from complete to milder grades of insufficiency. Incidence varies from 1 in 3,500 to 4,000 in USA and UK. The common causes of GHD are given in Table 13.2.1. The most common form however is idiopathic. F

linical eatures

The height is usually less than the third percentile for the age and the height gain is often as low as 1 cm/year.

Table 13.2.1 Causes of growth hormone deficiency  

R

Growth hormone deficiency is characterized by short stature. The growth impairment starts within a few months after birth, but a clinical diagnosis is usually not obvious till the child is about 1 or 2 years old.

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ongenital: Developmental defects of the hypothalamus and/or pituitary – Anencephaly, holoprosencephaly – Septo optic dysplasia, Hall Pallister syndrome – Midline brain and facial abnormalities: Single central incisor tooth, cleft lip/palate – Associated with abnormal pituitary morphology on MRI: Hypoplasia of anterior lobe, interruption or hypoplasia of stalk, ectopic posterior pituitary • Defects in genes necessary for pituitary development and function – Isolated GHD: Autosomal recessive, autosomal dominant, X–linked (mutations of GH 1, GHRHR, SOX3, HESX1) – Combined pituitary hormone deficiencies: Autosomal recessive [mutations of PIT 1 (POUF1), PROP 1, LHX3, LHX4, HESX1]; autosomal dominant [mutations of PIT 1 (POUF1), PROP 1]; and X linked, Rieger’s syndrome • cquired: – Tumors within the hypothalamic-pituitary axis: Craniopharyngioma, germinoma, teratoma – Cranial irradiation: Leukemia, medulloblastoma, astrocytoma/glioma, ependymoma, rhabdomyosarcoma – Trauma to the hypothalamic-pituitary region: Perinatal (breech, forceps) or postnatal – Infiltration: Langerhans cell histiocytosis, thalassemia major – Central nervous system infections: Tuberculosis •



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Growth Hormone eficiency

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The anterior pituitary develops from the Rathke’s pouch and the posterior pituitary from the infundibulum, which is a downgrowth from the floor of the diencephalon. The principal hormones produced by the anterior pituitary are: • Thyroid stimulating hormone (TSH) • Adrenocorticotropic hormone (ACTH) • Follicle stimulating hormone (FSH) • Luteinizing hormone (LH) • Growth hormone (GH) • Prolactin (PRL) These hormones act on target glands and a variety of tissues in the body. The hypothalamus produces a number of hormones which regulate pituitary function. These include: • Growth hormone releasing hormone (GH H): Regulates GH release • Gonadotropin releasing hormone (Gn H): Regulates LH and FSH release • Thyrotropin releasing hormone: Regulates TSH and PRL release • orticotropin releasing hormone: Regulates ACTH release • omatostatin or growth hormone release inhibiting hormone: Inhibits GH release • Prolactin inhibiting factor: nhibits release of PRL, TSH and GH • Ghrelin: Regulates GH release • rginine vasopressin ( VP): Has a role in ACTH release. Growth hormone has specific growth promoting actions on protein synthesis, skeletal growth and inter­ mediary metabolism. A number of regulatory proteins or transcription factors are important for the development and function of the pituitary. They act at different stages of pituitary development and trigger the expression of specific genes involved in hormone release and action. These transcription factors include HESX1, POU1F1 (PIT 1), PROP 1, LHX3, LHX4, GLI2 and SOX3. The growth hormone binding proteins (GHBP) act as a reservoir for circulating GH. Their levels reflect the GH receptor concentration, with the GHBP constituting the extracellular domain of the GH receptor. A single molecule of GH released from circulation binds to two GH receptors to form a dimer complex. The actions of GH are mediated through synthesis of insulin like growth factor I (IGF I). Insulin like growth factor I in turn circulates bound to binding proteins called IGFBP; the major one being IGFBP 3.

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The GH IGF 1 axis plays a key role in regulating growth and the growth promoting effects of IGF I can be both GH dependent and GH independent. -

Physiology



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iagnosis

Children with a height below third percentile and height gain less than 4 cm/year over a period of observation for at least 6 months, with a bone age below the chronologic age needs evaluation for GHD. The diagnosis of GHD depends on demonstration of absent or low levels of GH in response to stimulation. Since GH levels are fluctuating because of its pulsatile nature, random or fasting blood GH level measurements are not helpful in diagnosis. Pharmacological stimuli are preferred to physiological stimuli. Tests which are based on the physiological stimuli include physical exercise and deep sleep (Table 13.2.2).

 



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Figure 13.2.2 Ten-year-old boy with growth hormone deficiency— please note micropenis and hypoplastic scrotum

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Figure 13.2.1 Nine-year-old boy with growth hormone deficiency. Note immature facies, hypoplastic scrotum and micropenis



Thus, regular height monitoring may help in early detection. Hypoglycemia and prolonged jaundice in neonatal period are early pointers to the diagnosis of GHD. Neonatal hypoglycemia and convulsions are often associated with ACTH deficiency. Hypogonadism may be evident in boys as small sized genitalia (Fig. 13.2.2). Pubertal growth spurt is less than normal. Mental development and intelligence are normal.

ndocrinolo y

These children have normal body proportions and are somewhat overweight for their height with increased subcutaneous fat, truncal obesity and normal body proportions. Bone age is delayed to a variable extent. The height age is less than the bone age and both are less than chronological age. The typical child with GHD is very short and plump with immature facies and prominent forehead (Fig. 13.2.1). They look much younger than their actual age. Some of the features of congenital hypopituitarism include midline facial abnormalities such as cleft palate and lip, single central upper incisor tooth and prominent philtrum. The eyes appear very prominent with a depressed nasal bridge with a saddle shaped nose. In addition there may be underdeveloped mandible and chin, crowding of teeth, nystagmus with impaired vision and a high pitched voice. The hands and feet are small with slowly growing nails and hair. The skin is thin, with a tendency for premature wrinkling. Most children with GHD have normal length at birth. Only 2–5% of children with GHD have suggestive clinical signs in early infancy and present by the age of 2 years.

 

Table 13.2.2 Commonly employed growth hormone stimulation tests Test

Dose

Insulin

0.1 U/kg IV

0, 15, 30, 45, 60, 75, 90, 120 minutes

Hypoglycemia

Clonidine

0.15 mg/m2 PO

0, 30, 60, 90 minutes

Hypotension

L-Dopa

< 10 kg: 125 mg; 10–35 kg: 250 mg PO

0, 30, 60, 90 minutes

Headache, nausea

Glucagon

20 μg/kg IV

0, 30, 60, 90, 120, 150, 180 minutes

Nausea

GHRH

1 μg/kg IV

0, 15, 30, 45, 60, 90, 120 minutes

Flushing

Arginine

0.5 g/kg IV

0, 15, 30, 45, 60 minutes

Hypotension

Abbreviation: GHRH, Growth hormone releasing hormone

Blood collection at

Side effects

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–

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–

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•



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It is important to observe the child with regular growth records for 6 months to 1 year—a child who gains more than 4 cm/year is unlikely to have hypopituitarism. If GH levels are low, the child may be given recombinant GH in a dose of 0.23–0.3 mg/kg/week (1 mg = 3 IU) subcutaneously, till adequate growth is achieved. Dosage is titrated with the growth rate, pubertal stage, bone age and serum IGF I levels. Depot GH preparations are under investigation. Growth hormone therapy in children with GHD induces rapid catch up growth during the first 2–3 years of treatment, increasing the height gain 2–4 fold above the pretreatment rate. The child on an average gains a height of 10–12 cm in the first year of therapy and 6–8 cm/year thereafter every year. In subsequent years, the height gain typically declines and follows normal patterns of growth. Younger children and those receiving a higher dose show a better response than older children with conventional dose. Growth hormone is administered daily by subcutaneous injection in the evening 6–7 times a week, varying the site of injection. Pen devices and prefilled syringes are available which simplify daily administration. Many centers start GH therapy at half the normal replacement dose and increase the dose during the first month to avoid the possible adverse effects of fluid retention. In addition to growth, serum IGF I levels should act as a guide during GH dose titration. If IGF I levels are low, an assessment of injection technique and compliance might be necessary before dose adjustment. If IGF I levels are above the normal range and height gain is adequate, a reduction in dose should be considered. The cessation of GH therapy at the end of linear growth is guided by the following criteria: • Height gain decreasing to 1 cm/year • Attainment of an acceptable height close to target height • Bone age is over 16 years in boys and 14 years in girls. After final height has been achieved, GH therapy should be discontinued and GH status reassessed to identify those with persistent severe GHD (peak GH < 5 ng/mL). Discontinuation of GH therapy is recommended for a period of 1–3 months or longer before retesting. Growth hormone therapy is relatively safe. Contrary to earlier suggestions, there is no report of increased susceptibility to tumors or leukemia in treated children. Salt and water retention occurs within the first few months of initiation. Treatment with GH increases the risk for slipped capital femoral epiphysis, pseudotumor cerebri and worsening of scoliosis. Impaired glucose tolerance may develop in a few, hence blood glucose and HbA1c estimation is recommended periodically. There is also need for regular monitoring of thyroid function during therapy with GH, as some patients develop reversible hypothyroidism. Pituitary thyroid axis should be checked annually. The dose required to maintain euthyroid status is lower than in children with primary hypothyroidism.

•

Treatment



Standard provocation tests use insulin, clonidine, arginine, L dopa, glucagon or GHRH. Of these insulin (0.05–0.1 IU/kg IV) and clonidine (0.15 mg/m2 orally) are the most preferred stimuli. Blood samples are collected before and at 15–30 minute intervals for 2 hours. Diagnosis of GHD is suspected when the peak GH level is less than 10 ng/mL following stimulation. The tests are not foolproof and there is often an overlap between normal short children and children with GHD. Hence, two standard provocative tests are usually suggested before recommending GH therapy. Insulin administration carries the risk of hypoglycemia and seizures. Hence in infancy glucagon test is preferred. Priming with sex steroids is required in short children with delayed puberty and a bone age of 10 years or more (Boys: Depot testosterone 100 mg IM 3–5 days before the test; Girls: Premarin 5 mg orally the night before and morning of the test). Euthyroid state is essential before GH testing: – The spontaneous secretion of GH can be evaluated by measuring GH levels every 15–20 minutes during a 12 or 24 hour period. However, this is not a practice in India. – IGF I and IGFBP 3 are increasingly used for initial testing in the diagnosis of GHD. There are technical limitations to IGF I assays. Their levels vary with age, nutritional status and certain disease states. IGF I is low in infancy and less dependable in young children (< 5 years of age) and there may be an overlap with GHD. It is not dependable in GHD associated with brain tumors and/or cranial irradiation. IGFBP 3, not IGF I, is helpful for diagnosis during infancy and can be used in suspected neonatal GHD. The IGFBP 3 assay is technically simple, and plasma concentrations vary much less with age and nutritional status. It is a good predictor of GHD in a child with short stature. – Growth hormone deficiency may be associated with deficiencies of other anterior pituitary hormones. Hence a complete evaluation of anterior pituitary function is undertaken in each patient with GHD. – CT or MRI of brain is useful in the evaluation of GHD to rule out organic causes and study pituitary morphology—ectopic posterior pituitary, anterior pituitary hypoplasia, interruption or absence of pituitary stalk, midline anomalies and tumors. Approximately 15% of children with GHD have an abnormality of pituitary on imaging. – Molecular genetic testing provides an additional useful diagnostic tool. Inherited forms of genetic abnormality may be the probable underlying cause of GHD in 10–15% of all patients. – Increased serum concentrations of GH, both basal and stimulated, together with low IGF I and low IGFBP 3 levels, suggest GH insensitivity. Estimation of GHBP is helpful in the diagnosis of GH insensitivity. -

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A

cromegaly and Gigantism

Excess secretion of GH in children, usually due to a pituitary adenoma, results in somatic overgrowth or gigantism. When hypersecretion of the hormone occurs after the fusion of skeletal epiphyses, it causes acromegaly which is seen in adults.

linical eatures F

C

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-

There is rapid linear growth and the child is taller than his/ her peers. Peripheral parts of the body, the hands, feet, nose and mandible are large. The head circumference is increased. Facial features are coarse with prominent jaw, broad nose, enlarged tongue, bushy eyebrows, thick skin and subcutaneous tissue, with dorsal kyphosis. Muscle weakness, bony and cartilaginous overgrowth, cardiomyopathies and pigmentation of skin may be present. Diffuse or nodular goiter or hyperthyroidism may be present. Involvement of other endocrine organs may lead to hypogonadism, hypocortisolism or diabetes mellitus. Headaches, visual field defects including bitemporal hemianopsia, papilledema followed by optic atrophy and external ophthalmoplegia are common. Behavioral problems may be present. A GH secreting adenoma may occur in association with McCune Albright syndrome or multiple endocrine neoplasia (MEN 1).

iagnosis

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D

-

Insulin like growth factor I deficiency can result from genetic or non genetic effects and has been found to be an important underlying cause of short stature in children. One of the first examples of insensitivity to GH was reported by Laron and colleagues in 1966 in three Israeli Jewish siblings presenting with hypoglycemia, and a clinical phenotype of

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eficiency and Growth Hormone nsensitivity I

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The diagnosis is based on clinical examination, periodic growth assessment and investigations. Enlarged sella turcica with erosion of margins is seen on X ray. Tufting of phalanges and increased heel pad thickness may be present. Skeletal 791 -

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S

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N

Growth hormone enhances growth of many non GH deficient short children and is recommended in the following situations: • Turner syndrome: A number of early studies demonstrated that GH therapy with or without anabolic steroids accelerated growth velocity and led to an improved final height. The current practice is to use approximately 0.35 mg/kg/week. In clinical practice, it may be useful to add oxandrolone as a synergistic agent if response to GH becomes attenuated in late childhood. • hronic renal insufficiency prior to undergoing renal transplantation: Food and Drug Administration has approved GH (0.3 mg/kg/week) in children with chronic renal insufficiency with poor height gain over 6 months, prior to undergoing renal transplantation. • mall-for-gestational age: Small for gestational age children aged 4 years or older with failure to catch up, height below 2.5 SD, and height SDS more than 1 SD below midparental height SDS are eligible for GH treatment in US since 2001 and in Europe since 2003. The recommended dose is 0.23–0.35 mg/kg/week. • Prader-Willi syndrome: The indications for GH therapy in Prader Willi syndrome are for the improvement of both growth and body composition. The recommended dose is 0.16–0.23 mg/kg/week. • diopathic short stature: Idiopathic short stature (ISS) is a heterogeneous group of disorders with two common features: (1) short stature (height less than 2 SD or below the third percentile for age and gender) and (2) normal GH response to stimulation tests. The tempo of growth may be slow or normal. It is a diagnosis of exclusion. Long term GH therapy (0.24–0.37 mg/kg/week) can lead to increased adult height in children with ISS, but the degree and predictability is uncertain.







GH for on-GH- eficient hort tature

GHD, but with marked elevation of immunoreactive serum GH. Similar cases have been reported from India. This is a hereditary disorder with primary resistance to actions of GH due to a molecular defect in the GH receptor. The primary genetic form of growth hormone intensity (GHI) is associated with abnormalities of the GH receptor, required to mediate actions of GH. It may also follow post GH receptor defects or molecular defects in IGF I. Children with primary GH insensitivity have the classic clinical phenotype of severe isolated GH deficiency in its most severe form. The craniofacial features may be more prominent with characteristic midfacial hypoplasia, depressed nasal bridge and protruding forehead. Height age is more severely retarded in relation to bone age. Basal serum GH concentration may be normal or elevated, with excessive GH response to provocative stimuli. Typically these children have low levels of IGF I, IGFBP 3, and very low or absent GHBP. Administration of GH does not bring about a rise in IGF I levels, which forms the basis of the IGF I generation test. The final diagnosis of GHI is based on the demonstration of the specific molecular defect in GH receptor gene, in the presence of clinical phenotype and laboratory criteria. Initial results of treatment with IGF I appear to be promising, but there are a number of limitations.

ndocrinolo y

Supplementation of other pituitary/hypothalamic hor­ mones along with GH depending upon concomitant pituitary deficiencies is important. Care should be taken while replacing steroid replacement in children with ACTH deficiency as hydrocortisone dose should usually not exceed 10 mg/m2/24 hour. Sex steroid replacement should be at the normal age around 11–12 years in girls and 12–13 years in boys. Concurrent treatment with GH and a GnRH analog or aromatase inhibitor (anastrozole or letrozole) has been recommended in some children presuming that interrup­ tion of puberty will delay epiphyseal fusion and prolonged growth to give a better final height.

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Treatment of adenoma includes surgery, irradiation and medical therapy. The pituitary microadenoma is resected by transsphenoidal route if there is evidence for raised intracranial tension. Larger tumors can be removed by transcranial route. Conventional or high voltage radiotherapy may halt the progress of the disease but may not cause clinical improvement. Pituitary radiation can also be carried out by implanting radioactive isotopes. A long acting SS analog, octreotide has been found to be better than bromocriptine in suppressing the levels of GH, IGF I and IGFBP 3 concentrations and reducing the size of tumor mass.

These children are thirsty and pass large quantities of urine and often report with nocturnal enuresis. The symptoms are often not recognized by the parents. Infants with DI thus may present with intermittent high fever, irritability, loss of weight, poor feeding, dehydration and collapse. Abnormal behavior and hyperactivity are common. In children who have acquired bladder control, enuresis may be the first symptom. Signs and symptoms of causative lesions may be present and include growth retardation, cachexia, obesity, sleep disturbances, precocious puberty, visual disturbances and emotional disorders. D

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-

tiology



The deficiency may be partial, complete or transient. • Central or nephrogenic DI results from various abnor­ malities of AVP synthesis and/or action due to lesions of neurohypophysis, such as suprasellar tumors (cranio­ pharyngioma, optic glioma), histiocytosis, reticuloen­ dotheliosis, encephalitis, tuberculosis, granulomas and trauma. Diabetes insipidus can occur in the newborn following asphyxia, intracranial bleeding, and meningi­ tis. Diabetes insipidus with diabetes mellitus, optic atro­ phy and deafness is known as Wolfram syndrome. • Nephrogenic DI is due to the inability of the kidney tubules to respond to AVP—failure to increase renal water reabsorption in the presence of adequate AVP. It is often due to abnormalities in kidney function and structure affecting collecting duct or mutations that affect the V2 receptors. • There is a psychogenic form of polydipsia with associated polyuria due to compulsive water drinking. In central and nephrogenic DI, diffusion of water from the distal tubules and collecting ducts is reduced due to lack 792



-

-

-

Polyuria and polydipsia should be confirmed by 24 hour intake and output records. Urinary specific gravity varies from 1.001 to 1.005 and osmolality 50–200 mOsm/kg. Serum osmolality may vary depending on the degree of dehydration. Other renal function studies are normal. Often DI is suspected in the presence of life threatening hypernatremia. Serum AVP levels are helpful in establishing the diagnosis with the child in a hyperosmolar state with voiding hypo osmotic urine. Often the distinction between central and nephrogenic DI requires a water deprivation test or DDAVP test. During water deprivation test for a minimum of 3–6 hours, children with central and nephrogenic DI fail to concentrate urine and plasma more than 300 mOsm/kg, whereas, there is urinary concentration in children with compulsory water drinking. The interpretation of water deprivation test is given in Table 13.2.3. If there is concentration of urine following DDAVP, (5 µg intranasal), the cause is primary AVP deficiency. Failure to concentrate urine and absence of response to DDAVP indicates nephrogenic DI. Radiologic studies including MRI may reveal evidence for intracranial tumor such as calcification, enlargement of sella, erosion of clinoid process and increased width of suture lines or evidence of reticuloendotheliosis such as rarefaction. MRI also can demonstrate the absence of the bright hyperintense spot in hypothalamic pituitary lesions. -

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Diabetes insipidus (DI) results from lack of antidiuretic hormone or AVP. Arginine vasopressin is secreted from the supraoptic and paraventricular nuclei of the hypothalamus. It is transported through axons to posterior pituitary where it is stored until release. It acts on receptors (V1 and V2) especially in the collecting ducts of kidney. Binding of AVP to the V2 receptor leads to a cascade of actions through the G protein adenyl cyclase system and release of a second messenger known as aquaporin 2, which allows transport of water. Arginine vasopressin release is primarily controlled by alterations in plasma osmolality.

iagnosis



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Treatment

of AVP. Since sodium and water transport from the loop of Henle and distal tubule remains unchanged, urine becomes hypotonic and cannot be concentrated beyond 150 mOsm/ kg.

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maturation is normal. CT or MRI scan should be done to determine the extent of the tumor. The diagnosis is confirmed by detection of raised IGF I levels and lack of suppression of GH (levels < 1 ng/mL) following administration of oral glucose, 1.75 g/kg. Secretion of ACTH, TSH, LH and FSH may be impaired.

Treatment Central DI can be treated by administration of desmopressin (DDAVP), an analog of AVP given as a nasal spray, nasal solution or tablets. The usual dose is 5–10 µg daily either as a single dose or divided into two doses. Children under 2 years require lesser doses (0.15–0.50 µg/kg). Oral administration of chlorpropamide 20 mg/kg/24 hours in two divided doses may reduce polyuria and polydipsia in partial deficiency. Hydrochlorothiazide and indomethacin may offer some relief in nephrogenic DI.

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growth hormone deficiency: Factors influencing outcome. Indian Pediatr. 2006;43(7):593 9. Bajpai A, Menon PS. Growth hormone therapy. Indian J Pediatr. 2005;72(2);139 44. Bajpai A, Menon PS. Insulin like growth factors axis and growth disorders. Indian J Pediatr. 2006;73(1):67 71. Carr M, Gill D. Polyuria, polydipsia, polypopsia: “Mummy I want a drink”. Arch Dis Child Educ Pract Ed. 2007;92(5):ep139 43. Desai MP, Menon PS, Bhatia V (Eds). Pediatric Endocrine Disorders. Hyderabad: Universities Press; 2008. pp. 60 179. Desai MP, Upadhye PS, Kamijo T, et al. Growth hormone releasing hormone receptor (GHRH r) gene mutation in Indian children with familial isolated growth hormone deficiency: a study from western India. J Pediatr Endocrinol Metab. 2005;18(10):955 73. Growth Hormone Research Society. Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society. GH Research Society. J Clin Endocrinol Metab. 2000;85(11):3990 3. Laron Z. Laron syndrome (primary growth hormone resistance or insensitivity): the personal experience 1958 2003. J Clin Endocrinol Metab. 2004;89(3):1031 44. Rivkees SA, Dunbar N, Wilson TA. The management of central diabetes insipidus in infancy. Desmopressin, low renal solute load formula, thiazide diuretics. J Pediatr Endocrinol Metab. 2007;20(4):459 69. Rosenfeld RG. Molecular mechanisms of IGF I deficiency. Horm Res. 2006;65(Suppl 1):15 20. Rosenthal S, Cohen P, Clayton P, et al. Treatment perspectives in idiopathic short stature with a focus on IGF I deficiency. Pediatr Endocrinol Rev. 2007;4 (Suppl 2):252 71.

ndocrinolo y

Table 13.2.3 Interpretation of water deprivation test

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8.





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1. Bajpai A, Kabra M, Gupta AK, et al. Growth pattern and skeletal maturation following growth hormone therapy in

10.

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Note: *Conversion of urine osmolality to urine specific gravity: 300 mOsm/kg greater than or equal to 1.005; 750 mOsm/kg greater than or equal to 1.010.

g

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-





2.



































• Initial evaluation – Serum sodium – Plasma osmolality – Urine osmolality – Weight (calculate 5% weight) • Test not required if urine osmolality greater than 750 mOsm/kg or plasma osmolality greater than 300 mOsm/kg • Monitoring – Urine osmolality and plasma osmolality hourly – Urine output and weight hourly – Look for features of dehydration • Termination of test – Weight loss greater than 5% – Urine osmolality greater than 750 mOsm/kg – Plasma osmolality greater than 300 mOsm/kg • Vasopressin response test – Aqueous vasopressin (0.1–0.5 unit/kg, IM) – DDAVP (1–2 mg subcutaneously) – Avoid intranasal DDAVP. • Classification: Increase in urine osmolality: – Less than 50% of baseline: Nephrogenic DI – Greater than 50% of baseline: Central DI

793

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besity

The problem of obesity is increasing in children and adolescents in urban and semi-urban India. The problem is not just cosmetic, but a disease which causes impaired mobility and interference with daily living activities, serious morbidity (Table 13.3.1), even mortality. Almost 50% obese children become obese adolescents, and almost 80% of them become obese adults. They in turn, in addition to the listed disorders, have more coronary heart disease, osteoarthritis, liver and renal disease, malignancies, and asthma. With childhood onset, and thus longer duration, the health burden of obesity will rise in the coming decades. Much of the morbidity is related to visceral rather than peripheral fat, and can be reversed with weight loss. However, established obesity is very frustrating to manage, as sustained weight loss is difficult to achieve, and lost weight returns rapidly. It is critical that the entire family be involved in the weight loss process—if family members are unwilling to change habits, the child alone should not be forced to make drastic changes. The goal of management is not attainment of ideal body weight, which may be near impossible, but achieving and maintaining steady weight loss to the extent possible. Because loss is difficult, prevention is crucial. Pediatricians must be vigilant in preventing obesity, while trying to reduce the health impact in those already obese.

efinitions and pidemiology E

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Body mass index (BMI = weight in kg ÷ height in m2) is most commonly used to quantify obesity. In adults, obesity is defined as BMI greater than 25 kg/m2, morbid obesity as BMI greater than 40, and super-obesity as BMI greater than 60. South Asians tend to be “fat-thin” (i.e. have more body fat for the same BMI and more adverse body fat patterning, including abdominal adiposity), so their recommended cut-off is 23 kg/m2. In children, ideal BMI for age and gender can be derived from CDC charts (free to download from the internet), and percent BMI (actual BMI/ideal BMI) calculated. Obesity and overweight are often used interchangeably, but specifically “overweight” implies a BMI 85–95 percentile for age and gender, while “obesity” is greater than 95 percentile. Alternatively, weight for height can be calculated (“overweight”: up to 120% of ideal; “obese”: > 120%). These weight/height norms may sometimes be misleading, e.g. muscular persons or those with early or delayed puberty. However, they are relatively robust and widely used. Other parameters are waist circumference measured at the level of the iliac crest and waist-to-hip ratio (WHR), interpreted according to age, gender and ethnicity. They have the additional benefit of emphasizing abdominal obesity, which is better correlated with insulin resistance (IR) and cardiovascular (CV) risk. In the United States, the 2007–2008 National Health and Nutrition Examination Survey (NHANES) results showed 17% of children and adolescents (ages 2–19 years) were obese. Interestingly, prevalence increased rapidly between 1970s and 2000, but in 2008–2010, this spiraling increase appears to have plateaued in the US, France, Switzerland, Australia and other developed countries perhaps due to aggressive preventive measures. In urban Indian adolescents, studies have shown a prevalence of 5–15%, and rising.



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Table 13.3.1 Comorbidities of obesity

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• Type 2 diabetes: With hyperinsulinemia • Hypertension: Rises from about 4–6% in under 5 to 15% in adolescents • Dyslipidemia: Generally low HDL, raised LDL and triglycerides—in up to 20% obese adolescents • Polycystic ovarian syndrome: With hyperandrogenemia and hyperinsulinism • Renal dysfunction: Higher rate of glomerulosclerosis; proteinuria and focal segmental glomerulosclerosis; and end stage renal disease • Hepatic dysfunction: Higher rate of raised transaminases, fatty liver on ultrasound, non-alcoholic fatty liver disease, gallstones, and even progression to cirrhosis • Sleep apnea: Rate much higher; apnea in turn can worsen hypertension, behavior and school performance • Mechanical problems: Slipped capital femoral epiphysis, genu valgus, tibia vara, Legg-Calve-Perthes disease, low back pain, scoliosis and osteoarthritis • Psychological problems and eating disorders: Feelings of inadequacy and being different; being stereotyped as greedy, clumsy, lazy, stupid, or worthless • Miscellaneous: Acanthosis nigricans, skin tags, intertriginous infections, hyperuricemia

Pathogenesis Several hormones (e.g. insulin and leptin) and nutrients (glucose and fatty acids) link the brain, GI tract and adipose tissue, influencing appetite, energy expenditure, and growth. A number of orexicants (including ghrelin, cholecystokinin, cortisol, agouti-related protein, neuropeptide-Y, GABA, melanin-concentrating hormone and endocannabinoids) and anorexiants (leptin, g-MSH, proopiomelanocortin (POMC), insulin, serotonin, dopamine and glucagon-like peptide 1 and glucose-dependent insulinotropic peptide) are involved in the complex processes of energy intake and expenditure and maintenance of body weight. Many of them

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Table 13.3.2 Causes of pathological obesity  

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• Endocrine: – Hypothyroidism – Growth hormone deficiency – Cushing syndrome • Hypothalamic: – Laurence-Moon-Biedl syndrome – Prader-Willi syndrome – Craniopharyngioma • Drugs: – Corticosteroids – Sodium valproate • Miscellaneous: – Achondroplasia – Muscular dystrophy – Severe mental retardation

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The most important clinical feature which distinguishes pathological from exogenous obesity is height. Children

Figure 13.3.1 An infant with Cushing syndrome: please note that unlike children, in infants the obesity may be generalized obesity  

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Obesity is, simplistically, caused by an imbalance of energy intake and output, but exact mechanisms are unclear. Genetic influences are strong, as shown by studies on adopted children and twins. Environmental factors are equally important, e.g. differences in food choices, levels of physical activity, attitudes to food, activity, body image, etc. A consistently strong correlation is seen with TV viewing (reduces activity, increases calorie intake, pushes wrong messages about food, encourages intake of junk foods). In general, obesity runs in families, as they share both genes and environment; parental obesity is a strong risk factor. Eighty percent of children of both obese parents, and 40% of one obese parent are overweight. Maternal weight, weight gain during the prenatal period, and diabetes are important predictors. Low birth weight (LBW) with subsequent obesity confers high risk for hyperinsulinemia and CV disease. Keeping these factors in mind, health personnel must start delivering appropriate messages early, e.g. warning obese parents, discouraging force feeding especially of LBW babies, educating new parents about healthy diets. Pathologic causes account for less than 1% of all cases (Table 13.3.2). Corticosteroid or other drug therapy is most common. Endocrine causes are almost universally associated with decreased height velocity. In Cushing syndrome, obesity distribution is truncal, but in infants distribution can be generalized (Fig. 13.3.1). Several single gene mutations can result in variable degrees of obesity syndromes-like Prader-Willi, Laurence-Moon-Biedl, pseudo hypoparathyroidism type 1A, Alstrom, Carpenter, Cohen and POMC deficiency. In craniopharyngioma, obesity is multifactorial, and tends to worsen after surgery.



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with exogenous obesity are taller than expected for age and family; those with pathology are shorter than expected (unless they also have precocious puberty or virilization). Detailed history is necessary (Table 13.3.3). Parents may describe that during sleep the child snores loudly, and sometimes appears to stop breathing—this should be taken seriously, and sleep apnea investigated for. Examination should include accurate auxology (Table 13.3.4), including measuring parents’ heights (for calculating midparental or target height). Acanthosis is seen in skin folds (neck, axillae, knuckles and groin) (Fig. 13.3.2). With rapid weight gain pinkish striae may appear, fading gradually, and not to be confused with those seen in Cushing syndrome. Rashes in skin folds might interfere with exercise programs unless treated. Careful genital examination is needed, including SPL in boys, since the penis is usually buried in abdominal fat.

ndocrinology

act via the melanocortin-4 receptor (MC4R) in the arcuate nucleus of the hypothalamus. Loss-of-function mutations of MC4R cause severe obesity by disrupting hypothalamic appetite control centers, and promoting binge eating. Leptin, produced by adipose tissue, suppresses food intake and increases energy expenditure, but early hopes of therapeutic possibilities were belied as obese individuals are relatively leptin resistant. Other compounds are being explored for possible therapeutic use. Adipose tissue itself is an active endocrine organ. It metabolizes sex steroids (e.g. converts androstenedione to testosterone, and estrone to estradiol), which in turn may play a role in fat distribution. Thus increased fat deposits are seen in hypogonadal states-like Turner and Klinefelter syndromes. Adipose tissue also secretes inflammatory cytokines (e.g. TNF-g, interleukin-6, plasma activator inhibitor type 1, adiponectin, visfatin), linking central or visceral obesity with CV disease.

795

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aboratory valuation

Investigations are guided by the clinical presentation. The tall child, with normal growth velocity, normal BP or mild hypertension, no clinical evidence of pathology, advanced bone age (usually close to height age) is likely to have exogenous obesity. The Endocrine Society’s guidelines recommend against routine testing for endocrinopathies in such children. However, fasting blood glucose, lipids, and insulin can be tested. Fasting insulin greater than 20 IU/mL denotes hyperinsulinemia (normal < 15 IU/mL). Homeostasis model assessment-estimated insulin resistance (HOMA-IR) index can be calculated as a marker of IR (significant > 4.39). [HOMA-IR = (fasting insulin in μU/mL × fasting glucose in mmol/L) divided by 22.5]. Further work-up is hardly ever required. If tested in exogenous obesity, mildly raised TSH (TSH < 10 µIU/mL with normal T4 is not an indication for thyroxine replacement), and cortisol (easily suppressible) may be seen; urinary free cortisol is normal. Similarly, GH may be low in stimulation tests, but IGF-1 and IGF-BP3 are normal. Changes of polycystic ovary syndrome (PCOS) may be seen in the adolescent girl [raised testosterone and/or dehydroepiandrosterone sulfate (DHEAS), altered LH/FSH ratio, polycystic changes in the ovaries]. Other findings include proteinuria, fatty liver, raised serum T3, decreased sex-hormone binding globulin, and pubertal levels of FSH in 7–9-year-old girls (with no increase in LH). In adults, serum parathyroid hormone (PTH) may be raised and is an independent predictor of obesity. Sleep studies, if the child has marked snoring, may reveal sleep apnea (obstructive, central, or combined). The short or slowly growing child (bone age usually retarded) needs T4, TSH, 8 am cortisol, and other tests as guided by the clinical examination. If features of any genetic syndrome are present, evaluation by a geneticist and appropriate tests are needed. Children with steady weight gain from early infancy may have MC4R mutations, but the test is positive in less than 5% obese children, and does not change the management.



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• Auxology: – Height, weight, BP – Waist circumference, WHR – Pattern of fat distribution – Parents’ height, weight • General Physical: – Skin: Striae, acanthosis, acne, hirsutism, rashes in skin folds – Dysmorphism, features of any syndromes – Features of endocrine disease (Cushing, hypothyroidism) • Systemic: – Pubertal staging, including stretched penile length (SPL) in boys – Fundus examination – Orthopedic problems – Mental development – Self-esteem, behavior – Mental development and school performance



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Table 13.3.4 Examination



The small looking penis may be misinterpreted by parents concerned about small genitalia and even doctors as “hypogonadism”. True micropenis (SPL < 2 SD for age) may be seen in GHD and some syndromes. Adolescent boys may also be brought to medical attention for large breasts, which could be due to gynecomastia, lipomastia or both. The child’s behavior should be assessed, as those who are embarrassed, withdrawn or depressed, are less likely to exercise and may be more prone to binge eating.





































• Early influences: – Maternal diabetes, parental obesity – Weight gain during pregnancy – Birth weight, growth measurement – Duration of breast feeding – Early obesity rebound • Diseases: – Central nervous system disease – Drug intake – Polyuria, nocturia, polyphagia – Menstrual history, acne, hirsutism • Environment: – Details of activity patterns – Availability of safe play areas – Duration of TV viewing – Diet details, including total fat intake – Attitudes toward food – Mental development and school performance – Past attempts at dieting (child or parents)

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Table 13.3.3 History

Prevention

Figure 13.3.2 Acanthosis nigricans seen as dark velvety area at the folds of the neck in an obese boy  

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All children and adolescents should have weights and heights measured and plotted on a growth chart annually till growth is complete. Those at risk (LBW, one or both obese parents, obese sibling(s), maternal age greater than 35 years at birth, single child, single parent, taking

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Management of pathological obesity depends on the underlying cause, e.g. replacement of thyroxine in hypothyroidism or GH in GHD; treatment of Cushing syndrome, etc. In exogenous obesity, not only weight loss, but also maintenance of loss is critical. Efforts to motivate the entire family to make long-term diet and activity changes are needed. Small, permanent changes are more useful than drastic, short-lived changes. Very low calorie diets should be planned only in life-saving situations, i.e. extreme obesity, severe sleep apnea, or cardiopulmonary manifestations (Pickwickian syndrome) under careful supervision. Dietary measures and increased activity, supported by behavioral modification techniques, should be advised. Drug therapy and surgery are less frequently advised in childhood and adolescence. Comorbidities should be adequately managed.

 

Table 13.3.5 Prevention of obesity

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All physical activity (purposeful exercise or non-exercise activity thermogenesis) increases energy expenditure, and is essential for good health and healthy weight loss. Other benefits include psychological well-being, lesser irritability, lesser acne and hirsutism, more regular menses, better lipid profiles/BP/insulin levels; reduced appetite, and increased metabolic rate (while calorie restriction alone causes decreased metabolic rate). For compliance, ensure active games are viewed as fun (walking with friends, swimming, dancing, and sports). Initially low impact, moderate-intensity exercise (30 minutes × 5 days/week) should be advised; later, the time and intensity of exercise should be increased to about an hour daily. Screen time of less than 2 hours/day has been recommended.































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• Family: – Adequate breast feeding, no force feeding – Get low fat milk or products; keep cooking fat low – Avoid junk food, aerated drinks and fried foods – Encourage fruits, salads and whole dals and water as drink – No missed meals – Look for calorie content of packaged foods – Encourage physical activity – Controlled screen time: TV, computers, video games – Avoid tuitions, academic over-competitiveness – Express affection or approval in non-food ways – Avoid shaming behavior • Schools: – No sugary or sports drinks, juices, fried snacks available in or near school – No high calories foods or snacks in school meals – Offer fruits, low fat dairy drinks – Make exercise mandatory, ensure all children participate – Identify, counsel those at risk – Specific counseling for those already obese – Avoid shaming behavior – Early referral if there is rapid weight gain • Community: – Provide adequate, safe spaces for play – Ensure cycle tracks on roads

Standard diet therapy restricts calories, while maintaining a normal balanced pattern—fat intake less than 25% of total calories, protein 15–20%, rest 55% as complex carbohydrates, adequate fiber and micronutrients, plenty of liquids. Even with severe obesity, calorie restriction should be moderate, aiming for weight loss of 0.5 kg/ week, while ensuring adequate protein (0.8–1 g/kg/day). Nutritional deficiencies (iron, calcium, vitamin D, etc.) are corrected, and ongoing minimal supplementation given as required. Principles of prevention above should be strongly advocated, including encouraging intake of foods with low glycemic index (GI)—fruits, salads, whole wheat products, brown rice, whole legumes, low fat dairy, nuts in small quantities, and drinking plenty of water, and discouraging undesirable and “diet foods”. Diet colas, sugar-free desserts, chocolates, baked chips, etc. often have very high calorie content. Large meals with long gaps, and missed meals should also be avoided—“grazing” is better than “gorging”. Care must be taken to make small changes initially, and not to over-restrict fat intake—low fat, high carb, high GI foods (e.g. polished rice, potatoes, packaged cereals, bread, other maida products) cause sharp insulin spikes, which actually promote weight gain. At no time should diet restrictions be viewed as punishments. Very low calorie diets (400–800 calories/day) for 2–6 weeks result in rapid weight loss and marked improvement in BP and levels of blood glucose, insulin, leptin, and lipids. However, they are dangerous unless closely monitored and adequately supplemented with minerals and vitamins. Long-term results are poor, with weight gain returning within 1–5 years. Stringent dieting can cause poor height gain, slowed pubertal development, osteopenia, irritability, behavioral problems, and a weight loss plateau because of a slower metabolic rate.



Management

iet Therapy

ndocrinology

certain medications), and especially those showing rapid weight gain (crossing percentile lines), need early family attention. Children with obesity-related comorbidities should have early intervention. Diet control alone, or exercise alone, will not prevent or manage obesity: a sustained combination of both is required. Consistency is critical (Table 13.3.5). Recent unhealthy trends in urban areas include leaving few parks, forbidding games in even those, discouraging cycling (crowded roads without cycle tracks), and discouraging use of school fields after hours. Pediatricians must lobby actively with schools and society in general, for children to be given enough space and time to play actively.

These are absolutely critical, especially maintaining diaries of food intake, activity and screen-time; and motivational 797 techniques-like small, zero calories, awards (hug, stationery or sports item, star on a chart). Several other techniques also

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bariatric surgery, after suitable psychological preparation. An experienced surgeon should be available, and the child and family should be willing to continue following a healthy diet and exercise pattern. It should not be offered if there is an uncontrolled psychiatric illness, unresolved eating disorder, or Prader-Willi syndrome. Side effects can be significant—pulmonary embolism, wound infection, micro- and macronutrient malabsorption, diarrhea, anemia, cholecystitis, and dumping syndrome. Some patients may regain lost weight within 1–5 years.

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Monitoring Goal setting Contracting Stimulus control Social reinforcement Reward and punishment Aversion therapy Managing high-risk situations Relapse prevention



 

Table 13.3.6 Behavior modification techniques • • • • • • • • •

1. August GP, Caprio S, Fennoy I, et al. Prevention and treatment of pediatric obesity: an Endocrine Society Clinical Practice uideline based on expert opinion. J Clin Endocrinol Metab. 2008;93(12):4576-99. 2. Bhargava SK, Sachdev HS, Fall CH, et al. Relation of serial changes in childhood body-mass index to impaired glucose tolerance in young adulthood. N Engl J Med. 2004;350(9):86575. 3. Bhatia V. IAP National Task Force for Childhood Prevention of Adult Diseases: insulin resistance and Type 2 diabetes mellitus in childhood. Indian Pediatr. 2004;41(5):443-57. 4. Dennison BA, Erb TA, Jenkins PL. Television viewing and television in bedroom associated with overweight risk among low-income preschool children. Pediatrics. 2002;109(6):102835. 5. Dubey S, Kabra M, Bajpai A, et al. Serum leptin levels in obese Indian children: relation to clinical and biochemical parameters. Indian Pediatr. 2007;44(4):257-62. 6. Laxmaiah A, Nagalla B, Vijayaraghavan K, et al. Factors affecting prevalence of overweight among 12- to 17-yearold urban adolescents in Hyderabad, India. Obesity (Silver Spring). 2007;15(6):1384-90. 7. Marwaha RK, Tandon N, Singh Y, et al. A study of growth parameters and prevalence of overweight and obesity in school children from Delhi. Indian Pediatr. 2006;43(11):94352. 8. Reinehr T, Hinney A, de Sousa G, et al. Definable somatic disorders in overweight children and adolescents. J Pediatr. 2007;150(6):618-22. 9. Singh R, Bhansali A, Sialy R, et al. Prevalence of metabolic syndrome in adolescents from a north Indian population. Diabet Med. 2007;24(2):195-9. 10. Warren JM, Henry CJ, Simonite V. Low glycemic index breakfasts and reduced food intake in preadolescent children. Pediatrics. 2003;112(5):e414.



Surgical treatment, only considered for morbid obesity after intensive lifestyle modification and medication have failed, is relatively contraindicated in patients less than 18 years old. Body mass index (BMI) greater than 50 kg/m2, or severe complications-like sleep apnea with BMI greater than 40 kg/ m2, not responding to nonsurgical treatment, may call for

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Several anorexic agents (amphetamines, non-amphetamine appetite suppressants) and antidepressants have come into the market, become popular, and then been banned because of adverse effects. Medication should be considered only after significant efforts at diet, exercise and behavior control have failed, and only as an add-on to these efforts. Metformin, an insulin sensitizer, has been shown to safely achieve weight loss, decrease body fat, and decrease plasma leptin/insulin/lipids, in PCOS and other hyperinsulinemic adolescents with or without diabetes. Other insulin sensitizers, like thiazolidinones, are not so safe. Orlistat, approved by the FDA for use in children over 12 years of age, is a potent reversible inhibitor of gastrointestinal lipases. Given with meals, it decreases fat absorption by 30%, causing weight loss, and improving lipid and glycemic profiles. The adult dose is 120 mg thrice daily. It causes oil spotting, flatulence, frequent stools, and deficiency of fat soluble vitamins like A and D.

Weight loss may be difficult to achieve and sustain, but a loss of even 5–10% results in substantial metabolic improvement. The high relapse rates should not discourage health personnel from providing as intensive counseling as possible to every family. Rather they should motivate them to aim for prevention by actively educating all parents about healthy lifestyles, and focusing especially on high risk groups (LBW babies, obese parents, single parent, only or precious child, chronic illnesses and drug intake, etc.), and on the community at large.



Medications

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Associated problems—hypertension, type 2 diabetes, dyslipidemia, PCOS, psychological, orthopedic and skin problems, sleep apnea—are often paid inadequate attention by health personnel. This not only impacts general health, it also interferes with weight loss. Comorbidities should be actively looked for, and adequately treated.



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available (Table 13.3.6) may be used in various combinations. Reasonable, clear goals must be set by the family and health personnel working together. Occasional treats should be given so that frustration and dysfunctional behavior do not occur. Unhealthy family habits and disparagement of the child should be discouraged. Initially a monthly review with reinforcement may be necessary. Yo-yo weight patterns are undesirable, because each weight loss or gain cycle causes metabolic and psychological changes which make subsequent weight loss more difficult.

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Endocrinology

13.4

isorders of Puberty Prisca Colaco

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entral Precocious Puberty

Central precocious puberty (CPP) is the most common form of precocious puberty and is about five times more common in girls than in boys (Fig. 13.4.1.). • Central precocious puberty in girls is most often idiopathic (about 75%). In contrast to girls, in about twothirds of boys, CPP is secondary to CNS pathology • The younger the child the greater is the likelihood of underlying pathology • In idiopathic CPP the appearance of sexual characteristics is merely a normal event occurring early and puberty progresses normally • Hypothalamic hamartomas are the most common tumors causing precocious puberty • In India CNS infections, particularly TB meningitis, are important causes of neurogenic CPP.  

Table 13.4.1 Causes of precocious puberty



















The age threshold for the definition of precocious puberty is controversial. Puberty is considered precocious if its onset occurs before the lower limits of normal (the age at which 95% of children achieve Tanner stage 2 or 2 SD below the mean age of pubertal onset in normal children). This was considered to be 8 years in girls and 9 years in boys. New guidelines, based on a large study in the US, recommended that puberty be considered precocious if the onset is before the age of 7 years in white girls and 6 years in black girls. However, rapid progression of puberty in children below the age of 8 years or the occurrence of menarche before the age of 9 years needs evaluation. As a significant incidence of underlying pathology was found in girls in the 6–8 years age group, many still use the traditional threshold of 8 years to define precocious pubertal development in girls. For boys, the onset of puberty before the age of 9 years is considered precocious.



Definition



Precocious Puberty











A. Central or gonadotropin-dependent precocious puberty due to the premature activation of the hypothalamicpituitary-gonadal (HPG) axis and therefore isosexual • Idiopathic • Neurogenic: – Tumors: Hypothalamic hamartoma, glioma, astrocytoma, ependymoma, germ-cell tumor, pinealoma – Infections – Cerebral malformations – Perinatal insults, trauma – Cranial irradiation B. Peripheral or gonadotropin-independent precocious puberty results from the production of sex steroids independent of the HPG axis. May be isosexual or heterosexual. • Autonomous gonadal activation: – Ovarian cysts – McCune-Albright syndrome – Familial male limited precocious puberty (testotoxicosis) • Tumors of the ovary or testis: – Granulosa cell tumor, androgen-producing ovarian tumor, Testicular Leydig cell tumors, hCG producing tumors • Adrenal disorders: – Congenital adrenal hyperplasia, adrenal tumor • Exposure to exogenous sex steroids • Severe, untreated primary hypothyroidism C. Pubertal variants: • Premature thelarche • Premature pubarche • Premature menarche

Pubertal development is usually assessed by Tanner’s stages also known as sexual maturity rating, SMR. Tanner stage 1 is prepubertal, whereas Tanner stage 5 is adult maturity. In boys, penis and testis development, as well as pubic hair growth are assessed. In girls, breast development and pubic hair growth are assessed. In girls, puberty usually begins with breast development (thelarche) but occasionally with the appearance of pubic hair (pubarche). Menarche usually occurs about 2 years after breast development begins. In boys, testicular enlargement (> 3 mL) marks the onset of puberty and is followed by the appearance of pubic hair and development of the external genitalia. The pubertal growth spurt is an early event in girls usually at Tanner stage B2, while in boys the growth occurs late, usually at the time when a testicular volume of 10 mL is achieved.

Table 13.4.1 depicts the classification and causes of sexual precocity.



Assessment of Puberty

Classification





The term “puberty” is derived from the Latin word ‘“puberatum’” which means age at maturity or manhood. What triggers the onset of puberty is still hypothetical. The onset of puberty is associated with an increase in the frequency and amplitude of GnRH pulses, which precedes the rise in LH and FSH. There is a wide range of normal of the age at which puberty usually begins. The age at onset is controlled by both genetic and extrinsic factors, and therefore may occur earlier or later than normal. The 4–5 years physiological variation in age at onset of puberty that is observed among normal individuals involves genetic factors, ethnicity, and environmental factors such as nutrition, light, stressors and endocrine disruptors.

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Figure 13.4.1 A 4-year-old girl with idiopathic central precocious puberty

Peripheral Precocious Puberty Peripheral precocious puberty (PPP) is only about onefifth as common as CPP. While CPP is always isosexual, PPP may be iso- or heterosexual and may be due to adrenal or gonadal causes. Adrenal disorders, most commonly congenital adrenal hyperplasia (CAH), are the most common causes of PPP in boys (Fig. 13.4.2). Peripheral

precocious puberty is, therefore, much more common in boys as compared to girls. The prepubertal size of the testes suggests the diagnosis. • Some forms of PPP predominate in boys, such as chorionic gonadotropin-secreting tumors and familial gonadotropin-independent precocious puberty or testotoxicosis, which is caused by activating mutations of the LH receptor • Ovarian, rather than adrenal disorders are much more likely in girls with isosexual PPP • McCune-Albright syndrome (MAS) consists of fibrous bony dysplasia, skin pigmentation and precocious puberty and predominantly affects girls • Autonomous secreting follicular cysts of the ovary without any evidence of MAS may also result in sexual precocity. These cysts are often more than 2 cm in diameter in contrast to the smaller cysts which may be normally present in the prepubertal ovary or in CPP. Pubertal signs often develop rapidly. Subsequent atresia of the cysts results in withdrawal bleeding. • Adrenal disorders, CAH and tumors result in heterosexual puberty in girls • Hypothyroidism, untreated or inadequately treated, is sometimes associated with precocious puberty. The cause is not clear but it is thought to be due to the effect of markedly elevated TSH levels on the FSH receptor.

Pubertal Variants The incomplete forms of sexual precocity can be differentiated from precocious puberty by the absence of other signs of puberty and a normal growth rate. Premature thelarche: Breast development persists beyond 6 months of age or occurs anew. It usually occurs before 3 years of age and rarely after 4 years. There is no other evidence of estrogen effects such as increase in uterine size, changes in external genitalia, growth acceleration or bone age advancement. The cause is unknown. It could be caused by transient estrogen secretion by follicular cysts of the ovary. Exogenous estrogens in food or environmental exposure could also lead to breast development. Premature pubarche: This is due to increased adrenal dehydroepiandrosterone sulfate (DHEAS) secretion (adrenarche), which results in the appearance of pubic hair. It is more commonly seen in girls in the 3–8 years age group. Pubarche is not progressive. Occasionally these children may develop slight acne, axillary hair, and adult type body odor but no other secondary sexual characteristics. Skeletal maturation and linear growth are at upper normal limits. Signs of severe androgen excess should prompt a search for a virilizing condition such as an adrenal tumor or CAH.

 

Figure 13.4.2 A 3-year-old boy with peripheral precocious puberty due to congenital adrenal hyperplasia. Sexual maturity rating stage IV. Testicular volume 2 mL. Note the generalized hyperpigmentation

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Premature menarche: This is a rare condition and local lesions must be ruled out. It is due to transient ovarian activity resulting in an isolated follicular cyst. It may occasionally be the first sign of puberty.

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A detailed history and clinical evaluation are helpful in arriving at a diagnosis and directing investigations.

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Hormonal Evaluation

History

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• Age at onset: Idiopathic CPP usually presents between 6 years and 7 years of age. The earlier the onset, the greater the likelihood of an underlying organic cause. Hypothalamic hamartomas and familial testotoxicosis present very early in the first 3–4 years of life • Pubertal progression: In idiopathic CPP the rate of progression may sometimes be very slow with menarche occurring up to 5 years after breast development. Very rapid progression of puberty is seen in androgen producing tumors, ovarian cysts and some CNS tumors such as hypothalamic hamartomas • Accelerated growth is a feature of both central and peripheral precocious puberty but is not seen in pubertal variants • Irregular vaginal bleeding is more common in functioning ovarian tumors and hypothalamic hamartomas • History of past CNS infection, headaches, visual distur bances, personality changes, developmental delay and seizures would suggest a neurologic disorder • Drug exposure should be enquired into • Symptoms suggestive of hypothyroidism should be looked for • A family history of precocious puberty would suggest constitutional precocious puberty or familial testo toxicosis. A history of precocious puberty in boys and genital ambiguity in girls of the same family would suggest CAH. ­







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Evaluate Androgen effects: Acne, hirsutism, increased muscle mass and clitoromegaly Estrogen effects: Breast development and changes in vaginal mucosa Pubertal staging according to Tanner Abdominal and rectal examination for uterine size, ovarian masses and adrenal tumors Testicular palpation: A testicular volume greater than 3 mL indicates the onset of CPP. Scrotal masses suggest testicular tumors or adrenal rests Inspection of the skin is helpful in McCune-Albright syndrome (MAS), neurofibromatosis and tuberous sclerosis Neurologic examination should include fundus examination and perimetry Examination for signs of hypothyroidism.

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Precocious puberty stage 3 or higher Stage 2 with additional criteria such as increased growth velocity Evidence of CNS dysfunction or PP.

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nvestigations

It is recommended that all boys with precocious pubertal development and all girls with the following features should be evaluated for the mechanism and potential for progression of puberty:

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Sex steroids: In girls serum estradiol levels are not very helpful in determining the stage of puberty. Levels overlap between normal prepuberty, early puberty, precocious puberty and premature thelarche. Levels greater than 20 pg/mL suggest that puberty has started. Markedly elevated levels greater than 100 pg/ mL are seen in estrogen secreting ovarian tumors and sometimes in follicular cysts In boys, serum testosterone levels less than 30 ng/mL are generally prepubertal, though in some laboratories levels of 10–30 ng/mL may indicate early puberty. Testosterone levels may be very high related to the stage of puberty in boys with primary gonadotropin excess Serum gonadotropins and the response to GnRH stimulation: Gonadotropin levels are elevated in CPP and suppressed in PPP. Basal serum FSH and LH are of limited value in early puberty. But random LH estimated by sensitive third-generation assays is a good screening test for CPP. A level of less than 0.1 IU/L is prepubertal and 0.3 IU/L or more, pubertal. Random FSH levels are not helpful in discriminating between prepubertal and pubertal children GnRH stimulation is more helpful in distinguishing CPP from PPP. In CPP an LH predominant response is seen. An increase in FSH levels much more than LH indicates that the child is prepubertal. In PPP gonadotropin levels do not rise in response to GnRH stimulation Serum dehydroepiandrosterone sulfate (DHEAS) levels are elevated in premature adrenarche and can be very high in virilizing adrenal problems Serum 17 hydroxyprogesterone and the response to ACTH or serum 11-deoxycortisol may be required to rule out CAH. Serum hCG levels if an human chorionic gonadotropin (hCG)-secreting tumor is suspected in boys. Thyroid function studies in suspected hypothyroidism.

Endocrinology

Evaluation

adiology Bone age: Skeletal maturation is advanced in all cases of precocious puberty, except if associated with hypothyroidism, but remains normal in the incomplete forms. It is also helpful in predicting adult height. CT or MRI of brain to determine the etiology of CPP Pelvic and abdominal sonography: To evaluate the size and morphology of the uterus, ovaries and adrenals. This is essential in peripheral precocious puberty (PPP) to find the cause. In CPP the size of the uterus is increased (> 2 mL in volume or > 3.4 cm in length) and an endometrial shadow is seen. The ovaries will also be enlarged bilaterally, and may show multiple small 801 follicular cysts. Testicular sonography: If a tumor is suspected Skeletal survey: In suspected cases of MAS. vip.persianss.ir

History should focus on a review of symptoms which may indicate a chronic systemic disease, prolonged drug therapy, poor nutrition, head trauma and anosmia. Family history of delayed puberty or hypogonadism and a history of parental consanguinity should be enquired into. In CDGP, a history of delayed puberty is often obtained in either a parent or sibling. • Growth assessment often helps in distinguishing the causes of delayed puberty and is an important part of the evaluation. The height of those with primary gonadal failure is usually normal unless associated with syndromes (Fig. 13.4.3.). Children with temporary

n H Analog Therapy

Table 13.4.2 Causes of delayed puberty



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802 Puberty is considered to be delayed if sexual maturation is



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elayed Puberty



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Psychological support for the child and parents is an essential part of the general management scheme. The child’s psychological development corresponds with the chronologic age. No major psychopathology is associated with precocious puberty. Future fertility is maintained.

Hypogonadotropic ( econdary hypogonadism) C. Temporary causes (Functional): • Constitutional delay in growth and puberty(CDGP): Sporadic or familial • Nutritional disorders • Chronic systemic disease • Hormonal disturbances, e.g. hypothyroidism, isolated GH deficiency and excess glucocorticoids D. Permanent causes: • Congenital: – Isolated gonadotropin deficiency – LH deficiency – Associated with syndromes, e.g. Kallmann, Prader-Willi – Panhypopituitarism • Acquired: – Tumors, surgery – Irradiation – Trauma – Hyperprolactinemia

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Hypergonadotropic (Primary gonadal failure) A. Congenital: • Sex chromosome anomalies, e.g. Turner syndrome, XO/ XY, Klinefelter • Anomalies of testosterone synthesis or action • Pure gonadal dysgenesis • Associated with other syndromes, e.g. Noonan’s, Alstrom, Smith-Lemli-Opitz B. Acquired: • Surgical or traumatic castration • Orchitis/oophoritis • Chemotherapy, radiotherapy • Idiopathic





Therapy aims at reversing the development of sexual characteristics and decreasing the acceleration of growth and bone age by using GnRH analog (GnRHa) therapy. A suppressed LH response to GnRH or GnRHa indicates that the therapy is having the desired effect. Mean gains over predicted height in several studies ranged from 3 cm to 10 cm. Factors which affected height gain include baseline bone-age and duration of treatment. Discontinuation of therapy at 11 years was found to be associated with optimum height outcomes. Pubertal manifestations reappear within months of stopping treatment with a mean time to menarche of 16 months. Antigonadotropic and antiandrogen drugs such as medroxyprogesterone and cyproterone acetate cause regression of pubertal signs but have no effect on growth acceleration and bone age progression. Other drugs which may be used in PPP include ketoconazole, spironolactone and testolactone.

 

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Not all children with precocious puberty need to be treated. The only long-term complication of CPP is compromised adult height which may be improved with treatment. Treatment of progressive CPP is indicated if: • There is evidence that adult height may be significantly compromised. • Menarche occurs before 6 years of age. • Pubertal development is psychologically distressing to the child. • Pubertal development progresses rapidly over an observation period of about 6 months.

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Medical Treatment

Evaluation



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Delayed puberty results from inadequate gonadal steroid secretion caused by hypothalamic, pituitary, and gonadal disorders and is classified according to the circulating levels of the gonadotropins, FSH and LH as shown in the Table 13.4.2.



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Any underlying cause should be identified and treated, e.g. intracranial, gonadal and adrenal tumors Surgery of hypothalamic hamartoma is hazardous and not recommended because they do not grow or become malignant Ovarian cysts greater than 3 cm in size should be explored surgically. Smaller cysts require repeated evaluation.



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The absence of menarche by age 16 years or within 5 years of pubertal onset is also included in the diagnosis.

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Figure 13.4.3 A 14-year-old girl with hypergonadotropic hypogonadism—Turner syndrome

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Hormonal Evaluation •

Serum gonadotropin levels, FSH and LH, distinguish between hypogonadotropic and hypergonadotropic hypogonadism

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Treatment of the cause whenever possible will result in subsequent pubertal development. Patients with CDGP require reassurance that there is nothing wrong and that puberty though delayed will progress normally. In a few cases of profound delay short-term low-dose hormonal treatment with testosterone or estrogens for 3–6 months may occasionally be required if the patient is psychologically stressed. Permanent hypogonadism (primary or secondary) requires long-term replacement therapy with gradually increasing doses of sex steroids over 2–3 years.

ibliography

1. Carel JC, Eugster EA, Rogol A, et al. Consensus statement on the use of gonadotropin-releasing hormone analogs in children. Pediatrics.  2009;123(4):e752-62. 2. Carel JC, Leger J. Clinical practice. Precocious puberty. N Engl J Med. 2008;358(22):2366-77. 3. De Luca F, Argente J, Cavallo L, et al. Management of puberty in constitutional delay of growth and puberty. J Pediatr Endocrinol Metab. 2001;14( Suppl 2):952-7. 4. Kaplowitz PB, Oberfield SE. Reexamination of the age limit for defining when puberty is precocious in girls in the United States: implications for evaluation and treatment. Drug and Therapeutics and Executive Committees of the Lawson Wilkins Pediatric Endocrine Society. Pediatrics. 1999;104(4 pt 1):936-41. 5. Klein KO. Precocious puberty: who was it? Who should be treated? J Clin Endocrinol Metab. 1999;84(2):411-4. 6. Rosen DS, Foster C. Delayed puberty. Pediatr Rev. 2001; 22(9):309-31.

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Management



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Bone age evaluation to distinguish CDGP from gonadotropin deficiency. In CDGP the bone age corresponds with the height, age and stage of puberty and evidence of sexual maturation should be evident by a bone age of 13 years in isolated gonadotropin deficiency bone age is usually slightly delayed. But with multiple pituitary hormone deficiency the bone age is markedly delayed. Pelvic ultrasonography provides information about the development of the uterus and ovaries CT/MRI if indicated.



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delay are commonly short. In CDGP the growth velocity is appropriate for bone age while in GHD it is subnormal. In isolated gonadotropin deficiency childhood growth is normal but the pubertal growth spurt does not occur. Growth is subnormal if there is associated growth hormone deficiency or secondary hypothyroidism. Body proportions: Children with isolated gonadotropin deficiency and Klinefelter syndrome have eunuchoid proportions due to delayed epiphyseal closure because of subnormal conversion of serum testosterone to estradiol Weight related to height is decreased in malnutrition and chronic disease and increased in most hormonal disorders. Obesity is a feature of many syndromes associated with hypogonadism Signs of puberty should be staged according to Tanner’s staging. In gonadotropin deficiency pubertal development is absent or incomplete. Slow progression suggests a partial gonadotropin deficiency. In CDGP, the rate of pubertal progression is normal Search for the presence of chronic disease, malnutrition, anosmia, midline defects, endocrine disorders, and dysmorphic syndromes Neurological assessment includes fundus examination and evaluation of visual fields Male babies born with congenital gonadotropin deficiency have normal sexual differentiation but micropenis.

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Serum gonadotropin response to GnRH stimulation may show a pubertal response in CDGP but is not usually helpful in distinguishing it from isolated gonadotropin deficiency Serum testosterone/estradiol Serum DHEAS levels are usually normal for chronologic age in hypogonadotropic hypogonadism but are low for age and correspond with the bone age in CDGP, where the tempo of maturation is delayed Serum thyroxine, prolactin, IGF-1 and GH stimulation tests if indicated.

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isorders of Thyroid Gland Meena P Desai

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Thyroid evelopment, Physiology, ctions and egulatory ontrol



The human thyroid originates embryologically from an evagination of the pharyngeal epithelium with cellular contributions from the lateral pharyngeal pouches around 4 weeks, followed by its descent to the neck between 5 weeks and 7 weeks of embryonic life, with occasional persistence of the remnants along the tract as ”lingual thyroid”, ectopic thyroid, thyroglossal cyst or nodules. Thyroid-specific transcription factors, TTF-1, TTF-2 and PAX8, are important for thyroid gland morphogenesis and differentiation and Pit-1 is important for growth and differentiation of pituitary thyrotrophs. The thyroid gland concentrates iodide from blood and synthesizes and secretes thyroxine (T4) along with smaller amount of 3, 3’5-tri-iodothyronine (T3). The capacity to concentrate iodine appears by about 12 weeks followed by synthesis and secretion of thyroid hormones through a series of enzyme dependent steps. The thyroglobin so formed is stored in colloid, functioning as a thyroid hormone 804 precursor, releasing thyroid hormones in circulation as required and permitting storage of iodine.





T4 and T3 circulate bound to transport proteins— the thyroxine binding globulin and thyroxine-binding prealbumin and albumin. Seventy-five percent of circulating T3 in blood is derived by monodeiodination of T4 in liver, kidney and other peripheral tissues with the simultaneous formation of reverse T3 (rT3), which is metabolically inactive. There is a certain amount of tissue autonomy in the production of T3 from T4. The concentrations of free T4 and free T3, active at the cellular level approximately 0.03% and 0.30% respectively, of the total hormone concentration. T3 is almost four times more potent than T4 and 85% of the bioactivity of T4 is attributed to T3. Approximately 100 mg of thyroxine (T4) is secreted by the thyroid gland daily and about 90 mg of iodide (15 mg/kg) is the recommended daily intake during infancy and childhood with higher requirements in preterms. Thyroid gland is under the regulatory control of the pituitary thyrotropin or thyroid-stimulating hormone (TSH) which in turn is regulated by the hypothalamic, thyrotropin-releasing hormone (TRH) which is established in the fetus around 18 weeks. The fetal thyroid gland and the hypothalamic-pituitary-thyroid axis function largely independent of the mother. Maternal TRH can cross the placenta but not TSH. Placenta is less pervious to the passage of maternal thyroid hormones normally but presence of T4 in cord blood of athyrotic fetus suggests passage of maternal T4 in third trimester. During first half of pregnancy, maternal euthyroid status and optimal levels of maternal thyroid hormones seem to be neuroprotective for the fetus. Simultaneous presence of maternal and fetal hypothyroidism is detrimental to neurocognitive outcome as in endemic iodine deficiency or in presence of other abnormalities of thyroid function. This justifies biochemical screening of women with a personal or family history of thyroid disease prior to contemplating pregnancy. After birth, there is an acute surge in TSH level within 30 minutes in response to relative hypothermia, followed by rise in serum T3 and T4 levels by 24 hours, with a gradual end of first week. If TSH is the primary neonatal screening procedure, sample collection should be delayed beyond 24 hours of birth. Thyroid-stimulating hormone and/or T4 screening is often undertaken between 3 days and 5 days of birth. Thyroid-stimulating hormone surge in the premature infant is of a lesser magnitude with a greater decline in T4 concentration in the following 2 weeks. Hence, appropriate interpretation of TSH, T3, and T4 values obtained in neonatal period is important for correct diagnosis and management. T3 and T4 levels are higher in the pediatric age group as compared to adults with TSH levels up to 10 µIU/mL considered normal in early infancy.

Congenital and acquired disorders of thyroid gland predominate among children and adolescents referred to our pediatric endocrine service, constituting nearly 25–30% of all endocrinopathies in his age group. The three major clinical forms of thyroid disorders are primary hypothyroidism (75%) with insufficient secretion of thyroid hormones, goiters (thyromegaly), nearly 20% without alteration in thyroid function and occasionally hyperthyroidism or thyrotoxicosis in 5% with excessive hormone secretion. Thyroid neoplasia is uncommon. Endemic cretinism or hypothyroidism is more common in certain endemic regions of iodine deficiency. Thyroid hormones influence physical growth and maturation, play a crucial role in fetal and early postnatal brain development, and govern various biologic and metabolic functions of the body. They increase oxygen consumption, stimulate protein synthesis, affect carbohydrate, lipid and vitamin metabolism, influence enzyme systems, affect growth factors and promote growth and cell differentiation. The actions of thyroid hormones to a large extent are age and target tissue dependent, and their effects on growth, development, maturation and brain functions are unique to pediatric age group. Undiagnosed or suboptimally treated congenital hypothyroidism (CH) in early infancy can lead to irreversible impairment in neurocognitive function emphasizing the role of thyroid hormones in fetal and early postnatal life.

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Symptoms and signs of CH in neonatal period and early infancy are vague, nonspecific, with difficulties in clinical diagnosis. In early infancy symptoms often predominate over signs. Growth retardation so characteristic of CH in postnatal life is not seen at birth, some of them being large and postmature. Prolonged physiological jaundice, constipation, feeding difficulties, inactivity, macroglossia, constipation, wide fontanels, dry and mottled skin,

Table 13.5.2 The American Academy of Pediatrics Guidelines and Recommendations for neonatal screening  

Amongst all neonatal screening programs, screening for CH is most cost effective. Clinical recognition of CH in the newborn and during early infancy may be difficult. Less

linical Manifestations



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Hypothyroidism in infancy can be congenital or acquired, permanent or transient and secondary or tertiary (Table 13.5.1). Congenital form of primary hypothyroidism due to thyroid dysgenesis is most common. About 80–90% of cases with permanent primary CH have thyroid dysgenesis. It denotes developmental abnormalities of the thyroid gland ranging from agenesis, hypoplasia to ectopia. Recent studies indicate the role of genetic factors in some cases. Occasionally lingual or sublingual thyroid or thyroglossal cyst may be the only source of thyroid hormone production. Hypothyroidism acquired later in childhood or adole scence is usually due to autoimmune thyroid disease (AITD) or less frequently due to other causes listed in Table 13.5.1. A variety of inherited biosynthetic defects causing dyshormonogenesis leading to hypothyroidism with varying degrees of goitrous enlargement of thyroid gland have been identified. Autoimmune thyroid disease is a common cause of hypothyroidism beyond mid-childhood and in adolescents. Endemic iodine deficiency still remains an important cause of endemic cretinism and hypothyroidism in some parts of the world as in Europe and in northern regions of India. Pituitary or hypothalamic disease can cause secondary or tertiary forms of hypothyroidism which may be congenital or acquired, is less common and is usually associated with deficiency of other pituitary hormones.

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than 5–10% of newborns detected on screening can be diagnosed clinically. As classical symptoms and signs evolve gradually, a high index of clinical suspicion is important in early life in absence of routine neonatal screening. In the neonatal period serum T4 less than 6.5 µg/dL and TSH greater than 10 µU/mL (new generation assay) may be suggestive of CH. Large majority of newborns with primary CH have TSH values exceeding 50 µU/mL. Serum thyroglobulin and imaging studies (ultrasono graphy and technetium scan) delineating thyroid gland help in confirming the diagnosis and prognosticate the outcome. The worldwide incidence of CH on neonatal screening is about 1:3,500 to 4,000 with racial and ethnic differences. Studies from UK indicate higher prevalence in Asians. Studies from India have reported higher prevalence of 1:1,700 to 1:2,600. Now almost all neonatal screening programs are based on obtaining filter paper (FP) TSH, T4, or T4/TSH concentrations. Threshold value for TSH differs but usually less than 10 µIU/L is considered normal. Confirmation with venous serum samples is essential when FP values are abnormal (Table 13.5.2). Thyroid imaging may be undertaken if feasible.

ndocrinolo y

Hypothyroidism





































































A. Primary hypothyroidism: • Thyroid dysgenesis: – Aplasia, hypoplasia – Ectopic or lingual thyroid gland • Inborn errors of thyroid hormone synthesis, secretion or utilization • Endemic iodine deficiency • Autoimmune thyroiditis • Iatrogenic: – Antithyroid drugs and goitrogens – Irradiation – Post-thyroidectomy B. Secondary/tertiary hypothyroidism (pituitary/hypothalamic): • Congenital: – Isolated or panhypopituitarism • Acquired: – Trauma – Infection – Neoplastic/Postsurgical – Irradiation



• Initial workup: – Detailed history and physical examination – Referral to pediatric endocrinologist – Recheck serum TSH and FT4 – Thyroid ultrasonography and/or thyroid scan • Medications: – Levothyroxine: 10–15 µg/kg by mouth once daily • Monitoring (Recheck T4, TSH): – Around 2–4 weeks after initial treatment is begun – Every 1–2 months in the first 6 months – Every 3–4 months between 6 months and 3 years of age – Every 6–12 months from 3 years of age to end of growth • Goal of therapy: – Normalize TSH and maintain T4 and FT4 in upper half of reference range • Assess permanence of congenital hypothyroidism: – In initial thyroid scan shows ectopic/absent gland, CH is permanent – If initial TSH is less than 50 mU/L and there is no increase in TSH after newborn period, then trial off therapy at 3 years of age – If TSH increases off therapy, consider permanent CH

 

Table 13.5.1 Causes of hypothyroidism in childhood and adolescence

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hypothermia, and hoarse cry should arouse suspicion. Over the following weeks coarse hypothyroid facies, puffiness of eyes, protruding tongue, pallor, lethargy, fullness in supraclavicular regions, altered skin and hair texture, hypotonia, distended abdomen with umbilical hernia, low pitched irritable prolonged cry, are features which combine to give a characteristic appearance (Fig. 13.5.1). Bradycardia, muffled heart sounds, delayed relaxation while eliciting deep tendon reflexes are helpful signs. Growth failure and delayed milestones become increasingly obvious. Children with dyshormonogenesis may present with goiter at birth, or later. Careful thyroid palpation should be routinely done. The incidence of other associated congenital abnormalities with CH is around 8%. Hypothyroidism in older children is usually caused by AITD but occasionally children with hypoplastic or ectopic thyroid gland or dyshormonogenesis may present late. Symptoms and signs may be subtle. Lassitude, growth failure/short stature, excess weight gain, scholastic problems, delayed sexual maturation or uncommonly sexual precocity, muscular hypertrophy and goiter with insidious onset may be noted. Small goiter which is firm in consistency with a pebbly surface favors the possibility of thyroiditis as opposed to dyshormonogenesis where the goiter may be small or large, with soft to firm, consistency and occasional presence of a bruit (Fig. 13.5.2). Dyshormonogenesis with autosomal recessive transmission can be familial with sibling involvement and familial occurrence with AITD in parents and other family members is known.

806

iagnosis

The diagnosis of primary hypothyroidism is confirmed by the presence of low serum T4 and T3 and elevated

Figure 13.5.2 Eight-year-old girl with goitrous hypothyroidism due to dyshormonogenesis. Note hypothyroid facies, puffiness of eyes, and goiter. (Had two more siblings with similar clinical picture)  

 

Figure 13.5.1 Five-month-old male child with congenital hypothyroidism presented for constipation, feeding difficulty, and failure to grow. Note the protruding tongue, little puffiness of eyes, distended abdomen and small umbilical hernia

serum TSH values. Estimation of free T4 and free T3 is also available. Thyroid-stimulating hormone is an extremely sensitive index of primary hypothyroidism. Presence of thyroglobulin in the serum is also indicative of functioning thyroid tissue. Significant delay in skeletal maturation and epiphyseal dysgenesis on X-rays are very helpful. The skeletal age can indicate the approximate age of onset of hypothyroidism. Imaging studies like ultrasonography and radioisotope scans, help in delineating the anatomical and functional status of the gland but are not mandatory. Thyroid antibody studies—anti-thyroglobulin and antimitochondrial or antiperoxidase antibodies in particular— help in identifying autoimmune basis of the disease. Fine needle aspiration cytology (FNAC) is helpful. In secondary and tertiary forms of disease, the TSH concentration may be low or undetectable with subnormal levels of T3 and T4 as well as free T4 and T3. Usually associated deficiency of other pituitary hormones is also present.

Treatment Once the diagnosis is established, the need for lifelong therapy in CH should be adequately stressed. The goal of therapy is to maintain the circulating serum T4 level in the upper normal range and normalize the elevated TSH. The preferred preparation is sodium-levothyroxine because of its uniform potency, reliable absorption and good bioavailability. In newborns detected on screening and in early infancy, 10 mg/kg has been recommended. Full replacement therapy can be initiated promptly. In longstanding thyroid deprivation where the diagnosis is delayed for months or occasionally for years, one-fourth of the daily dose can be administered initially and stepped-up gradually to full replacement dose, in 3–6 weeks. The daily requirement is about 100 mg/m2, with the required dose

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Serum levels of T4, T3, free T4 and free T3 are elevated. In some patients, T3 may be higher with T4 levels in the upper normal range or minimally elevated. Thyroid stimulating hormone is suppressed below normal and thyroid antibodies are present. Radioiodine uptake and assay for TSH receptor antibodies are not essential for diagnosis but helpful.

The final outcome in CH is closely related to the nature and severity of the underlying thyroid abnormality, the age at diagnosis and onset of treatment, the adequacy and regularity of therapy with the required degree of clinical and laboratory follow-up. Worldwide neonatal screening programs for CH have had a significant impact on reducing intellectual deficits in hypothyroid infants diagnosed and treated early.

Hyperthyroidism

C

Hyperthyroidism (thyrotoxicosis) is an uncommon disorder of childhood and adolescence. It results from excessive secretion of thyroid hormones (Grave’s disease). Other uncommon causes are thyrotoxicosis factitia (ingestion of thyroid hormones), thyroid neoplasia or very rarely due to TSH producing pituitary tumors. In infants born of mothers with Grave’s disease, hyperthyroidism may occur as a transitory phenomenon during neonatal period due to transplacental passage of thyroid stimulating immunoglobulin. Germ line mutations of the TSH receptor known as gain of function mutations can cause familial or sporadic hyperthyroidism, and can manifest early in life.

linical Manifestations

About 5–10% of all patients with hyperthyroidism are under 15 years of age with peak incidence in adolescence. The incidence is almost five times higher in girls. The clinical course is variable but less severe than in adults. The onset of symptoms is often insidious with the interval between the onset of the disorder and diagnosis ranging between 3 months and 12 months. Emotional disturbances, behavioral changes characterized by excitability, irritability and tendency to emotional outbursts may herald the onset of the disease. Motor hyperactivity and restlessness may be misdiagnosed as chorea. Increased appetite with no increase in weight or actual loss of weight, diarrhea, heat intolerance, excessive sweating and mild fever are some of the other findings. Tremors of the hands become evident with further progression. Exophthalmos may be present but not severe. Lid lag on looking downward, impairment of convergence, and retraction of upper eyelids with infrequent blinking may be noticeable. Accelerated linear growth and advanced skeletal maturation may be noted. Craniosynostosis may occur in infants. The degree of thyroid enlargement is variable but never marked with presence of goiter in almost 90%. It may escape detection. Bruit may be

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Prognosis

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heard. Palms may be warm and moist. Muscular weakness is uncommon. Patient may complain of feeling of weakness, tiredness and palpitations. Tachycardia is appreciable and a wide pulse pressure is often noted. Dyspnea, cardiac decompensation and rarely atrial fibrillation may occur. Thyroid “crisis” or “storm” and the apathetic, cachectic type of hyperthyroidism are uncommon in childhood.

ndocrinolo y

administered as one single dose, preferably at a convenient fixed time daily on empty stomach to maximize absorption. Regular therapy is extremely important. Therapeutic monitoring is recommended with blood samples obtained at periodic intervals for TSH, T3 and T4 estimations in all children permitting individualization of treatment. Clinical evaluation and growth monitoring during therapy are important.

Treatment The therapy is directed toward reducing the production of thyroid hormones and blunting their effects. Medical therapy is the preferred modality of treatment in children rather than subtotal thyroidectomy or radioiodine therapy. The thionamide drugs in use are propylthiouracil (PTU), methimazole, and carbimazole. Therapy has to be continued for 1–2 years or longer to prevent relapses. Periodic therapeutic monitoring is essential. Toxic reactions like agranulocytosis, hepatic dysfunction and lupus like syndrome do occur. Transient urticarial rashes are most common. Propranolol helps in controlling symptoms due to hyperactivity of the sympathetic nervous system. Other modalities of therapy such as radioiodine thyroid ablation or subtotal surgical excision are indicated, if medical therapy fails after adequate trial.

Goiter Presence of goiter may be the initial complaint for which children and adolescents may seek medical attention. In these patients underlying cause of the thyromegaly needs to be determined and the functional status of the thyroid gland whether euthyroid, hypothyroid or hyperthyroid needs to be ascertained. Common causes which lead to goitrous enlargement in this age group are simple goiter or physiological enlargement chronic lymphocytic thyroiditis, dyshormonogenesis, iodine deficiency, thyroid hormone resistance or rarely malignancy. WHO has defined goiter as a thyroid gland where the size of the lateral lobes exceed the size of the terminal phalanx of the subject examined. Prevalence of small asymptomatic goiters in school children to the extent of 6% have been noted though the incidence is higher in regions of endemic iodine deficiency. Further strategies for management are planned based on the functional status of the thyroid gland and the underlying cause of goiter. Nodular goiter or single nodules need careful evaluation for the presence of thyroid malignancy. Besides laboratory investigations, imaging studies and FNAC may be undertaken to rule out possibility of papillary or follicular carcinoma which are uncommon in childhood. 807

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1. American Academy of Pediatrics and American Thyroid Association—Newborn Screening for Congenital Hypothyroidism. Recommended Guidelines, 2006. 2. Brown RS, Huang S. The thyroid and its disorders. Brooke CGD, Clayton PE, Brown RS, Savage MO (Eds), 5th edition. Blackwell; 2005. pp. 218-53. 3. Delange F. Iodine deficiency as a cause of brain damage. Postgrad Med J. 2001;77(906):217-20. 4. Desai MP. Disorders of the thyroid gland. In: Desai M, Menon PSN, Bhatia V (Eds). Pediatric Endocrine Disorders, 2nd edition. Hyderabad: Universities Press; 2008. p. 282-310. 5. Desai MP. Thyroid function in children. J Assoc Physicians India. 2011;59 suppl:35-42. 6. Fisher DA. Disorders of the thyroid in the newborn and infants. In: Sperling MA (Ed). Pediatric Endocrinology. Philadelphia: WB Saunders; 2002. pp. 161-86. 7. Halac I, Zimmerman D. Thyroid nodules and cancers in children. Endocrinol Metab Clin North Am. 2005;34(3):725-44. 8. Huang SA. Hypothyroidism: In: Lifshitz F (Ed). Pediatric Endocrinology, 5th edition; 2007.pp.405-13. 9. Koch CA, Sarlis NJ. The spectrum of thyroid diseases in childhood and its evolution during transition to adulthood: natural history, diagnosis, differential diagnosis and management. J Endocrinol Invest. 2001;24(9):659-75. 10. Kraiem Z, Newfield RS. Graves’ disease in children. J Pediatr Endocrinol Metab. 2001;14(3):229-43.



ibliography



K

• In neonates and infants, high index of suspicion in absence of neonatal screening • Confirmation of diagnosis in neonates detected on screening by laboratory evaluation a nd imaging if feasible • Prompt optimal therapy with levothyroxine 10 µg/kg in newborns and infants. Per kg dose reduces to 8–6 µg/kg early childhood, 6–5/4 µg/kg later childhood; 3/2 µg/kg during adolescence (100 µg/m2 applicable at all ages) • In CH: emphasize need for life long, regular treatment and explain consequences with periodic clinical and laboratory monitoring • Beyond early childhood, gradual stepping up of levothyroxine dose over 3–6 weeks is advisable • In AITD with mild hypothyroidism, therapy can be withdrawn after 2–3 years for a period of 6 weeks to ascertain the need for continuation • In hyperthyroidism therapy may be needed for 2–3 years based on severity. Periodic monitoring and adjustment of dose. Monitoring complete blood count and liver function test • Simple goiters with no thyroid dysfunction need observation and follow-up. Repeat laboratory evaluation, if necessary



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Endocrinology

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Minerals alcium

Serum calcium ranges from 9 mg/dL to 10.5 mg/dL in children. Approximately half the plasma calcium is present bound to plasma proteins and half in the free ionized form. Intestinal absorption of calcium is vitamin D-dependent when present in the gut in smaller quantities. Urinary calcium excretion is of the order of 4 mg/kg/day. Dietary sources of calcium are mainly milk products and fish; smaller amounts are available from green vegetables, ragi and til. The daily requirement of calcium ranges from about 300 mg in infants to 600–800 mg in childhood and 1,000 mg in adolescence, pregnancy and lactation.

Phosphorus Serum phosphorus is higher in infancy (4.5–7.5 mg/dL) and falls gradually during childhood to adult levels of 2.5–4.5 mg/dL. Serum phosphorus concentration is largely maintained by variable renal reabsorption. Normally about 85% of the filtered load is reabsorbed. Reabsorption of phosphate is decreased by PTH and calcium. Phosphorus deficiency results in effective and complete reabsorption. Phosphorus is available in commonly eaten staple foods such as cereals and lentils. Its deficiency is encountered only in special circumstances such as prematurity or parenteral nutrition.

Magnesium Magnesium is an important component of the adenylate cyclase system. Its deficiency leads to hypocalcemia, both by inhibiting PTH release and inducing resistance to its action. Hypomagnesemia may be seen in the setting of diarrhea, malnutrition, malabsorption, and parenteral nutrition. Normal serum magnesium level is 1.8–3.0 mg/dL.

alciotropic Hormones

Parathyroid Hormone Parathyroid hormone is an 84-amino acid chain, but its biologic activity resides in the first 34 residues. The major stimulus to the secretion of PTH is a fall in the ionized fraction of plasma calcium, detected by the calcium-sensing receptor on the parathyroid gland. Parathyroid hormone stimulates activity of 1-α-hydroxylase in the kidney, enhancing production of calcitriol. The increased level of calcitriol induces synthesis of a calcium-binding protein in the intestinal mucosa with resultant absorption of calcium. Parathyroid hormone also mobilizes calcium by directly enhancing bone resorption. The effects of PTH on bone and kidney are mediated through binding to specific receptors on the membranes of target cells and through activation of a transduction pathway involving a “G” protein, coupled to the adenylate cyclase system.

Vitamin

D

­

The role of the skeleton in maintaining mechanical stability of the body and aiding locomotion is easily appreciable. Its role as an important metabolic organ is more subtle but equally important. The skeleton is vital for extracellular concentrations of calcium to be maintained within a narrow range. This is brought about via the actions of hormones such as parathyroid hormone (PTH) and 1, 25-dihydroxycholecalciferol (1, 25(OH)2D or calcitriol) on bone, kidney and gut. In bone, the osteoblast cells are responsible for bone formation, the osteocytes are the mature bone cells and the osteoclasts bring about bone resorption to restore serum calcium as well as to enable bone remodeling.

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Vijayalakshmi Bhatia

Vitamin D (cholecalciferol) is produced in the dermis, by conversion from cholesterol, under the influence of ultraviolet rays from sun exposure. Latitude, season, cloud cover, pollution, skin pigment, clothing and sunscreen affect dermal vitamin D. Cholecalciferol is hydroxylated to form 25 hydroxyvitamin D (25-OHD) in the liver. 25-OHD is further hydroxylated in the kidney to produce the active form of the hormone 1, 25(OH)2D (calcitriol). The production of 1, 25(OH)2D is enhanced by PTH, vitamin D and dietary calcium depletion, hypocalcemia and hypophosphatemia. 25-OHD (calcidiol) is the major transport form of vitamin D and its circulating concentration reflects an individual’s vitamin D nutritional status. Serum 25-OHD less than 20 ng/mL indicates vitamin D deficiency. Diet is a poor source of vitamin D, with the exception of fatty fish such as salmon, sardine, mackerel, hilsa and tuna. Therefore in many temperate countries, where sunshine is poorly available during winter, food is fortified with vitamin D. Vitamin D deficiency is extremely common in India, despite abundant sunshine, possibly due to sun exposure being insufficient for a pigmented race. Neonatal hypocalcemia due to vitamin D deficiency is commonly documented. The American Academy of Pediatrics and the NIH recommend 400 IU of vitamin D as a supplement for all infants (and 600 units for older children) daily, for those at risk. For India, the “at risk” group has been documented to include infants, adolescent girls, and pregnant women. However, vitamin D is a fat soluble vitamin, there is a real danger of toxicity with overdosage, and care must be exercised while prescribing it.

809

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linical Presentation

Hypocalcemia in the older child presents with tetanic spasms of the fingers and wrist or toes and foot, perioral numbness, tingling, or seizures. Mental changes include irritability, impairment of memory, paranoia, depression, and frank psychosis. Papilledema may be present. Subclinical hypocalcemia may be elicited by the Chvostek or Trousseau signs. Chronic hypocalcemia leads to cataracts and basal ganglia calcification. However, in neonates, hypocalcemia may present quite differently, with jitteriness, apneic spells or laryngeal stridor, in addition to seizures.

Etiology The causes of hypocalcemia are highlighted in Table 13.6.1. They can be categorized into “early” (typical neonatal) causes occurring in the first 4–5 days of life and “late” causes occurring thereafter. A brief discussion of some of the etiologies follows below:

Early Neonatal Hypocalcemia The fetus is supplied with calcium via active transport across the placenta. Interruption of this enriched supply at birth, compounded by a relatively poor PTH response to hypocalcemia, makes the newborn baby vulnerable to hypocalcemia. Various neonatal situations such as prematurity, birth asphyxia, infant of a diabetic mother, IUGR, polycythemia, alkali therapy, and sepsis, among others, enhance the risk.



Hypocalcemia

the high phosphorus content of cow milk (six times the concentration in breast milk) is commonly encountered. An increasingly diagnosed cause for late neonatal hypocalcemia is maternal (and hence neonatal) vitamin D deficiency. This may present as late as 1 or 2 months of age, and is often characterized by resistance to the phosphaturic action of PTH, exhibiting hyperphosphatemia instead of low phosphorus as expected. Renal failure is another condition associated with high serum phosphorus. Various causes of hypoparathyroidism are responsible for hypocalcemia in childhood (Table 13.6.1). Mucocutaneous candidiasis, Addison disease, and hypoparathyroidism form the diagnostic triad for autoimmune polyendocrinopathy candidiasis ectodermal dysplasia syndrome. Dental enamel hypoplasia may be seen as part of any cause of chronic hypocalcemia (Fig. 13.6.1). Pseudohypoparathyroidism (PHP) describes a group of disorders characterized by biochemical hypoparathyroidism (i.e. hypocalcemia and hyperphosphatemia), increased secretion of PTH, and target tissue unresponsiveness to the biological actions of PTH due to mutations in the alpha subunit of G proteins. There is an association between PHP and somatic abnormalities. These include short stature, round face, short neck, and shortening of the metacarpals and metatarsals. Characteristic radiographic findings include shortening of the fourth, fifth or all metacarpals and metatarsal bones. Resistance to other hormones with G protein-mediated actions may coexist. D

C

Calcitonin is a 32-amino acid polypeptide secreted by the parafollicular or C cells of the thyroid. Its role in postnatal life is not clear. It is a useful marker for medullary carcinoma of the thyroid.

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alcitonin

iagnosis

Besides confirmation by serum total and ionized calcium, an electrocardiography is useful as it may reveal a prolonged QT interval. Serum magnesium should be performed in all cases of hypocalcemia. CT head may show calcification of the basal ganglia. Serum creatinine, albumin (every g/dL of serum albumin below normal decreases total calcium

Late Neonatal Hypocalcemia Conditions which generally present with hypocalcemia after the fourth or fifth day of life are included in this category (Table 13.6.1). Precipitation of hypocalcemia by  

Table 13.6.1 Etiology of hypocalcemia



























Figure 13.6.1 Enamel hypoplasia (highlighted with arrows) in a child with hypoparathyroidism. The same could be seen in children with calcipenic rickets of any etiology  







810























• Early neonatal hypocalcemia: – Prematurity – IUGR – Infant of diabetic mother – Birth asphyxia • Late neonatal and childhood hypocalcemia: – Cow milk ingestion – Hypoparathyroidism – Familial hypercalciuric hypocalcemia – Secondary to maternal hyperparathyroidism – Pseudohypoparathyroidism – Severe vitamin D deficiency – Hypomagnesemia – Critical illness

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linical Presentation

The symptoms of hypercalcemia may be non-specific and include anorexia, constipation, vomiting, failure to thrive, polyuria, muscular weakness, dehydration.

Etiology Table 13.6.2 highlights the causes of hypercalcemia. Inactivating mutations of the calcium sensing receptor, which cause mild asymptomatic hypercalcemia when inherited heterozygously, result in severe neonatal hypercalcemia when inherited homozygously. Parathyroid hormone is low or inappropriately normal for the state of hypercalcemia.

 

Table 13.6.2 Etiology of hypercalcemia • Transient neonatal hyperparathyroidism (secondary to maternal hypoparathyroidism) • William syndrome • Granulomatous disease, e.g. sarcoidosis • Vitamin D toxicity • Primary hyperparathyroidism • Multiple endocrine neoplasia • Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism • Tertiary hyperparathyroidism • Non-endocrine malignancies. (PTHrP excess)

D

Treatment Hydration and forced diuresis with a loop diuretic are the cornerstones of treatment of hypercalcemia. Reduction of calcium absorption by corticosteroid administration is useful in vitamin D intoxication, William syndrome and sarcoidosis. Inhibition of bone resorption can be brought about by calcitonin or bisphosphonate (pamidronate) administration. Life threatening hypercalcemia can be reversed by dialysis. Surgery is the treatment for primary hyperparathyroidism. R

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Hypercalcemia

iagnosis

Serum calcium, phosphorus, potassium, urinary calcium or calcium/creatinine ratio, PTH, and 25-OHD are relevant investigations. Plain radiology of the hand shows subperiosteal resorption and endosteal and intracortical tunneling. There may be tufting of the terminal phalanges. The skull is characterized by salt and pepper erosions. Hyperparathyroidism in growing children causes appearances which radiologically resemble rickets but which are quite different histologically. This is due to resorption of metaphyseal bone which may give rise to crippling, skeletal deformities.

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Calcium gluconate (10% solution) 0.2 mL/kg slow intra venous injection (over 10 minutes at least), corrects hypocalcemia initially. Maintenance doses are about 50–75 mg of elemental calcium/kg/day. Hypoparathyroidism is treated with oral calcium and calcitriol in a dose of 30–70 ng/kg/day. Calcitriol has a short half-life and hence should be given in two equal divided doses. It has a rapid onset of effect (1–4 days) and rapid reversal of hypercalcemia after discontinuation, in the event of over dosage. Hypovitaminosis D must be treated with calcium and vitamin D. While there is no objective evidence at this time for recommendation of doses of vitamin D for nutritional rickets, about 30,000–60,000 units orally monthly (the lower end dose to be used in neonates to avoid any risk of hypercalcemia), followed by one sachet (60,000 units) every 2 months approximately for another 3–6 doses should suffice. During this time the importance of sun exposure is reinforced. Hypomagnesemia is treated with 0.2 mL/kg/dose of a 50% solution of magnesium sulfate. The oral maintenance dose of elemental magnesium is 12–20 mg/kg/day, best provided as gluconate, lactate or chloride to minimize the side effect of diarrhea.

ickets utritional ickets R

Treatment

This condition is a mirror image of the hypocalcemic disease, which is due to activating mutations of the same receptor. Primary hyperparathyroidism, due to an adenoma or hyperplasia of the parathyroid glands, in India is still dominated by the manifestations that are characteristic of advanced disease, bones (fractures and brown tumors due to osteitis fibrosa cystica), stones (renal), groans (bone pain), and psychic overtones, though in developed countries it is often diagnosed incidentally by routine serum chemistry. William syndrome is characterized by hypercalcemia, elfin facies and supravalvular aortic stenosis. A deletion of part of the long arm of chromosome 7 is seen in a majority of the patients. Hypercalcemia subsides after 2–3 years of age. Till then, low calcium diet and sunscreen are used to minimize calcium absorption.

Endocrinology

by 0.8 mg/dL), blood gases, 25-OHD, PTH, and 24 hour urinary calcium or calcium/creatinine ratio, complete the armamentarium for investigation.

Rickets occurs due to deficiency of vitamin D or calcium or both. Deficiency of phosphorus leading to rickets is found only in special circumstances such as prematurity or parenteral nutrition where adequate care has not been given to supplementation of all minerals, as dietary sources of phosphorus are common. In India, vitamin D deficiency is particularly encountered in the neonate or infant, due to poor maternal stores. Thereafter, it is prominent during adolescence, especially in girls, who cannot take advantage of sunshine due to modest clothing and poor outdoor activity. In toddlers and mid-childhood (and also in older age groups), dietary calcium deficiency plays a predominant role. Nutritional rickets is discussed in detail in the Chapter 811 4.5 on fat soluble vitamins.

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Etiology and Presentation Children with renal tubular acidosis (RTA) may present with polyuria, failure to thrive, hypokalemia, and in the case of distal RTA, with dental enamel hypoplasia, nephrocalcinosis or nephrolithiasis. Anemia, abdominal pain, diarrhea, Bitot’s spots or night blindness, or hypoalbuminemia may alert the pediatrician to the presence of malabsorption. Hypophosphatemic rickets typically presents at the end of

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iagnosis

Typical clinical differentiating features of calcium versus phosphorus deficiency rickets are highlighted in Table 13.6.4. If a good clinical examination does not provide a clue to etiology, then PTH should guide further workup. Primary and secondary hyperparathyroidism result in increased phosphorus leak from the proximal tubule. Thus, a child with any cause of calcipenic rickets, such as malabsorption or distal renal tubular acidosis, due to concomitant secondary hyper parathyroidism, may appear to have hypophosphatemic rickets. Serum PTH is a useful investigation at this juncture, being only marginally elevated in hypophosphatemic rickets, and significantly raised in calcipenic rickets. Cases with high PTH should be investigated for distal RTA by serum potassium, blood and urine pH, ammonium chloride loading test if necessary, and ultrasound of kidneys for nephrocalcinosis. Malabsorption tests include ESR, anti-endomysial or tissue transglutaminase antibodies, D-xylose test and endoscopic duodenal biopsy. If these are negative, serum 25OHD and 1, 25(OH)2D can throw light on 1α-hydroxylase defect and calcitriol receptor defect [Vitamin D-resistant rickets (VDRR) 1 and 2]. Low PTH type of resistant rickets should be worked up for phosphate clearance (phosphate clearance/creatinine clearance) and TmP/GFR measurement. Proximal RTA is tested by bicarbonate loading test and documenting aminoaciduria, glycosuria and uric aciduria in addition to phosphaturia. Plain radiology reveals coarse trabecular pattern in RTA and renal failure, and dense bone in hypophosphatemic rickets. ­

R

N

N

When vitamin D and calcium supplementation has been given in adequate doses for at least 2 months without onset of radiological healing or improvement in serum alkaline phosphatase, non-nutritional or resistant rickets should be suspected. Alternatively, in the presence of clues to a non-nutritional cause, it may be investigated for without waiting. Such clues include alopecia, features of malabsorption, hypokalemia, nephrocalcinosis, polyuria, or dense bones, among others (Fig. 13.6.2). Resistant rickets may be categorized into calcium deficiency or phosphorus deficiency rickets for ease of differential diagnosis and investigative pathway (Table 13.6.3).

the first year of life. Rachetic features predominantly affect the skull and lower limbs, with relative sparing of upper limbs and chest.



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on- utritional ickets

Treatment

 

Figure 13.6.2 Skeletal radiograph of a child with calcitriol receptor abnormality (vitamin D-resistant rickets type 2), showing alopecia, rachitic rosary and widened malleoli at the ankles (highlighted by arrows)

Renal tubular acidosis is treated with alkali, the distal variety requiring 3–5 mmol/kg/day and proximal RTA a greater amount such as 10–15 mmol/kg/day of bicarbonate. Citrate as the source of alkali is useful in distal RTA, to diminish renal calcium deposition. Potassium replenishment is provided as necessary. Investigation and treatment of the primary disease, if any, producing RTA, must be performed. Anticonvulsant therapy should be accompanied by 500–1,000 units of daily vitamin D supplementation. Vitamin D-resistant rickets 1 is treated with calcitriol in physiological or minimally higher

Table 13.6.3 Causes of rickets

812

Calcipenic rickets

Phosphopenic rickets

Vitamin D/calcium deficiency

Prematurity (calcium plus phosphorus deficiency)

Anticonvulsant induced

Fanconi syndrome (proximal RTA)

Malabsorption

Congenital hypophosphatemic rickets - X linked/autosomal dominant

Distal renal tubular acidosis

Hypophosphatemic rickets with hypercalciuria

Chronic renal failure

Tumor induced (mesenchymal tumor, epidermal nevus)

1 hydroxylase defect Calcitriol receptor defect

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Endocrinology

Table 13.6.4 Features of calcipenic versus phosphopenic rickets Features

Calcipenic rickets

Phosphopenic rickets

Hypotonia

Present

Absent

Bone pain

Present

Absent

Tetany/seizure

Present

Absent

Dental enamel hypoplasia

Present

Absent

Dental caries

Absent

Present

Serum calcium

Low

Normal

Serum phosphorus

Low

Low

Alkaline phosphatase

Markedly raised

Moderately raised

Parathyroid hormone

Raised

Normal/minimally raised

Plain radiology

Lucent bone, osteitis fibrosa cystica

Dense bone

















While the prototype disease of fragile bones in children is osteogenesis imperfecta, the most common condition in this category encountered by pediatricians is glucocorticoidinduced osteoporosis (GIO). Since pediatricians care for children on pharmacological doses of glucocorticoids for diverse conditions, they must be familiar with the precautions to be taken for preventing or minimizing GIO. These include adequate calcium, protein and vitamin D nutrition, institution of gonadal steroids in a timely manner in adolescents, in whom pubertal delay has occurred due to the basic systemic disease, avoiding immobilization and encouraging regular

1. Bagga A, Sinha A. Evaluation of renal tubular acidosis. Indian J Pediatr. 2007;74(7):679-86. 2. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3): 266-81 3. Institute of Medicine. Dietary reference intakes for calcium and vitamin D. Washington DC: National Academies Press; 2011. 4. Klaus G, Watson A, Edefonti A, et al. Prevention and treatment of renal osteodystrophy in children on chronic renal failure: European guidelines. Pediatr Nephrol. 2006;21(2):151-9. 5. Nutrient requirements and recommended dietary allowances for Indians. A report of the expert group of Indian Council Medical Research 2009. Available at www.icmr.nic.in. 6. Rauch F, Schöenau E. Skeletal development in premature infants: a review of bone physiology beyond nutritional aspects. Arch Dis Child Fetal Neonatal Ed. 2002;86(2):F82-5. 7. Thornton J, Ashcroft DM, Mughal MZ, et al. Systematic review of effectiveness of bisphosphonates in treatment of low bone mineral density and fragility fractures in juvenile idiopathic arthritis. Arch Dis Child. 2006;91(9):753-61. 8. Van Staa TP, Cooper C, Leufkens HG, et al. Children and the risk of fractures caused by oral corticosteroids. J Bone Miner Res. 2003;18(5):913-8. 9. Wagner CL, Greer FR. American Academy of Pediatrics Section on Breast-feeding, et al. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics. 2008;122(5):1142-52.

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onditions of ncreased Bone ragility I

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The preterm baby is deprived of the large supply of calcium normally accrued during the third trimester of pregnancy via active transport across the placenta. Breast milk is not adequate to supply similar amounts of calcium and phosphorus. The resulting bone disease presents with fractures upon minimal handling, and X-ray picture showing lucent bones. It can be prevented by using commercially available human milk fortifiers providing the required 200 mg/kg/day of calcium and 100 mg/kg/day of phosphorus.

Bibliography



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Metabolic Bone isease of Prematurity

appropriate weight bearing exercise. Needless to say, the minimum effective dose of glucocorticoid should be used, to minimize bone fragility as well as diverse other side effects of systemic glucocorticoid therapy. A discussion on osteogenesis imperfecta, fibrous dysplasia and osteopetrosis is beyond the scope of this book. A few useful bibliographies are mentioned below.



doses, and VDRR 2 with very high doses of calcitriol or with intravenous calcium. Hypophosphatemic rickets requires phosphorus supplementation to produce healing of bone and calcitriol to suppress the secondary hyperparathyroidism which is invariably produced. Deformity often normalizes with years of growth and remodeling, in all etiologies of rickets. Therefore, one need not rush for corrective osteotomy unless deformities come in the way of locomotion.

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isorders of drenal Glands Preeti Dabadghao

lassification

Adrenal insufficiency can be caused by primary abnormality of adrenal gland—primary adrenal insufficiency or Addison disease (AD) or secondarily due to defects in the hypothalamus or pituitary gland—secondary adrenal insufficiency. Primary adrenal insufficiency can be congenital related to specific gene abnormality or acquired due to infection, infiltration or hemorrhage. In these cases there is homeostatic increase in ACTH and CRH. E

tiology 814 The common causes of adrenal cortical insufficiency

are given in Table 13.7.1. In a large pediatrics series, CAH

 















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Primary adrenal insufficiency is relatively rare in children and is a potentially lethal condition. Signs and symptoms are often nonspecific—as a result the diagnosis is delayed, a median delay of 2.3–3 years has been reported between onset of symptoms and diagnosis. If unrecognized, adrenal insufficiency may present with life-threatening cardiovascular collapse.





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A. Primary: Congenital: 1. Congenital adrenal hyperplasia: • 21-hydroxylase deficiency (CYP21) • 3β-hydroxysteroid dehydrogenase deficiency (3β-HSD2) • CYP17 • CYP 21 • CYP11B1 • POR (P450 oxidoreductase) • 11β-hydroxylase deficiency (CYP11B2) • CYP11A/steroidogenic acute regulatory protein • Smith-Lemli-Opitz syndrome (DCHR7) 2. Congenital adrenal hypoplasia (SF1, DAX1, IMAGE association) 3. Triple A or Allgrove syndrome 4. ACTH resistance 5. Glucocorticoid resistance 6. Metabolic diseases: Adrenoleukodystrophy (ABCD1), Zellweger syndrome (peroxins), Wolman disease (LIPA) 7. Mitochondrial diseases: Kearns-Sayre syndrome 8. Autoimmune adrenalitis: • Isolated • Polyglandular syndromes: Types I (AIRE) and II Acquired: 1. Hemorrhage and infarction: Trauma, Waterhouse-Friderichsen syndrome 2. Drugs: Aminoglutethimide, mitotane, ketoconazole, metyrapone 3. Infections: • Viral: HIV, cytomegalovirus • Fungal: Coccidioidomycosis, Histoplasmosis • Mycobacterial: Tuberculosis 4. Infiltration: Histiocytosis, amyloidosis, sarcoidosis, neoplasm B. Secondary: Hypothalamus: 1. Congenital: Septo-optic dysplasia (HESX1), CRH deficiency 2. Acquired: • Steroid withdrawal after prolonged administration • Inflammatory disorders • Trauma • Radiation therapy • Surgery • Tumors • Infiltrative disease: Sarcoidosis, histiocytosis X Pituitary: 1. Congenital: • Aplasia/hypoplasia • Multiple anterior pituitary hormone deficiencies (PROP1) • Isolated ACTH deficiency 2. Acquired: • Steroid withdrawal after prolonged administration • Trauma • Tumors: Craniopharyngioma • Radiation therapy • Lymphocytic hypophysitis • Hemochromatosis 





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Table 13.7.1 Etiology of adrenal insufficiency









The adrenal gland is made up of two distinct parts the cortex and the medulla which have different embryonic origins. In turn the cortex comprises of three distinct anatomical areas: 1. Outer zona glomerulosa secretes mineralocorticoids. 2. Middle zona fasciculata produces glucocorticoids. 3. Inner zona reticularis secrete androgens. The adrenocortical hormones are crucial for maintenance of fluid and electrolyte balance (mineralocorticoids), intermediary metabolism (glucocorticoids) and sexual development (androgens). Steroidogenesis involves conversion of cholesterol to steroid hormones in a process that requires sequential action of a series of six enzymes, a group of P450 enzymes. The disorders resulting from various enzyme deficiency states are discussed in Chapter 13.8. The hypothalamic-pituitary-adrenal (HPA) axis is responsible for the maintenance of normal cortisol levels. This involves close interaction of three hormones: 1. Corticotropin secreting hormone (CRH) produced by the hypothalamus. 2. ACTH produced by the anterior pituitary. 3. Cortisol secreted by the adrenals. Aldosterone and androgen secretions are independent of the HPA axis. This explains why mineralocorticoid replacement is not required in secondary (pituitary or hypothalamic defect) adrenal insufficiency.

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Hyponatremia and hyperkalemia are characteristically seen in primary adrenal insufficiency due to aldosterone deficiency. Hypoglycemia is common in both primary and secondary adrenal insufficiency. Diagnosis of AD is based on an elevated plasma ACTH level (> 100 pg/mL) and a low serum cortisol level (generally < 10 µg/dL). The diagnosis is confirmed by ACTH stimulation test. Blood samples are obtained at 0 minutes and 60 minutes after ACTH administration (250 µg or 15 µg/kg for infants < 2 years, IV). In AD, the peak cortisol level is less than 18 µg/dL. Mineralocorticoid deficiency is confirmed by relatively low aldosterone levels with high renin or PRA, with or without hyponatremia and/or hyperkalemia. Secondary adrenal insufficiency is associated with low serum cortisol and low plasma ACTH levels. Confirmation of HPA axis insufficiency is done by insulin-induced hypoglycemia or CRH test. Serum cortisol is measured 60 minutes after insulin-induced hypoglycemia (0.05–0.15 U/ kg of IV regular insulin); greater than 18 µg/dL is considered as a normal response. It is not a preferred test because of the risk of hypoglycemic seizure. Other alternatives include CRH test (1 µg/kg IV over 2 minutes; expected response— twofold increase in ACTH level at 15 minutes and 3–4 fold

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Management of acute adrenal crisis should be immediate to restore intravascular volume with IV infusion of 20–25 mL/ kg of 0.9% saline in 5% dextrose in the first hour followed by 60 mL/kg in the next 24 hours. Additional dextrose should be administered as required to treat hypoglycemia. Glucocorticoid in stress doses should be given simul taneously. Hydrocortisone is the treatment of choice because it has mineralocorticoid activity also. The recommended stress dose of hydrocortisone is 50–75 mg/ m2 IV initially, followed by 50–75 mg/m2/day IV divided in four doses or as a continuous infusion. Once acute manifestations are controlled, oral steroid therapy with hydrocortisone 10–12 mg/m2 in 2–3 divided doses or equivalent dose of prednisolone in two divided doses is started. 9-alpha-fluoro-cortisol acetate or fludrocortisone is the only available mineralocorticoid. It is given in a dose of 0.05–0.15 mg/day. Extra salt is required in early infancy for effective action of fludrocortisone. Dose of steroids should be increased in stress situations and is given only for the short period that stress lasts.

Cessation of Glucocorticoid Therapy Exogenous steroid replacement used for various disorders suppresses CRH and ACTH secretion leading to decreased production of cortical hormones and in the long-term cortical atrophy. The degree of suppression depends on the drug used, dosage and duration of therapy. Treatment with steroids should aim at optimal disease control with normal growth and development. After stopping steroid therapy recovery usually occurs in half of the patients by 6 weeks and in almost all by 6 months. Adrenocorticotropic hormone stimulation test should be performed to check recovery of the adrenal glands prior to cessation of steroids. Sometimes the baseline cortisol value may be normal with low stimulated value; in these cases stress dose of glucocorticoids should be advised.

Hyperfunction of the drenal ortex C

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Clinical features depend on the severity and the etiology of the disease. Children with acute adrenal insufficiency generally present with acute dehydration, hypotension, hypoglycemia, or altered mental status. Acute adrenal insufficiency may be triggered by infection, trauma or abrupt cessation of steroid replacement in children on longterm replacement therapy. Hypoglycemia is most common in young children. Patients with chronic adrenal insufficiency usually complain of fatigue, muscle weakness, nausea, vomiting, appetite loss, weight loss and recurrent abdominal pain. Blood pressure is often low. Hyperpigmentation and salt craving are exclusively seen in Addison disease. Hyperpigmentation is seen over genitalia, axillae, nipple, joints, umbilicus, palmar creases, buccal mucosa, recent scars and other exposed parts of skin due to elevation of proopiomelanocortin and melanocyte-stimulating hormone. Unless there is a history of recent pharmacologic glucocorticoid therapy, secondary adrenal insufficiency is usually associated with signs of other pituitary hormone deficiencies such as growth failure, delayed puberty, secondary hypothyroidism, and/or diabetes insipidus (polyuria and polydipsia).



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increase in cortisol levels at 15–30 minutes) and glucagon test (0.1 mg/kg SC). Adrenal imaging by ultrasonography or computed tomography and autoantibody testing is indicated in AD to establish etiology. MRI of brain is required to rule out adrenoleukodystrophy in a male child with AD. In cases of secondary adrenal insufficiency evaluation for other pituitary hormone deficiencies and MRI of brain is recommended to look for any developmental defects or space occupying lesion.

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accounted for over 70% of cases of AD; autoimmune being the second most common. Compared to primary, secondary form is much more common. The most common cause of acute adrenal insufficiency is withdrawal or omission of glucocorticoids in patients who are on long-term steroid therapy for various reasons.

Hyperfunction of the adrenal cortex may be associated with excess production of glucocorticoids, mineralocorticoids, androgens or estrogens. These disorders are rare in childhood. A high index of suspicion is essential for diagnosis as most of them present with nonspecific features.

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tiology ­

Hypercortisolism in Cushing syndrome may be due to increased endogenous production or exogenous adminis tration, which could be prescribed or over the counter medication. Exogenous CS is the most common cause of CS in all age groups. Increased adrenal glucocorticoid production might occur in response to increased ACTH levels or represent autonomous adrenal hyperfunction (Table 13.7.2). The etiology varies according to age; adrenal pathology is more likely in young children, while pituitary causes are more common after puberty. Adrenal adenomas are pure secretors, secreting cortisol, aldosterone or androgen while carcinomas are plurihormonal. Cushing syndrome may be secondary to an ACTHsecreting tumor of the pituitary, termed Cushing disease, often a basophilic pituitary adenoma. It leads to bilateral adrenal hyperplasia. Cushing syndrome due to ectopic ACTH production is extremely rare in children. McCune-Albright syndrome due to a somatic mutation of Gsa protein, may present with ACTH-independent CS due to constitutional activation of ACTH receptor. It is associated with fibrous dysplasia, café-au-lait spots and other endocrinopathies including precocious puberty and hyperthyroidism.



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Cushing syndrome (CS) is the most common disorder of adrenocortical hyperfunction. It is a generic term used to describe clinical findings caused by prolonged glucocorticoid excess.

common feature. However, it is an extremely rare cause of childhood obesity. The fat distribution is often centripetal with accumulation on the face, neck and abdomen. The extremities appear wasted with muscle weakness (Figs 13.7.1 and 13.7.2). Other clinical features include hypertension, delayed puberty, lethargy, bone pain, and obsessive-compulsive beavioral disorders. There may be thinning of skin with violaceous striae (frequently seen on the abdomen, buttocks, thighs and axillae) and easy bruising. Adrenocorticotropic hormone-dependent CS is characterized by hyperpigmentation. Androgen excess leads to hirsutism, acne, deepening of voice and rarely clitoral hypertrophy. Children with ectopic ACTH production usually present with hypertension and hypokalemic alkalosis.

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The classical features such as central obesity, striae, moon facies and buffalo hump are uncommon in children. Growth failure coupled with weight gain is the most

Figure 13.7.1 Eight-year-old girl with Cushing syndrome due to pituitary microadenoma. Note central obesity and moon facies  

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Glucocorticoid xcess tates: ushing yndrome

 

Table 13.7.2 Etiology of Cushing syndrome in children

















Abbreviations: ACTH, Adrenocorticotropic hormone; CRH, Corticotropin releasing hormone.

Figure 13.7.2 Eight-year-old girl with Cushing syndrome. Note buffalo hump and hypertrichosis  

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• ACTH-dependent: – Hypothalamic: Increased CRH production by tumor – Pituitary: Increased ACTH production: Microadenoma, macroadenoma – Ectopic: Carcinoids, neuroblastoma, Wilms tumor, islet cell tumor • ACTH-independent: – Adrenal tumors: Carcinoma, adenoma – Primary pigmented nodular adrenal hyperplasia – Macronodular adrenal hyperplasia – McCune-Albright syndrome • Exogenous: – Glucocorticoid: High dose or prolonged oral, parenteral, topical, inhaled – ACTH

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Step 1: The first step in the evaluation of a child suspected to have CS is to exclude exogenous CS, by detail history

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The evaluation of children with CS after exclusion of an adrenal tumor is more complex because most of the diagnostic tests are based on studies in adults, and then extrapolated for children. An algorithmic approach to diagnosis of CS is given in Flow chart 13.7.1.

and estimation of 8.00 AM basal serum cortisol. If serum cortisol is undetectable, ACTH stimulation test is required to document suppression of HPA axis. Step 2: Second step is to document autonomous cortisol production. Two out of the following screening tests namely 24 hours urinary free cortisol (UFC), late night salivary cortisol, 1 mg overnight dexamethasone suppression test or low-dose longer dexamethasone suppression test should be abnormal for a diagnosis of CS.

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iagnosis

 

Flow chart 13.7.1 Approach to a child with Cushing syndrome

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Abbreviations: BIPSS, Bilateral inferior petrosal sinus sampling; CS, Cushing syndrome; LDDST, Low-dose dexamethasone suppression test; ONDST, Overnight dexamethasone suppression test; UFC, Urinary free cortisol

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Management



Resection of adrenal lesion—unilateral adrenalectomy for adenoma or carcinoma and subtotal adrenalectomy for bilateral lesion is recommended. Prolonged cortisol excess causes suppression of the normal contralateral adrenal. This mandates close monitoring for adrenal insufficiency in the perioperative period. Recovery of HPA axis may be delayed up to 6 months after surgery. Transsphenoidal resection of pituitary adenoma is recommended for children with Cushing disease. The success rate varies from 66% to 80%. Pituitary irradiation or bilateral adrenalectomy is recommended in children with failed pituitary surgery or recurrent disease. Nelson syndrome characterized by enlargement of sella and hyperpigmentation is a dreaded complication after bilateral adrenalectomy in these patients. Lifelong followup is required after pituitary surgery. Adrenal carcinoma is highly malignant and has a high rate of recurrence. Chemotherapy with mitotane or cisplatin is ineffective in children with recurrence of the disease. Medical management of childhood CS with inhibitors of steroidogenesis (ketoconazole, cyproheptadine and mitotane) has been tried but is largely disappointing.

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for identifying the source of ACTH production and is performed in children with ACTH-dependent CS with normal neuroimaging. The experience with children is limited. Radiological evaluation shows retarded bone age usually, but may be advanced in children with virilization. Osteoporosis and pathological fractures may be present.

Hyperaldosteronism Primary hyperaldosteronism due to increased adrenal aldosterone production is extremely rare in children. These include aldosterone producing adrenal adenoma, familial primary hyperaldosteronism and much rarely adrenal carcinoma. Secondary hyperaldosteronism results from factors that activate renin-angiotensin system. The most common clinical features of primary hyperaldosteronism are due to hypertension and hypokalemic alkalosis manifesting as fatigue, muscle cramps and weakness, polyuria, nocturia and poor growth. This condition needs to be differentiated from Bartter syndrome, in which plasma renin activity is elevated with normal blood pressure. Hyperaldosteronism should be managed with salt restriction and anti-aldosterone agent, spironolactone. Surgery is indicated only if an aldosterone producing adenoma has been conclusively proven.

Loss of diurnal rhythm is the earliest biochemical marker of hypercortisolism. Usually cortisol is highest at 9 AM and lowest at midnight. The normal plasma cortisol levels range between 5 µg/dL and 25 µg/dL (140–690 nmol/L) in the early morning, which is reduced to less than half by 11 . Morning cortisol levels are not elevated in many patients with CS, whereas late-night cortisol is usually increased • Estimation of excretion of UFC is a good screening test for CS. Normal levels vary between 25 µg/m2/day and 75 µg/m2/day and UFC levels greater than 75 µg/m2/day are suggestive of CS • Salivary cortisol is a better alternative and cortisol level greater than 8.6 nmol/L is suggestive of CS • Overnight dexamethasone suppression: Following administration of 1 mg of dexamethasone at 12 midnight, plasma cortisol is estimated in the morning sample. Cortisol levels below 1.8 µg/dL are suggestive of CS • Low-dose dexamethasone suppression test is based on the principle that dexamethasone will suppress ACTH, and hence cortisol release in normal subjects, whereas patients with autonomous cortisol production will not suppress below a specified cut-off. This test involves the measurement of serum cortisol or UFC before and after oral dexamethasone (5 µg/kg per dose, every 6 hours for 2 days or 1.25 mg/m2/day divided into four doses given over 2 days). Serum cortisol levels greater than 1.8 µg/ dL is diagnostic of CS. Step 3: Third step is to decide whether CS is ACTH-dependent or independent by estimation of plasma ACTH. • If circulating ACTH is suppressed to less than 10 pg/mL, it suggests ACTH-independent CS, most likely due to adrenal cause • Plasma ACTH value greater than 10 pg/mL suggests ACTH-dependent CS due to pituitary lesion or ectopic production of ACTH. There is a wide overlap in ACTH values in pituitary and ectopic ACTH production • Children with ACTH levels between 10 pg/mL and 20 pg/mL are best evaluated by the CRH stimulation test. Increase in ACTH levels after intravenous CRH (1 µg/kg, maximum 100 µg, sampling basal and after 30 minutes and 60 minutes) is suggestive of pituitary ACTH-dependent etiology while no increase is seen in children with adrenal pathology or ectopic ACTH production. Step 4: Fourth step is to determine the anatomical site of lesion by radiological investigations. • Once ACTH-independent CS is confirmed, adrenal computed tomography or magnetic resonance imaging should be performed to detect the type of adrenal lesion: unilateral or bilateral, or benign adenoma or carcinoma • Pituitary MRI is recommended for ACTH-dependent CS. The use of dynamic MRI (with IV gadolinium) with spoiled gradient sequences may increase the sensitivity 818 • Inferior petrosal sinus sampling (IPSS) is the test available

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Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor which arises from the chromaffin cells of adrenal medulla. It can also arise from abdominal sympathetic chain,

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Surgical removal of the tumor is the choice of treatment after adequate alpha-blockade with phenoxybenzamine



Management







Demonstration of increased plasma catecholamine levels or urinary excretion of catecholamines and their derivatives confirms the diagnosis. Abdominal imaging with ultrasound, CT scan or MRI scans is done to localize the lesion. Radionuclide imaging with 123I-MIBG is also used for localization of the tumor. Often the tumors are multiple. Family screening is required if stigmata of syndromes are present.



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Clinical features are due to hypersecretion of catecholamines. These include hypertension, sustained more often than paroxysmal. There may be associated headache, palpitation, pallor, sweating, nausea, vomiting, visual disturbances, polyuria and polydipsia. Convulsions due to hypertensive encephalopathy may occur. Unexplained fever and weight loss due to hypercatabolism are seen more commonly in children than adults.

1. Boscaro M, Arnaldi G. Approach to the patient with possible Cushing’s syndrome. J Clin Endocrinol Metab. 2009;94(9):3121-31. 2. Desai MP, Menon PSN, Bhatia V (Eds), 2nd edition. Hyderabad: Orient Longman; 2008. pp. 326-98. 3. Lindsay JR, Nieman LK. Differential diagnosis and imaging in Cushing syndrome. Endocrinol Metab Clin North Am. 2005;34(2):403-23. 4. Migeon CJ, Lanes R. Adrenal Cortex: Hypo- and Hyperfunction. In: Lifshitz F (Ed). Pediatric Endocrinology. New York: Informa Healthcare; 2007. pp. 195-226. 5. Miller WL. The adrenal cortex. In: Brook C, Clayton P, Brown R (Eds). Clinical Pediatric Endocrinology, 5th edition. Oxford: Blackwell Scientific; 2005. pp. 293-351. 6. Moshang T. Cushing’s disease, 70 years later. and the beat goes on. J Clin Endocrinol Metab. 2003;88(1):31-3. 7. Nieman L, Biller BM, Findling JW, et al. The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008;93(5):1526-40. 8. Perry R, Kecha O, Paquette J, et al. Primary adrenal insufficiency in children: twenty years experience at the Sainte-Justine Hospital, Montreal. J Clin Endocrinol Metab. 2005;90(6):3243-50. 9. Pivonello R, De Martino MC, De Leo MC, et al. Cushing’s Syndrome. Endocrinol Metab Clin North Am. 2008;37(1):135-49. 10. Shulman DI, Palmer MR, Kemp SF, et al. Adrenal insufficiency: still a cause of morbidity and death in childhood. Pediatrics. 2007;119(2):e484-94. 11. Storr HL, Chan LF, Grossman AB, et al. Paediatric Cushing’s syndrome: epidemiology, investigation and therapeutic advances. Trends Endocrinol Metab. 2007;18(4):167-74.

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or prazosin. Recently calcium channel blocking agent, nifedipine, has been tried with some success.

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periadrenal area, urinary bladder, thoracic cavity or cervical region. It is rare in children and accounts for only 2% of cases of secondary hypertension. It usually coexists with other familial syndromes or tumors such as neurofibromatosis (von Recklinghausen disease and von Hippel-Lindau disease) and multiple endocrine neoplasia type II. Mutations in the RET proto-oncogene and succinate dehydrogenase enzyme gene have been reported in these patients.

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isorders of drenocortical iosynthesis P Raghupathy

teroidogenesis

ongenital drenal Hyperplasia

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Salt wasting type in nearly 75% of 21-OHD. This is the classic disorder presenting usually between 1 week and 1 month of age occurring with cortisol deficiency along with salt wasting and hypovolemia arising from aldosterone deficiency and the natriuretic effect of accumulated precursors like 17-OHP. The effects of this enzyme deficiency begin in the intrauterine period. Hence, the accumulation of excessive adrenal androgens causes virilization of the external genitalia of a female infant seen at birth, in both the salt wasting and simple virilizing types • Simple virilizing type without salt loss. Non-salt losers with virilization account for nearly 25% of cases. The absence of salt loss can be explained by a partial defect in 21-OHD. Virilization is seen at birth in girls • Non-classic (late onset) type: The presentation may also be varied, such as adrenarche, early growth spurt, or accelerated skeletal maturation. The mani festations can also occur for the first time during adulthood as hirsutism in women or reduced fertility in both sexes. There is no hypertension. Use of appropriate sized cuffs for measurement of blood pressure is essential. If siblings are affected, they tend to have the same clinical type. • Salt loss: Salt loss may present as hypovolemic shock, especially as unexplained dehydration and may also occur beyond neonatal period in cases infectioninduced stress situations • Virilization: The diagnosis of 21-OHD is easily identified in girls because of genital ambiguity. In boys, however, the condition can go unnoticed until toddler years, when increased height velocity, increase in the size of the external genitalia, appearance of pubic hair and other signs of male secondary sexual characteristics are observed. Hyperpigmentation involving external genitalia, nipples and umbilicus with a ‘tanned appearance’ of skin may be a very important clue for early diagnosis.

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The adrenal cortex functions as two separate units because of the enzymatic differences between the zona glomerulosa and the inner two zones: zona fasciculata and zona reticularis. The zona glomerulosa lacks 17α-hydroxylase activity and therefore, cannot synthesize 17α-hydroxypregnenolone and 17α-hydroxyprogesterone (17-OHP), the precursors of cortisol and androgens. The synthesis of aldosterone by this zone is totally regulated by the renin-angiotensin system and by potassium. The two inner zones produce cortisol, androgens and small quantities of estrogens. These two zones are directly controlled by ACTH. They lack 18-dehydrogenase and so cannot synthesize aldosterone. The various enzymes involved in the biosynthetic pathway of cortisol are given in Flow chart 13.8.1. Corticotropinreleasing factor produced by the hypothalamus regulates ACTH. Adrenocorticotropic hormone in turn induces synthesis and secretion of steroids within minutes. The conversion of cholesterol to pregnenolone is the major site of ACTH action on the adrenal cortex and is the rate-limiting step.

CAH. The exact incidence of 21-OHD in India is unknown. In the West, the incidence is reported to be 1 in 10,000 to 1 in 20,000. 17-hydroxyprogesterone accumulates in the serum because it is not converted to 11-deoxycortisol in the absence of 21-hydroxylase. Similarly progesterone accumulates following lack of conversion to 11-deoxycorticosterone (DOC) (Flow chart 13.8.1). The ultimate effect is cortisol deficiency and ACTH elevation giving rise to adrenocortical hyperplasia. As the formation of mineralocorticoids and glucocorticoids from cholesterol is blocked, the conversion of cholesterol flows largely into the androgen pathway. The clinical varieties of this deficiency are:

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The adrenal cortex produces several steroid hormones such as cortisol, aldosterone and androgens. The ability to convert cholesterol into steroidal hormones (steroid biosynthesis) is present only in the adrenal cortex, gonads of both sexes and the placenta. An enzymatic defect of steroidogenesis may not affect the adrenal cortex and gonads equally. Hence, disorders of sexual differentiation may result from the biosynthetic pathway defects in the adrenal cortex or the gonads or both. S

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13.8

In CAH, cortisol synthesis from cholesterol is affected due to deficiency of one of the several enzymes in the adrenal cortex (Flow chart 13.8.1). Adrenocorticotropic hormone elevation is secondary to plasma cortisol deficiency via the negative feedback mechanism. Overproduction of the hormone precursors proximal to the block and deficiency of the hormones distal to the blocked enzymatic step are responsible for the clinical features encountered. The enzymatic defects are inherited by an autosomal recessive mode and produce characteristic clinical and biochemical pictures. The genes and enzymes involved in adrenal steroidogenesis are listed in the Table 13.8.1. D

21-Hydroxylase eficiency 820 21-hydroxylase deficiency (21-OHD) is the most common enzyme deficiency seen in nearly 95% of individuals with

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Flow chart 13.8.1 Scheme of adrenal steroidogenesis. Chemical names of enzymes are shown next to the arrows; enclosed numbers indicate traditional names of the enzymes: 1. 20, 22-desmolase, 2. 3b-hydroxysteroid dehydrogenase/isomerase, 3. 17a-hydroxylase, 4. 17, 20-lyase, 5. 21-hydroxylase, 6. 11b-hydroxylase, 7. 18-hydroxylase, 8. 18-oxidase, 9. 17b-hydroxysteroid dehydrogenase, 10. Aromatase. Abbreviations: StAR, Steroidogenic acute regulatory protein; 11. DOC, deoxycorticosterone.

 

Table 13.8.1 Genes and enzymes involved in adrenal steroidogenesis Gene

Chromosomal location

Enzyme

Enzymatic activity

Cellular location

CYP11A1

15q23-q24

P450scc (CYP11A1)

Cholesterol desmolase (side chain cleavage)

Mitochondrion

HSD3B2

1p13.1

3βHSD (3βHSDII)

3β-Hydroxysteroid dehydrogenase

Endoplasmic reticulum

CYP17

10q24.3

P450c17 (CYP17)

17α-Hydroxylase/17,20 lyase

Endoplasmic reticulum

CYP21A2

6p21.3

P450c21 (CYP21A2)

21-Hydroxylase

Endoplasmic reticulum

CYP11B1

8q21-22

P450c11 (CYP11B1)

11β-Hydroxylase

Mitochondrion

CYP11B2

8q21-22

P450c18 (CYP11B2)

Aldosterone synthase (corticosterone 18-methylcorticosterone oxidase/lyase)

Mitochondrion

genitalia but with an empty scrotum. Thus, absence of testes would be helpful in diagnosis. Apart from the external virilizing and biochemical features, there are no abnormalities in genetic sex, gonadal 821



The degree of genital ambiguity does not correlate with the form of 21-OHD. Virilization in the female may present as mild clitoral hypertrophy, varying degrees of ambiguity or complete masculinization with normal looking male

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Prenatal Treatment In families with an affected infant, prenatal treatment of the mother has been tried in subsequent pregnancies. The aim of prenatal treatment is to prevent external genital deformity in the female fetus due to virilization. This mode of treatment is best considered experimental at present.

Neonatal Screening Screening of all newborns with filter paper 17-OHP is carried out in many developed nations. It is not yet determined whether this is mandatory.

11β-Hydroxylase eficiency In this disorder which accounts for nearly 5% of cases of CAH, cortisol and corticosterone are deficient with overproduction of 11-deoxycortisol and 11-DOC. The precursor hormones are shunted into the androgen pathway causing prenatal and postnatal virilization. The accumulation of DOC results in sodium and water retention, increased plasma volume and hence causes hypertension. Serum level of 11-deoxycortisol elevation is diagnostic. Plasma renin activity is suppressed, serum aldosterone is lowered and hypokalemia may be present. Glucocorticoid therapy is effective in reversing all the abnormalities and remission.

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The essential principles of treatment are to replace the deficient hormones and to suppress the overproduction of precursor hormones. Hydrocortisone is required in the dose of 10–20 mg/m2/day in two or three divided doses. Salt wasters require, in addition, 9α-fluorohydrocortisone 0.1–0.3 mg (100–300 µg) per day. Sodium chloride supplementation up to 1–3 g daily may be needed in the infants and young child. This is generally not required beyond infancy. The hormonal profile reverts to the normal range with appropriate treatment which is monitored 3–6 monthly by estimating 17-OHP and PRA values and appropriate dosage adjustment is effected. The daily dose of hydrocortisone may be doubled during acute stress periods like infection. In the newborn period at presentation, a large dose of hydrocortisone and fluorohydrocortisone may be required. Dosages are modified by monitoring serum sodium and potassium daily and ideally, by frequent serum17-OHP and PRA estimations. Dose of hydrocortisone is gradually reduced and changed over to 5 mg twice a day orally. In older children, when higher dosage is given, a few endocrinologists advise a larger dose at night, e.g. if the 822 child needs 12.5 mg of hydrocortisone per day, 5 mg is given in the morning and 7.5 mg in the evening. This is done with

Assigning the appropriate sex is of paramount importance. The affected female with CAH has the potential for a normal fertile female role. Surgical correction of the genital abnormality (feminizing genitoplasty) is carried out in girls around 1 year of age by doing reduction clitoroplasty. Definitive vaginoplasty with routine dilatation will also be required in late adolescence. It is very important that the parents understand the nature of the disease, chronicity of the treatment required lifelong, the complication arising from poor compliance, and how steroids play an essential role in stress situations such as surgery, infection, or shock, which can be lifethreatening if inappropriately managed. Early epiphyseal fusion in both sexes will eventually cause short stature, if treatment is irregular and incomplete with the disease being poorly controlled. The parents are given adequate health education regarding this condition. They are advised that daily dose of hydrocortisone must be doubled or tripled for a few days during stress situations. If oral doses are not tolerated, intramuscular injections are given.

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Appropriate Sex Assignment

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Hyponatremia, hyperkalemia, increased urinary sodium losses due to renal salt wasting, high plasma renin activity (PRA), accompanied by low serum and urinary aldosterone levels, acidosis and uremia are the biochemical features in salt wasting type. Hypoglycemia may also be present. Elevated serum 17-OHP, markedly lowered serum cortisol, elevated levels of serum DHEAS, and testosterone are diagnostic. On short synacthen (ACTH) stimulation test, serum 17-OHP and DHEAS rise more than 2–3 folds but there is no significant elevation of serum cortisol. Urinary estimation of steroid metabolites is not preferred nowadays. The difficulty experienced in the 24-hour urine collection from an infant with ambiguous genitalia is considerable. The results are quite often difficult to interpret. Nonclassic 21-OHD may be totally asymptomatic and presents only with biochemical abnormalities as in the classic cases and may be picked up only during family studies. Prenatal virilization is absent and postnatal virilization is variable. Nonclassic cases may have only milder elevation of 17-OHP, especially when performed in the afternoon or late forenoon. Hence it is preferable to get the hormonal profile always in the mornings. Salt wasting is absent and cortisol deficiency is rare.

a view to suppress ACTH pulses during the night, although insufficient data exist to recommend this as a routine. Nonclassic CAH does not always require treatment but when treatment is required at puberty or later, lower glucocorticoid doses are used.



Laboratory Features



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differentiation, or development of the internal genitalia. The female infant will have normal ovaries, fallopian tubes, uterus and proximal vagina. Postnatally in untreated cases there will be continued virilization effects with clitoromegaly or penile enlargement, accelerated growth, advanced skeletal maturation far in excess of the height age and premature appearance of secondary sexual characteristics.

This is a rare disorder occurring with cortisol deficiency, ACTH excess, overproduction of DOC causing hypertension and hypokalemia. Affected males are incompletely

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1. Ahmed SF, Rodie M. Investigation and initial management of ambiguous genitalia. Best Pract Res Clin Endocrinol Metab. 2010;24(2):197-218. 2. Nimkarn, S., Lin-Su K, New MI. Steroid 21 hydroxylase deficiency congenital adrenal hyperplasia. Endocrinol Metab Clin North Am. 2009;38(4):699-718. 3. Speiser PW, Azziz R, Baskin LS, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(9):4133-60.

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In this rare StAR protein deficiency disorder which affects adrenal cortex and gonads, there is a global deficiency of all adrenal hormones—glucocorticoids, mineralocorticoids and sex hormones. Gonadal steroids are also absent. Clinical presentation is very early in life with salt wasting



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ipoid drenal Hyperplasia

Knowledge regarding CAH is widening constantly. The chromosomal locations and nature of the genes encoding the various enzymes needed for adrenocortical biosynthesis, the cellular locations, functions and abnormalities of these enzymes, the pathophysiology of adrenocortical disorders, the clinical features and laboratory parameters have been documented further. Prenatal diagnosis and treatment as well as newborn screening are practised widely. However, we are yet to find an ideal way of keeping the disease under good control in an effort to mimic normal physiology.



Classic and nonclassic forms are seen in this disorder. Salt wasting, deficiency of cortisol and aldosterone are the usual manifestations of this condition. In the nonclassic form, there is no aldosterone deficiency. Males with this condition may show undervirilization with ambiguity of external genitalia owing to underproduction of testosterone in utero. Pseudovaginal hypospadias may be present in the males due to absence of potent androgens. But the excessive collection of the weak androgen, DHEAS, may cause clitoral enlargement in the female. Most of them have aldosterone deficiency with elevation of PRA. Hyperpigmentation is seen and serum ACTH level is high. Treatment is with glucocorticoids. L

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3β Hydroxysteroid ehydrogenase/ 4, 5 somerase eficiency

crisis. Females have no abnormality of internal or external genitalia. Males are phenotypically female but may have inguinal gonads. Sex hormone replacement will be necessary in those with undervirilization or in those with delayed puberty with the objective of achieving normal pubertal development, normal sexual function, and fertility.

ndocrinology

virilized owing to diminished androgen production and may be phenotypically female or ambiguous. In addition, ACTH excess driven by cortisol deficiency causes mineralocorticoid excess and hypertension. Plasma renin activity and aldosterone are low. Glucocorticoid therapy suppresses overproduction of the hormones.

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isorders of exual evelopment P Raghupathy

The SRY gene (with 204 amino acids) located on the short arm of Y chromosome (Yp11.3) is the trigger for testicular differentiation, by inducing development of Sertoli cells and subsequently, seminiferous tubules and Leydig cell formation in that order. The sex-determining region on the Y chromosome activates SOX 9 (SRY-homeobox-like gene), an autosomal gene (chromosome 17q24) and steroidogenic factor (SF1) to induce differentiation of the bipotential gonad into a testis. The sex-determining region on the Y chromosome suppresses DAX 1 which normally inhibits SOX 9. The testis induces male sex differentiation including testicular descent through a hormone-mediated process.

Ovarian Differentiation DAX 1, SOX 3 and Wnt 4 are the three candidate genes currently known to suppress testicular differentiation. DAX 1 and SOX 3 inhibit SF 1 and SOX 9, preventing Sertoli cell 824 differentiation, favoring granulosa cell development. Wnt 4

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From the initial undifferentiated stage of the external genitalia, masculinizing features develop in the male under the influence of dihydrotestosterone (DHT) formed peripherally from testosterone by the action of 5α-reductase. This process is dependent on an adequate number of functioning androgen receptors in the pubic skin. Formation of the female external genitalia does not require any active process and will persist with normal ovaries, in androgen insensitivity or even in the absence of gonads, sex chromosome abnormalities, streak gonads or non-functioning testes.

bnormalities of exual ifferentiation

Terms such as intersex, hermaphroditism, pseudoherma phroditism, sex reversal and gender-based diagnostic conditions are currently recommended to be avoided. These terms may be deemed derogatory and confusing to parents and practitioners as well. Hence changes in terminology have been proposed (Table 13.9.1). It is advisable to use terminology that are precise, descriptive, clear in expressing the genetic, etiologic or diagnostic condition, and at the same time sensitive to the concerns of parents. The revised classification of disorders of sexual development is presented in Table 13.9.2. When SRY gene undergoes mutation in its high mobility group box protein, testicular failure or genital ambiguity will result. SOX 9 mutation in 46, XY males leads to a female phenotype and streak ovarian-like gonads. ­

Testicular Differentiation

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The gonads in the embryo remain undifferentiated until the sixth week of gestation. Subsequent development into either a testis or ovary is directed by the genetic sex (XY or XX). The testis develops more rapidly than the ovary. Fetal testicular differentiation begins in the seventh week of gestation, whereas ovarian development begins not earlier than the 16th week of gestation. Female sex differentiation is not dependent on ovarian hormones, but there is evidence that Wnt signaling molecules play a role in Müllerian duct development and suppression of Leydig cell differentiation in ovary.

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Testosterone initially under the control of human chorionic gonadotropin is produced locally (paracrine) by Leydig cells of the fetal testis on either side. It helps in ipsilateral differentiation of the Wolffian ducts into epididymis, vas deferens, seminal vesicles and ejaculatory ducts. AntiMüllerian hormones (AMH) secreted by the Sertoli cells cause ipsilateral involution of the Müllerian structures. In female fetuses, Wolffian structures regress in the absence of testosterone and Müllerian ducts persist in the absence of AMH. However, Wnt 4 gene appears to play an important role in Müllerian duct differentiation and fetal ovarian function. E

The undifferentiated human embryos of the two sexes differ only by their karyotypes. The gender of the individual is normally determined by factors that direct the gonads as early as the third gestational week in the male to differentiate along male line and, the process is continued in turn, by gonadal hormones which determine the development of the phenotypic sex. The sex-determining region on the Y chromosome (SRY) gene residing in the Y chromosome has now been documented as the mammalian sex-determining gene, which actively induces the formation of the testis and the male phenotype during embryonic life. The gonads, internal genitalia (genital ducts) and the external genitalia, which are all bipotential are influenced by several genes and other factors necessary for sexual differentiation.

arrests the Leydig cell precursors and induces development of Müllerian ducts into Fallopian tubes, uterus, cervix and upper third of vagina. Though the effects of these genes have been considered to result in ovarian differentiation, it should be remembered that active testicular differentiation occurs much earlier when compared to the ovarian.

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Table 13.9.1 Revised nomenclature

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Revised

Intersex

Disorders of sex development

Male pseudohermaphrodite  Undervirilization of an XY male Undermasculinization of an XY male

46, XY DSD

Female pseudohermaphrodite  Virilization of an XX female Masculinization of an XX female

46, XX DSD

True hermaphrodite

Ovotesticular DSD

XX male or XX sex reversal

46, XX testicular DSD

XY sex reversal

46, XY complete gonadal dysgenesis





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Abbreviations: DSD: Disorders of sex development

 

Table 13.9.2 Revised classification of disorders of sex development •  45, X (Turner syndrome and variants) •  47, XXY (Klinefelter syndrome and variants) •  45, X/46, XY(mixed gonadal dysgenesis, ovotesticular dysgenesis) •  46, XX/46, XY (chimeric, ovotesticular dysgenesis)

•  Disorders of gonadal (testicular development –  Complete gonadal dysgenesis –  Partial gonadal dysgenesis –  Gonadal regression –  Ovotesticular DSD) •  Disorders in androgen synthesis or action –  Androgen biosynthesis defect, (e.g. 17β-hydroxysteroid dehydrogenase deficiency, 5α-reductase deficiency, StAR mutations) –  Defects of androgen action, (e.g. CAIS, PAIS) –  LH receptor defects (e.g. Leydig cell hypoplasia, aplasia) –  Disorders of AMH and AMH receptor (persistent Müllerian duct syndrome) –  Other (e.g. severe hypospadias, cloacal exstrophy)

•  Disorders of gonadal (ovarian) development –  Ovotesticular DSD –  Testicular DSD (e.g. SRY, dup SOX 9) –  Gonadal dysgenesis •  Androgen excess –  Fetal (e.g. 21-hydroxylase deficiency, –  11β-hydroxylase deficiency) –  Feto-placental (aromatase  deficiency, POR) –  Maternal (Luteoma, exogenous, etc.) •  Other (e.g. cloacal exstrophy, vaginal atresia, MURCS, other syndromes)        



     

   





         

 

 

 

 





XX DSD



XY DSD



Sex chromosome disorders of sex development

Abbreviations: CAIS, Complete androgen insensitivity syndrome; PAIS, Partial androgen insensitivity syndrome; MURCS, Müllerian, renal, cervicothoracic somite dysplasia; SRY, Sex-determining region on the Y chromosome; AMH, Anti-Müllerian hormone; POR, P450 oxidoreductase.





Chromosomal abnormalities may lead to disorders of male gonadal differentiation or give rise to ovotesticular differentiation. Wolffian development and Müllerian regression on each side are dependent on the ipsilateral production or testosterone and AMH respectively. Hence, abnormalities of the internal genitalia will be encountered, based on the presence of gonadal elements on that side. A streak gonad which produces neither testosterone nor AMH, will give rise to poorly formed Müllerian structures such as a hypoplastic or hemiuterus on the side of the defective gonad. Variable degrees of virilization of the female external genitalia leading to sexual ambiguity will result when exposed to androgens, either from the mother (intake or excessive production of androgens in her body), or from the fetus [congenital adrenal hyperplasia, aromatase

deficiency, ovotesticular disorder of sexual development (DSD), or mixed gonadal dysgenesis]. Partial virilization producing ambiguity of the external genitalia or complete virilization with normal-looking male external genitalia (penis and a fully formed but empty scrotum) may occur in a genetic female with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. A normal looking female external genitalia (with testes in the labioscrotal folds) may be a case of complete androgen insensitivity syndrome. A genetic male may have undervirilization and present with underdeveloped and ambiguous genitalia as in 17α-hydroxylase deficiency or 3β-hydroxysteroid dehydrogenase deficiency. The appearance of the external genitalia does not always give any diagnostic clinical clues, e.g. an infant with ovotesticular DSD and a virilized female with genital ambiguity may look similar.

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Figure 13.9.1 A 3-year-old girl with marked clitoromegaly due to untreated congenital adrenal hyperplasia 21-hydroxylase deficiency (nonsalt-loser)  

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Ambiguous genitalia may be defined as discordance between the external genitalia and the gonads. • If the genotype is XX, and the impalpable gonads are ovaries, but the external genitalia are virilized partially or fully, this is likely to be due to the exposure of a female fetus to excessive androgens during the period of sexual differentiation in early gestation, e.g. CAH due to 21-hydroxylase deficiency, 11-β hydroxylase deficiency, 3-β hydroxysteroid dehydrogenase deficiency or maternal androgen excess due to a tumor or therapy (Figs 13.9.1 and 13.9.2) • If the genotype is XY, the gonads which are palpable are testes and the external genitalia is incompletely virilized or ambiguous, this may be due to a testosterone biosynthetic defect, or if the external genitalia is completely female, this may be a case of complete androgen insensitivity syndrome. • If both ovarian and testicular tissues are present either in the same gonad (ovotestis) or opposite gonads—one gonad may be palpable or both gonads impalpable— this may be a case of ovotesticular DSD. C

Clinical evaluation of the infant with a suspected DSD should be done to decide assignment of sex and to plan the long-term management of the infant’s condition. However, it is highly essential to rule out associated life-threatening metabolic conditions such as adrenal insufficiency. History taking should include details regarding parental consanguinity, maternal drug intake, history of previous sibling deaths due to salt loss in the neonatal period, affected siblings or family members with DSD, history of low-birth weight or intrauterine growth retardation and X-linked mode of inheritance (in cases of androgen insensitivity). Physical assessment should include examination for dysmorphic features, midline defects in cases of microphallus due to pituitary defects (Figs 13.9.3 and 13.9.4); hypo- or hypertension, dehydration, virilization in case of girls, undervirilization in case of boys, presence or absence of gonads, hyperpigmentation of the skin, etc. Severe hyponatremia, hyperkalemia, dehydration, hypo tension and shock usually in the second week after birth, with increased pigmentation of the skin in a virilized female infant or an infant with normal male genitalia strongly suggests the possibility of CAH due to salt-losing 21-hydroxylase deficiency (Fig. 13.9.1). Non-salt-losers with this condition will present with the combination of increased pigmentation and virilization but without the dramatic signs of salt loss. Female infants presenting with increased pigmentation, hypokalemia, hypertension and virilization are most likely to have 11β-hydroxylase deficiency (Fig. 13.9.2). These 826 signs may not be present universally, especially during



infancy. Boys with this condition will exhibit subtle changes in the external genitalia. Low cortisol and renin values are encountered. If physical examination reveals the presence of a gonad, it is most often a testis and the infant is a case of 46, XY DSD. If there is no gonad palpable, the genetic sex cannot be identified clinically and further workup is essential. The phallus is measured for its length and width of erectile tissue and examined for chordee. Presence of separate openings of vagina and urethra should be looked for as also pigmentation and rugosity of labioscrotal folds.

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Figure 13.9.2 Marked virilization external genitalia in a  4-year-old girl with 11β-hydroxylase deficiency

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• • • •

Serum sodium and potassium Blood glucose Arterial blood gases Serum 17-hydroxyprogesterone

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Management



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ibliography 1. Brown J, Warne G. Practical management of the intersex infant. J Pediatr Endocrinol Metab. 2005;18(1):3-23. 2. Dreger AD, Chase C, Sousa A, et al. Changing the nomenclature/taxonomy for intersex: a scientific and clinical rationale. J Pediatr Endocrinol Metab. 2005;18(8):729-33. 3. Hughes IA, Houk C, Ahmed SF, et al. Consensus statement on management of intersex disorders. Arch Dis Child. 2006;91(7):554-63.



Plasma rennin activity Serum cortisol Serum dehydroepiandrosterone Serum testosterone Urine analysis for albumin Ultrasound pelvis and abdomen Retrograde genitogram Karyotype Laparoscopy



• • • • • • • • •



 

Figure 13.9.4 Severe hypogonadism due to panhypopituitarism in a 1-year-old boy

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Figure 13.9.3 Hypogonadism with microphallus in a 2-year-old boy with panhypopituitarism

investigations to establish the diagnosis, the sex of rearing best suited for the infant. It is important to allay the anxiety and guilt of the parents and other family members in repeated sessions and to explain the available modalities and plan of treatment. To deal with the DSD optimally, a full team is ideal, viz. pediatric endocrinologist, neonatologist, family pediatrician, pediatric surgeon or urologist, gynecologist, radiologist, ultrasonologist, biochemist, cytogeneticist, pediatric psychologist/psychiatrist as well as nursing colleagues and social workers. Support group of parents with similarly affected children will also be helpful. Most importantly, the parents should be included in all discussions concerning the evaluation and management of the infant with a DSD. It is always important to collect together all possible evidence for arriving at a diagnosis and then have discussions with the parents. Although urgency is still necessary, most parents will be willing to wait for a few days longer before making their decision about their child’s future. Until the decision is made, it is better to refer to the infant as “baby”, and not as “he” or “she”. The most common cause of ambiguous genitalia is 21-hydroxylase deficiency in genetic females. Nearly 75% present with salt loss typically during the second week of life. Hyperpigmentation of the skin, especially the nipples, umbilicus and external genitalia should alert one to the diagnosis even before salt losing manifestations appear. This clinical sign is particularly useful in males with CAH as they do not present with any abnormality of the external genitalia but have a high risk of shock due to salt loss. In the presence of the history of a previous sibling or family member involved, biochemical investigations may be performed earlier to hasten the diagnosis. Virilized females with CAH having a uterus and ovaries are assigned the female sex. Clitoral reduction and genitoplasty are usually undertaken around 1 year of age and care is taken to preserve the glans and the neurovascular bundle. Recommendations for assignment of sex in an individual with fully virilized male external genitalia and presence of female internal sex structures are still controversial. Reconstructive surgery for hypospadias is needed in those with 5α-reductase deficiency at the time of puberty. Assignment of a female sex to an individual with microphallus and fused scrotum is being reconsidered and not always accepted today by many. Testosterone therapy is recommended for microphallus and fused scrotum. In summary, there are no easy answers always for the assignment of sex in disorders of sexual differentiation.

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iabetes Mellitus Vijayalakshmi Bhatia

Diabetes mellitus is a common disorder of fuel metabolism. In children, it is found most frequently due to an absolute deficiency of insulin secretion, due to destruction of the beta cells of the pancreatic islets. The disease is associated with a number of short and long-term complications, many of which are linked with the degree of blood glucose control. In addition, diabetes in childhood and adolescence affects growth and puberty, and often psychological well-being. Diabetes is best managed by a team of personnel including a diabetes nurse/educator, dietician and psychologist in addition to the doctor.

 

Table 13.10.1 Etiological classification of diabetes mellitus









    











Diabetes mellitus is not a single entity. It is a group of disorders of varying etiology and pathogenesis, resulting in the same metabolic syndrome. The World Health Organization in 1997 published a classification of diabetes based on etiology (Table 13.10.1). The typical insulindependent, ketosis-prone patient is classified as having type 1 diabetes. The non-insulin-requiring, non-ketosisprone, usually obese patient seen during adolescence is classified as type 2 diabetes. Pediatricians in India may occasionally encounter an additional type of diabetes that is due to a calcific chronic pancreatitis, which may clinically be insulin-dependent or non-insulin-dependent, which is classified under diseases of the pancreas. Another type of diabetes presentation seen in developing countries is that of a non-obese patient requiring insulin for glucose control but not exhibiting ketosis when off insulin. This was earlier termed protein deficient pancreatic diabetes by the WHO. This terminology has largely been discarded now, as no direct role of protein deficiency in the etiology of permanent diabetes has been found. This entity has not found a place in the new classification because its etiology is not clear. The cut-off limits for the diagnosis of diabetes mellitus have also been lowered in the last decade (Table 13.10.2). Most children with diabetes present with classical symptoms, and hence need only two random blood sugar values to confirm the diagnosis. Only type 1 diabetes will be further discussed.



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• Type 1 diabetes: – Immune mediated – Idiopathic • Type 2 diabetes • Other specific types: – Genetic defects of beta-cell function: - HNF-1 alpha, 4 alpha and glucokinase (formerly MODY 3, 1 and 2) - Mitochondrial DNA – Genetic defects in insulin action: - Type-A insulin resistance, leprechaunism, RabsonMendenhall syndrome, lipoatrophic diabetes – Diseases of exocrine pancreas: - Fibrocalcific pancreatopathy, cystic fibrosis, hemochromatosis – Endocrinopathies: - Cushing syndrome, pheochromocytoma, hyperthyroidism, gigantism/acromegaly – Drug or chemical induced: - Pentamidine, glucocorticoids, phenytoin, thiazides, diazoxide – Infections: - Congenital rubella, cytomegalovirus – Uncommon forms of immune-mediated diabetes: - Stiffman syndrome, anti-insulin receptor antibodies – Other genetic syndromes associated with diabetes: - Down, Klinefelter, Turner, Wolfram, Friedreich ataxia, Laurence-Moon-Biedl, Prader-Willi, myotonic dystrophy • Gestational diabetes mellitus

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Table 13.10.2 Diagnostic criteria for diabetes mellitus





• Symptoms of diabetes plus random plasma glucose ≥ 200 mg/dL (on two separate occasions if symptoms not typical or hyperglycemia not unequivocal) • Fasting plasma glucose ≥ 126 mg/dL on two occasions • Two-hour plasma glucose ≥ 200 mg/dL during oral glucose tolerance test on two occasions (glucose load 1.75 gm/kg) • HbA1c > 6.5% (taking care the laboratory reporting the HbA1c is NGSP certified and it is standardized to the diabetes control and complications trial) along with one of the above criteria.

pidemiology

The prevalence of diabetes among school children (up to 18 years of age) in USA is approximately 1 in 500. Reliable prevalence and incidence data from India are not available. The incidence of new cases varies with geographical 828 location, being highest in Finland and Sweden (40 per 100,000 children per year) and lowest in Japan (less than 1

per 100,000 children per year). Boys and girls are equally at risk. The incidence in European countries is increasing at the rate of 3% per year. E

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Type 1 diabetes is a chronic autoimmune disease involving only the beta cells, with gradual loss of insulin secretion.

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Diabetes in childhood typically present with polyuria, polydipsia, polyphagia, weight loss and weakness. Keto acidosis is heralded by vomiting, dehydration, abdominal pain, deep and rapid (Kussmaul) respiration and the fruity odor of acetone in the breath. Ketoacidosis may mimic an abdominal surgical emergency. Severe acidosis is accompanied by decreasing consciousness and hypotension. The presence of fever is an important clue to infection. Laboratory findings include glycosuria, hyperglycemia, ketonemia and ketonuria. Leukocytosis may be present without infection. Hypertriglyceridemia is typical. Diabetic ketoacidosis (DKA) is usually characterized by normal serum sodium, normal or initially raised serum potassium, significant ketonemia (serum ketone positive on a qualitative test even on 1:1 dilution), blood pH below 7.3 and bicarbonate below 15 mEq/L. The metabolic acidosis of DKA exhibits an increased anion gap (> 10 mmol), due to 829 unmeasurable anions of ketoacids. ­

Numerous evidences exist for an autoimmune etiology of type 1 diabetes. Diabetes is frequently associated with conditions of known autoimmune etiology like Hashimoto thyroiditis, pernicious anemia and Addison disease. It is also associated with the presence of many autoantibodies. About 80–90% of newly diagnosed type 1 diabetes patients (30–40% in India) have islet cell antibodies. A similar number is also positive for antibodies against glutamic acid decarboxylase, an enzyme present in the islet and other neuroendocrine tissue. Anti-insulin autoantibodies are present in 30–40% of newly diagnosed patients. Studies in siblings of type 1 diabetes probands have shown that 60–80% of first degree relatives positive for more than two autoantibodies go on to develop diabetes within 5 years. Lastly, abnormalities in “T” lymphocyte function exist in type 1 diabetes patients and animal models. With these evidences, a clearer picture of the pathogenesis is emerging. Some crucial antigen(s) of the beta cell, presented by the antigen

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Pathogenesis of Autoimmune Destruction



Viruses especially coxsackie and other enteroviruses, are the most commonly implicated environmental factor. Evidences include seasonal differences in the incidence of diabetes and episodes of viral infection frequently preceding the onset of diabetes. However, the only viral infection directly predisposing to diabetes is congenital rubella infection, in which 20% of affected children develop diabetes. Other proposed environmental agents include the role of early weaning to cow’s milk (through albumin/ casein), toxins (e.g. nitrosamines) and stress. Environmental factors may induce autoimmunity by molecular mimicry or by directly stimulating cytokine production.

Insulin acts mainly on three tissues: liver, muscle and adipose tissue. It induces glucose-uptake, glycogen synthesis and lipogenesis in the liver, and stops gluconeogenesis. In muscle, insulin brings about glucose uptake and oxidation, and glycogen synthesis. In adipose tissue, glucose-uptake and lipid synthesis occur. Thus, in diabetes mellitus, hyperglycemia results due to glycogenolysis, gluconeogenesis, lipolysis and absence of glucose uptake. Concomitant rise in the counterregulatory hormones (glucagon, epinephrine, cortisol and growth hormone) aggravates hyperglycemia and ketogenesis. While lipolysis is caused by insulin deficiency, enhanced oxidation of the fatty acids so produced is induced by glucagon. Glucagon induces the carnitine palmitoyl transferase system of enzymes, which translocates fatty acids into mitochondria for beta oxidation, and thus causes ketogenesis. When blood sugar exceeds the renal threshold of 180 mg/dL, glycosuria, diuresis, electrolyte loss, dehydration and hyperosmolality result. Untreated dehydration and acidosis cause cerebral obtundation as well as circulatory failure.

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The inheritance of diabetes is polygenic. In comparison to a 0.6% lifetime risk (for a white Caucasian) to develop diabetes, a sibling of a proband may be said to have a 3–6% risk of developing diabetes, and an offspring a 2–6% risk (with a diabetic father conferring greater risk than a diabetic mother). The major susceptibility loci are the human leukocyte antigen (HLA) Class II genes, and the insulin gene. Two other important loci are the cytotoxic T-lymphocyte antigen 4 and protein tyrosine phosphatase N22 gene. Genome wide association studies have shown that greater than 14 loci contribute to the risk of type 1 diabetes mellitus. In almost all races, HLA-DR3-DQ2 and DR4-DQ8 antigens are associated with increased risk of type 1 diabetes, whereas HLA-DR15/DQ6 confers protection.



Genetics of Type 1 Diabetes

presenting cells of the immune system, are presented to specific “T” lymphocytes in conjunction with specific HLA-D locus molecules. The activation of “T” lymphocytes sets off a series of responses including cytokine production, which amplify the immune response, ultimately resulting in beta cell destruction. These evidences of the autoimmune nature of type 1 diabetes, together with the possibility, albeit imperfect, of predicting which siblings of a proband will go on to develop diabetes, have led to the commencement of many trials (using insulin, nicotinamide, etc.) for the prevention of type 1 diabetes. A discussion of these is beyond the scope of this book. It may be said that all trials for the prevention of type 1 diabetes are at best experimental at present.

ndocrinology

Patients have a genetic predisposition to the disease, though only a few subjects so predisposed develop the disease. It is thought that an environmental factor is necessary to trigger the onset of autoimmunity. Autoimmune destruction is a slow process, and the decline in insulin production occurs over a period of months to years, overt diabetes becoming manifest when beta cell reserve is below 20% of normal.

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Treatment of etoacidosis



Initial laboratory evaluation should include blood sugar, blood and/or urine ketone, serum sodium, potassium, chloride, bicarbonate, calcium, phosphorus, arterial blood gas analysis, electrocardiogram, blood culture and urine microscopic examination. The bladder should be catheterized in comatose patients. In mild DKA (with blood glucose 200–250 mg/dL, mild dehydration, pH 7.2–7.3 and bicarbonate 10–15 mmol/L), the child can be given oral rehydration with appropriate (sugar-free) fluid and subcutaneous insulin therapy started as below (see post-acidosis insulin therapy). K

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The child in DKA is usually moderately to severely dehydrated. Therefore, the quantity of deficit fluid to be replaced is 75– 85 mL/kg of current weight, and this is given evenly over 48 hours. If the child is hypotensive, a rate of 10–20 mL/kg within the first hour is given to establish circulatory stability. The remainder of the deficit fluid is given over the next 48 hours, along with the maintenance for the period. Sudden introduction of hypo-osmolal fluids has been implicated in the etiology of cerebral edema, a dreaded complication of DKA. The most commonly used approach in children is to start therapy with normal saline, but to switch to half normal saline after the first 6 hours or so. Potassium (40 mEq/L) should be added to the infusion as soon as urine formation is ascertained, after the first hour of fluids, as body potassium is severely depleted in DKA. It may be temporarily delayed it there is evidence of hyperkalemia on the electrocardiogram. Though total body phosphorus is also depleted in DKA, 830 its administration has not been shown to alter the course

Unnecessary alkali therapy in DKA is dangerous. It can precipitate cerebral edema by increasing central nervous system acidosis, precipitating hypokalemia, shifting the oxygen dissociation curve to the left and causing alkalosis. Sodium bicarbonate may be indicated for symptomatic hyperkalemia or if the blood pH persists at less than 6.9 after the first hour of rehydration, with cardiovascular instability. The dose to be infused is calculated by the formula: (mL of sodium bicarbonate = 0.15 × base deficit × kg body weight). The amount (usually 40 mL) is never given as a bolus, but added to a 0.5 N saline infusion over 2 hours. Alkali therapy should be stopped when pH is greater than 7.0.

Insulin Therapy The continuous low-dose insulin infusion is the method of choice for treating children with DKA. Regular insulin, 0.1 units per kg, is given as a continuous normal saline infusion at the rate of 0.1 units/kg/hour (recent recommendations do not advise an insulin bolus for children). The goal is to slowly decrease blood sugar by 50–100 mg/dL every hour. The infusion of insulin is stopped only when acidosis has normalized, not just after normalization of hyperglycemia. Therefore, when blood glucose decreases to 250–300 mg/ dL, 5% dextrose is added to the intravenous fluid infusion. After correction of acidosis (which may take 24 hours or longer in severe DKA), the child is ready to be started on subcutaneous insulin therapy. An initial dose (0.2–0.4 units/ kg) of regular insulin is given, half an hour after which the insulin infusion is stopped and the child allowed to eat. Such a regimen of insulin plus meal is carried out every 6–8 hours until the child can be reliably predicted to eat, after which twice daily doses of regular (plain) plus intermediateacting [neutral protamine Hagedorn (NPH)] insulin before breakfast and dinner are started, with a lunch time dose of plain insulin if needed.

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Management of diabetes mellitus includes treatment of DKA, post-acidosis therapy in hospital and management of diabetes at home.

Alkali Therapy

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In a patient who presents with the classical symptoms of polyuria, thirst and weight loss, the diagnosis of diabetes is straightforward, and requires only the demonstration of hyperglycemia. In a child with an accidental finding of glycosuria, one must differentiate diabetes mellitus from renal glycosuria or Fanconi syndrome. Ketonuria can occur in starvation, and, in adolescents, after an alcohol binge on an empty stomach. Both these conditions will not be accompanied by hyperglycemia and ketonemia will be mild (not positive in dilute serum). The child presenting with acidosis must be differentiated from other causes of metabolic acidosis with increased anion gap, like uremia, lactic acidosis and salicylate poisoning. Every child presenting in a coma must have a blood sugar and urine ketone test to detect DKA.

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Clinical parameters like vital signs, hydration, sensorium, pupils, urine output, fluid infused, insulin infusion rate, etc. must be monitored every hour and a flow sheet should be carefully maintained. Capillary blood glucose by finger prick should be done at the bedside every hour initially and later every 2 hours. Serum sodium, potassium and bicarbonate should be measured every 4 hours initially and later 6 hourly. Urine ketones, serum phosphorus and calcium may be done every 8–12 hours. Urine ketones may seem to worsen or persist for long, despite clinical improvement. This is because with insulin therapy, β-hydroxybutyrate, an unmeasured ketone present in larger quantities in DKA, is converted to acetone and acetoacetate, the measured ketones. This should not be interpreted as indicative of worsening.

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After stabilization of the acidotic state, the following issues must be addressed: • Management of precipitating factor for DKA, like infection or emotional stress • Subcutaneous insulin therapy • Nutrition • Education of the family for home management of diabetes • Psychological and social support for the patient and the family.



Subcutaneous insulin therapy should be started when acidosis subsides. A mixture of regular and intermediateacting (neutral protamine Hagedorn) insulin is given twice a day, half an hour before breakfast and dinner. This is the so-called split-mix regimen. The total daily dose (0.5–1.0 units/kg) is roughly divided into two-third to be given before breakfast and one-third before dinner. Two-third of each dose should consist of NPH insulin, and one-third, approximately, of regular insulin. These are just initial guidelines. From the next day, doses should be titrated according to blood sugar responses obtained the previous day. In most instances, for the first 1–2 months, much higher doses of insulin (1.5–2 units/kg) are needed, which automatically come down to about 1–0.5 unit per kg subsequently. The addition of a plain insulin dose at lunch time is useful for better control of blood sugars. Insulins available in India contain 40 units/mL or 100 units/mL. Care must be taken to administer U40 insulin only with a U40 syringe and likewise U100 insulin must be matched with a U100 syringe. The two insulins (regular and NPH) can be drawn into the same syringe, first regular, followed by NPH, to be given as a single subcutaneous injection. Disposable insulin syringes have clearer markings and less dead space than glass ones. Suitable sites for insulin injection are the back of upper arm, front of thigh,

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Cerebral edema: Clinically symptomatic cerebral edema occurs in 1–2% of children with DKA and has a high mortality of 50%. It usually occurs during insulin therapy, when the child actually appears to be responding to treatment. The etiology is not clear, but has been linked to too rapid correction of hyperosmolality, excessive use of alkali, high initial blood urea and greater hypocapnia, and lack of rise of serum sodium during treatment. Early signs include change in sensorium (drowsiness or agitation), headache, vomiting, comparative decrease in heart rate or increase in blood pressure. Pupillary changes, papilledema and upgoing plantars are late signs. Prompt therapy with mannitol (without necessarily waiting for a confirmatory CT scan) is indicated at the earliest suspicion. Others: Acute gastric dilatation or erosive gastritis, vascular thrombosis and respiratory distress syndrome.

abdomen and buttocks. The injection site must be different each time, to avoid lipodystrophy. Insulin is ideally stored in a refrigerator (never frozen). Families who do not have the facility can store it in a damp cloth in the coolest portion of the house. In addition to insulin, analogs of insulin are now available, which have unique features providing greater flexibility and lower chances of hypoglycemia. Insulin lispro and aspart, which have minor amino acid differences from insulin, have a quicker onset and shorter duration of action than regular insulin. This makes them suitable for use in toddlers, who cannot be depended upon to eat at a particular time, as the injection can be given after the child has actually started eating. The analogs glargine and detemir are poorly soluble at the pH of subcutaneous tissue and hence are peakless. They provide basal 24 hour insulin in blood, without the extent of hypoglycemia found with NPH. Unfortunately, these analogs are costlier than regular and NPH insulins at the time of writing.

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omplications of iabetic etoacidosis

utrition

The ideal diet for a child with diabetes is nothing but a healthy meal plan for any member of the family, with the additional requirement of avoidance of simple sugars. The total daily calories should be calculated from age, weight, pubertal status and recommended dietary allowance calculations, tempered with the knowledge of the child’s dietary pattern before the illness. A rough guideline is 1,000 calories at 1 year age, and additional 100 calories per year of age after that, up to puberty. Approximately 55–65% of calories should derive from carbohydrates, 15% from protein and 20–30% from fat. Foods rich in fiber (whole pulses, whole grain cereal, vegetable, and fruit) should be encouraged as they have a low glycemic index. Foods rich in fat, especially saturated fat, are to be avoided. The day’s meal plan should be divided into three meals (breakfast, lunch and dinner) and 2–3 snacks (midmorning, evening and bedtime). However, these schedules can be tailored according to the individual needs of the child and family, with insulin doses adjusted accordingly. It must be borne in mind that the patient is a child, for whose emotional wellbeing we must accept some flexibility in the do’s and don’ts of dietary management. Hence, items with simple sugar or excess fat must be allowed on special occasions like birthdays or festivals.

Monitoring The importance of excellent blood glucose control in minimizing, preventing or delaying long-term complications of diabetes is now well-established. To this end, it is essential for blood sugars to be monitored frequently so as to take steps to prevent or treat high blood sugars.

Home Monitoring With the advent of glucose oxidase strips, blood glucose can be measured at home using strips with a reflectance 831 meter. Urine glucose (positive only when blood glucose

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Hypoglycemic eaction Mismatch between insulin dose on the one hand, and meal and exercise on the other, results in hypoglycemia quite frequently in the life of a child with diabetes. Defined as a blood sugar of less than 60 mg/dL, it is heralded by adrenergic symptoms like sweating, pallor, trembling and tachycardia. Patients are taught to recognize these symptoms and institute treatment (see below). If unrecognized, blood glucose levels may drop further, leading to neuroglycopenic symptoms like drowsiness, confusion, coma or seizures. Most often, though, the release of counter-regulatory hormones at a level of 55–60 mg/dL leads not only to the warning (adrenergic) signs, but also to a rebound rise in blood glucose.

Treatment of Hypoglycemia It is always advisable to first confirm the symptoms of hypoglycemia with a blood sugar test. For immediate rise in blood sugar, simple sugar (5–10 g) in the form of sugar, glucose, fruit juice or a carbonated drink must be taken. In addition, a small snack of protein plus carbohydrate must be eaten. The unconscious child with hypoglycemia can be treated at home with 0.5 mg (1.0 mg in the adolescent) of glucagon given subcutaneously. If glucagon is not available, the child should receive intravenous glucose in the nearest emergency center. After an episode of severe hypoglycemia is treated, the family must assess the reasons for its happening. Preventable factors like missed meals or exercise uncompensated with food, must be recognized. Necessary reductions in insulin dosage must be instituted, if hypoglycemia shows a recurring pattern.

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Home glucose monitoring does not give an integrated picture of blood glucose control over the long term. This deficiency is made up by performing glycosylated hemoglobin (HbA1c) measurement once in 3 months. It represents the fraction of hemoglobin to which glucose has got attached, over the lifespan of a red blood cell. The normal value in people without diabetes is 4–6%. A value of up to 7% in a patient indicates excellent blood glucose control; a value between 7% and 8% is regarded as good and greater than 8% indicates scope for much improvement. However, these goals must be relaxed for children younger than 7–10 years, as recurrent hypoglycemia is detrimental for cognitive development.

management techniques. Diabetes management, as well as teaching, is best carried by a team consisting of the doctor, diabetes nurse/educator, dietician, psychologist and social worker. In addition to insulin therapy, nutrition, monitoring, and hypoglycemia, patients must be taught the importance of exercise as well as management during days of unrelated sickness. Perhaps the single most important message for patients, in relation to sick days, is that insulin must not be stopped. On the other hand, insulin requirement may actually rise during illness. C



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rises above 180–200 mg/dL) is less informative than blood glucose testing. Unfortunately, blood glucose testing is expensive. A combination of blood and urine glucose testing schedules can be used. Ideally, capillary blood glucose should be tested daily fasting, prelunch, predinner and at bedtime. Post-meal sugars may be tested on 1 or 2 days a week, and a test at 1 or 2 am to rule out nocturnal hypoglycemia, once in 2 weeks. Blood glucose should also be tested to confirm symptoms of hypoglycemia, whenever possible. A high blood sugar before a meal may be dealt with by taking a small additional dose of regular insulin. When blood sugar is persistently high (> 300 mg/dL) and on days of fever/other sickness, urine must be tested for ketones. This rigorous schedule of testing requires a motivated patient and supportive family interested in excellent blood glucose control. The pediatrician must be careful to individualize these instructions. Table 13.10.3 describes the blood glucose goals for intensive therapy as well as conventional therapy. Those who test urine sugar must do so on a second void specimen. Urine sugar testing by test strips does not work out costlier than using Benedict’s reagent, and due to far greater convenience, is likely to encourage compliance.

 

Table 13.10.3 Goals of conventional and intensive therapy

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Conventional therapy: – HbA1c 7.5–8.5% – Pre-meal blood glucose 120–160 mg/dL – Absence of polyuria and ketonuria Intensive therapy: – HbA1c 6.0–7.0% – Pre-meal blood glucose 80–120 mg/dL – Post-meal blood glucose < 180 mg/dL

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Blood sugar patterns in diabetes are not necessarily stable from day to day. Variations are brought about by changes in exercise and meal pattern, emotional status, etc. Thus, successful therapy of diabetes is not possible without the patient and/or family assuming responsibility for day to day care. This requires that the family be educated in diabetes

Microvascular (affecting the eye, kidneys and nerves) and macrovascular (causing cerebrovascular and coronary heart disease) complications are responsible for longterm morbidity and mortality in diabetes mellitus. Growth retardation and pubertal delay are additional issues in childhood and adolescent diabetes. Pathogenetic mechanisms implicated include glycosylation of proteins, abnormalities in the polyol pathway, growth factors, platelet function defects, hyperinsulinemia, and free radicalinduced damage. While the pathogenesis of each is not yet

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1. American Diabetes Association. Clinical practice recommendations. Updated yearly and available free of cost at www.diabetes.org. 2. Atkinson MA, Bluestone JA, Eisenbarth GS, et al. How does type 1 diabetes develop? The notion of homicide or beta-cell suicide revisited. Diabetes. 2011;60(5):1370-9. 3. Daneman D. Type 1 diabetes. Lancet. 2006;367(9513):847-58. 4. Dunger DB, Sperling MA, Acerini CL, et al. ESPE/LWPES consensus statement on diabetic ketoacidosis in children and adolescents. Arch Dis Child. 2004;89(2):188-94. 5. Glaser N, Barnett P, McCaslin I, et al. Risk factors for cerebral edema in children with diabetic ketoacidosis. The Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics. N Eng J Med. 2001;344(4):264-9. 6. Indian Society for Pediatric and Adolescent Endocrinology. Guidelines for Management of Type 1 Diabetes Mellitus in Children; 2009. 7. ISPAD Clinical Practice Consensus Guidelines 2009 Compendium. The complete set of guidelines can be found at www.ispad.org. 8. Rachmeil M, Perlman K, Daneman D. Insulin analogues in children and teens with type 1 diabetes: advantages and caveats. Pediatr Clin North Am. 2005;52(6):1651-75. 9. Reichard P, Nilsson BY, Rosenqvist U. The effect of longterm intensified insulin treatment on the development of microvascular complications of diabetes mellitus. N Engl J Med. 1993;329(5):304-9.



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perfectly clear, large follow-up studies like the diabetes control and complications trial have clearly established a strong correlation between poor blood glucose control and frequency of complications. Thus, the onus is on all those who care for children with diabetes, to encourage the best possible metabolic control. Intensive insulin therapy aimed at maintaining near normal blood sugars is however, associated with three times greater risk of severe hypoglycemia (coma/convulsions) than conventional insulin therapy. Therefore, it is not advisable in young children (particularly below 7 years of age), or for those who do not have constant access to emergency care. Complications of diabetes usually do not set in before a duration of diabetes of at least 3–5 years. Background retinopathy occurs in almost 90% after 15 year’s duration, but vision-threatening (proliferative) retinopathy occurs in only 25% patients after 25 years. Similarly, end-stage renal disease occurs in 15–20% of patients after a similar duration. These figures have almost halved in the last 3 decades, the fall in complication rate being attributable to improved blood glucose control due to availability of home blood glucose testing strips. It has been hitherto believed that complications do not occur in the prepubertal diabetic child, irrespective of duration of diabetes. However, recent prospective studies indicate that this may not be entirely true, and that prepubertal children must be screened for complications after duration of diabetes of 3–5 years.

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Section

14 Genetics



14.1 14.2 14.3 14.4 14.5













Section Editor : Shubha R Phadke Basic Genetics: VH Sankar Clinical Dysmorphology: ML Kulkarni Common Genetic Disorders: Madhulika Kabra Advances in Genetics: Ishwar C Verma Genetic Metabolic Disorders: Shubha Phadke

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Genetics is the science of human biologic variation. Medical genetics is the application of this knowledge for understanding health and disease, while clinical genetics is the application for diagnosis, prevention and management of patients with genetic disorders. Deoxyribonucleic acid (DNA) is the hereditary material which is present in the nucleus of the cell. The DNA is packaged into 23 pairs of chromosomes in each cell. Nucleic acid is composed of a long polymer of individual molecules called nucleotides. Each nucleotide is composed of a nitrogenous base, a sugar molecule and, a phosphate molecule. The nitrogenous base fall into two types: (1) purines (adenine and guanine) and (2) pyrimidines (cytosine, thymine and uracil). Gene which is the fundamental unit of heredity is a segment of DNA molecule which codes for a polypeptide. Each human is estimated to have approximately 30,000 genes. Alterations in these genes, alone or in combinations of them can produce genetic disorders. These disorders are classified into the following major groups: • Chromosomal disorders: Entire chromosome or segments of them are missing, duplicated or altered. Examples: Down syndrome (DS), Turner syndrome • ingle gene disorders (also known as monogenic disorders): Disorders in which single genes are altered – often called “Mendelian” conditions since they follow, Mendelian mode of inheritance. Examples: Thalassemia, Spinal muscular atrophy, Hemophilia • Mitochondrial disorders: A relatively small number of diseases are caused by alterations in the small cytoplasmic mitochondrial DNA and are inherited in non-Mendelian fashion • Multifactorial disorders: Results from a combination of multiple genetic and environmental causes. Examples: Birth defects like cleft palate/cleft lip, neural tube defect, and common diseases like diabetes, psychiatric illnesses and hypertension • omatic cell genetic disorders: Cancers are caused by additive effects of mutations in several genes in a somatic cell. Other disorders included in this group are autoimmune disorders and aging process.

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mpact of Genetic Diseases

The incidence of genetic disorders and their impact on health can be gauged from the following observations: • A chromosomal abnormality is present in 40–50% of all recognized first trimester pregnancy losses

In neonates, 2–3% has at least one major congenital malformation The incidence of chromosomal abnormalities and single gene disorders in neonates are approximately 0.5% and 1% respectively As per the neonatal perinatal database of the National Neonatology Forum (NNF) congenital malformations were the second commonest cause (9.9%) of stillbirths and the fourth commonest cause (9.6%) of neonatal mortality Genetic disorders account for 50% of all cases of mental retardation and 50% cases of childhood deafness Approximately 5–10% of common cancers such as breast, colon and ovary have a strong genetic component All common disorders like hypertension, psychiatric illnesses, diabetes and coronary artery disease have a strong genetic susceptibility factor.

Chromosomes and Cell Division



At conception human cell zygote consists of a single cell. This undergoes rapid division leading ultimately to the mature human adult, consisting of approximately one hundred trillion (1014) cells. This process of cell division is called mitosis. During mitosis each chromosome divides into two daughter chromosomes and one will segregate to each cell. Mitosis is a continuous process lasting for 1–2 hours. However, for convenience of description it is divided into five distinct stages: (1) prophase, (2) prometaphase, (3) metaphase, (4) anaphase and (5) telophase (Fig. 14.1.1). Meiosis is a specialized cell division process in which a diploid cell gives rise to haploid gametes. This occurs only in the final division of gametogenesis. In contrast to mitosis, meiosis occurs as two rounds of cell division (meiosis I and meiosis II) (Fig. 14.1.2). The word “chromosome” is derived from the Greek words for “colored body”. Human cells contain 46 chromosomes comprising 22 pairs of autosomes numbered from 1 to 22 and a pair of sex chromosomes (two X chromosomes in females and one X and one Y in males). The numbers are assigned in descending order of lengths of chromosomes and are classified into groups depending on the sizes of chromosomes and position of centromere in each chromosome. Each chromosome is made up of a short “p” arm and the longer “q” arm joined at the centromere. Various types of chromosomes are shown in Figure. 14.1.3. The study of chromosomes is referred to as cytogenetics. Karyotype refers to the orderly arrangement of chromosomes of one cell starting from the largest 835

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ext ook of Pe i tri s Chromosome Abnormalities Chromosome abnormalities can be divided into numerical or structural. Numerical abnormalities involve the loss or gain of one or more chromosome, referred as aneuploidy. 836 In trisomy a single extra chromosome is present (DS-

igure 14.1.2 The stages of meiosis during which haploid gametes are formed from a diploid cell  

chromosome 1 to chromosome 22 followed by sex chromosomes. Chromosomes can be analyzed from any actively dividing cells. Figure 14.1.4 shows a G banded normal karyotype. The word “karyotype” is also used to describe the chromosome complement of an individual. For example, 46,XY means the individual has normal 46 chromosomes with one X and one Y chromosome. Newly developed molecular cytogenetic techniques, such as fluorescent in situ hybridization (FISH) and microarray based cytogenetic analysis do not need live dividing cells and can detect chromosomal abnormalities of very small size which are not detectable by traditional karyotyping.

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igure 14.1.1 The stages of mitosis resulting in two identical diploid cells formed from one original diploid cell

trisomy 21) whereas in monosomy there is a loss of one chromosome (Turner syndrome-monosomy X). The addition of complete haploid set of chromosomes is called polyploidy. Structural chromosomal abnormalities include translocation, deletions, inversions, insertions, ring chromosome and isochromosome (Table 14.1.1). A Robertsonian translocation results from breakage of two acrocentric chromosomes (numbers 13, 14, 15, 21 and 22) at or close to the centromere, with subsequent fusion of their long arms.

Mosaicism Mosaicism is being defined as the presence in an individual or in a tissue of two or more cell lines which differ in their genetic constitution but are derived from a single zygote, i.e.

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Table 14.1.1 Structural chromosomal abnormalities Type Description Examples A deletion involves loss of part of a chromosome results in monosomy for that segment of the chromosome

igure 14.1.4 G banded karyotype of a normal female

Ph chromosome: involving chromosomes 9 and 22

Inversion can be pericentric inversion (involving centromere) or paracentric inversion (only one arm of the chromosome)

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Robertsonian This results from breakage translocation of two acrocentric chromosome (13, 14, 15, 21 and 22) at or close to the centromere, with subsequent fusion of their long arms Reciprocal This involve breakage of translocation at least two chromosomes with exchange of the fragments Insertion An insertion occurs when segment of one chromosome become inserted into another chromosome Inversion An inversion is a two break rearrangement involving a single chromosome in which a segment is reversed in position, i.e. inverted

•  Wolf-Hirschhorn syndrome (partial monosomy involving short arm of chromosome 4) •  Cri du chat syndrome (partial monosomy involving short arm of chromosome 5) Down syndrome due to translocation between chromosomes 14 and 21

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Disorders caused by alterations in single genes are often called “Mendelian” conditions since they follow Mendelian

igure 14.1.3 Different types of chromosomes: metacentric, submeta­ centric and acrocentric chromosomes. The classification is based on the location of the centromere

Geneti s

they have the same genetic origin. Chimeras can be defined as the presence in an individual of two or more genetically distinct cell lines derived from more than one zygote, i.e. they have different genetic origins. Mosaicism can be of chromosomal abnormality or a single gene mutation.

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Principle of independent assortment states that genes at different loci are transmitted independently.

Basic Concepts Pedigree Diagrammatic representation of family history is known as a pedigree. The symbols are used to depict males, females, their relationships and disease status (Fig. 14.1.5). The affected individual who brings the family to notice is called as “proband” and the one who comes or genetic counseling is the “consultand”.

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mode of inheritance. Examples are Thalassemia, Spinal muscular atrophy (SMA) and Hemophilia. Gregor Johann Mendel who is considered to be the “father” of genetics designed experiment on garden peas and formulated a series of fundamental principles of heredity. Two important principles include: • Principle of segregation, which states that sexually reproducing organisms possess genes that occur in pairs and that only one member of this pair, is transmitted to the offspring (i.e. alleles on homologous chromosomes segregate)

igure 14.1.5 Symbols for pedigree drawing  

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Locus and Allele The site of a gene on a chromosome is locus and allele is the alternative form of a gene found at the same locus on homologous chromosomes.

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The term “genotype” has been defined as an individual’s genetic constitution at a locus. The “phenotype”, which is physically observable, results from interaction of genotype and environment.

(Fig. 14.1.7). Though clinically normal both the parents of an individual with an autosomal recessive disorder are always heterozygous carriers. X-linked recessive inheritance is due to a gene present on the X chromosome, and manifest only in males (Fig. 14.1.8). Affected males are related through carrier females. The X-linked disorders which manifests in the heterozygous females as well are termed as X-linked dominant disorders (Fig. 14.1.9). In this mode of inheritance,

Geneti s

Genotype and Phenotype

Dominance and Recessive Dominance is not a property intrinsic to a particular allele but describes the relationship between it and the corresponding allele on the homologous chromosomes.

Heterozygote and Homozygote

 

igure 14.1.7 A pedigree showing the inheritance of an autosomal recessive inheritance. Solid symbols represent affected individuals, double line indicates consanguinity. Note the horizontal transmission

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An individual who possesses two different alleles (different versions of a gene) at one particular locus on a pair of homologous chromosomes is called heterozygote whereas an individual who possesses two identical alleles at a particular locus on a pair of homologous chromosomes is called homozygote. I

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igure 14.1.6 A pedigree showing the inheritance of an AD inheritance. Solid symbols represent affected individuals

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igure 14.1.8 A pedigree showing the inheritance of an X linked recessive inheritance. Solid symbols represent affected individuals and dotted symbol represent heterozygous carriers. Note the oblique transmission

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igure 14.1.9 A pedigree showing the inheritance of an X linked dominant inheritance. Solid symbols represent affected individuals. Almost similar to AD but no male to male transmission

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A trait or disorder which is determined by a gene on an autosome is said to be followed an autosomal inheritance, whereas a trait or disorder determined by a gene on one of the sex chromosome is said to be sex-linked disorder. Autosomal dominant (AD) disorders are those in which both heterozygous and homozygous individuals show the abnormal phenotype, and the disease is transmitted from one generation to the other (Fig. 14.1.6). One copy of the mutant gene is sufficient for expression of the abnormal phenotype. An autosomal recessive disorder manifests only when both the copies of a gene are mutated in an individual and manifestations are seen in both male and female progeny of unaffected individuals. The autosomal recessive disorders usually manifest in the siblings and there is no clinically affected individual in generations above and below

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Autosomal dominant inheritance

Autosomal recessive inheritance

•  Successive or multiple generations in a family are affected •  Males and females are both affected in approximately equal proportions •  Males and females can both be responsible for transmission •  There is at least one instance of male to male transmission Examples: •  Neurofibromatosis (NF) •  Tuberous sclerosis (TS) •  Marfan syndrome •  Familial hypercholesterolemia

•  The disorder normally occurs in only one generation, usually within a single sib ship •  Both males and females are affected •  The parents may be consanguineous Examples: •  Thalassemia •  Spinal muscular atrophy •  Mucopolysaccharidosis

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Table 14.1.2 Characteristics of autosomal dominant inheritance and autosomal recessive inheritance

Reduced Penetrance An individual who has the genotype for a disease may not exhibit the disease phenotype at all, even though he/she can transmit the disease gene to the next generation. For example, in case of retinoblastoma 10% of the obligate carriers of mutation in the retinoblastoma susceptibility gene do not get the disease and penetrance of the gene is then said to be 90%. Some genetic conditions like Huntington chorea, a delay in the age of onset of the disease may occur which is described as age dependent penetrance.

 

Table 14.1.3 Characteristics of X-linked recessive and X-linked dominant inheritance

to new mutation. For example, it is estimated that 7 out of 8 cases of achondroplasia are caused by a new mutation. The recurrence risk for the individual’s sibling is very low if the parents are normal, but it will be substantially high for the individual’s offspring (50% in case of AD disorders like achondroplasia). New mutations are common in X-linked disorders as well contributing to about one-third cases of Duchenne muscular dystrophy.

X-linked recessive inheritance

X-linked dominant inheritance

•  Males are affected and females are carriers •  No male to male transmission •  50% of the sons of the carrier females are affected; 50% of the daughters are carriers •  All daughters of affected male are carriers •  Affected individuals are related through transmitting (carrier) females •  Pedigree is described as Oblique transmission •  A significant proportion of isolated cases are due to new mutations (some affected males do not reproduce) Examples: Hemophilia, Duchenne muscular dystrophy (DMD), Hunter syndrome

•  Looks like AD •  Daughters of affected male always inherit the disorder •  More females are affected, but have milder phenotype •  No male-to-male transmission •  Affected males with normal mates have no affected sons and no normal daughters •  Some disorders may be lethal in males Examples: Familial hypophosphatasia, Rett syndrome, Aicardi syndrome

males and females are both affected but the severity of disorder is usually less in females than males. The number of affected females is more than that of affected males. The Y-linked (holandric inheritance) implies that only males are affected (e.g. hairy ears). The characteristic pattern of each mode of inheritance is explained in the Tables 14.1.2 and 14.1.3.

Here, penetrance may be complete, but the severity of the disease amongst affected family members may vary. The classical example is of tuberous sclerosis where a parent with milder manifestations like adenoma sebaceum may not be aware of the disease till his or her offspring develops seizures or rhabdomyosarcoma which are severe manifestation of the same disease. The cause of variable expression may be environmental effects, or modifier gene (interaction of other genes).

Germline Mosaicism Mosaicism describes presence of more than one genetically distinct cell lines in the body. When two or more offspring presented with an AD or an X-linked disease in family with no history of similar genetic disorder or carrier parent, the mechanism most likely to be responsible is germ line mosaicism. During the embryonic development of one of the parents, a mutation occurred that affected all or part of the germ line but few or none of the somatic cell of the body. This mechanism is extensively studied in osteogenesis imperfecta type II and also described in DMD and Hemophilia A.

Locus Heterogeneity The causation of same disease phenotype by mutations at distinct loci is termed locus heterogeneity. Genetic conditions with significant locus heterogeneity are sensorineural deafness, retinitis pigmentosa, tuberous sclerosis and Charcot-Marie-Tooth disease.

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Variable Expression

New Mutation A child may be born with an AD disorder without any similar diseases in parents or other family members (a sporadic 840 case). This is usually due to new mutation in the affected child. A large proportion of observed AD disorders are due

Pleitrophy Genes that have more than one discernible effect on the body are said to be pleiotropic. A classic example of pleiotropic effects is Marfan syndrome: gene mutation affects eye, skeletal system and cardiovascular system.

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Because relatives share disease causing genes inherited from common ancestor, consanguinity is likely to be more frequent amongst the parents of an individual with an autosomal recessive disorder; especially so if the disorder in concern is rare. For genetic counseling, it is considered that prevalence of genetic diseases is roughly one to two times in the offspring of first-cousin marriages as compared to non-consanguineous population. Quantification of sharing of genes between two relatives can be done by estimating the coefficient of relationship. This shows that sibling share ½ of their genes (first degree relatives), uncle/aunt share ¼ of their gene (second degree relatives) and first cousins share 1/8 of their genes (third degree relatives), and so on.

An individual normally inherits one of the pair of homologous chromosomes from each parent. On the contrary if an individual inherits two copies of the same homologue from one parent, through an error in meiosis, this is called uniparental disomy (UPD). This mechanism has been identified as molecular pathology from a situation where a child with cystic fibrosis had only one parent who was carrier of cystic fibrosis mutation and the other parent was not carrier of cystic fibrosis. This mechanism is a cause in disorders of growth disturbances like Beckwith Wiedemann syndrome (UPD of chromosome 11) and Silver Russell syndrome (UPD chromosome 7).

Manifesting Female Carriers of X-Linked Recessive Disorders

Each human cell contains several hundreds of mitochondria in the cytoplasm. Mitochondria produce adenosine triphosphate (ATP), the energy source essential for cellular metabolism. They are having their own DNA molecule (mtDNA). Some important principles in mitochondrial inheritance are as follows: • Since mtDNA is present in the cytoplasm, it is exclusively derived from the maternal side. The pattern of inheritance is shown in the pedigree (Fig. 14.1.10) suggest that only females can transmit the disease to their offspring • The mutation rate in mitochondrial DNA is 10 times higher than that of nuclear DNA. The reason for this is high replication rate, lack of DNA repair and damage by oxygen free radicals in mtDNA • Heteroplasmy indicates a cell with heterogeneous population of mitochondria with or without mutations. It often results in incomplete penetrance of mitochondrial inheritance • At the cellular level, the proportion of mutated mtDNA (mutation load) determines phenotypic expression called threshold of expression. Central nervous system (CNS) and heart need high energy are commonly involved in mitochondrial disorders.

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Although female carriers of X-linked recessive disorders are usually asymptomatic, they can manifest the disease in following situations: • Homozygous for -linked recessive disorders: Female offspring of an affected father and a carrier mother • umerical chromosome abnormalities: Female carrier with only one X chromosome (Turner syndrome) • emale carrier with non-random or skewed -inactivation: In this situation, there is a departure from the normal random process of X-inactivation, with a greater proportion of normal X chromosome getting inactivated than the other one with a mutation of an X-linked disease • X-autosome translocation when the breakpoint of the translocation disrupts a gene on the X chromosome.

X-Inactivation (Lyon Hypothesis)

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Mitochondrial Inheritance

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This states that one X chromosome in each cell is randomly inactivated early in the embryonic development of females. This would result in dosage compensation, an equalization of X-linked gene products in males and females.

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Consanguinity

igure 14.1.10 A pedigree showing the inheritance of a disease caused by mitochondrial DNA mutation  

One of the Mendel’s law states that the phenotype is the same whether a given allele is inherited from father or the mother. Now, it has been recognized that different clinical features can result depending on whether the gene is inherited from the father or the mother. This “parent of origin” effect is referred to as genomic imprinting. Evidence of genomic imprinting has been classically observed in two dysmorphic syndromes associated with learning difficulties known as the Prader-Willi syndrome and Angelman syndrome. Prader Willi syndrome is caused by absence of a small part of chromosome 15 of paternal origin whereas the deletion of the same region on chromosome 15 from maternal origin gives rise to Angelman syndrome.

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Genomic Imprinting

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One assumption of Mendelian genetics is that mutant allele is transmitted from parent to offspring unchanged. Recently increasing number of disorders were identified in which the underlying mutation is an expansion of a triplet nucleotide repeat sequence that is unstable and can change in size on transmission from parent to offspring. The disorders with triplet repeat disorder are summarized in Table 14.1.4.

•

Multifactorial Disorders



Multifactorial disorders are the result of a combination of small variations in genes which predispose to serious defect, often in combination with environmental factors. This group includes common diseases diabetes mellitus, hypertension, obesity and schizophrenia, etc. Another important group of multifactorial disorders include congenital malformation like neural tube defect and congenital heart disease (CHD). For counseling of multifactorial disorders empiric recurrence risk derived from observational studies in families with the given disorder are used. Major characteristics of multifactorial disorders are: • Affected individuals tend to be cluster in families • The disease is more common among the close relatives of the proband and become less common as the relationship becomes distant • Heritability is defined as the function of total phenotypic variance of a quantitative trait that is caused by genes. For condition like asthama it is 0.80 whereas for CHD it is 0.35 .



Accurate and definitive diagnosis is the prerequisite for the prediction of prognosis and recurrence risk. Like any other clinical specialty, history taking including three-generation pedigree and clinical examination is important. Various hematological, biochemical and imaging investigations are needed. Specialized tests like chromosomal analysis, enzyme analysis, metabolic studies and DNA analysis are important for definitive diagnosis. Clinical situation where genetic counseling is important are listed in Table 14.1.5.

Pedigree Analysis The pedigree of at least three generations is to be constructed using standard set of pedigree symbols (Fig. 14.1.5). It illustrates the relationship among family members, and their disease status. The individual affected with a genetic disease who brings the family to notice is described as the “proband” for the family and indicated by an arrow. Roman numerals are used for labeling generations whereas Arabic numerals are used to indicate each individual within the generation.

Table 14.1.5 Clinical situation where genetic counseling is important  

Genetic Counseling

Choose the course of action, which seems to them appropriate in view of this risk, their family goals, their ethical and religious standards and act in accordance with that decision Make the best possible adjustments to the disorder in an affected family member and or to the risk of recurrence of that disorder.

 

 

 

1.  2. 3. 4. 5. 

 

 

6. 7.  8. 9. 10.  11.  12. 13.  14. 15. 16. 17. 18.

 

Table 14.1.4 Triplet repeat disorders Gene

Repeat

Fragile X syndrome (FXS)

FMR 1

CGG

Myotonic dystrophy

DMPK

CTG

Huntington disease

HD

CAG

Friedreich ataxia

X5

GAA

Spinocerebellar ataxia 1

FRATAXIN

CAG

 

 

 

 

Genetic disorder

 

 

American Society of Human Genetics in 1975 has defined genetic counseling as communicative process, which deals with human problems associated with the occurrence and or recurrence of a genetic disorder in a family. This process involves an attempt by one or more appropriately trained persons to help the individual or family to: • Comprehend the medical facts, including diagnosis, probable course of disorder and available management • Appreciate the way heredity contributes to the disorder and the risk of recurrence in relatives • Understand the alternatives for dealing with the risk of recurrence

 

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ext ook of Pe i tri s T

Triplet Repeat Disorders

 

19. 20. 

Congenital malformations Unexplained stillbirth with or without malformations Developmental delay/mental retardation Neurodegenerative diseases Myopathy, neuropathy, seizures, focal neurological abnormality, abnormalities of tone and power Ambiguous genitalia Hypogonadism Recurrent reproductive losses, infertility Short stature: proportionate or disproportionate Acutely sick infant, neonate: inborn error of metabolism (IEM) Known genetic disease: Wilson disease, DS, mucopolysaccharidosis, etc. Relatives of a person with chromosomal translocation Childhood deafness Familial cancer or cancer prone disease Any familial disease Any unusual disease of skin, bones and eyes Advanced maternal age Positive screening test for a genetic disorder, e.g. Triple test, increased alpha-fetoprotein (AFP) in mother Prenatal diagnosis of malformation Exposure to known or suspected teratogen in pregnancy

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1. Gardner RJM, Sutherland GR, Shaffer LG. Chromosome Abnormalities and Genetic Counseling. Oxford University Press; 2011. 2. Jorde LB, Carey JC, Bamshad MJ. Medical Genetics, 4th edition. Missouri: Mosby; 2009. 3. Keagle MB, Gersen SL. Principles of Clinical Cytogenetics, 2nd edition. New Jersey: Humana Press; 2005. 4. Koene S, Smeitink J. Mitochondrial medicine. J Inherit Metab Dis. 2011;34(2):247-8. 5. Phadke SR. Genetics for Clinicians, 1st edition. Bangalore: Prism Books; 2007. 6. Santos R, Lefevre S, Sliwa D, et al. Friedreich ataxia: molecular mechanisms, redox considerations, and therapeutic opportunities. Antioxid Redox Signal. 2010;13(5):651-90. 7. Strachan T, Read AP. Human Molecular Genetics, 3rd edition. Oxford UK: Garland Publishing; 2004. 8. Turnpenny PD, Ellard S. Emery’s Elements of Medical Genetics, 14th edition. London: Churchill Livingston; 2010.

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• Taking detailed three generation family history and drawing in the form of pedigree is the first step in evaluation of a case with possibly genetic disorder • Chromosomal disorders are an important cause of malformations and mental retardation and chromosomal study need to be ordered in these situations • Single gene disorders follow Mendelian inheritances: AD, Autosomal recessive, X linked recessive and X linked dominant • Factors complicating Mendelian inheritance like new mutations, reduced penetrance, variable expression and locus heterogeneity need to be considered while providing genetic counseling • Genomic imprinting, UPD, mitochondrial inheritance and triple repeat disorders are non-Mendelian forms of inheritances • Multifactorial disorders are the result of a combination of small variations in genes predispose to serious defect, often in combination with environmental factors • Genetic counseling should be an integral part of management of any disorder with genetic or probable genetic etiology -

Geneti s

Bibliography

ey Messages

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ntroduction

Dysmorphology is a word coined by Dr David W Smith in 1966 and is derived from the Greek words “dys” (disordered, abnormal) and “morph” (shape, form). Simply put it is the study of human congenital defects – abnormalities of body structure that originate before birth. Individual birth defects are rare, but together they account for a large proportion of childhood mortality and morbidity. More than 4,000 dysmorphic; multiple congenital anomalies and mental retardation syndromes have been reported with more being added with time. One to three percent of children are born with multiple or serious congenital defects. Knowledge and expertise are needed not only for identification of these serious defects but also other minor anomalies which may give clues to a more serious underlying pathology. Prompt recognition of the condition helps in prognostication, investigations, treatment and also helps the family by way of genetic counseling about recurrence risk and prevention.

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When multiple birth defects are encountered, it is useful to classify them first in order to arrive at an appropriate diagnosis. The most commonly used system for classification is as follows: • yndrome (“running together” in Greek): A pattern of features, often with a unifying underlying cause that arise from several different errors in morphogenesis (e.g. Down syndrome). Most dysmorphic syndromes are a constellation of major and minor anomalies. The presence of only one feature is never diagnostic but the unique combination gives the diagnosis of a syndrome • equence: A pattern of multiple anomalies derived from a single prior anomaly or mechanical factor – Example: In case of the Pierre-Robin sequence (micrognathia, glossoptosis and U-shaped cleft palate); the primary anomaly is the early mandibular hypoplasia which results in a posteriorly located tongue (secondary anomaly) thereby impairing the closure of palatal shelves resulting in a cleft palate (tertiary anomaly) (Figs 14.2.2A and B). Roughly 17% of Pierre-Robin sequence cases are isolated and non-syndromic; in remaining cases it is a part of syndromes like Stickler syndrome, Velo-Cardio-Facial syndrome and Beckwith Wiedemann syndrome. • ssociation: Non-random tendency of some mal formations to occur together more commonly than would be expected by chance, without being part of a syndrome. ­

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It is probably impossible to know all the congenital defects and the associated conditions by heart; hence it is necessary to categorize them into manageable subdivisions. A dysmorphic feature or anomaly is an abnormality of shape, size or structure. These features are traditionally classified as major or minor anomalies. A major anomaly is one that has severe medical or cosmetic consequences if untreated, such as a congenital heart defect or a cleft lip. A minor anomaly represents a medically insignificant departure from normal development, such as wide-set eyes or a single palmar crease. Three or more minor malformations are associated with multiple major anomalies in 90% of the patients and hence warrant a thorough evaluation. Before ascribing an anomaly to be significant an astute clinician should first take into consideration the ethnical background and the familial occurrence. Based on the pathogenesis birth defects can be classified as following: • Malformation: Early embryological developmental error (e.g. Cleft palate) • eformation: Internal or external mechanical forces alters normally forming structure (e.g. Club foot) • isruption: Breakdown of a previously normal tissue (e.g. Amniotic band sequence) (Fig. 14.2.1) • ysplasia: Abnormal cellular organization within a tissue resulting in structural changes of organs containing the tissue involved (e.g. Achondroplasia). 844

igure 14.2.1 Amnion rupture sequence, note the amputation and disruption of the finger morphogenesis

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Examples: VATERR association (Vertebral defects, Anal atresia, Cardiovascular anomalies, Tracheo esophageal fistula, Esophageal atresia, Radial dysplasia, Renal dysplasia) and MURCS association (Müllerian duct aplasia, Renal aplasia, Cervicothoracic Somite dysplasia) Many cases of CHARGE association (Coloboma of the eye, Heart defects, Atresia of the nasal choanae, Retardation of growth and/or development, Genito urinary abnormalities, and Ear abnormalities and deafness) have recently found to be caused by CHD7 gene and hence, CHARGE is now grouped as a syndrome and not an association.

Gene ics

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The first step in evaluation of dysmorphic child is “suspicion of genetic etiology” which should be suspected in any child who presents with: • ongenital anomalies: Major anomaly or more than two minor anomalies • Growth deficit: Short stature or failure to thrive • Developmental delay, mental subnormality or develop mental regression • Failure to develop secondary sexual characteristics • Ambiguous genitalia • Or simply does not look right”.

History Any mystery can be solved with a proper history. Some of the important historical points to be elicited are mentioneds in the Tables 14.2.1 and 14.2.2.

Physical xamination E

 

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igures 14.2.2 and Pierre robin sequence, note the micrognathia and unusual round shaped palatal cleft unique to this sequence

In addition to routine examination certain additional examination should be performed in a child with dysmorphic

Table 14.2.1 Personal/family history  

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History

Significance

Three generation pedigree chart using standard symbols

Indicates pattern of inheritance

Elderly mother (>35 years)

Chromosomal aneuploidy Example: Down syndrome

Elderly father (>45 years)

New AD mutation Examples: Achondroplasia and Marfan syndrome

Maternal disease Example: Diabetes mellitus

Known associated fetal abnormalities Diabetic embryopathy (Caudal regression, congenital heart defects, ear anomalies)

Poor social history

Possible alcohol/drug ingestion

Racial origin of parents

Known genes of high frequency in certain racial groups Example: Ellis-van Creveld syndrome in the Amish population

Parental consanguinity

Autosomal recessive disorders

Possible maternal uterine abnormalities

Deformations

Other affected family members or multiple single gene or chromosomal disorder

For diagnostic purpose and to know the pattern of inheritance

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History

Significance

Antenatal ultrasound

Aids prenatal diagnosis, holds clues to the diagnosis and to assess fetal growth

Maternal drug or alcohol ingestion Examples: Warfarin, anticonvulsants, cocaine

Teratogenic effects Examples: Warfarin – hypoplasia of nasal cartilage, CNS abnormality Valproate – Spina bifida, craniofacial dysmorphism Cocaine – vascular disruptions

Exposure to radiation (especially therapeutic)

Possible mutagenic or teratogenic effects

Early rupture of membranes

Possible fetal compression leading to deformation

Oligohydramnios

Renal agenesis or outflow obstruction with Potter sequence

Polyhydramnios

Esophageal atresia, neuromuscular disorders

Poor fetal movements

Fetal compression, neuromuscular disorders

Breech presentation

Neuromuscular disorders

ecognition of Genetic yndromes S

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atabases

Databases have become an integral aspect of practice in clinical genetics and dysmorphology. Some of the important textbooks and online catalogues of genetic syndromes are mentioned in Table 14.2.5. When using these databases one should keep in mind, that they are systems for experts and not expert systems. The Smith’s approach to a child with multiple malformations is a way of classifying syndromes based on the combination of major handles. The author considers this particular approach to be extremely effective and time tested. The following is the major list of classification that is used in the Smith’s approach. • •

•



Some syndromes are so striking to the eye of the pediatrician that a diagnosis is made instantaneously based on the general gist of the patient. This termed as “gestalt diagnosis” is exemplified in the diagnosis of a patient with Rubinstein Taybi syndrome (Figs 14.2.3A to E), wherein multiple minor anomalies make a combination so unique that a diagnosis is rarely missed. In order to have expertise in this mode of “gestalt diagnosis” one has to have a vast experience in seeing similar patients previously in order to create a mental snapshot of the condition. Given the rarity of individual syndromes, such an experience is seldom gained but by a few, hence repeated visual scanning of pictures of various syndromes from authoritative resources will have to suffice. When immediate recognition is not possible, it is necessary to identify one or more features (handles) which might lead to syndrome diagnosis. The best handle or anomaly to be taken to consideration is one which is least likely to be a normal variant. Features like mental retardation, microcephaly, simian crease, clinodactyly are nonspecific and act as poor handles for syndrome delineation. The anomalies which are less common but more specific are more useful for the search of diagnosis. Examples are microphthalmia, preaxial polydactyly, midline cleft lip, etc. Once a suitable handle is identified, reference should be made to standard monograph on syndromology or computer databases.

Sometimes some clinical features suggest specific diagnosis which could be called as “Pearls of dysmorphology” and few examples are mentioned below (Table 14.2.4). D



features. Table 14.2.3 lists some of the salient features that point to underlying dysmorphic syndrome. The importance of major anomalies is well known in syndrome delineation. When it comes to minor anomalies, presence of two or more features warrant further evaluation for syndrome association.



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Table 14.2.2 Pregnancy history

•

• • • •

Very small and proportionate stature, not skeletal dysplasia (e.g. Seckel syndrome) (Fig. 14.2.4) Moderate short stature, facial ± genital (e.g. Aarskog syndrome, Williams syndrome) (Figs 14.2.5A to D and Figs 14.2.6A to C) Senile like appearance (e.g. Cockayne syndrome, Werner syndrome) (Figs 14.2.7 A and B) Unusual brain and/or neuromuscular findings, with associated defects (e.g. Acrocallousal syndrome) (Figs 14.2.8A and B) Early overgrowth with associated defects (e.g. Sotos syndrome) (Fig. 14.2.9) Facial defects as major feature (e.g. Frontonasal dysplasia syndrome) (Fig. 14.2.10) Facial-Limb defects as major feature (e.g. Hay-wells syndrome of ectodermal dysplasia) (Fig. 14.2.11) Limb defects as major feature (e.g. Femoral hypoplasia) (Fig. 14.2.12)

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Table 14.2.3 Findings that suggest underlying genetic etiology •  •  •  •  • 

Short stature or tall stature Failure to thrive or obesity Unusual head circumference: Microcephaly or macrocephaly Unusual head shape: Brachycephaly, scaphocephaly, trigonocephaly Altered body proportion: Short spine, short limbs, long limbs

Facial features

•  •  •  •  •  •  •  •  •  •  •  • 

Synophrys (fused eyebrows) Hypotelorism or hypertelorism* Palpebral fissures that are upslanting or downslanting* Short palpebral fissures (normally the length of palpebral fissure is equal to the distance between two eyes) Short or long nose (the nose is usually 2/3–3/4 the length of the distance between the nasal bridge and the upper lip) Ears that are low set or posteriorly rotated* Ears that are simple or abnormally shaped Lips that are thin full, tented, down turned or cleft Philtrum that is long or smooth Palate that is high arched or cleft Uvula that is bifid or absent Prognathia or micrognathia*

Hands and feet

•  •  •  •  •  •  • 

Brachydactyly (short fingers) Arachnodactyly (long fingers) Clinodactyly (incurved fingers, usually the fifth)* Syndactyly (fusion of digits) Polydactyly (extra digits) Dysplastic nails Abnormal creases*

Skin and hair

•  •  •  •  • 

Abnormal skin pigmentation, e.g. hemangioma, cafe-au-lait Spots, streaks or whorls Abnormal amounts of hair, e.g. alopecia, hirsutism or hypertrichosis Abnormal hair line, e.g. low hairline (posteriorly or anteriorly) or receding hair line Altered hair color, e.g. white forelock

Musculoskeletal

•  •  •  •  •  •  •  •  • 

Short neck Abnormal chest shape or size, e.g. pectus carinatum, pectus excavatum, short sternum Abnormalities of nipples, e.g. widely spaced, supernumerary* Inverted nipples Abnormalities of the spine, e.g. anencephaly, encephalecele Myelomeningocele or stigmata of spina bifida occulta (hair, lipoma, deep dimple*) Unusual joint shape, e.g. flaring Abnormal joint mobility, e.g. hypermobility or reduced range of Motion

Abdomen

•  •  •  • 

Abdominal wall defects, e.g. omphalocele, gastroschisis Hepatosplenomegaly Nephromegaly Ambiguous genitalia

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General

*Indicate minor anomalies: 1.  Whenever an anomaly is noted, it should be described keeping in mind the following directives: •  Appropriate terminology •  Minor or major anomaly •  Etiology: Malformation/disruption/deformation •  Time of onset. 2.  Examination should not be restricted to the patient but should be extended to include all the available family members. 3.  Whenever feasible objective criteria should be used in diagnosing anomalies. The reader can refer to various Indian and foreign data useful in anthropometry. 4.  Cross consultation should be taken from specialists of other fields in medicine when dealing with a child with multiple anomalies (e.g. ophthalmology consults in Reiger syndrome). 5.  Consultation with a specialist in the field of dysmorphology is of utmost importance in the field of dysmorphology for the prompt diagnosis and for further evaluation. 6.  The camera plays the role of a stethoscope in the field of dysmorphology. Pictures are not only useful for record purposes and second opinions, but also help in the appraisal of the morphological evolution of a syndrome. 7.  Radiography goes hand in hand with physical examination when it comes to anomalies, since they are diagnostic in several conditions such as the group of skeletal dysplasias.

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igures 14.2.3 to

C

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E

Unrelated children with Rubinstein Taybi syndrome. Note the facial characteristics–downslanting palpebral fissures, overhanging columella of nose. Great toe is broad and medially rotated

Table 14.2.5 Important textbooks and online databases of genetic syndromes

Clinical sign

Specific diagnosis

Reference texts*

Pursed lips

Whistling face syndrome

Online and computerized databases

Broad thumbs and great toes

Rubinstein-Taybi syndrome

Absent clavicle

Cleidocranial dysostosis

Smith’s recognizable pattern of human malformations (Editor: Jones KL)

Online Mendelian inheritance in man (www.ncbi.nlm.nih.gov/omim)

Heterochromia iridis

Waardenburg syndrome

Mitten hands

Apert syndrome

GeneClinics and GeneTests (www. geneclinics.com)

Inverted nipples

Congenital disorder of glycosylation

Atlas of skeletal dysplasias (Editors: Wynne-Davies, Hall and Apley)

Webbing of neck

Turner and Noonan syndrome

Eversion of the lateral third of lower eyelid

Kabuki makeup syndrome

Syndromes of the head and neck (Editors: Gorlin, Cohen and Hennekam)

London dysmorphology database (www.lmdatabases.com)

Management of genetic syndromes (Author: Cassidy and Allanson)

POSSUM (Pictures of Standard Syndromes and Undiagnosed Malformations) (www.possum.net)

 

 

Table 14.2.4 Some clinical features which suggest specific diagnosis

•

TERIS (The teratogen information system) (depts.washington.edu/ terisweb/teris)



Craniosynostosis syndromes (e.g. Apert syndrome) (Figs 14.2.13A and B). A special mention is warranted in the case of skeletal dysplasia, since the huge list and the varied presentations of this group of enigmatic condition is a challenge even to the astute clinician. The following approach based on that suggested by Bryan D Hall is considered to be extremely effective in reaching a diagnosis: • Diagnosing short stature • Diagnosing disproportionate short stature • Diagnosing what causes this disproportion, is it short trunk (e.g. Spondyloepiphyseal dysplasias) or short limbs (e.g. Achondroplasia) • If short limbed which part of the limbs are affected: – Rhizomelia: Proximal shortening, i.e. humerus and femur (e.g. Chondrodysplasia punctata) – Mesomelia: Shortening of the middle segment, i.e. radius, ulna, tibia and fibula (e.g. Mesomelic dysplasia) – Acromelia: Distal shortening, i.e. hand and foot (e.g. Acromesomelic dysplasia) – Combination: Ellis van Creveld syndrome, Achond roplasia • Diagnosing deformations caused by the osseous 848 abnormalities (e.g. Craniosynostosis in thanatophoric dysplasia)

*

•

Diagnosing associated malformations which herald a clue to the actual condition (e.g. Heart defects in Ellis van Creveld syndrome) Categorizing based on the areas involved radiologically: Epiphyseal dysplasias, Diaphyseal dysplasias, Meta physeal dysplasias, Spine involvement, Cranial involve ment, Hand involvement Categorizing based on clinical and radiological grounds: Pure skeletal dysplasia (e.g. Achondroplasia): – Malformations associated (e.g. Stickler syndrome) – Malformation/Mental retardation associated (e.g. Campomelic dysplasia). ­

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•

See suggested reading for details.

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ttributes of a ysmorphologist

•

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–

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–

–

•

• •

He/she should be a meticulous and keen observer and must record any deviation from the norms He/she must see a number of cases and if not possible, must visually scan photographs and pictures Always use objective criteria and appropriate ter minology ­

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As in any field a person interested in dysmorphology should be a learner forever One has to be honest in his/her approach, Hungry for knowledge and Humble in acquiring it.

Gene ics

•

Intusion (the Unteachable and the Undefinable) Irrespective of their experience, training, extent of reading, clinical ability and observational skills, there exists a small group of individuals whose instinctive ability gives them better diagnostic expertise than their counterparts. Such individuals stand out in the field of dysmorphology.

igure 14.2.4 Seckel syndrome, note the sever microcephaly with prominent nose  

F

E

Laboratory valuation

a

B

Deformations seldom require any laboratory based diagnostic evaluation, whereas in this post-genomic era genetic testing plays a key role in the evaluation of malformations and associated syndromes. In addition to investigations to identify the etiology, investigations play an important role in detecting internal malformations of heart, brain, kidneys, etc. Diagnosis of malformation is not

C

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igures 14.2.5 to Aarskog syndrome. Note the hypertelorism and broad philtrum, hand showing brachydactyly with mild interdigital webbing (arrow), swan neck deformities of fingers and characteristic shawl scrotum. Scars due to operation for bilateral inguinal hernia are also seen. Patient was of moderate short stature

B  

C

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igures 14.2.6 to Williams syndrome. Note the periorbital fullness with medial eyebrow flare, prominent lips with an open mouth. Slit lamp examination revealed characteristic stellate iris pattern. Echocardiogram confirmed the diagnosis of supravalvular aortic stenosis

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A

F

a igures 14.2.7 and

Cockayne syndrome: Deep set eyes, rash on cheeks and changes of premature aging. The same child at (A) 5 years and (B) 12 years of age

 

F

igure 14.2.10 Frontonasal dysplasia sequence: the completely divided nostrils with hypoplasia of the prolabium with a median cleft lip  

B

A

igure 14.2.9 Sotos syndrome: macrocephaly, mild hypertelorism, prominent forehead and chin  

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igures 14.2.8 and Acrocallosal syndrome: the hypertelorism, downslanting palpebral fissures, broad nasal bridge and short philtrum. Post axial polydactyly is seen in both the upper limbs. Magnetic resonance imaging revealed absent corpus callosum

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igure 14.2.12 Femoral hypoplasia-Unusual facies syndrome: the short lower limbs; upslanting palpebral fissures with a short nose, hypoplastic alae nasie, set ears

igures 14.2.13 and Apert syndrome: (A) High full forehead, hypertelorism and downslanting palpebral fissures. Limbs show varying degree of syndactyly (Mitten hand); (B) Computed tomography (CT) head reconstruction shows bilateral coronal suture synostosis

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only useful in providing clue to the etiology but it is also important as the malformation may be surgically treatable.

aryotyping

F

Unless a non-chromosomal etiology is apparent in a child with multiple malformations it is a useful diagnostic approach to start with a karyotype (chromosome analysis). It is the definitive diagnostic test for aneuploidy syndromes such as Down syndrome, Turner syndrome and other structural abnormalities of chromosomes.

luorescent In Situ Hybridization ­

The FISH technique has revolutionized the field of cyto genetics having tremendous implications in the diagnosis of malformation syndromes. Fluorescent in situ hybridization

 

B

A

probes by their ability to attach to specific locus on a chromosome bring to light microdeletions that are not visible in the standard karyotype (Figs 14.2.14A and B). Table 14.2.6 lists the more commonly used and available FISH probes for syndrome delineation. As FISH can look at only a specific area of a chromosome it is important to clinically suspect the condition before ordering the FISH test. N

 

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igure 14.2.11 Hay-Wells syndrome of ectodermal dysplasia: the obvious ankyloblepharon, broad nasal bridge with bilateral cleft lip and palate. Child had associate dystrophic nails and supernumerary nipples

ew Genetic Tests

Comparative Genomic Hybridization Comparative genomic hybridization combined with microarray technique is a newer addition to the armamentarium of the dysmorphologists. It can detect very small deletions/duplications anywhere in the genome 851 in one test. The microarray based cytogenetic analysis has

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Now the sequencing of whole genome has become possible and if there are 2–3 patients of a disorder in a family, the causative gene can be identified using DNA samples of such a few cases. Table 14.2.7 provides a summary of the approach to diagnosis and management of common genetic disorders in children.

iochemical Testing

Many biochemical genetic defects are associated with dysmorphic features such as mucopolysaccharidosis, Zellweger syndrome and Smith-Lemli-Opitz syndrome. Testing for specific enzyme defect may be diagnostic in these conditions and can be supplemented by finding the underlying genetic defect. D

Mutation etection Genes for many malformation syndromes like Cornelia de Lange syndrome, Apert syndrome, Treacher Collins syndrome, etc. are known and many others are getting identified. However, due to large size of genes and large number of mutations observed in each syndrome use of mutation detection by DNA based techniques in clinical practice is not easy. For some disorders like Apert syndrome, Achondroplasia only one common mutation is identified in most of the cases. That is why mutation detection for such disorders is easy and available in India.

Genetic ounseling Genetic counseling is the process of helping people understand and adapt to the medical, psychological and familial implications of genetic contributions to the disease. The counselor offers investigations, options and support whereas the “consultand” (the person who seeks the advice) makes his/her own decision which is known as non-directive counseling. The essential steps include accurate diagnosis of the affected member in the family, risk assessment, proper communication, discussion of options and longterm contact and support. Assistance in enrolment of the patient in support groups may be paramount in this era of global communication.

ifficulties in ysmorphology D

 

B

A

F B

been advocated as a first line of test for cases with mental retardation/malformation without obvious cause and the diagnostic yield of the test is 7–10%.

C

B

igures 14.2.14 and Thanatophoric dysplasia, severe shortening of the limbs, i.e. acromesorhizomelic, loose folds of skin, macrocephaly with low nasal bridge, narrow thorax. Curved femora and flat vertebrae are seen in the radiograph

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a

In essence it is determination of the status (genetic or otherwise) of the fetus by a variety of techniques (ultrasonography (USG), chromosomal, biochemical, DNA, etc.), using a variety of procedures. These include chorionic villus sampling (CVS) (8–11 weeks), amniocentesis (11–16 weeks) and blood analysis by cordocentesis. Radiological investigations like antenatal ultrasound, fetal magnetic resonance imaging (MRI) and fetal echocardiogram (ECHO) play an important role in prenatal diagnosis of malformations.

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Prenatal iagnosis

eonatal Period

It is a common occurrence in India, to be faced with a neonate with no antenatal ultrasound presenting with gross dysmorphic features. This is exemplified in cases such as thanatophoric dysplasia (Fig. 14.2.15), where early neonatal death is the rule. The attending pediatrician

 

Table 14.2.6 Microdeletion syndromes commonly diagnosed using the FISH technique

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Syndrome

Chromosomal region

Clinical features

Angelman syndrome

15q11-q13

Magnetic resonance (MR), spastic gait, happy temperament

Prader-Willi syndrome

15q11-q13

MR, hypotonia, hypogonadism, obesity, almond shaped eyes

Williams syndrome

7q11.2

Aortic stenosis, facial dysmorphism, friendly behavior

Cri-Du-Chat syndrome

5p15.2

MR, cat like cry in infancy, microcephaly

Miller-Dieker syndrome

17p13.3

MR, microcephaly, lissencephaly, furrowing of forehead while crying

Rubenstein-Taybi syndrome

16p13.3

MR, beaked nose, broad thumbs and toes

Velocardiofacial syndrome

22q11.2

Conotruncal heart defects, cleft palate, prominent nose

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Table 14.2.7 Summary of approach to dysmorphic child Analysis

Previous laboratory and X-ray studies

Physical examination

Congenital abnormalities Growth problems Mental deficit

•  •  •  •  •  • 

Other

Synthesis

Confirmation

Intervention

Family investigation Watchful waiting

•  “Pivotal“ findings •  Pattern recognition •  Comparison with known cases – Personal experience –  Literature

•  Laboratory •  Clinical course •  Birth of affected relatives

•  Treatment •  Counseling

Follow-up

•  •  •  • 

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Suspicion

•  •  •  • 

Anatomic regions Organ systems Measurements Photographs

 

History Pedigree Family Pregnancy and birth Health Growth and development

Lack of diagnosis Counseling other family members New diagnostic technique Natural history

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and hence a diagnosis is rarely made in the neonatal period, whereas in certain conditions such as the BeckwithWidemann syndrome the phenotype tends to dissolve as the age progress. These caveats reinforce the need for proper documentation and photography to study the evolving nature of the condition.

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Three- imensional ace hape Modeling

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Human tendency to give objective criteria for subjective intuition has not overlooked the field of dysmorphology. A new modality of three-dimensional (3D) models of facial morphology is showing potential in objective syndrome delineation and discrimination.

A well-known phenomenon is the unique behavior associated with specific syndrome. This is exemplified in the friendly social nature of patients with William’s syndrome, tendency to overeat in case of Prader-Willi syndrome, self-mutilating and destructive behavior of Lesch-Nyhan syndrome, autistic behavior in Fragile X syndrome and Rett syndrome, happy nature of Angelman syndrome and the lovable, friendly and music loving nature of Down syndrome. This old phenomenon termed as the “behavioral phenotype” is gaining more interest, not only as an aid to diagnosis but also in the comprehensive treatment of the patient.

Some phenotypes evolve with time, such as Proteus syndrome; and it is the rule in many of the metabolic conditions such as the group of mucopolysaccharidosis

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should be able to quickly assess such condition so as to stop futile resuscitation measures. Neonatal presentation of certain conditions such as Pierre-Robin sequence may be with feeding difficulties or failure to thrive with metabolic encephalopathy in cases such as Smith-Lemli-Opitz syndrome or Zellweger syndrome. Adequate expertise is needed for anticipation of difficulties in these conditions.

ehavioral Phenotypes

ibliography 1. Aase JM. Dysmorphologic diagnosis for the pediatric practitioner. Pediatr Clin North Am. 1992;39(1):135-56.

 

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igure 14.2.15 Normal result of FISH technique. Two red (target region) and green (control probe) signals indicate the presence of two copies of a particular region of interest in the interphase nucleus and absence of microdeletion

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9. Jones KL. Smith’s Recognizable Pattern of Human Malformation, 6th edition. Philadelphia: Elsevier Saunders; 2006. 10. Kulkarni ML. An Atlas of Neonatology. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2005. 11. Kulkarni ML. Clinical Methods in Paediatrics (Vol 2-Part A). New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2005. 12. Taybi H, Lachman RS. Radiology of Syndromes, Metabolic Disorders, and Skeletal Dysplasias, 4th edition. New York: Mosby-Year Book Inc; 1996. 13. Toriello HV. Role of the dysmorphic evaluation in the child with developmental delay. Pediatr Clin North Am. 2008;55(5):1085-98. 14. Wynee-Davies R, Hall CM, Apley AG. Atlas of Skeletal Dysplasias, 1st edition. Edinburgh: Churchill Livingstone; 1985.



















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2. Allanson JE, Biesecker LG, Carey JC, et al. Elements of morphology: introduction. Am J Med Genet Part A. 2009;149A(1):2-5. 3. Cassidy SB, Allanson JE. Management of Genetic Syndromes, 3rd edition. Willey Blackwell; 2010. 4. Cohen MM Jr. The Child with Multiple Birth Defects, 2nd edition. New York, Oxford: Oxford University Press; 1997. 5. Falk MJ, Robin NH. The primary care physician’s approach to congenital anomalies. Prim Care. 2004;31(3):605-19. 6. Gorlin RJ, Cohen MM, Hennekam RCM. Syndromes of the Head and Neck, 4th edition. New York: Oxford University Press; 2001. 7. Hall J, Allanson J, Gripp K, et al. Handbook of Physical Measurements, 2nd edition. New York: Oxford University Press; 2006. 8. Hammon P. The use of 3D face shape modelling in dysmorphology. Arch Dis Child. 2007;92(12):1120-6.

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syndrome) and trisomy 13 (Patau syndrome). They differ in phenotype and course of disease. Other trisomies are not observed in live-born infants because they are lethal in early embryonic life and are not compatible with life at birth. The presence of an additional sex chromosome (X or Y) has only mild phenotypic effects. The presence of only 1 chromosome of the pair is referred to as monosomy. Monosomy for an autosome is almost always incompatible with survival to term. Monosomy X (karyotype 45,X or Turner syndrome) is a frequent chromosomal aberration diagnosed in postnatal period. Structural chromosome rearrangements result from chromosome breakage with subsequent reunion in a different configuration. These can be balanced or unbalanced.

ntroduction





With the increasing recognition that almost all disorders have a probable genetic basis; no clinician can escape learning about diagnosis and management of common genetic disorders. The fact that some of these disorders are now amenable to therapy and most of the severe/lethal disorders can be prevented; it is all the more important that the pediatricians who are usually the first contact expand their knowledge and interest in this field. Genetic disorders can be classified as follows: • • • • •

Chromosomal disorders Single-gene disorders Polygenic or multifactorial disorders Mitochondrial disorders Somatic cell (genetic) disorders (resulting in cancer).

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In this chapter, we have discussed about clinical features, diagnosis, management and counseling issues of common genetic disorders encountered in clinical practice.

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These account for approximately 6% of all recognized congenital abnormalities and can be divided into numerical and structural, with a third category consisting of different chromosome constitutions in two or more cell lines, i.e. mosaicism. The presence of an extra chromosome is referred to as trisomy. Common trisomies seen in live-born infants include trisomy 21 (Down syndrome), trisomy 18 (Edward

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Down syndrome is the most common chromosomal anomaly present at birth. The incidence in India varies from 1 per 800–1,200 live births. Down syndrome is also known as trisomy 21 since chromosome 21 is present in triplicate. There is a strong association between the incidence of DS and advancing maternal age and studies have shown that this arises most commonly as a result of non-disjunction in maternal meiosis I.

Clinical Features Clinical phenotype is easily identifiable clinically though diagnosis may be difficult in a neonate especially a preterm one. Table 14.3.1 provides a short check list of clinical

 

Table 14.3.1 Check list for clinical diagnosis of Down syndrome System/organ affected

Abnormality detected

Head

Brachycephaly with flat occiput, wide open fontanel

Face

Flat facial profile,* flat nasal bridge

Mouth

Habitually open furrowed/protruding tongue

Ears

Dysplastic,* small, low set

Eyes

Upward slant of palpebral fissures,* epicanthic folds, squint, speckled iris

Neck

Short and broad, abundant neck skin*

Hands

Short and broad, small fingers especially 5th finger, hypoplastic middle phalanx of 5th finger*(clinodactyly), Simian crease*

Feet

Increased space between 1 and 2 toes*, furrow on the sole extending from space between 1 and 2 toes

Joints

Hypotonia*

Muscles

Hyper-extensibility/hyper-flexibility*

Heart

Murmur, cyanotic or acyanotic defect

Reflexes

Lack of Moro reflex*

*Useful for making a diagnosis in the newborn.

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Associated Problems ongenital heart disease: About 40% of children with DS have CHD. Endocardial cushion defects account for about 40– 60%. Presence of CHD is the most significant factor in determining survival – All children with DS should have a cardiac evaluation during neonatal period or as early as possible and it should ideally include an ECHO. • Gastrointestinal malformations: – Look for atresias (present in around 12% of cases) especially duodenal and Hirschsprung disease – Manage accordingly. C

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igures 14.3.1 to D (A) Facial phenotype of DS; (B) Increased gap in between first and second toes; (C) Single palmer crease; (D) Karyotype of DS A

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ye problems: Increased risk of cataract, nystagmus and squint, abnormalities of visual acuity – Routine evaluation in first year (or earlier if indicated) and then every year. • Hearing defect: – Forty to sixty percent of patients have conductive hearing loss and are also prone for serous otitis media (50–70% during first year) – Routine evaluation in first year and then every year – Examine for otitis media at each visit – Audiologic evaluation at least once between 5 and 13 years and then every year is recommended. • hyroid dysfunction: – Thirteen to fifty-four percent of children with DS have hypothyroidism –

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features. Figures 14.3.1A to C show a child with DS with characteristic facies.

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Counseling

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Counseling of parents having a child with Down syndrome varies with the age at presentation for consultation and preparedness of the parents. The counselor has to be passionate and truthful. It is also important to discuss the attributes of patients not only the problems. Diagnosis should be disclosed as early as one is sure, preferably after karyotyping particularly in a neonate. It is important to discuss with both parents together using simple language and giving sufficient time. It is usually not necessary to discuss about rare complications like malignancies. One should give hope and emphasize need for early stimulation and its benefits. Counseling regarding risk of recurrence is important but may be postponed for a future date if the baby is very young. Parents should be encouraged to join a local parent group if existing. A regular follow-up needs to be ensured.

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Laboratory Diagnosis

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Diagnosis is confirmed by karyotype testing, i.e. chromosomal analysis. In about 94% of cases the cause of Downs syndrome is trisomy 21 (Fig. 14.3.1D), about 1% of cases are mosaics and the rest 4% are due to translocations, most commonly involving chromosomes 21 and 14. Karyotyping of the parents is only required if baby has DS due to translocation.

Management Early stimulation: Early stimulation is recommended for all children with DS and should be started as soon as possible. Ideally should be done by a child psychologist but any pediatrician can guide the parents for the same. There has to be active involvement of the parents. The basic objectives of early stimulation are as follows: •

To involve parents for effectively teaching the relevant skills in different areas of development

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Risk of recurrence: Women 35 years of age or less who have a child with trisomy have a 1% risk of having another, which is significantly greater than the general population. The risk is little increased, if any, over the usual maternal agedependent frequency if the mother at risk is 35 years or older. For translocations inherited from the mother, the risk is about 10%, whereas it is about 4–5% when father is the carrier. The risk is 100% if either of the parent is a carrier of translocation between two chromosomes 21. Prenatal diagnosis: Mothers having a child with DS and those conceiving after age of 35 years can opt for definite prenatal diagnosis by invasive techniques. Chorionic villus sampling is done at 10–12 weeks of gestation or amniocentesis around 16 weeks of pregnancy can be offered to determine the chromosomal status of the fetus. In other women with less risk, or who do need not go for invasive testing biochemical screening for chromosomal abnormality can be carried out. Second trimester maternal serum screening includes alpha-fetoprotein (MSAFP), human chorionic gonadotropin (hCG) and estriol assays. In DS pregnancies AFP and estriol are low whereas hCG is high. Second trimester screen (16–20 weeks of gestation) gives a detection rate of about 70%. Quadruple screen which includes Inhibin A increases detection rates further. First trimester screening by βhCG and pregnancy associated plasma protein A (PAPP-A) are very promising with almost equal detection rates. Another reliable screening modality for DS is fetal USG. Important markers in first trimester are increased nuchal translucency and absent nasal bone. Second trimester stigmata include nuchal fold thickness, short femur, duodenal atresia, renal pyelectasis, etc. Fetal USG helps to detect fetuses that are at high-risk for chromosomal abnormalities. Important findings which are suggestive of DS are increased nuchal fold thickness

•

To individualize the training program To impart basic knowledge and change unfavorable altitudes of parents toward children with Down syndrome.

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Thyroid function tests [T4 and thyroid-stimulating hormone (TSH)] are recommended once in the neonatal period/at first contact and then every year. tlanto-occipital subluxation: – Variable incidence – reported in 10–30% – Evaluation by CT scan is recommended before surgery, for participation in special games or if signs and symptoms suggest cord compression. Physical growth: – Regular follow-up for height and weight – Linear growth is retarded as compared to normal children and these children tend to become obese with age – Special growth charts for DS children should ideally be used – Special growth charts for Indian children with DS are not available charts published in western literature may be used. Malignancy: – Hematological malignancies are more common in DS than in general population – In newborns and infants transient myeloproliferative disorder can be seen – Increased incidence of acute leukemia during the first decade of life is reported. mmunity and infections: – Pneumonia and other infections are more common in DS – Respiratory tract infections are more frequent due to associated CHD and hypotonia – Defects in immunological system, both in B cells and T cell function contribute to infections. exual development: – Both males and females with DS display fairly normal sexual development – The girls attain menarche and can be fertile but males are always infertile.

Genetics

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Screening using second trimester biochemical markers is useful for detecting mothers having high risk for trisomy 18. Classically all three markers are low in the maternal blood. Definitive prenatal diagnosis can be offered using same modalities as for Down syndrome.

The incidence is about 1 in 5,000 births. Most babies would die in first few days of life. Only 5% survive the first 6 months and have severe mental defects, often have seizures and fail to thrive.

Clinical Features

This disorder is characterized by developmental retardation, hypertonia, occipital prominence, low set and malformed ears, micrognathia, shield-shaped chest and short sternum, joint abnormalities including flexion deformity of fingers, limited hip abduction and short dorsiflexed hallux. Congenital heart disease is also common mostly ventricular septal defect and patent ductus arteriosus.

Recurrence Risk The recurrence risk is lower than the 1% unless one of the parents is a carrier of balanced chromosomal rearrangement involving chromosome 18 and most trisomy 18 fetuses are spontaneously aborted.

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Turner syndrome has an incidence of about 1 in 5,000 live births but is much more common at conception and in spontaneous abortions.

Clinical Features Clinical picture is highly variable; at birth these girls may be totally normal or may show non-pitting edema of hands and feet, neck webbing, deep set nails, etc. Table 14.3.2 gives list of suggestive clinical features. Common features include short stature, gonadal dysgenesis, low posterior hair line, webbing of neck, shield chest, cubitus valgus, behavioral problems, etc. All short prepubertal girls and girls with primary amenorrhea should be investigated for Turner syndrome. Figures 14.3.2A to C show a girl with Turner syndrome with a characteristic phenotype.

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Most cases have full trisomy 18, higher maternal age being a risk factor. Mosaicism or partial trisomy or translocation cases are rare.

linical features: It is characterized by severe developmental and physical retardation, microcephaly with sloping forehead and holoprosencephaly type of defect with varying degrees of incomplete development of forebrain, olfactory and optic nerves. There may be microphthalmia, coloboma of iris, retinal dysplasia and hypertonia. Malformations of ears and cleft lip with or without cleft palate are common and many children are deaf. Capillary hemangiomas are characteristic. There are frequent abnormalities of fingers and toes such as polydactyly, flexion deformities and long and hyperconvex nails. Congenital heart defects are present in almost 80% of cases and the common defects are ventricular septal defect, patent ductus arteriosus, and atrial septal defect Risk of recurrence in subsequent pregnancies is less than 1% Prenatal testing is possible by doing karyotype on CVS or amniotic fluid sample.

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Edward syndrome is the second most common autosomal trisomy, with an incidence of about 1 in 3,000 newborn babies. These babies have high mortality early in life. Half of them may die within the first week and many of the remaining die in the next 1 year. Only 5–10% survives the first year as severely mentally handicapped individuals. Most of the surviving individuals have partial trisomies.

Cytogenetics

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Prenatal Diagnosis

(measured over the occiput and not over the spine), short femur and humerus length and duodenal atresia. Ultrasound findings help in counseling especially if the parents have opted for initial screening with maternal serum markers. Software is used to calculate the risk of DS and the couple is offered prenatal diagnosis if the risk cut-off is high. For second trimester screening the cut-off is taken as 1:250 or 1:350. Prenatal karyotyping can be done by various invasive procedures. Chorionic villus sampling can be carried out between 10 and 12 weeks of pregnancy (transcervical or transabdominal). This allows diagnosis in the first trimester. The options for the couples who come late or opt for the initial screening with serum markers and USG are karyotyping by amniocentesis (16–18 weeks) or transabdominal placental biopsy, or cordocentesis (after 18 weeks). The karyotype results are available within a week with cord blood samples and direct CVS preparations. Amniotic fluid cultures take about 2–3 weeks for the results. The risk of fetal loss after CVS is about 2% and with cordocentesis it is about 3%. Amniocentesis poses the lowest risk of about 0.5% or less. Rapid prenatal diagnosis of trisomy 21 can be done by FISH or quantitative fluorescent polymerase chain reaction (QF-PCR) on amniotic fluid sample as these test results are available in 2 days.

Diagnosis Investigations include hormonal profile which shows a high follicle stimulating hormone (FSH) and luteinizing hormone (LH) in girls older than 13–14 years; suggestive

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Table 14.3.2 Clinical features of turner syndrome Features Retarded growth and reduced final height:

 

 

 

 

 

 

 

 

 

•  Gonadal dysgenesis: – No pubertal development – Infertility •  Endocrine disturbances: – Glucose intolerance (adults) – Non-insulin dependent diabetes mellitus – Insulin dependent diabetes mellitus – Autoimmune hypothyroidism (adults) – Thyroid autoantibodies •  Physical abnormalities: Mouth – Triangular facies – Micrognathia (small mandibular bone) – High arched palate – Abnormal dental development Eyes – Epicanthic folds – Near sightedness – Strabismus – Ptosis Ears – Prominent anomalous ears – Hearing impairment – Infection of middle ear Neck – Low posterior hair line – Short broad appearing neck – Pterygium colli (webbed neck) – Excess loose skin in the back of the new born Thorax – Broad chest (shield chest) with widely spaced nipples – Inverted nipples Skin, nail and hair – Lymphedema of hands and feet at birth or later – Multiple pigmented nevi – Nail hypoplasia, deep set nails – Vitiligo – Alopecia Skeleton – Bone age retardation – Decreased bone mineral content – Cubitus valgus – Short IV metacarpal – Genu valgum – Congenital hip subluxation – Scoliosis – Madelung deformity Heart – Bicuspid aortic valve – Coarctation aorta Kidneys – Horse-shoe kidney – Abnormal positioning or duplication of renal pelvis, ureter or vessels – Renal aplasia or hypoplasia •  Psychological problems: Others – Failure to thrive during first year of life  

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Height monitoring: Normal growth charts for Turner syndrome girls may be followed Cardiac evaluation base line and every year. Measurement of blood pressure, echocardiography – base line and every year Growth hormone therapy has been found to be beneficial and has been recommended by food and drug administration (FDA). Decision to treat should be left to the parents as the cost of treatment is high and height gain may be up to 10 cm Counsel regarding behavioral problems due to short stature, amenorrhea and sterility (usually)

 



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Management

 

 

of hypergonadotropic hypogonadism. Ultrasonography of pelvis commonly shows hypoplastic uterus and ovaries. Renal abnormalities may also be identified. Karyotype from peripheral blood is diagnostic which commonly shows 45,X. Other karyotype abnormalities could be 46,X,i(Xq); 45,X/46,XX; 45,X/46XY; 45,X/46,X,i(Xq). Search for Y cell line is warranted especially if masculinization is present or mosaicism, unidentified marker or ring chromosome X is found in karyotype. Routine scoring of 20 metaphases is recommended but if karyotype is normal and there is high index of suspicion score 100 metaphases.

 

 

 

 

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Figures 14.3.2A to C Girl with Turner syndrome: (A) Short stature, neck webbing and increased carrying angle; (B) Short 4th and 5th metacarpals; (C) Short 4th and 5th metatarsals

 

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with or without malformations is indicated especially if no other cause is detected.

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Prenatal Diagnosis

It is one of the most common causes of hypogonadism and infertility, affecting about 1.32 per 1,000 among newborns. There is failure of development of secondary sex characters and increased gonadotropin levels. The testis and penis are smaller in size for the age and they tend to have tall and slim stature with low upper and lower segment ratio. Pubertal development is delayed. The growth of pubic and facial hair is often late, while the pubic hair is generally feminine in distribution. Infertility is present, with hyalinization and fibrosis of seminiferous tubules. Virilization is partial and inadequate, with gynecomastia occurring in one-third of adolescents.

Chromosomal Analysis

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Chromosomal analysis reveals 47,XXY karyotype. Errors in paternal meiosis I account for about one-half of 47,XXY males while the remainders are due to maternal meiosis II errors, and in a very small number of cases to a post-zygotic mitotic error. Individuals with XXY/XY mosaicism have a better potential prognosis.

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Structural Abnormalities There can be partial deletion or duplications involving any part of any chromosome. These patients usually present with multiple major or minor malformations 860 and developmental delay or mental retardation. Hence, karyotype of all children presenting with mental retardation

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Autosomal dominant trait is one which manifests in the heterozygous state, i.e. in a person possessing both an abnormal or mutant allele and the normal allele. Examples are NF, achondroplasia, Marfan syndrome, etc. Autosomal recessive disorders only manifest when the mutant allele is present in a double dose, i.e. homozygosity. Examples of autosomal recessive disorders are β-thalassemia, SMA, sickle cell anemia and almost all IEM Sex-linked inheritance refers to the pattern of inheritance shown by genes which are located on either of the sex chromosomes. X-linked dominant inheritance although is uncommon; there are disorders which manifests in the heterozygous female as well as in the male who has the mutant allele on his single X chromosome. Examples include hypophosphatemic type of vitamin D-resistant rickets, Orofaciodigital syndrome, etc. X-linked recessive diseases usually manifest only in males. A male with a mutant allele on his single X chromosome is said to be hemizygous for that allele. Examples include: hemophilia A and B, Duchene muscular dystrophy, etc. Mitochondrial inheritance is due to mutation in a mitochondrial gene; it is passed from a mother to all her children; sons will not pass it on, but daughters will pass it on to all of their children and so on. Examples include mitochondrial encephalopathy, lactic acidosis and stroke like syndrome (MELAS), Leber hereditary optic neuropathy (LHON). Author will discuss clinical features and management of some of the common single gene disorders.

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Risk of recurrence in subsequent pregnancy is low (<1%). Diagnosis of Turner syndrome can be suspected prenatally on first trimester USG scan with increased nuchal translucency or in second trimester showing cystic hygroma, generalized hydrops, or swelling localized to the neck (increased nuchal pad). Confirmation can be done by karyotype of fetal sample collected by CVS, amniocentesis or cordocentesis (blood from umbilical cord).

ingle Gene Disorders

To date over 5,000 single gene traits and disorders have been identified. Each of these single gene disorders, often called Mendelian traits or diseases, is relatively uncommon. Most Mendelian diseases are rare, affecting about 1/10,000 to 1/100,000 live births as an order of magnitude estimate. In total they will add to the 1% of live births. Since only a single gene is involved in each case, these diseases generally have simple inheritance patterns in family pedigrees. This means they can be traced through families and their occurrence in later generations can be predicted. The defective version of the gene responsible for the disease is known as a mutant allele or a disease allele. The mode of inheritance is recognized by the pedigree chart. Details of Mendelian inheritance are discussed elsewhere. At minimum, a pedigree includes first degree relatives (parents and siblings), second degree relatives (aunts and uncles) and third degree relatives (cousins and grandparents).

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valuation for thyroid dysfunction: Infancy and early childhood especially after 10 years of age. Hypothyroidism is often autoimmune. Replacement therapy should be given accordingly varian hormone replacement: – Start at 14 years [12 years if patient has received and completed growth hormone (GH) therapy] – Start with conjugated estrogen at 0.3 mg/d or ethinyl estradiol 5–10 µg/d for 36 months; then increase to 0.625 mg or 1.25 mg (conjugated estrogen) or 20–50 µg/d (ethinyl estradiol) – After 6 months to 1 year: Cyclical therapy with adding progesterone. Regular audiometry in adults or earlier if indicated Evaluation for renal malformation by USG and if abnormal manage accordingly Prophylactic gonadectomy in Turner syndrome patients with Y chromosome. –

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chondroplasia

Achondroplasia is an AD disorder. More than half of the cases are due to de novo mutations. This disorder is caused by a common point mutation in Fibroblast Growth Factor

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Receptor 3 (FGFR3) gene. The mutations in the same gene also cause a lethal dysplasia called thanatophoric dysplasia and a relatively mild dysplasia known as hypochondroplasia.

The clinical manifestations include short stature with predominant short limbs. There is rhizomelic shortening, large head, frontal bossing, depressed nasal bridge, short and broad trident shaped hands, lumbar lordosis and hypotonia, and delayed motor development. Cognitive development is usually normal. Complications include hydrocephalus, otitis media and hearing loss in adulthood, lumbar cord and nerve root compression syndromes. Figures 14.3.3A to C show typical phenotype of Achondroplasia. Characteristic radiological findings are small cuboid shaped vertebral bodies with short pedicles and progressive narrowing of lumbar interpedicular distance (normally

Risk of Recurrence



Risk of recurrence is 50% if either of the parents is affected but is very low if the disorder is caused by a de novo mutation.

Management



There is no specific treatment. Prompt recognition and appropriate treatment of complications, management of psychological problems due to unusual appearance and prevention of obesity is important. Growth hormone therapy though may add a few inches to the final height but is not routinely recommended. Limb lengthening though very cumbersome has been tried to improve height.

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igures 14.3.4 to D Radiological features of achondroplasia: (A) Small cuboid shaped vertebral bodies with short pedicles and progressive narrowing of lumbar interpedicular distance (normally there is caudal widening); (B) Scalloping of posterior borders of vertebrae and anterior breaking of lower thoracic or upper lumbar vertebrae; (C) Rectangular iliac wings, narrow greater sciatic notches, horizontal acetabular roofs, metaphysical flare; (D) Short and wide tubular bones of the hands with trident appearance F

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Clinical Manifestations

there is caudal widening), rectangular iliac wings, narrow greater sciatic notches, horizontal acetabular roofs, anterior breaking of lower thoracic or upper lumbar vertebrae, small foramen magnum, metaphysical flare, short and wide tubular bones of the hands and feet. Figures 14.3.4A to D show characteristic radiological findings of Achondroplasia. Although the diagnosis is essentially clinic-radiological, molecular testing is easily available and is confirmatory.

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Marfan syndrome is an AD disorder caused by mutations in the fibrillin gene located on chromosome 15q21.1. It has a high penetrance but expression may be variable.

Clinical Manifestations The diagnosis of Marfan syndrome is made on clinical evaluation. The disorder primarily includes skeletal system, eyes and cardiovascular system. Common skeletal manifestations include tall stature, long limbs with increased arm span, arachnodactyly, joint laxity, scoliosis, kyphosis, decreased subcutaneous fat, pectus deformities (excavatum/carinatum), flat feet, etc. Characteristic eye abnormality is lens subluxation. Myopia, increased axial length of the globe and retinal detachment may be present. Cardiovascular defects include dilatation and aneurysm of aorta (commonly ascending), aortic and mitral regurgitation, mitral valve prolapse, etc. Figures 14.3.5A to C show a patient with Marfan syndrome.

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Diagnosis Molecular studies are not routinely done for diagnostic purposes as the gene is very big.

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Risk of recurrence in subsequent pregnancies is 50% if either of the parents is affected.

igures 14.3.5 to

Tuberous sclerosis is an AD neurocutaneous syndrome with multisystem involvement. The disorder can include brain, skin, kidney, eyes and cardiovascular system. Tuberous sclerosis type 1 (TSC1) and tuberous sclerosis type 2 (TSC2) are the genes for TS.

Marfan’s syndrome: (A) ncreased arm span; (B) Wrist sign; (C) Thumb sign i

Patients with Marfan syndrome need regular followup for early detection and prevention of complications, primarily cardiac. Beta blockers are used to reduce cardiac complications. Recently antagonist of the angiotensin II type 1 receptor-losartan has been found useful to prevent cardiac complications of Marfan syndrome.

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Marfan Syndrome

Clinical Features

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Figures 14.3.6 A and B Skin lesions in a patient with TS: (A) Hyper pigmented thickened (Shagreen) patch on forehead; (B) Adenoma sebaceum on cheeks in butterfly distribution  

Major criteria include facial angiofibromas, subungal fibromas, hypomelanotic macules typically described as “ash leaf”, Shagreen patch (flesh colored elevated orange peel like lesions), retinal hamartomas, cortical tubers (on neuro imaging), subependymal nodules, astrocytomas, cardiac rhabdomyoma, renal angiomyolipoma and pulmonary lymphangiomyomatosis. Half of the patients have developmental delay. Seizures difficult to control, behavioral problems and autistic features are common. Figures 14.3.6A and B show skin manifestations in a patient with TS.

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Management





In NF2, skin manifestations may be there are less common. The most characteristic feature of NF2 is the development in early adult life of tumors involving 8th cranial nerves commonly called acoustic neuromas which may require surgical intervention. For detailed discussion please refer to Chapter 6.4.

Genetics

The unique skin lesions and neuroimaging findings are most helpful for confirming diagnosis. Confirmation of diagnosis can be made by mutation testing for the two genes: (1) TSC1 and (2) TSC2, but it is very expensive. For detailed discussion please refer to Chapter 6.4.

 

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Risk of Recurrence Risk of recurrence in the siblings of a patient with thalassemia major is 25%. Prenatal diagnosis is possible as early as 10–11 weeks by molecular studies on chorionic villus tissue. Before doing prenatal diagnosis the mutations in the family need to be identified by testing the affected child or both the parents who are obligate carriers. In view of high frequency, carrier screening should be recommended to all pregnant mothers early in pregnancy or before planning pregnancy. S

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Figure 14.3.7 Skin lesions in NF1 (Café au lait spots)

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Neurofibromatosis

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Risk of recurrence is 50% if one of the parents is affected. Parents should be examined carefully and investigated for stigmata of TS as some of them may have very few features.

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-Thalassemia is an inherited autosomal recessive blood disorder. It is probably the most common autosomal recessive disorder in North India, the carrier frequency (about 3%) is approximately comparable to cystic fibrosis in Caucasians. In thalassemia, the genetic defect results in reduced rate of synthesis of one of the globin chains that makeup hemoglobin. Reduced synthesis of one of the globin chains can cause the formation of abnormal hemoglobin molecules, and this in turn causes the anemia which is the characteristic presenting symptom. These children usually become symptomatic in first year of life and present with severe anemia and splenomegaly. Repeated blood transfusions are required for survival. Details are discussed in Chapter 11.5. β-Thalassemia is due to mutations in the hemoglobin beta (HBB) gene on chromosome 11 (also inherited in an autosomal-recessive fashion). The severity of the disease depends on the nature of the mutation. If only one β globin allele bears a mutation, the individual is clinically asymptomatic and is called -thalassemia minor (or sometimes called -thalassemia carrier). If both alleles have thalassemia mutations, the disease is -thalassemia major or intermedia depending on the severity of anemia. b

Risk of Recurrence

Neurofibromatosis is a common AD neurocutaneous syndrome with variable expression. It is classified in two types: (1) NF1 and (2) NF2. • linical features: Clinical features of NF1 include cafe au lait spots (six or more, 1.5 cm or larger in postpubertal patients, 0.5 cm or larger in prepubertal patients), two or more neurofibromas, freckling of axillary or inguinal regions, optic pathway tumors, iris hamartomas (Lisch nodules), pseudoarthrosis of tibia and family history of affected first degree relative. For labeling as NF two or more of these features should be present. Figure 14.3.7 shows a patient with NF1 • Diagnosis: Diagnosis is invariably clinical but can be confirmed by molecular studies • Management: There is no specific treatment for NF1 and management consists of regular follow-up and evaluation for complications like focal neurological dysfunction, optic gliomas, skeletal abnormalities, cognitive/learning problems, hypertension, etc. and provision of symptomatic therapy.

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Treatment of TS is largely symptomatic. Seizures may be refractory to treat. Some patients show a good response to vigabatrin therapy. Surgical interventions may be required for some patients.

Spinal muscular atrophy is an autosomal recessive disorder and is a term applied to a number of different disorders, all having in common a genetic cause and the manifestation of weakness due to loss of the motor neurons of the spinal cord and brainstem. Infantile SMA (Type 1) is the most severe form. These babies present in first few weeks/months of life with motor delay and floppiness. Characteristic tongue fasciculation’s are seen in most cases. Patients with type I SMA die in early infancy. Spinal muscular atrophy Types II and III are milder forms. Electromyography (EMG) shows neurogenic pattern, and muscle biopsy shows group atrophy. In most cases (>95%) diagnosis can be made by the survival motor neuron (SMN) gene test, which shows 863 homozygous deletion of exon 7 of SMN1 gene. Risk of

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Duchenne/ ecker Muscular Dystrophy Muscular dystrophies form a group of genetically determined progressive disorder primarily involving the muscles. The various forms of muscular dystrophies are distinguished by a combination of clinical, pathological features and genetic investigations. The common muscular dystrophies following X-linked pattern of inheritance are DMD and Becker muscular dystrophy (BMD). Duchenne muscular dystrophy is a severe muscle wasting disorder, and BMD is a milder form of the disease with later onset and slow progression. In DMD, children usually present around 3–4 years of age with calf hypertrophy and proximal muscle weakness. Gower’s sign is characteristically seen. Duchenne muscular dystrophy is also discussed in Chapter 6.15. Dystrophin gene responsible for DMD/BMD maps to the short arm of the X chromosome at band Xp21. Duchenne muscular dystrophy being a severe form, there is little or no functional dystrophin protein. In BMD, a milder form, dystrophin may be reduced in amount or altered in size. Approximately 60% of the affected males have a deletion of one or more exons while the remaining patients have duplications and point mutations.

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igure 14.3.8 A child with FXS: long face, large head and large ears



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recurrence is 25% in subsequent pregnancies and prenatal diagnosis is possible using chorionic villus tissue. Details of SMA are discussed in Chapter 6.15.



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Rett syndrome is an X linked dominant pervasive neurodevelopmental disorder. Majority of Rett syndrome cases are caused by sporadic mutations in the gene methylCpG-binding domain protein 2 (MECP2) located on the X chromosome. It almost exclusively affects girls—male fetuses with the disorder rarely survive to term. Recently MECP2 mutations have also been identified in some mentally retarded males. Methyl-CpG-binding domain protein 2 is found near the end of the long arm of the X chromosome at Xq28. An atypical form of Rett syndrome, characterized by infantile spasms or early onset epilepsy, can also be caused by a mutation to the gene encoding cyclin-dependent kinase-like 5 (CDKL5). Revised clinical criteria for Rett syndrome are as follows: • Main criteria – Partial or complete loss of acquired purposeful hand skills –

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Fragile X syndrome is an X-linked semi-dominantly inherited disorder with reduced penetrance and does not follow a classical Mendelian pattern of inheritance. Initially it was thought to be a chromosomal disorder because of presence of a fragile site at Xq27.3. Fragile X syndrome is the most common heritable form of moderate mental retardation and is second only to DS among all causes of moderate mental retardation in males. Clinical features are nonspecific and include overgrowth, large dolichocephalic head, large ears, joint hyperextensibility, hyperactivity, autistic features and behavioral problems. Large testes become evident around puberty. Various scoring systems for the clinical phenotype have been used but it should be suspected in all idiopathic mentally retarded males with a normal or increased head size. It is due to a mutation in a gene on X chromosome leading to expansion of a trinucleotide repeat sequence. Fig. 14.3.8 shows typical facial features of FXS. The clinical presentation may be nonspecific especially in early childhood and hence all males with mental retardation without obvious cause should be tested for FXS. This disorder is caused by the expansion of the (CGGn) 864 repeat in the 5’ untranslated region of the first exon of a gene called fragile X mental retardation 1 (FMR1).

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Risk of recurrence in subsequent pregnancies is 50% for male offspring if mother is a carrier. There are 50% chances of the daughters being carriers. Prenatal diagnosis is possible on chorionic villus tissue using molecular techniques.

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Inheritance of this X-linked disorder is unusual, where it is passed on by an unaffected transmitting male but only can be expressed after being passed through a female. The normal repeat size is less than 50. In permutation carriers of FXS the number of repeated CGG sequences is greater than 50 but less than 200. In full mutation the number of repeats is more than 200. In general the expression of phenotypic manifestation is less severe in females, as seen in X-linked dominant inheritance. • Diagnosis is confirmed by DNA testing which has now replaced the cytogenetic analysis. The gold standard for testing is Southern blotting which can differentiate normal genotype, premutation, and the full mutation. Polymerase chain reaction based screening tests are available and are very reliable • Treatment includes supportive measures and sympto matic therapy for the psychological and behavioral disorders.

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Table 14.3.3 Empiric risk of recurrence of isolated malformation Malformation

Frequency per 1,000 births

Recurrence for normal parents of one affected child (%)

Anencephaly/Spina bifida

4–5

5

Cardiac malformation

6–8

3–4

Cleft lip and cleft palate

2

4–5

–

–

–

Partial or complete loss of acquired spoken language Gait abnormalities: Impaired (dyspraxic) or absence of ability – Stereotypic hand movements such as hand wringing/squeezing, clapping/tapping, mouthing and washing/rubbing automatisms. Exclusion criteria – Brain injury secondary to trauma (perinatally or postnatally), neurometabolic disease, or severe infection that causes neurological problems – Grossly abnormal psychomotor development in first 6 months of life. Supportive criteria – Breathing disturbances when awake – Bruxism when awake – Impaired sleep pattern – Abnormal muscle tone – Peripheral vasomotor disturbances – Scoliosis/kyphosis.

Cleft palate alone

0.5

2–6

Pyloric stenosis

2–3

3

Talipes equinovarus

3–4

2–8

–

–

•

Genetics

– –

Dislocation of hip

3–4

3–4

Hirschsprung disease

0.1

6

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1. American Academy of Pediatrics. Committee on Genetics. American Academy of Pediatrics: Health supervision for children with Down syndrome. Pediatrics. 2001;107(2):442-9. 2. Frías JL, Davenport ML. Committee on Genetics and Section on Endocrinology. Health supervision for children with Turner syndrome. Pediatrics. 2003;111(3):692-702. 3. Hersh JH. American Academy of Pediatrics Committee on Genetics. Health supervision for children with neurofibromatosis. Pediatrics. 2008;121(3):633-42. 4. Kandt RS. Tuberous sclerosis complex and NF type l: the two most common neurocutaneous syndrome. Neurol Clin. 2003;21(4):983-1004. 5. Neul JL, Kaufmann WE, Glaze DG, et al. Rett syndrome: revised diagnostic criteria and nomenclature. Ann Neurol. 2010;68(6):944-50. 6. Trotter TL, Hall JG. American Academy of Pediatrics Committee on Genetics. Health supervision for children with achondroplasia. Pediatrics. 2005;116(3):771-83.

 

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igure 14.3.9 A girl with Rett syndrome: characteristic hand stereotype

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When expression of a phenotype is determined by many genes at different loci, with each gene exerting a small additive effect is called polygenic or quantitative inheritance. Additive implies that the effects of the genes are cumulative, i.e. no one gene is dominant or recessive to another. A trait is called multifactorial if multiple genes are assumed to interact with environmental factors.



Polygenic Disorders



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Important criteria for diagnosis include a period of regression followed by recovery or stabilization, all main criteria and all exclusion criteria but supportive criteria are not required. Figure 14.3.9 shows a girl with Rett syndrome. The treatment is essentially symptomatic and sup portive. Risk of recurrence in subsequent pregnancies is low as most mutations are de novo mutations.

Since neither the environmental factors nor the genetic factors can be identified individually, the differentiation of polygenic and multifactorial is somewhat arbitrary. Example: most single malformations like neural tube defects, CHD, cleft lip/palate, diabetes mellitus, ischemic heart disease, etc. Congenital malformations are seen in about 3% of newborns. Neural tube defects are the commonest major malformation reported in India. Table 14.3.3 lists common malformations and their risk of recurrence. Management in these situations is surgical correction and symptomatic therapy. Many of these defects can be detected antenatally by USG. Antenatal screening with maternal serum Alpha feto protein is very useful for open neural tube defects. More than 90% of anencephaly and about 80% of open neural tube defects can be detected by high AFP levels between 16 and 18 weeks of pregnancy. Folic acid supplementation (4 mg/day) started 2 months before to three months after conception (periconceptional) prevents recurrence in about 72% of cases of neural tube defects. Primary prevention (about 50%) by use of 0.4 mg of folic acid periconceptionally has also been recommended.



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In spite of all the technological advances clinical examination remaines paramount to determine the phenotype, because this is crucially important in order to delineate the function of genes. Human structural malformations (anomalies or birth defects) have an enormous and complex range of manifestations and severity. Diagnosis of multiple malformation syndromes is a challenge to the clinician. The description of these findings can be challenging because the variation of many of the features is continuous and only some of them can be objectively assessed by measurement. An international group of clinicians working in the field of dysmorphology have standardized the terms used to describe human morphology, and have reached consensus regarding their definitions. This will increase the utility of descriptions of the human phenotype and facilitate reliable comparisons of findings among patients. These definitions along with illustrations have been set forth in a series of articles that have been published in the American Journal of Medical Genetics and these are freely accessible, and should be consulted to clarify the precise definitions of malformations and structural variations of various organs. With availability of advancing techniques like microarray, mutation detection, tandem mass spectroscopy pedi atricians can diagnose many patients correctly. ­

It has become necessary for a practicing pediatrician to be acquainted with advances in genetics. Firstly, with the lowering of the infant mortality rate in India resulting from control of infectious and nutritional disorders, pediatricians encounter more and more children with genetic disorders. Secondly, treatment is now available for many genetic disorders. Not diagnosing a treatable disorder is a misfortune for the patient, and in this day of consumer courts can end in misfortune for the pediatrician too. Thirdly, the recent advances have made possible precise genetic counseling and prenatal diagnosis. Therefore, it is imperative that genetic disorders be included as a differential diagnosis in the evaluation of all children, and they should no longer be a diagnosis of exclusion. The recent advances in genetic technologies were fuelled by the human genome project that involved determining the entire human sequence. The use of these technologies led to the discovery of new genes at an unprecedented rate. Researching the whole genome resulted in improved understanding of the pathways of disease causation, recognition of genes predisposing to common genetic disorders, identification of markers to monitor the progress of disease and the discovery of new drug targets. What is remarkable is that the time for the application of these discoveries at the bench to the bedside has become progressively shorter. This chapter describes briefly the recent advances that have taken place in genetics and shows their application in clinical practice. The addition of microarrays for detecting small copy number variations in chromosomes has been a spectacular advance for evaluating dysmorphic children as well as those with autism. Microarrays have also proved useful for studying gene expressions in cancer and other disorders. Singlenucleotide polymorphism (SNP) microarrays have been helpful to identify areas of homozygosity in the genome and led to discovery of many new genes in consanguineous families. Whole genome sequencing has become possible, although the cost is rather high, and the analysis of the data obtained is a real challenge. Exome sequencing of the coding regions of the genome has been successfully used to identify the mutant gene in many children with obscure disorders. Next generation sequencing has been found clinical utility in finding the specific gene carrying the mutation in disorders where a similar phenotype results from many genes, e.g. in life threatening cardiac arrhythmias, familial cardiomyopathies, limb girdle muscle dystrophies, etc.

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Microarray Technology One of the greatest advances in recent times has been the development of microarrays. The word “array” simply means to “place in an orderly arrangement”. The underlying principle is the same for all microarrays, no matter how they are made. Each array has thousands of different DNA probe sequences arranged in a defined matrix on a glass or silicon support. An unknown sample is then hybridized to these immobilized DNA molecules. As per basic principle adenine hybridizes with guanine and cytosine hybridizes with thymine. Because each microarray chip has millions of oligonucleotides it can detect extremely small deletions and duplications in the genome and has replaced traditional karyotype in the evaluation of a child with mental retardation or autism. Microarray based cytogenetic analysis can detect etiology of mental retardation in 10–20% of cases and thus help in genetic counseling. Deoxyribonucleic acid microarrays or “chips” are currently applied to a wide range of other applications in medicine like study of gene expression analysis, study of

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Whole-genome sequencing (WGS) has been applied for discovering the interaction of various genes in cancer, or other complex disorders likes diabetes mellitus, coronary artery disease, inflammatory bowel disease, etc. It is the key technology being used in the International Cancer Genome Project, which aims at determining whole genomes of the commonest cancers around the world. This will yield crucial information about how cancer is caused, how it progresses and pathways to be targeted to cure it. Indian scientists have joined the International project and are undertaking sequencing of patients with oral cancer. Whole genome sequencing has also revolutionized medical diagnostics through rapid identification of alleles that cause disease. For example, Lupski, a famous molecular scientist and his four siblings were affected with an autosomal recessive form of Charcot Marie Tooth (CMT) disease. He and his colleagues carried out whole genome sequencing of the family members, identified all potential functional variants in genes likely to be related to the disease, and genotyped these variants in the affected family members. The group identified and validated the two causative alleles in SH3TC2 gene. Others have used this technology for identification of a gene defect responsible for severe hypercholesterolemia, a novel TP53 cancer susceptibility mutation of a patient with therapy-related acute myeloid leukemia (AML); a variant in dehydrodolichol diphosphate synthase (DHDDS) in retinitis pigmentosa, etc. Currently, whole genome sequencing has great promise in clinical practice, but it has to overcome several barriers (cost, availability, limited experience) before it is ready for widespread use. S

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Whole xome equencing Whole exome sequencing (WES) targets the subset of the human genome that is protein coding. It is a powerful and cost-effective new tool for dissecting the genetic basis of diseases and traits that have proved to be intractable to

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Homozygosity Mapping Consanguinity (union between related individuals) is common in many communities in India. The degree of inbreeding is computed as a percentage of chances for two alleles to be identical by descent. The same phenomenon increases the probability of disease-causing mutations to reside in blocks of homozygosity as the neighboring parts of genome are transmitted together to the offspring. This has made it possible for researchers to identify diseasecausing mutations by pursuing genome wide search for blocks of homozygosity. One has to filter out the homozygous regions leaving a few genes for downstream mutation analysis. This is a shortcut method to identify causative genes in autosomal recessive disorders and has been extensively used in identification of many new genes in consanguineous Pakistani families in UK, in the Amish population in USA and other consanguineous communities around the world.

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In the early years finding new genes and the mutations therein depended upon sequencing of the DNA fragments. The sequencing technology developed by Frederick Sanger proved most useful in these discoveries and led to the success of human genome project. This has been termed as the first generation sequencing technology. Next generation sequencing (NGS) dramatically reduced the cost and the time taken to do so. It is now possible to sequence the entire human genome at a cost of US $7,500 or so. Analysis of the large amount of data generated by NGS is a major challenge. Next generation sequencing has been used in clinical and research settings in a number of ways – whole genome and exome sequencing.



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conventional gene-discovery strategies. Over the past 2 years, experimental and analytical approaches relating to exome sequencing have established a rich framework for discovering the genes underlying unsolved Mendelian disorders. The cost is now considerably reduced and it is possible to carry out exome sequencing for US$ 3,000. Exome sequencing is beginning to be used to facilitate clinical diagnosis and personalized disease-risk. For example, WES has identified a new genetic etiology for familial hypobetalipoproteinemia. This is of great practical value in clinical cases as it permits the identification of a gene or genes connected with the phenotype in cases with de novo chromosomal rearrangements. Next generation sequencing is now used to identify the molecular defect when multiple genes cause a similar phenotype. For example, in X-Linked intellectual disability an NGS for panel of 92 genes is available. Similar strategy is used for disorders like cardiomyopathy, retinitis pigmentosa, deafness where the number of causative genes is too large to sequence each gene one after other. Recently, NGS was employed in the care of a child with a severe Crohn’s disease-like illness, in which other testing had not been able to establish a diagnosis. Whole exome sequencing was able to identify a mutation in X-linked inhibitor of apoptosis protein (XIAP). This case was important because the diagnosis led to the choice of an effective treatment, hematopoietic stem cell transplant. These examples provide proof-of-concept that exome sequencing is not only a technique for research but can be used as a clinical tool for evaluating patients with an undiagnosed genetic disease.

Gene ics

single nucleotide polymorphisms and has proved extremely useful in cancer genetics.

This method searches the genome for small variations, called single nucleotide polymorphisms or SNPs (pronounced “snips”), that occur more frequently in people with a 867

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Enzyme replacement therapy (ERT) for lysosomal storage disorders is one of the success stories of the last one decade. Enzyme replacement therapy is available now for Gaucher disease, Pompe disease, Fabry disease and mucopolysaccharidosis types I and II. With ERT there is miraculous improvement in signs and symptoms of these 868 diseases. For the success of Pompe the treatment needs to

Spinal muscular atrophy is a genetic neuromuscular disease characterized by muscle atrophy and weakness leading to death during infancy in severe variety. It is the second commonest single gene disorder in India, second only to thalassemia. Spinal muscular atrophy is caused by a loss of, or defect in, the SMN1 gene. There is another gene – SMN2 which differs from SMN1 by only a single nucleotide (c.849C>T) and hence cannot produce adequate amount of protein. Researchers showed that the anti-sense drugs designed to modulate the alternative splicing of the SMN2 gene increased production of functional SMN protein in multiple animal models of SMA, and resulted in an increase in the number of motor neurons and improvements in behavior and survival. This represents a real breakthrough in the treatment of SMA (http//www.isispharm.com).

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The common perception among pediatricians is that genetic disorders have no treatment. This is partially true, but so is the case for many disorders other than infectious, nutritional and parasitic disorders. With improved understanding of pathogenesis of genetic disorders the situation is set to change. For example a recent review listed 81 “treatable IEM” presenting with intellectual disability as a major feature. This included disorders of amino acids, lysosomes, vitamins/co-factors, urea cycle, hyperhomocysteinemia and others. The diseases are presented on the www.treatable-id. org as an interactive tool for the clinician and scientist. The information is presented in several different ways: ranging from the biochemical categories, signs and symptoms, diagnostic tests, to therapies and evidence. For each condition a disease page has been designed as information portal with access to specific genetics, biochemistry, phenotype, diagnostic tests and therapeutic options. This is an extremely useful website.

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Duchenne muscular dystrophy is an X-linked disorder caused by mutations in the dystrophin gene. Patients have severe, progressive muscle wasting, leading to death in the twenties. Almost 70% of patients have deletions of one or more exons. The insertion of normal functioning copy of gene by gene therapy has not yet become possible as the gene is too big to be transferred. Hence, a smaller version of effective dystrophin is being tried for gene therapy. The other strategies which are in trial include exon skipping by antisense oligonucleotides or read through the stop codon by using drugs like PTC. All these strategies have excellent scientific logic behind them and have shown success in vitro trials or animal models; but yet none has shown clinically significant success. The extensive research in the area holds great promise for DMD and other genetic disorders. A

With technical advances molecular tests on single cell are possible. This has made pre-implantation diagnosis a reality. Diagnosis of an embryo by taking one cell biopsy from a blastocyst after in vitro fertilization is being done for chromosomal disorders and many monogenic disorders like beta thalassemia and spinal muscular atrophy. This provides an option of implanting only the blastocyst which does not have the genetic disorder in question. This technology is a boon to the families for whom termination of pregnancy is not acceptable for various reasons. Another remarkable advance is the non-invasive prenatal diagnosis of genetic disorders by testing fetal DNA in mother’s plasma. This has been successfully done for Down syndrome, some single gene disorders and is being used to determine fetal Rh group typing in the management of Rh immunized pregnancies.

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be started during the early course of the disease. With the success of technique of biochemical modification of the enzyme synthesized in vitro to target it to the lysosomes, ERT is likely to become available for many other lysosomal storage disorders in the near future. At present ERT is not useful in cases with involvement of CNS as artificially synthesized enzyme does not cross the blood brain barrier.

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particular disease than in people without the disease. Each study looks at hundreds or thousands of SNPs at the same time in patients and compares their frequencies in controls. Researchers use data from this type of study to pinpoint genes that may contribute to a person’s risk of developing common multifactorial diseases. This approach has already identified SNPs related to several disorders such as diabetes, coronary artery disease, inflammatory bowel disease, etc.

Marfan syndrome is caused by mutations in fibrillin 1 (FBN1) gene. Understanding of molecular events showed that the mutation leads to activation of transforming growth factor (TGF) beta and is the cause of the phenotype of Marfan syndrome. Losartan which reduces TGF beta expression was shown to prevent eye and cardiac manifestations in mice models of Marfan syndrome. A large trial of losartan in Marfan disease patients is in progress. Strategies based on understanding of molecular pathogenesis and pathways are being tried for other disorders like FXS and Rett syndrome.

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1. Alkuraya FS. Homozygosity mapping: one more tool in the clinical geneticist’s toolbox. Genet Med. 2010;12(4):236-9. 2. Allanson JE, Cunniff C, Hoyme HE, et al. Elements of morphology: standard terminology for the head and face. Am J Med Genet A. 2009;149A(1):6-28. 3. Bamshad MJ, Ng SB, Bigham AW, et al. Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet. 2011;12(11):745-55.

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The ultimate treatment in genetic disease is gene therapy. This may involve replacing a defective gene with a functional version, enhancing the baseline expression level of a gene or, contrastingly, suppressing the expression of genes that may contribute to the pathologic process. As the field of gene therapy continues its rapid advancement, it is likely that it will eventually become a standard clinical regimen. Gene therapy has been most successfully used to treat certain cases of primary immune deficiency disorders. Encouraging long-term follow-up data has been published for patients treated with retroviral vectors to correct adenosine deaminase-deficient severe combined immunodeficiency (SCID), X-linked SCID and chronic granulomatous disease, and a first-in-human study also reports clinical improvement for Wiskott–Aldrich syndrome. A recent remarkable study showed that a single intravenous injection of an adenovirus-associated virus (AAV) vector that expresses factor IX (FIX) can successfully treat patients with hemophilia B for more than a year.

4. Battista RN, Blancquaert I, Laberge AM, et al. Genetics in health care: an overview of current and emerging models. Public Health Genomics. 2012;15(1):34-45. 5. Booth C, Gaspar HB, Thrasher AJ. Gene therapy for primary immunodeficiency. Curr Opin Pediatr 2011;23(6):659-66. 6. Carey JC, Cohen MM Jr, Curry CJ, et al. Elements of morphology: standard terminology for the lips, mouth, and oral region. Am J Med Genet A. 2009;149A(1):77-92. 7. Ginsburg D. Genetics and genomics to the clinic: a long road ahead. Cell. 2011;147(1):17-9. 8. Kuhlenbäumer G, Hullmann J, Appenzeller S. Novel genomic techniques open new avenues in the analysis of monogenic disorders. Hum Mutat. 2011;32(2):144-51. 9. Li X, Quigg RJ, Zhou J, et al. Clinical utility of microarrays: current status, existing challenges and future outlook. Curr Genomics. 2008;9(7):466-74. 10. Link DC, Schuettpelz LG, Shen D, et al. Identification of a novel TP53 cancer susceptibility mutation through wholegenome sequencing of a patient with therapy-related AML. JAMA. 2011;305(15):1568-76. 11. Lupski JR, Reid JG, Gonzaga-Jauregui C, et al. Wholegenome sequencing in a patient with Charcot-Marie-Tooth neuropathy. N Engl J Med. 2010;362(13):1181-91. 12. Miller DT, Adam MP, Aradhya S, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010;86(5):749-64. 13. Nathwani AC, Tuddenham EG, Rangarajan S, et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med. 2011;365(25):2357-65. 14. Robin NH. Dysmorphology in the era of whole exome sequencing. Curr Opin Pediatr. 2011;23(6):579-80. 15. van Karnebeek CD, Stockler S. Treatable inborn errors of metabolism causing intellectual disability: a systematic literature review. Mol Genet Metab. 2012;105(3):368-81.

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In addition to enzyme deficiencies biochemical abnorm alities of various proteins like transport proteins, hormones, immunoglobulins, coagulation factors also give rise to diseases. The metabolic disorders are classified into the different categories (Table 14.5.1).

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The clinical features of category I group of genetic metabolic disorders depend on the function of the organ or system involved. The category II disorders are traditionally described as IEM and this chapter discusses this group of disorders. The clinical features of IEMs are varied and usually involve many systems. Involvement of nervous system is common. Many of these disorder manifest in neonatal period, infancy or early childhood. However, many disorders like hyperlipidemias, Fabry disease, some mitochondrial disorders may present in later part of life. Adult onset variants of diseases clinically manifesting during infancy like Tay Sachs disease, low chart 14.5.1 Metabolism of phenylalanine and tyrosine. On the left is an enzyme catalyzing the step and on the right is the disease caused by deficiency of the enzyme  

The body of a living organism is a biochemical factory with complex metabolic pathways working simultaneously and maintaining life processes in an efficient way. The metabolism proceeds in steps: each step being governed by an enzyme. Usually, there is one gene for one enzyme. If a gene gets mutated the enzyme will not be synthesized or will lose its function and the disease will manifest. These diseases are collectively known as inborn errors of metabolism (IEM). The enzymes are required in a very small quantity and hence most of the genetic metabolic disorders manifest only when both copies of a gene for an enzyme are mutated or abnormal. That is why most of the genetic metabolic disorders are inherited in autosomal recessive fashion. That means both the parents of an affected individual are clinically normal but carry one mutated copy of the gene in concern, i.e. they are carriers of the disease. A few genes for enzymes are located on X chromosome. IEM transmitted in X-linked fashion are mucopolysaccharidosis type II (MPS II) (Hunter syndrome), Fabry disease and Lesch Nyhan syndrome. As said previously the enzyme is required in very small amount and hence, the X-linked IEMs usually manifest only in males and females usually are asymptomatic carriers who can transmit the disorder to the sons. The rare cases of manifesting female are due to unusual situations like female with Turner syndrome (having only one X chromosome) or non-random Lyonization leading to preferential inactivation of X chromosome with normal copy of gene in disproportionately more cells of the body. Various types of porphyria caused due to abnormalities in Haem metabolism are inherited in AD fashion. The first IEM was described by Sir Archibald Garrod in 1902. The disorder was alkaptonuria, in which nappies of children suffering from the disease turned black on exposure to air. This was due to excretion of homogentisic acid (HGA) in urine due to block in metabolism of tyrosine (Flow chart 14.5.1). Later on inborn errors of various pathways involving metabolism of amino acids, carbohydrates, fatty acid, lipids, trace minerals and various complex molecules like lipoproteins, mucopolysaccharides and oligosaccharides were identified. The clinical manifestations occur either due to accumulation of metabolic products of the substrate (as in PKU) or because of deficiency of the downstream product of the enzymatic reaction (as in albinism or hemophilia). In lysosomal storage disorders the intracellular accumulation of complex molecules due to lack of their degradation leads to signs and symptoms of the disease.

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metachromatic leukodystrophy are known. Manifestations can be intermittent as well depending on exposure to offending agent as in porphyria, some cases of urea cycle disorder. Acute illness with neurological deterioration in a neonate or an infant is a presentation of many IEMs like aminoacidopathies, organic acidemias, galactosemia, disorders with lactic acidosis, glycogen storage disorder, and fatty acid oxidation defects. As neonates have limited manifestations and respond to any type of insult in the same way; the clinical picture of IEM, septicemia, birth asphyxia, and intracranial hemorrhage may superficially look similar. It is important to consider IEM in an acutely sick infant or neonate; especially if septicemia screen is negative, the delivery was uneventful and manifestations start 2–3 days after normal course in a neonate. Other indicators to point toward IEM are presence of consanguinity in parents, history of neonatal death in previous sibling. The basic investigations of an acutely sick child or a neonate can give clue to the type of IEM (Table 14.5.2). In addition to acute presentation some of the manifestations suggestive of IEM are given in Table 14.5.3. Some disorders have intermittent acute presentation due to exposure to precipitating causes like high protein diet or fasting. Many disorders like storage disorders have chronic progressive course.

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Inborn errors of metabolism are many, rare and the manifestations are overlapping. These make diagnosis difficult. Clinical diagnosis is not possible and diagnostic tests are many times not easily available. History and clinical examination are extremely important to search for diagnostic clues (Fig. 14.5.1). Table 14.5.4 gives some characteristic features of IEMs. Routine investigation can also help to reach diagnosis. For example, in a hypotonic infant with enlarged liver, presence of cataract, punctate ossifications of epiphyses lead to the diagnosis of Zellweger syndrome. Magnetic resonance imaging brain is useful especially if white matter disease of brain is suspected (Figs 14.5.2A and B). Bone marrow examination may help in diagnosis of Gaucher and Niemann Pick disease. However, confirmation of diagnosis is needed using specialized tests like enzyme assays, metabolite profile of plasma and urine using tandem mass spectrometry and gas chromatography mass spectrometry. Quantification of very long chain fatty acids and plasmalogen is necessary for diagnosis of peroxisomal disorders. Specific enzyme assays on white blood cells or cultured fibroblasts are necessary for confirmation of diagnosis of lysosomal storage disorders. Causative genes are known for most

 

Table 14.5.1 Classification of genetic metabolic disorders Category

Group

Clinical manifestations

Examples

Symptoms characteristic for the system/organ involved

Immunodeficiency disorder, Hemophilia, Renal tubular acidosis

•  Defects affecting the synthesis or catabolism of complex molecules; defects of intracellular trafficking and processing

Progressive manifestations not affected by diet, or environmental factors

Lysosomal storage disorder like Gaucher disease, Hunter syndrome, peroxisomal disorders, alpha I antitrypsin deficiency

•  Defects of intermediary metabolism that leads to acute or progressive intoxication due to accumulation of toxic compounds proximal to the block

Acute or intermittent manifestations. Onset may be late CNS involvement is frequent

Aminoacidurias, urea cycle defects

•  Disorder due to deficiency in energy production or utilization

Hypoglycemia, lactic acidosis, Mitochondrial disorders, disorders involvement of heart muscles, brain, associated with lactic acidosis, defects liver and multiple organ of neoglucogenesis

 

1. Disorders that involve only one functional system or one organ

 

2. Diseases due to defects in the basic metabolic pathway common to a large number of cells or organs, or the pathway is restricted to one organ but has systemic effects

Source: Saudubray JM, Charpentier C. Clinical phenotype diagnosis/algorithms. In: Scriver CR, Beaudet AL, Valle D, Sly WS (Eds). The Metabolic and Molecular Basis of Inherited Disorders, 8th edition; 2001. pp. 1329-30.

Table 14.5.2 Diagnostic approach to an acute sick neonate or child Acidosis

Ketosis

Lactic acidosis

Hypoglycemia

Hyperammonia

IEM

–

+++

–

–

+/–

Maple syrup urine disease

+++

++

+++

+/–

+/–

Organic acidemia

++

–

+

++

+

Fatty acid oxidation defect

+

+

+++

+/-

–

Lactic acidosis

–

–

–

–

+++

Urea cycle defects

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Presentations

Diseases

Manifestation

Disorder

Development delay, Seizures, Regression of milestones and tone abnormalities

•  •  •  •  •  •  • 

Cherry red spot in fundus of eye

Tay Sachs disease, Niemann Pick disease, Generalized gangliosidosis

Cataract

Galactosemia, Lowe syndrome, Zellweger syndrome

Coarse facies, Hepatosplenomegaly, Joint contractures and Corneal clouding

•  MPS •  Mucolipidosis •  Oligosaccharidosis

Inverted nipple, abnormal fat distribution on buttocks

Congenital defects of glycosylation

Corneal opacities

Hepatosplenomegaly and Neonatal cholestasis

•  •  •  •  •  •  •  • 

Tyrosinemia type II, Cystinosis, Fabry disease, Mucopolysaccharidosis

Alopecia, skin rash

Biotinidase deficiency

Pale, brittle, steely hair

Menkes kinky hair disease

Macrocephaly (large head)

Tay Sachs disease, Canavan disease, Van der Knapp disease, Glutaric aciduria type II, Alexander disease

Kayser-Fleischer ring in cornea

Wilson disease

Retinitis pigmentosa

Mitochondrial disease, Refsum disease, Neuronal ceroid lipofuscinosis

Muscle pain and myoglobinuria

Glycogen storage disease V, Fatty acid oxidation defect

Rickets

Tyrosinemia type I, Renal tubular acidosis

Macrocytic anemia

Abnormalities of folate and cobalamin metabolism

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Hepatosplenomegaly

Cardiomyopathy

Biotinidase deficiency Tay Sachs disease Metachromatic leukodystrophy Krabbe disease Neuronal ceroid lipofuscinosis Canavan disease Peroxisomal disorders

Alpha I antitrypsin deficiency Galactosemia Tyrosinemia Niemann Pick disease Peroxisomal disorder Cystic fibrosis Hemochromatosis Defects of bile acid synthesis

•  Glycogen storage disease •  Gaucher disease •  Niemann Pick disease •  Pompe disease •  Mitochondrial diseases

Extrapyramidal manifestations and •  Wilson disease Neuroregression Hepatic failure

•  Fatty acid oxidation defects •  Mitochondrial disorder

Vomiting, Diarrhea and Failure to thrive

•  •  •  •  • 

Lysinuric protein intolerance Wolman disease Abetalipoproteinemia Lactase deficiency Acrodermatitis enteropathica

 

Table 14.5.4 Characteristic manifestations of some IEM

 

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Table 14.5.3 Common clinical presentations of IEM

the IEMs and mutation detection helps in confirmation of diagnosis. It also helps in providing prenatal diagnosis.

igure 14.5.1 Angiokeratomas characteristic of Fabry disease (also seen in fucosidosis)  

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Management Successful treatments with various strategies have been available for some disorders for decades (Table 14.5.5). Over last few decades, the number of disorders for which partial improvement is possible is increasing. However, there is no curative treatment for many IEMs. Successful ERT for Gaucher disease (Fig. 14.5.3), Mucopolysaccharidosis I SH and Glycogen storage disease type II (Pompe disease) and Fabry disease has brought hope that similar success stories may be repeated for other 40 lysosomal storage disorders. Enzyme replacement therapy cannot prevent neurological involvement yet as the modified enzymes cannot cross the blood brain barrier. Bone marrow transplantation (BMT) is successful in preventing CNS involvement if done in early stages. Similarly, liver transplantation to replace the damaged liver or as a source of enzyme is successful in some disorders. Long-term success of gene therapy in more than 10 children with immunodeficiency disorder has not

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igures 14.5.2 and Magnetic resonance imaging brain showing cystic changes and leukodystrophy characteristics van der Knapp disease. (A) Axial T1 Flair image showing cystic changes in both temporal regions; (B) Coronal T2 weighted MR image shows extensive involvement and hyperintensity of central and peripheral white matter

 

Figure 14.5.3 Response to ERT in three patients with Gaucher disease type I (different colors are used for different patients)



Urine, plasma and blood for DNA should be stored for future analysis even if the affected child dies before diagnosis. Deoxyribonucleic acid test for mutation in the chorionic villi is the best option for prenatal diagnosis. But, for lack of mutation detection, metabolite estimation in amniotic fluid or enzyme assay on chorionic villi can be used for prenatal diagnosis. Deoxyribonucleic acid based mutation analysis has very minimal error rate as compared to prenatal diagnosis using biochemical tests. 873

yet been repeated for any other genetic disorders and gene therapy still continues to be a distant dream. Lack of curative treatment, difficult, lifelong, costly treatment and poor outcomes in many IEMs make genetic counseling and prenatal diagnosis important components of management. Accurate diagnosis of the affected patient in the family is the prerequisite for prenatal diagnosis. Hence, even if the child appears to be too serious to survive; all attempts should be made to confirm the diagnosis.

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Table 14.5.5 Treatment of IEM Disorder

Treatment

Phenylketonuria

Phenylalanine restricted diet, Tetrahydrobiopterin

Galactosemia

Lactose free diet

Biotinidase deficiency

Biotin

Tyrosinemia I

NTBC

Mucopolysaccharidosis

BMT, ERT

Wilson disease

Penicillamine, zinc

Pompe disease

ERT

Gaucher disease

BMT, ERT

Fatty acid oxidation defects

Prevent fasting, carnitine

Cobalamin metabolism disorder

B12

Homocystinuria

Pyridoxine

Porphyria

Load of glucose and acid hematin

Glycogen storage disorder type I

Corn Starch

Phenylketonuria





Phenylketonuria is one of the best studied IEM. Still there is limited understanding of pathology about how phenylalanine metabolites lead to neurological abnormalities. The history of PKU starting from diagnosis, diet therapy, new born screening, fetal effects of material PKU reflect the developments in IEM. The recent treatment with biopterin as a molecule which modulates folding of protein molecule and improves function of mutated protein opens up similar options for many other genetic disorders caused by mutations leading to abnormal folding and hence decreased function of the protein. Phenylketonuria is an autosomal recessive disorder caused by deficiency of phenylalanine hydroxylase (PAH); an enzyme which converts phenylalanine to tyrosine (Fig. 14.5.4). The enzyme is coded by PAH gene which expresses in hepatic cells. Tetrahydrobiopterin (BH4) is a cofactor for PAH gene which expresses in hepatic cells. In absence of PAH, the phenylalanine accumulates in body and some of it gets metabolized by alternate pathways to produce increased amount of phenylpyruvic acid (a keto acid) which gets excreted in urine. That is why the name “PKU”. The disease was described by Folling in 1934. In 1950, Horst Bickel performed successful intervention with dietary phenylalanine restriction in a patient with PKU. The phenylalanine levels in blood reduced and there was clinical improvement. However, soon it became obvious 874 that the treatment unless started during neonatal period could not prevent mental retardation. This led to the

 

Figure 14.5.4 Enzymes involved in phenylalanine and biopterin metabolism

beginning of newborn screening in the early 1960s. The prevalence of PKU varies from one in 10,000 to 1 in 100,000. Identification of PKU neonates through newborn screening and institution of diet therapy successfully prevented mental retardation. But, it soon became obvious that if diet therapy is relaxed after childhood hyperphenylalanemia leads to dysfunction of adult brain and lifelong continued control of phenylalanine levels in blood is necessary. Strict diet control is also necessary during pregnancy as hyperphenylalanemia invariably leads to microcephaly, mental retardation and cardiac malformation in the baby. One to two percent cases of hyperphenylalanemia are due to abnormalities of BH4 synthesis or recycling. They do not respond to phenylalanine restricted diet. The success of restriction of substrate in diet was completely or partially repeated in many other IEMs like galactosemia, urea cycle disorders, maple syrup urine disease, etc. The special diets are costly and to maintain compliance is difficult. It was found that 10–20% of cases of PKU respond partially or completely to tetrahydrobiopterin treatment. The response to biopterin was correlated with type of mutation in PAH gene. The BH4 treatment is effective in patients with mutations which lead to misfolding of protein and hence, loss of functional activity. Biopterin available as sapropterin for patient therapy acts as chaperone and stabilizes tertrameric form of mutated PAH in some cases and eliminates or reduces the need of phenylalanine restricted diet. Neonates diagnosed to have PKU need to be tested for biopterin response and it is indicated in biopterin responsive case. Long-term effects of biopterin use are yet to be evaluated. The other new option of treatment of PKU is phenylalanine ammonia lyase (PAL).

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Abbreviations: BMT, Bone marrow transplantation; ERT, Enzyme replacement therapy; NTBC-2-(2-nitro-4-trifluromethylbenzoyl)-1,3cyclohexanedione

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Hurler yndrome

igure 14.5.5 An eighteen-month-old child with GSD-I. A doll like facies is characteristic

igure 14.5.6 A child with characteristic features of MPS I (coarse facial features and corneal clouding). She is I SH type with normal IQ and has been showing improvement on ERT  

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Pompe disease is an autosomal recessive disease. The deficient enzyme is alpha glucosidase. It primarily involves muscles. The manifestations start in first 6 months of life. There is development delay, hypotonia, macroglosia, cardiomegaly and congestive cardiac failure. The diagnosis is confirmed by enzyme assay on lymphocytes or fibroblasts or mutation detection. Late onset variants are also described.

Hurler syndrome (HS) is type I of mucopolysaccharidosis (MPS I). It is a prototype of lysosomal storage disorder. Clinical features include coarse facies, joint contractures, thickened skin, short stature, corneal clouding and mental retardation (Fig. 14.5.6). There is cardiac involvement in the form of thickening of valves. Age of onset is usually one to two years. Mild form of MPS I-Scheie type (MPS I S) and MPS I SH are known and may be difficult to diagnose. Characteristic radiological changes (Figs 14.5.7A and B) known as dysostosis multiplex and screening test for presence of mucopolysaccharides in urine can help in diagnosis. There is a great overlap with different types of MPS and other lysosomal disorders like

Glycogen torage isease Type (Pompe isease)

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Ornithine transcarbamylase (OTC) is an enzyme in urea cycle pathway that functions in liver cells for the removal of nitrogen from amino acids arising due to normal turn over. Two molecules of ammonia and one molecule of bicarbonate combine to form urea. Deficiency of OTC is an X-linked disorder. Male infants with OTC deficiency have an intractable and lethal neonatal course. Milder cases can be managed by protein restriction. Although it is an X-linked disorder manifesting females are not uncommon. Manifestations in females are usually intermittent with episodes of vomiting, altered sensorium associated with hyperammonemia. S



Glycogen storage disease I A (GSD-IA) is an autosomal recessive disorder caused by deficiency of glucose-6phosphatase. Affected children present with hepatomegaly and episodes of seizures, sweating and tachycardia due to hypoglycemia (Fig. 14.5.5). The patient may have severe lactic acidosis during an episode of minor infection. Liver biopsy shows storage of glycogen. Enzyme assay can be done on liver biopsy sample. In appropriate clinical setting enzyme assay and mutation detection is not necessary for starting treatment. Treatment is simple with frequent day time feeds and a diet rich in uncooked corn starch (to release glucose slowly) at night to prevent hypoglycemia. Associated hyperuricemia and hyperlipidemia may also need treatment. Glycogen storage disease I B has similar presentation and may have associated neutropenia. It is caused by mutation in glucose6-phosphate transporter gene, which is an important component of glucose-6-phosphate activity.

rnithine Transcarbamylase eficiency D

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Glycogen torage isease

Treatment with ERT has shown good results especially when started early in the course of disease. For this reason some countries have included Pompe disease in newborn screening program and shown absolutely normal outcomes in patients who were started on ERT during neonatal period.

Gene ics

Phenylalanine ammonia lyase metabolizes phenylalanine in the gut to harmless cinnamic acid and insignificant amount of ammonia. This has shown great promise to avoid the need of special PKU diets. First clinical trials of pegylated molecule of PAL (PEG-PAL) are underway.

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Hypotonia

Acidosis

Development delay

Myoglobinuria

Spasticity

Cardiomyopathy

Ataxia

Diabetes

Leukodystrophy

Hepatomegaly

Seizures

Hypoglycemia

Myopathy

Hepatocellular dysfunction

Deafness

Gastrointestinal symptoms

Loss of vision

Anemia

Ptosis

Endocrinopathies

Microcephaly

Nephrotic syndrome

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features of any syndrome. Susceptibility to develop deafness on exposure to aminoglycoside is also known to be caused by a mutation in mitochondrial genome. Involvement of multiple organs with increased lactate, presence of ragged red fibers in muscle biopsy may support the diagnosis. Respiratory chain enzyme assays and mutation detection are confirmatory tests. The treatment is symptomatic and does not alter the course of the disease.

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Oxidative phosphorylation, i.e. ATP synthesis through the respiratory chain in mitochondria is a ubiquitous pathway that supplies energy to all organs and tissue. A defect of respiratory chain can affect any organ system at any age. The oxidative reaction takes place in mitochondria giving the name “mitochondrial disorders”. Mitochondria have their own DNA. Some of the genes of respiratory chain pathway are coded by mitochondrial DNA while many of the genes of this pathway are coded by nuclear gene. Hence, mitochondrial (also known as maternal) and autosomal modes of inheritance are observed. The manifestation can be varied (Table 14.5.6) and can involve any system of body and can present at any age. Symptoms involving multiple systems strongly suggest the possibility of mitochondrial disorder. The classical mitochondrial diseases include MELAS, MERFF (Myoclonic Epilepsy, Ragged Red Fibers), Lebers hereditary optic neuropathy, Leigh disease, Kearn Sayre syndromes, DIDMOAD (Diabetes Insipidus with Diabetes Mellitus with Optic Atrophy and Deafness) and MINGIE (mitochondrial neurogastrointestinal encephalomyopathy). 876 However, many cases may not have the characteristic

Table 14.5.6 Clinical features of respiratory chain disorders. There may be any of these features in isolation or in combination

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mucolipidosis, mannosidosis, fucosidosis, galactosidosis, etc. Enzyme replacement therapy with recombinant iduronidase (enzyme which is deficient in patients with MPS I) has become available at the beginning of 21st century. It has shown remarkable results in the form of improvement in joint contractures, decrease in the sizes of liver and spleen. However, it is not useful if the patient has classic Hurler variety; because the recombinant enzyme cannot cross blood brain barrier. The ERT is useful in mild variants of MPS I without mental retardation. Bone marrow transplantation is another form of successful treatment and can prevent brain involvement in HS cases, if done before there is significant decline in cognitive function.

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igures 14.5.7 and Dysostosis multiplex: (A) Radiograph of hands showing modeling deformities of metacarpals with pointed proximal ends; (B) Lateral radiograph of spine showing oval shaped vertebrae and anterior tongue like process in of MPS IV (Morquio syndrome)

Six-month-old child born of consanguineous marriage was brought with the complaint of not gaining milestones. Previous sibling of the child had similar problem and died at 15 months of age. The child was hypotonic, with no neck control and no social smile. At the click of camera he showed exaggerated startle suggestive of hyperacusis. There was no hepatosplenomegaly. The ophthalmological

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A non-consanguineous couple was referred for genetic counseling and prenatal diagnosis. The wife was 8 weeks pregnant. They had a daughter of 17 months with spasticity and scissoring of both lower limbs (Fig. 14.5.9). The child was normal till 1 year of age and had started standing and walking with support. She stopped that and the tone increased in lower limbs. The MRI brain showed demyelination of white matter consistent with leukodystrophy. The child was being following by a neurologist as a case of metachromatic leukodystrophy (MLD). The clinical features, history of regression of



of prenatal diagnosis the family decided to terminate the pregnancy. The family was informed that the chance that the fetus will be unaffected in the next pregnancy is 75%. However, prenatal diagnosis needs to be done in each subsequent pregnancy to avoid the birth of child with Tay Sachs disease. The family was also informed that avoidance of further consanguineous marriages in their extended family may help to avoid recurrences. It will be advisable to test their relatives for carrier status for Tay Sachs disease and genetic counseling should be offered to them.

Gene ics

examination showed cherry red spot in fundus. The enzyme assay on serum showed very low hexosaminidase A value confirming the diagnosis of Tay Sachs disease. Tay Sachs disease is a lysosomal storage disease of gangliosides; also known as gangliosidosis 2 type I (GM2 type I). There is no treatment for Tay Sachs disease. It is caused by mutation in hexosaminidase A (HEXA) gene. The DNA analysis of the patient was done by sequencing all exons (coding sequences) of HEXA gene. The patient was homozygous for insertional mutation of 4 bases (TATC) in exon 11, i.e. both copies of HEXA gene had the mutation (Figs 14.5.8A and B). Tay Sachs disease is autosomal recessively transmitted and hence, the risk of recurrence of the same disorder in the next pregnancy of the mother of this affected child will be 25% or 1 in 4. The mother was 12 weeks pregnant at the time the mutation was detected. The chorionic villus sample was collected by ultrasonographically guided procedure. The CVS was dissected under microscope to remove maternal deciduas. Deoxyribonucleic acid was extracted from CVS and was tested for the mutation. The CVS sample was also homozygous for the mutation indicating that the fetus would be affected by Tay Sachs disease. With this report

a

b  

Figures 14.5.8A and B Sequencing results of part of exon 11 HEXA gene [patient (A) and normal individual (B)]. The green line shows normal sequences flanking the region of mutation. Red line shows the extra 4 nucleotides inserted in the patient (Courtesy: Dr Parag Tamhankar)

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milestones after normal development up to 1 year and MRI picture was consistent with MLD. Metachromatic leukodystrophy is a progressive disease with no curative treatment. The risk of recurrence in sibs of affected child is 1 in 4 or 25%. For counseling and prenatal diagnosis, confirmation of the diagnosis by assay of aryl-sulphatase A enzyme on the white blood cells of the proband (affected child in the family) will be necessary. The enzyme assay was done in urgency and the enzyme level was very low confirming the diagnosis of MLD. As mutation detection would have taken long time, prenatal diagnosis in the current pregnancy was attempted by estimation of enzyme in the CVS. The enzyme level in CVS was normal and the family continued the pregnancy. It was informed to the family that there is small error rate of prenatal diagnosis test.

An 18 years medical student was admitted in ICU with coma and acute renal failure. She was alright a week ago and then developed diarrhea and was given intravenous fluids. She told that during childhood she was frequently hospitalized with documented attacks of hypoglycemia. Her brother also had attacks of hypoglycemia and died at 3 years of age. After early childhood she stopped getting hypoglycemia. After 1 day of IV fluids she was discharged and then was readmitted in serious condition.

Discussion With this past history and family history the most likely diagnosis is fatty acid oxidation defects. There are many types of fatty acid oxidation defects and the treatment is to prevent fasting and carnitine supplementation during

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A 12-year-old boy was referred to department of clinical immunology with 6–7 years history of fever off and on and limb pains. He told that he gets fever almost every evening and had serve pain in limbs. The symptoms were so incapacitating that he had stopped going to school and was going from doctor to doctor in search of cure. There was no positive family history there were no signs and symptoms of infection, autoimmune disorder. Erythrocyte sedimentation rate was normal. He was about to get label of neurosis. However, he was referred to medical genetics department. The only positive finding was documented 100ºF temperature in evening and agony on his face. The diagnosis of Fabry disease was suspected. Slit lamp examination of his eyes showed corneal deposits. Enzyme assay for alpha galactosidase A showed low level and confirmed the diagnosis of Fabry disease. He was put on ERT which reduced his pain, requirement of carbamazepine regularly and quality of life improved greatly. Fabry disease is an X-linked disease and difficult to diagnose because of vague complaints and lack of signs. Average duration between onset of symptoms and diagnosis is 10–20 years. This patient did not have characteristic angiokeratomas. In addition to neuropathic pain, there is increased risk of early stroke, cardiomyopathy and development of chronic renal failure. There is no involvement of CNS. Enzyme replacement therapy with recombinant enzyme has become available since 2003. It not only improves quality of life by reducing pain but is also supposed to decrease risk of involvement of heart, brain and kidneys. Enzyme replacement therapy increases excretion of ceramide deposited in blood vessels and various organs, thus it prevents organ damage.

igure 14.5.9 A child with metachromatic leukodystrophy, superficially looking like cerebral palsy  

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attack. She recovered with supportive treatment and was advised tandem mass spectrometry of plasma to study acylcarnitine profile. Later the enzyme assays may be needed to confirm the type of fatty acid oxidation defect. These groups of disorders are included in newborn screening programs of developed countries.

Follow-Up His brother was brought with complaints of short stature and chronic diarrhea; the symptoms could be due to Fabry disease. On investigation his alpha galactosidase was low. This means that the mother of these two boys is an obligate carrier. Her serum creatinine was normal but urine analysis showed protein in traces. Her corneas also showed some opacities. Through Fabry disease is an X-linked recessive disease, many of the carrier females show manifestation of varying severity. The mother and the brother need followup and are likely candidates for ERT. They have a clinically normal sister who can be tested for carrier status by DNA analysis and offered genetic counseling.

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It is important to be aware of rare genetic disorder so that these disorders can be suspected in appropriate situations. Presence of alopecia and seizures suggested the diagnosis of biotinidase deficiency. Even if the disorder is treatable for successful long-term treatment, patient education and compliance are important. Communication with local primary care physician and his/her support can play an important role in such situations. Biotinidase deficiency is also an autosomal recessive disorder; and the family can be offered prenatal diagnosis or new born screening and treatment of an affected child.

1. Anderson KE, Bloomer JR, Bonkovsky HL, et al. Recommond ations for the diagnosis and treatment of the acute prophyrias. Ann Intern Med. 2005;142(6):439-50. 2. Burton BK. Urea cycle disorders. Clin Liver Dis. 2000;4(4):81530. 3. Burton BK. Inborn errors of metabolism in infancy: a guide to diagnosis. Pediatrics. 1998:102(6):E69. 4. Das AM, Steuerwald U, Illsinger S. Inborn errors of energy metabolism associated with myopathies. J Biomed Biotechnol. 2010;2010:340849. 5. Fernhoff PM. Newborn screening for genetic disorders. Pediatr Clin North Am. 2009;56(3):505-13. 6. Muro S. New biotechnological and nanomedicine strategies for treatment of lysosomal storage disorders. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2010;2(2):189-204. 7. Nakamura K, Hattori K, Endo F. Newborn screening for lysosomal storage disorders. Am J Med Genet C Semin Med Genet. 2011;157(1):63-71. 8. Saundubray JM, Charpentier C. Clinical phenotype diagnosis/ algorithms. In: Scriver CR, Beaudet AL, Valle D, Sly WS (Eds). The Metabolic and Molecular Bases of Inherited Disorders, 8th edition; 2001. pp. 1329-30. 9. Staretz-Chacham O, Lang TC, LaMarca ME, et al. Lysosomal storage disorders in the newborn. Pediatrics. 2009;123(4):1191207. 10. Wang RY, Bodamer OA, Watson MS, et al. Lysosomal storage diseases: diagnostic confirmation and management of presymptomatic individuals. Genet Med. 2011;13(5):457-84.

Discussion

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A few months old child was admitted with uncontrolled seizures. He had development delay, alopecia and erythematous rash on face. His blood sample was collected for biotinidase assay and he was started on tablet biotin 10 mg/day. The convulsion stopped on second day. The biotinidase deficiency was confirmed by enzyme assay. This is an easily treatable disorder with oral biotin administration. If treated since neonatal period the outcome for neurological function is very good. Hence, the disorder is included in the newborn screening program of many countries. This child showed dramatic improvement and was informed by parents that he was developing normally.

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Section

15 Adolescent Health





















15.1. 15.2. 15.3. 15.4. 15.5. 15.6. 15.7. 15.8. 15.9.



Section Editor : MKC Nair Why Adolescent Care Counseling?: MKC Nair Family Life Education: Manorama Verma Adolescent Nutrition: Jugesh Chhatwal Adolescent Counseling: Sushila Russell Adolescent Mental Health: Paul Swamidhas Sudhakar Russell Adolescent Sexuality: MKC Nair Common Health Problems in Adolescents: Sukanta Chatterjee Adolescent Gynecology: Suneeta Mittal Adolescent Friendly School Initiatives: Abraham K Paul

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Why Adolescent Care Counseling?

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MKC Nair Life skill and career guidance (employability training) National capacity building for delivery of services. Child, adolescent and youth mental health is probably a continuum from a child development perspective— normal and abnormal, evolution of problems, causative and risk factors and ultimately the outcome. It is said that many of the adult psychiatric disorders have their onset in adolescence. Mental health issues of adolescents have to be addressed in the primary-care set-up itself, because there are far too many adolescents with behavioral and emotional problems in the community and only limited number of psychiatrists, clinical psychologists and trained counselors available. An adolescent pediatrician can make both parents and children comfortable in a nonstigmatizing service delivery system. All of us have fond memories of our adolescence. Traditionally, the societal norms were such that we mostly tried to limit our activities within the acceptable norms of the society. Our parents and teachers tried to instill in us the correct moral values as it was thought appropriate for the day. Time has changed. Very little societal control is perceived now, and whatever is still left is not appreciated. Present day parents themselves often feel inadequate to cope with the fast changing norms of society and hence, they are not sure about how to guide the youngster. Teachers, our traditional source of wisdom, are often confused about their role in society at least vis-à-vis the problems of adolescence. Yet, they have best opportunity to guide the destiny of millions of youngsters, only if we could empower them their legitimate role in the society.

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Adolescence is that period in our life where nothing seems to go smoothly, yet our best memories are about those wonderful days. The present day adolescent is considered to be more knowledgeable about world affairs, thanks to the onslaught of the media, so much so many questions needed for any special program for adolescents. On the other hand, some feel disillusioned about the way things are going and hence, point out the futility of any intervention program at this level. Adolescence is also that period in our lives where contradictions are the rule and not the exception. A period when they demand independence, yet are mostly dependent, a period when maximum hostility is shown to the parents, but they want to be loved and cared for, a period with maximum rebellion shown, yet want to be the pet baby of their mother, a period when they reject advice outright, yet love to be guided through difficulties. Surely any conventional approach is likely to fail with this group. Then, what do we do? Special problems of vulnerable and marginalized groups and problems of adolescent boys have to be addressed separately. Apart from these, we need to have a strategy for adolescents as a group in India, which should focus on: • Malnutrition, anemia, iodine deficiency, etc. • Obesity, diabetes, hypertension, all foundation for future heart problems • Adolescent reproductive sexual health (ARSH) service delivery • Scholastic backwardness issues and improving study habits • Adolescent counseling services in the community

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amily Life ducation

In the vast population of India, nearly one-fifth is comprised of adolescents, 10–19 years old. Adolescents stand at the threshold of adulthood with all its attendant responsibilities and rights. The young adults, coming out of the teenage period, are eager to go out in the world and “live life”. Very often, the urges and feelings of living life influence the adolescents in their teenage years, pushing them to experiment and take risks with their lives. As they evolve from teenagers to youth, the usual sources of information and guidance are peers and media and rarely parents/ teachers/doctors. In India, the social backgrounds are diverse. On one hand are the urban, well-educated parents usually working, and on the other hand, either illiterate or uneducated, conservative background parents. In either scenario, the parents are either not available or capable or comfortable talking to their children on various aspects of family life and sexual development. As a result, the adolescent is sandwiched between traditional parental controls and increasingly promiscuous media giving easily available unregulated information. The formal education provides little or no information or guidance on issues concerning family life. With this background, the adolescents experiment, make mistakes and learn their societal lessons or enter adulthood ill-equipped to deal with many social issues.

Family life education is a comprehensive program to educate the growing children, especially the adolescent age group regarding various aspects of living in a society and interacting with other individuals at different levels and in different ways along with imparting age appropriate knowledge of biological and sexual development. It can help in providing accurate and sufficient information for the youth to be able to make sensible choices and become responsible adults and citizens. It should not be considered a mere euphemism for sex education. Family life education for adolescents addresses two important kinds of needs: (1) their current normative needs associated with changing physical, sexual, cognitive, social and emotional development, and (2) their anticipatory or future family-related needs to help prepare them for adult roles and responsibilities in marriage and parenting.

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education for the first time. The third National Family Health Survey reported that among girls aged 15–19 years, 27.8% have had their first sexual encounter and in 8% earlier than 15 years of age. Most of these are within the marital context as the median age for marriage for girls is 17.2 years. Early marriage leads to early childbirth as well and this is evident from the fact that 53% of women had their first childbirth by 20 years of age. Among boys aged 15–19 years, 14.8% had two or more sexual partners in the preceding 12 months, 63% indulged in high-risk behavior and only 31.3% used condoms. About 10% of both girls and boys reported symptoms suggestive of sexually transmitted infections (STI). Although, awareness about human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) was present in nearly two-thirds of the girls and 86.4% of boys, comprehensive knowledge regarding HIV even among those with 12 years of education was seen to be about 55% for girls and 62% for boys. Awareness regarding condoms use was still lacking in 10–20% men and women even with 12 years of education. It is apparent that the adolescent sexual activity whether within the framework of marriage or otherwise is a reality. With the above facts and the social scenario, there is a definite need to address the issues of lack of awareness, ignorance or inappropriate knowledge among the youth so as to promote healthy behaviors and practices. E

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882 The third National Family Health Survey (NFHS-3)

conducted in 2005–2006 looked at adolescent sexual health and risk-taking behavior, and also, at family life

Family life education can help in: • Providing knowledge, skills and attitudes to the adolescents for healthy family life • Equipping the adolescents with the ability to make responsible decisions about social and sexual behavior • Increase their awareness about their own health and personal development • Enhance their life skills.

Curriculum Guidelines The curriculum for family life education should be appropriate for the targeted age group. An advisory board should be formed at the school level to formulate the guidelines, decide on the content and implementation. Such a board should include the school principal, teachers, school management board member, parent representatives, medical professionals and some other members like religious leaders, etc. The educators should have received training to conduct such sessions. An interactive approach and small group sessions are better for engaging the students. It has been shown that role play exercises also enhance the learning experience. Gender separation may be required for some sessions.

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1. Brindis CD. A public health success: understanding policy changes related to teen sexual activity and pregnancy. Annual Rev Public Health. 2006;27:277-95. 2. International Institute for Population Sciences (IIPS) and Macro International. National Family Health Survey (NFHS-3), 2005–06, India: Key Findings. Mumbai: International Institute for Population Sciences. 2007. 3. Nair MKC. Adolescence and Family Life Education. Bengaluru, Karnataka, India: Prism Books Private Limited; 2002. 4. USAID, Family Health International, Interagency Youth Wor king Group. Family Life Education: A Handbook for Adults Working with Youth. USA: Family Health International; 2008.

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ocietal cceptability

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In a nationwide survey, NFHS-3 assessed the acceptability of providing information in schools regarding moral values, body changes in boys and girls, sexual behavior, contraception and HIV/AIDS. Majority of the men and women has approved of teaching these topics, especially moral values and HIV/AIDS and then in decreasing percentages for sexual behavior, body changes and contraception. The preferred age at which most of these topics should be taught was about 15–16 years as per the opinion of the respondents.

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dolescent development: Physiological changes including growth and sexual development, emotional changes and responses, positive health practices Human relationships: Appropriate friendship/group activities, assertiveness, recognizing danger signs in interpersonal interactions, future family roles Values, morals, ethics: Honesty, trust, self-control and discipline amily as a basic unit of society: Family interactions, personality development within the family, preparing for adulthood and family support ecision making and problem solving: n the context of personal/social/peer pressure and messages from other sources like media, etc. areer goals and planning: Career choices, require ments, procedures exual activity: roblems of premarital/nonmarital sex, consequences of unplanned pregnancy, viz. effects on educational goals, reputation, mental health, financial problems, sexually transmitted diseases, abstinence as a 100% effective method for preventing pregnancy ontraception: Emergency contraceptives, temporary methods, permanent methods Pregnancy and childbirth: ormal changes, care during pregnancy, dangers of teenage pregnancy, delivery, postnatal care, care of the newborn, breastfeeding Parenting skills: Breast-feeding, infant feeding, child development Preventing and coping with violence: Misuse/ possession of firearm and other weapons, dealing with violence/assault, child abuse, sexual assault and abuse, family violence, electronic media threats

tress management: Coping with stress, e.g. examin ation stress, family-related problems, peer pressure, body image issues • ubstance abuse: Smoking and tobacco use, alcohol, drugs, etc. • exually transmitted diseases: Infections, HIV/AIDS— prevention, early signs and management • iet and fitness: Obesity, undernutrition, eating disor ders. S



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Given below are some of the topics, which can be included for adolescents’ Family Life Education Program.

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dolescent Nutrition







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urrent Nutritional tatus

dolescent Nutritional Needs

Early adolescence is marked by rapid growth phase and pubertal changes during which time the nutrient requirement is different as compared to late adolescence when growth has stabilized and the micronutrients have an important role. The current weight, gender, growth phase and the level of physical activity have a significant bearing on energy needs of the teenager. Daily requirements for adolescent age group as per the revised Indian Council of Medical Research (ICMR) Guidelines (2010) are given in Table 15.3.1.

Micronutrient equirements R

NN

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Various surveys have shown that the dietary intakes of Indian adolescents are significantly inadequate. The ational utrition Monitoring Bureau ( MB) Survey (2002) had shown that 30–40% of girls and 33–66% of boys consume less than 70% of the recommended daily allowance (RDA) for calories. Protein intake is also significantly less in more

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The hallmark of adolescent period is growth. It is apparent that for adequate and appropriate growth, nutrition is the most important factor. The major growth tasks that are to be completed during adolescence are: • ncrease in height: nearly one-fifth (20%) of the adult height is gained during adolescence • Weight gain: About 25–50% of the final adult, ideal weight is gained during adolescence • A little less than half (45%) of skeletal muscle mass is added • Almost 50% of bone mass is accumulated and by the end of 2nd decade of life, 90% of total bone mass is gained. In addition to the growth tasks, the adolescent nutrition is of significant importance as it has implications for future adult eating patterns. Also, in children entering the adolescent phase with a growth deficit secondary to childhood malnutrition, this period of growth provides another opportunity to catch up and improve their growth. The impact of inadequate or inappropriate dietary intake, at this phase of life, is also visible later in adult life. In addition to retarded physical growth, there can be delayed sexual maturation and effect on intellectual functioning. Associated micronutrient deficiencies can cause anemia, stunting and poor bone health. These eventually affect the outcome as an adult and lead to diminished work capacity, skills and cognitive functioning. In addition, in females, there is an increased obstetrical risk with poor pregnancy outcome and increased maternal morbidity and mortality.

than half of the adolescent girls and boys. The intake of micronutrients is much more seriously reduced with majority taking less than 50% of RDA for iron and more than 80% taking grossly inadequate amounts of vitamin A. A study on the beneficiaries of the Adolescent Girl Scheme in six rural blocks found that the intake for milk/milk products, pulses, vegetables and fruits was grossly inadequate while it was better for cereals, oils/fats and sugar (2007). The recent FHS-3 (2005–2006) has revealed that among adolescent girls aged 15–19 years, 46.8% have a body mass index (BMI) of below 18.5 with nearly one-fifth below 17 years of age. Amongst boys, 58.1% are undernourished and 29.3% have a BMI below 17 years of age. Prevalence of anemia in this age group is seen to be 55.8% among girls and 30.2% among boys. Assessment of iodine intake showed that only 51% of the households were using adequately iodized salt. Parallel to the problems of inadequate food intake is the situation of excessive consumption causing obesity and overweight in significant proportion of the population, especially among urban youth. Prevalence of these disorders has been reported to range from 5–14% in different parts of the country.

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The most important micronutrients during adolescent period are iron, calcium and zinc. At the onset of puberty,

Table 15.3.1 Dietary requirements for adolescents (Indian Council of Medical Research, 2010)

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Gender

Age (years)

Proteins (g)

Calories

Fat (g)

Calcium (mg) Iron (mg)

Zinc (mg)

Boys

10–12

39.9

2,190

35

800

21

9

Girls

10–12

40.4

2,010

35

800

27

9

Boys

13–15

54.3

2,750

45

800

32

11

Girls

13–15

51.9

2,330

40

800

28

11

Boys

16–17

61.5

3,020

50

800

28

12

Girls

16–17

55.5

2,440

35

800

26

12

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1. Adolescent utrition. In: Kleinman RE (Ed). Pediatric utrition Handbook, 6th edition. Policy of the American Academy of Pediatrics. ew Delhi: Jaypee Printers; 2010. pp. 175-82. 2. Adolescent utrition: A Review of the Situation in Selected South-East Asian Countries. ew Delhi: World Health Organization, Regional Office for South-East Asia; 2006. 3. International Institute for Population Sciences (IIPS) and Macro International. ational Family Health Survey ( FHS-3), 2005–06, India: Key Findings. Mumbai: International Institute for Population Sciences; 2007. 4. Malhotra A, Passi SJ. Diet quality and nutritional status of rural adolescent girl beneficiaries of ICDS in orth India. Asia Pac J Clin utr. 2007;16(Suppl 1):8-16. 5. ational Institute of utrition. Dietary Guidelines for Indians: A manual, 2nd edition. Hyderabad: Indian Council of Medical Research; 2010. 6. ational Institute of utrition. ational utrition Monitoring Bureau: Diet and utritional Status of Rural Population. Hyderabad: Indian Council of Medical Research; 2002.



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Adolescent obesity has been a cause for concern in developed nations and also emerging as an important problem in the developing countries. It is likely to track into adulthood and can lead to related lifestyle disorders; hence, it is important to prevent and manage obesity at this age. Different criteria have been used to define obesity. Body mass index cutoffs are most frequently used; although, addition of skin fold thickness is reported

ating isorders

Eating disorders refer to a group of conditions defined by abnormal eating habits that may involve either insufficient or excessive food intake leading to health problems. Some of the better known eating disorders are anorexia nervosa, bulimia nervosa, binge-eating disorder and eating disorders not otherwise specified. These are common in developed countries, especially among young girls or women. A combination of biological, psychological and environmental factors plays a role in causation. The treatment involves behavioral therapy along with nutritional rehabilitation and pharmacotherapy.



Adolescent period has its own behavioral complexities, which are closely linked with dietary intake. The growing teenager is breaking free from parental control and this is reflected in the decision making for food intake and accepting the norms and dietary guidelines. Dissatisfaction with body image, peer conformity, search for self-identity and a busy schedule add to the nutritional problems. Some of the common characteristics of food habits of adolescents are: (1) missing meals, especially breakfast; (2) frequent out of home meals; (3) snacking, especially on calorie dense fast foods and (4) fad diets. Some of the important nutritional disorders seen in adolescents are: • Undernutrition • Iron-deficiency anemia • Obesity • Eating disorders.

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Nutritional isorders

to make the assessment better. Obese adolescent needs a detailed dietary and clinical assessment, and usually, this is sufficient to rule out any significant pathological causes of obesity. Moderate-to-severe obesity can lead to a number of systemic disorders. Managing an obese teenager requires empathy as they usually have significant psychological problems. The first step is to motivate, as without motivation all modalities of treatment are likely to give poor results. Decreasing calorie intake along with increasing physical activity is the basis for management. Dietary and activity management are essential for other modalities of treatment like pharmacological interventions or bariatric surgery also.

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the preadolescent child may already have a preexisting iron deficiency and most Indian diets, even if adequate, otherwise are not a good source of iron. Iron is essential for both girls and boys. Girls with menarche will have additional requirements and boys require iron as they are adding muscle bulk (myoglobin) and also increase in red cell mass increases the demand for iron (hemoglobin). Calcium is essential for the bone mineral accretion, which reaches peak in mid-adolescence. Accelerated muscular and skeletal development increase the demand for dietary calcium at this age. Inadequate calcium intake during this period can decrease the bone mineral mass with sometimes lifelong consequences in the form of increased risk of osteoporosis. Zinc is required for physical growth as well as sexual development and deficiency can impair these processes.

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The choice and modality of providing the counseling depends on the developmental age of the adolescent. Patients in early adolescence (10–13 years of age) typically are concrete thinkers and are unable to clearly understand the cause and effect between their behaviors and their health. Therefore, counseling for patients in early adolescence should be clear and direct. These patients may also be relatively attached to their primary-care givers who can help reinforce counseling at home settings, and should therefore be ideally empowered as cotherapists. In view of their developing cognitive abilities, play and behavioral therapies are used to modify behaviors in older childhood and early adolescence. Children in mid-adolescence (14–17 years of age) are able to think more abstractly; typically, they are capable of

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ognitive evelopment and ounseling

Types of ounseling C

Adolescents are diverse in their age and developmental stage, social and geographical environments, economic circumstances, subculture, ethnicity, gender, sex, sexual orientation, disabilities and marital status. Despite all these variations, adolescence is a period of exaggerated physical, emotional, social, intellectual and spiritual growth with their complexities often resulting in a need for counseling. Adolescents might require preventive and therapeutic counseling to address their mental health needs. Counseling, with its elements of science and art, is one of the major interventions in helping adolescents with mental health needs and includes as many as 400 different types of therapies. Regardless of the different types, counseling is an interactive process involving a trained professional counselor and an adolescent with the aim of enhancing the adolescent’s level of functioning. Although, counseling is a part of any clinician-patient interaction; counseling using formal principles in an organized manner is seldom part of a PCPs therapeutic armamentarium. Globally, 20% of children and adolescents suffer from a major mental illness and 75% of them present to the primary-care pediatrician. However, only about 17% of these children are identified by their primary-care physicians and even if recognized, only a small fraction receives appropriate mental health treatment including counseling. In this section, the different types of counseling, their indication as well as the evidence to support their effectiveness are presented. The term “counseling” is used with psychotherapy interchangeably and a detailed discussion of any specific form of counseling is beyond the scope of this section.

complex, logical thinking; and sometimes, are allowed to make their own health care decisions. Children in late adolescence (18–19 years of age) have a longitudinal understanding of how their behaviors can affect their health than do patients in early or midadolescence. Counseling during late adolescence should continue to focus on risky behaviors (e.g. substance abuse, violence, sexual behaviors) and coping skills. It should be noted that the confidentiality requirements may change when working with mid- and late adolescence (15 years and above) or emancipated minors (17-years-old living on his own, away from parents) and most of the sessions with older adolescents are confidential unless there is a threat of suicide or homicide. Cognitive behavioral techniques (CBT) are used in early and mid-adolescence and cognitive techniques with late adolescence. While being invited into the counseling room for a therapy session, adolescents are invited first before their caregiver to overcome their autonomy related issues and enhance their cooperation.

Based on the process and function of the therapy being used, the counseling techniques could be generically classified as supportive counseling that provide support, guidance, advice and reassurance (e.g. guidance, milieu therapy); re-educational counseling that attempt to teach individuals new patterns of behavior and social functioning (e.g. cognitive therapy, behavior therapy) as well as reconstructive counseling that aims to dismantle and rebuild a new personality (e.g. psychoanalysis, psychodynamic therapy). More details about these forms of counseling are summarized in Table 15.4.1. Counselors in the primary-care settings, more frequently and effectively, use supportive psychotherapy than re-educational or reconstructive therapies as they need extensive training.

Preventive ounseling C

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Commonly, preventive counseling is provided for healthrelated concerns associated with lifestyle issues (e.g. obesity, nutrition, reproductive health) and substance abuse in primary-care pediatric setting. Unfortunately, even when adolescents visit physicians, valuable opportunities for prevention are missed in more than 50% of routine visits. It is partly, because the recommendations for screening and prevention are clear for adults and children, but are less clear for adolescents. The broad categories for which preventive counseling can be given from a mental health perspective are for adolescents who go through normative crises and who have significant life-events or accumulation of daily hassles.

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Table 15.4.1 Classification of counseling based on its therapeutic process Types

Function

Examples

Indications Personality disorders

Re-educative therapies

Emphasize on teaching alternative techniques that are Behavioral therapy often problem-specific Cognitive therapy Interpersonal Family therapy Play therapy

Anxiety disorders Depressive disorder Conduct disorder

Supportive therapies

Relief from the immediate crisis, and removal of symptoms Crisis intervention to premorbid levels using adolescents own emotional, Grief support intellectual and social skills

Suicidal attempt Grief

Normative crises happen as a part of the adolescent constructing oneself. Resolving this identity crisis successfully during the separation-individuation process gives the adolescent a coherent, purposeful sense of self. However, during this process of psychosocial growth while attempting autonomy and separation from his/ her family of origin, the individual problems of identity confusion, lack of self-esteem, problems with group and peer identity, troubles with gender identity, difficulties in organizing daily tasks, strained and disconnected family relationships can happen among other problems. The core issues in counseling normative crises of adolescence, using supportive principles, are summarized in Table 15.4.2.

Life Events Life events, like domiciliary violence, parental death or separation, teenage pregnancy, serious illness requiring hospitalization, relationship problems have been reported among adolescents in India and often had been associated with suicidal behaviors. They often unsettle the homeostatic

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mechanisms in the adolescent and his family. These adolescents need supportive counseling addressing the adjustment difficulty because of the changed life situation in addition to appropriately using crises intervention to resolve the crises. The basic techniques of crisis intervention are summarized in Table 15.4.2.

Therapeutic ounseling C

Normative Crises

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Reconstructive therapies Gives insights by focusing on psychological mechanisms, Psychoanalysis unlearning and relearning healthy relationships, behavior Psychodynamic and handling of emotions counseling

Indications for Psychotherapy in Primary Care Knowledge of the indications of therapeutic counseling, in treating the emotional problems and psychiatric illness, is essential for offering adolescents with counseling options. The basic indications include those circumstances where the only intervention available is nonpharmacological (e.g. dissociative and somatoform disorders, attachment disorders). When an adolescent presents with stress-related physical symptoms or worsening of physical illness (e.g. worsening of asthma or diabetes with stress) counseling is required. When psychotropic medications are expected to interact with prescribed medication(s), and therefore,

 

Table 15.4.2 Preventive counseling for normative crises and life events Indication

Focus of counseling

Normative crises

•  •  •  •  • 

General principles in crisis management











Life events



























•  Be nonjudgmental •  Treat the adolescent’s problems seriously and take all threats seriously •  Do not try to talk the person out of it •  Ask direct questions, such as “Have you been thinking of killing yourself?” •  Communicate your concern and support, offer yourself as a caring listener until professional help can be arranged (e.g. in case of imminent suicide) •  Help adolescent to realize the maladaptive response to the crisis (e.g. suicidal •  Try to evaluate the seriousness of the risk in behavior for failing in board exam) order to make the appropriate referral to a •  Assist one in crisis to identify the steps that lead to the crisis, identify the mental health care professional alternate steps that will not end in a crisis (e.g. failure in board exam) •  Do not swear to secrecy, especially when •  Special attention on identifying the first step in the pathway that leads to the there is a threat of suicide or homicide crisis and change to the adaptive pathway, termination of counseling •  Do not leave the person alone if you feel the threat is immediate

Accepting one’s body as it is and using the body effectively Help form new and more mature relationship with age mates of both sexes Achieve gender appropriate social role Achieve emotional independence from parents and other adults Prepare oneself to have economic independence through an enjoyable and productive career, prepare for marriage and family life •  Help to desire for and achieve socially responsible behavior •  Assist to acquire a set of values and ethical system and develop an ideology as a guide to one’s behavior

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Table 15.4.3 Therapeutic counseling for priority mental health disorders of adolescents as recommended by the World Health Organization*

t

Treatment modality as recommended by WHO Disorders

Family therapy

School intervention

Counseling

Specialized interventions

Others

CBT

LD

-

-

yes

yes

-

yes

ADHD

yes

-

yes

-

-

-

Tics

yes

yes

-

-

-

-

Depression

yes

yes

-

-

-

-

Psychoses

-

yes

yes

-

yes

-

Schizophrenia

-

yes

-

-

-

-

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Abbreviations: WHO, World Health Organization; CBT, Cognitive behavioral techniques; LD, earning disability; ADHD, Attention-deficit hyperactivity disorder. *Because of the propensity of the illnesses of childhood to progress into adolescence, nonpharmacological intervention strategies for childhood disorders have also been included.



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1. Neinstein LS. Adolescent Health Care: a Practical Guide, 4th edition. Philadelphia, Pa: Lippincott Williams and Wilkins; 2002. pp. 11-7. 2. Russell PS, Nair MK. Strengthening the Paediatricians Project 1: The need, content and process of a workshop to address the Priority Mental Health Disorders of adolescence in countries with low human resource for health. Asia Pac Fam Med. 2010;9(1):4. 3. Russell PS, Nair MK. Strengthening the Paediatricians Project 2: The effectiveness of a workshop to address the Priority Mental Health Disorders of adolescence in low-health related human resource countries. Asia Pac Fam Med. 2010;9(1):3. 4. Russell S, Russell PS, Kaur MS, et al. Priority mental health disorders of children and adolescents in primary-care pediatric settings in India 3: psychotherapy and other non-pharmacological interventions. Indian J Pediatr. 2012;79(Suppl 1):S33-8. Epub 2011. 5. Russell S, Subramanian B, Russell PS, et al. Psychopathology, traumatic life events, and coping skills among patients attending a primary-care adolescent clinic. Indian J Pediatr. 2012;79(Suppl 1):S52-9. Epub 2011. 6. Russell S, Subramanian B, Russell PS. Psychopathology and functional impairment among patients attending an adolescent health clinic: Implications for healthcare model reform. Osteopath Med Prim Care. 2008;2:3.



Psychotherapy has a principled tradition and a theoretical basis for their use. A number of techniques of proven effectiveness are available for helping adolescents with their normative crises, life event provoked difficulties or mental illnesses. Primary-care pediatricians should be able to include simple counseling strategies in their therapeutic options for adolescents with mental health needs. Existing literature readily supports to the evidence that various forms of counseling strategies are effective among

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adolescents with mental health needs. However, it should be noted that many of the current effectiveness evidence are a generalization of findings from the adult or childhood studies. It also seems that these therapies are acceptable and feasible in the primary-care settings in different cultural contexts.



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they have to be avoided, if intolerance for psychotropic adverse effects is noted or when potentiating of the psychotropic is required with combined interventions (e.g. psychotherapy for refractory symptoms in depression or for obsessive compulsive disorder) counseling has a significant role in minimizing or eliminating the symptoms among adolescents. Counseling for adolescents is prescribed when there is a high risk of deliberate self harm (e.g. potential to overdose on psychotropic medication as with tricyclic antidepressants), medication abuse (e.g. prescription medications like psychostimulants being misused), and to improve treatment compliance or the illness has been controlled but the impairment of the illness persists in the patient (e.g. depression is treated with antidepressant but the child has school refusal as an impairment of the mood disorder). Therapeutic counseling for Priority Mental Health Disorders of adolescents recommended by World Health Organization (WHO) is presented in Table 15.4.3.

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Priority Mental Health isorders Mental and behavioral disorders are common among adolescents in the community and in primary health care settings. Amongst the plethora of mental health illnesses the adolescents present with, the WHO has suggested the gate-keeping physicians to apply their resources, on a

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Currently, we have the largest adolescent generation ever in the human history. Noncommunicable diseases among adolescents and mental health illnesses, in particular, have been documented to result in high levels of medical, social and economic burden. Most of the adult mental health disorders have their onset during their childhood or adolescence. In low and middle income countries, including India, with paucity as well as skewed distribution of resources for health, adolescents with mental health needs become doubly disadvantaged and often remain or perilously drift outside the safety of any health care system. An effective way to address the resource paucity is by enhancing the primary-care pediatrician (PCP) in the recognition, treatment and when needed, referral of the adolescents to mental health specialists. This section will, therefore, brief the reader on the clinical skills of diagnosis, medical management and referral protocols for the priority mental health disorders (PMHD) in primary-care pediatric settings.

group of illnesses identified as the PMHD. Priority mental health disorders have been targeted for identification and intervention based on their higher prevalence, propensity to progress into adulthood, enduring impairment and therapeutic potentials in the primary-care settings. Although during adolescence, WHO suggests to address depression and associated suicide, as psychiatric disorders of childhood onset have a continuous course and will often continue into adolescence, other disorders [like autism and attention-deficit hyperactivity disorder (ADHD)] will also have to be addressed but in decreasing priority. The epidemiology and their intervention strategies are mentioned in Table 15.5.1. D

Introduction

iagnostic Practice

Missed diagnosis and misdiagnosis often result in failure to involve adolescents in treatment and poor follow-up care. These diagnostic difficulties by PCP can be minimized in several ways. Firstly, it is important to maintain a high index of suspicion for PMHD, which are widely prevalent in primary-care settings. Secondly, the PCP should be enabled to clinically recognize the common overt, and if possible, the covert symptom presentations of PMHD. Thirdly, training the pediatrician in using a two-tier diagnostic approach might lessen the diagnostic errors. As an initial approach, the PCP should administer a general psychiatric screening questionnaires (self, parent or clinician rated) routinely, or certainly, when a mental health need is suspected. The use

 

Table 15.5.1 The epidemiology and management of priority mental health disorders Stage

Adolescence

Childhood

Toddler

PMHD

Prevalence

Medication

Nonpharmacological

Depression

0.1

Yes

Yes

Psychoses*

-

Yes

Yes

Mania*

-

Yes

Yes

Conduct disorder

1.1

Yes

Yes

OB syndromes*

-

Yes

Yes

Tic

0.2

Yes

Yes

Enuresis

6.2

Yes

Yes

Anxiety disorder

4.1

Yes

Yes

ID

2.3

No†

Yes

†

No

Yes

Yes

Yes

Autism ADHD

1.7 o

p

Abbreviations: PMHD, riority mental health disorders; OB, rganic brain; ID, Intellectual disability; ADHD, Attention-deficit hyperactivity disorder. *No recent epidemiological data from India is available † Medication is prescribed only for targeted symptoms

889

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Medication Use

R

­

All PMHD, except the developmental disabilities (like intellectual disability and autism) need pharmacological treatment and can be effectively treated in the primarycare setting. However, even adolescents with develop mental disabilities will require medications if medication responsive symptom (like self-injurious behaviors or stereotypic movements) is documented or a superimposed mental illness is diagnosed. The primary-care pediatrician can effectively treat all PMHD with a thorough knowledge in using five psychotropic medications at the appropriate dose and dosing schedules (Table 15.5.3). Best psychopharmacologic treatment in this population requires an appreciation that adolescents have an increased disposition to comorbidities, awareness of pharmacokinetic and pharmacodynamic aspects of specific medications and medication classes, in particular the elimination half-life, developmental considerations, drug interactions and adverse effects. In this context, it should also be noted that many of the psychotropic drugs prescribed for adolescents have not been tested for their use in well-controlled trials. Instead, from the evidences available with adults, a weight-based dosing is used to estimate the necessary dosage in this population.

eferral Pattern

Majority of the mental health problems are managed in primary care and only a handful of adolescents are referred to expert mental health care providers. However, not all cases of PMHD are suited for treatment in a primary-care setting and the PCP should be aware of the indications to refer an adolescent to a specialist adolescent psychiatric care. If there is poor response to pharmacotherapy or failure to attain remission status (like in refractory depression), or a rapidly deteriorating clinical picture, then the adolescents need to be referred to a specialist setting. Adolescents with comorbidities that significantly complicate treatment with the need for a complex regimen (like depression with substance abuse) or multiple medications (like depression





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of screening instruments has been documented to improve the case identification among those who are suffering from mental disorders, and clinicians support the use of screening instruments, as they are usually brief and easy-to-use in busy primary-care practice. As using only brief screening measures can result in the under or over recognition of the PMHD, it is a good practice to confirm the potential mental illness with diagnostic clinical criteria. Among the screening measures available, the most favored instruments for use in primary-care settings are pediatric symptom checklist (PSC), the child and adolescent psychiatric screen (CAPS) and child behavior checklist (CBCL). It should, however, be noted that none of the above or other measures (scales, inventories, questionnaires) in the mental health field is diagnostic in nature and only the clinical diagnostic criteria [e.g. International Classification of Diseases (ICD) and Diagnostic and Statistical Manual of Mental Disorders (DSM) systems] supported with extensive field trials have the diagnostic accuracy, reliability and validity characteristics to act as diagnostic tools. For the confirmatory assessment, using the Diagnostic and Statistical Manual of Mental Disorders, IVth edition, text revised (DSM-IV-TR) is recommended. The difficulty in using these clinical criteria is that it needs an extensive degree of training to achieve high inter-rater reliability in diagnosing adolescent psychiatric disorders, and hence in primary-care settings, untrained PCP may attain only low inter-rater reliability. But if DSM-IV-TR can be used effectively, with training for PCP during their pediatric training or with follow-up workshops, then the advantages are the ability to confirm the primary diagnosis, identify comorbidities (as presence of comorbidity is a rule than an exception in child and adolescent psychiatry), quantify the impairments (in the areas of education, peers and home) and recognize the unhealthy psychosocial situations (like unstable family background) to help formulate a multiaxial treatment approach, the norm in treating adolescent mental health issues. The various characteristics of these screening and confirmatory measures are summarized in Table 15.5.2.

 

Table 15.5.2 Screening and confirmatory instruments for priority mental health disorders Number of PMHD addressed

Brevity

Age

Availability

Psychometric properties

PSC

Not specific

35 items; 5–10 min

6–16 years

Available free of cost in public domain

Strong

CAPS

10/11 disorders except attachment disorders

85 items; 15–20 min

3–21 years

Available free of cost in public domain

Published data could not be located

CBCL

5/11 disorders

96 items; 15–20 min

5–14 years

Has to be purchased

Strong

Confirmatory Number of PMHD addressed measure

Brevity

Age

Availability

Psychometric properties

ICD-10

All PMHD

Reference criteria

All ages

Has to be purchased

Strong

DSM-PC

All PMHD

Reference criteria

All ages

Has to be purchased

Strong

p

Abbreviations: PMHD, riority mental health disorders; PSC, ediatric symptom checklist; CAPS, Child and adolescent psychiatric screen; CBCL, Child behavior checklist; ICD-10, International Classification of Diseases-10; DSM-PC, Diagnostic and Statistical Manual for primary care. p

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Screening measures

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Adolescent He lt

 

Table 15.5.3 Pharmacological treatment for the priority mental health disorders in primary-care pediatric setting

Childhood

Toddler

Medications

Doses/day

Dosing/day

Depression

Fluoxetine

10–20 mg

OD (breakfast)

Psychoses

Risperidone

2–4 mg

OD-TID

Mania

Risperidone ± valproate sodium

2–4 mg 20 mg/kg

OD-TID OD (dinner)

Conduct disorder

Valproate sodium

20 mg/kg

OD (dinner)

OB syndromes

Risperidone

0.25–1 mg

OD-TID

Tic

Risperidone

0.25–2 mg

OD (dinner)

Enuresis*

Imipramine

0.5 mg/kg/BW

OD (dinner)

Anxiety disorder

Fluoxetine

10–40 mg

OD (breakfast)

Autism

Risperidone

0.25–1 mg

OD-BD

ADHD

Atomoxetine

1.2–1.8 mg/kg

OD-BD (breakfast, lunch)

a

Adolescence

Disorders

h

Stages

o

o

















Priority mental health disorders affect a substantial number of adolescents. Making an accurate diagnosis, using

1. Nair MK, Russell PS. Adolescent health care in India: progressive, regressive or at the cross-roads? Indian J Pediatr. 2012;79(Suppl 1):S1-5. Epub 2011. 2. Patel V, Flisher AJ, Hetrick S, et al. Mental health of young people: a global public-health challenge. Lancet. 2007;369(9569):1302-13. 3. Russell PS, Mammen P, Nair MK, et al. Priority mental health disorders of children and adolescents in primary-care pediatric setting in India 1: developing a child and adolescent mental health policy, program, and service model. Indian J Pediatr. 2012;79(Suppl 1):S19-26. Epub 2011. 4. Russell PS, Nair MK, Mammen P, et al. Priority mental health disorders of children and adolescents in primary-care pediatric settings in India 2: diagnosis, pharmacological treatment and referral. Indian J Pediatr. 2012;79(Suppl 1):S27-32. Epub 2011. 5. Russell PS, Tsheringla S, Nair MK, et al. Priority mental health disorders of children and adolescents in primary-care pediatric settings in India 4: training and capacity building. Indian J Pediatr. 2012;79(Suppl 1):S39-44. Epub 2011. 6. Russell S, Russell PS, Kaur MS, et al. Priority mental health disorders of children and adolescents in primary-care pediatric settings in India 3: psychotherapy and other non-pharmacological interventions. Indian J Pediatr. 2012;79(Suppl 1):S33-8. Epub 2011.



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onclusion

ibliography

7. Srinath S, Girimaji SC, Gururaj G, et al. Epidemiological study of child and adolescent psychiatric disorders in urban and rural areas of Bangalore, India. Indian J Med Res. 2005;122(1):6779.

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appropriate psychotropic medications and proper referral when required, is an important part of the clinical practice of primary-care pediatrician.



with catatonic symptoms), disorders that require high doses of psychotropic medication (like acute psychosis) and treatment that can result in significant side effects (like monoamine oxidase inhibitors) should be referred. When the patient requires specialized psychotherapy as the only modality of treatment (like conflict resolution in dissociative disorder), when the adolescent needs a strong component of adjuvant psychotherapy (like exposure and response prevention in obsessive compulsive disorder) or formal family support (like empowering parents for conduct disorder), an appropriate referral is needed. Psychiatric disorders with significant impairment (like school or occupational impairment), atypical presentation (like atypical depression), cases with diagnostic uncertainties (like the overactivity disorder with stereotypic movements), multiple axis I or multiaxial comorbidities, primary-care treatment failure in the past, those who had been in contact with specialist mental health care, need of mental health referral of parent, patients with homicidal or suicidal risk, adolescents with serious abuse, inability to maintain selfcare or survival skill and polysubstance abuse need referral to specialist adolescent psychiatric care. In addition, it is known that despite the appropriate referral, many families are not effectively engaged in mental health services. To minimize this therapy attrition along the referral pathway, prior to the referral, the PCP has to firstly, establish a good working relationship with a psychiatrist knowledgeable in current psychiatric diagnosis and pedi atric psychopharmacology, and secondly, prepare the adolescent and his family to visit the mental health expert in a collaborative manner.

8. World Health Organization: Caring for children and adolescents with mental disorders. Geneva: World Health Organization; 2003.

o

o

Abbreviations: OD, ne day; OD-TID, ne day-three times a day; OB, rganic brain; BW, Body weight; OD-BD, ne day–twice a day; ADHD, Attentiondeficit hyperactivity disorder. *Enuresis is not a PMHD, but it is added in this schedule because of its high prevalence in primary-care settings.

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dolescent exuality

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oncepts in exuality

imensions of exuality

Biological need Safety and security Love and belonging Acceptance Self-esteem Caring and affection Self-awareness Self-actualization Transcendence

















: : : : : : : : :





















Physical Legal Romantic Social/cultural Aesthetic Emotional Existential Psychological Spiritual

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evelopment of exuality B

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exuality oncepts in oys versus Girls

Boys and girls develop gender-based differences in their sexual selves. Men are often bombarded with sexual information from childhood. Society’s view that men are by nature sexual, is in contrast with a women’s sense of herself, in which her sexuality is usually kept private even from her partner.

Puberty Puberty is the stage of physical maturation in which an individual becomes physiologically capable of sexual reproduction. The biological changes that occur during puberty are mainly indicated by the development of the sexual characteristics. Secondary sexual development in girls involves the enlargement of the ovaries, uterus, vagina, labia and breasts and growth of pubic hair. Secondary sexual development in boys involves the enlargement of the testes, penis and growth of pubic hair.

oncept of Virginity

The concept of virginity is an emotional issue with a lot of gender bias and an obsession for an intact female hymen. Hence, one’s viewpoint may not be acceptable to all. A person who has never undergone sexual intercourse is considered a virgin, male or female. The customs and traditions of our society consider marriage as a religious ceremony conducted invoking blessings of God. To be or not to be a virgin is a personnel choice, but the concept of keeping oneself for the one and only one person in your life can be a pleasant decision. However, much the younger generation may want to disagree, it is a fact that we tend to get more emotionally attached to the first person with whom we have physical or sexual relationship. Female virginity is counted unnecessarily as the presence of a thin skin membrane in the outer vagina, the hymen. But there are situations in which this skin can be destroyed other than by sexual acts. For example, females engaged in heavy works, athletes, cyclists, dancers, vigorous exercises,

S

D

Sexual behavior of people finds many expressions, and it seems extremely difficult to classify behavior as normal or abnormal. However, it can be said that sexual behavior is inappropriate, when it is uncomfortable for the other person, and has the intention of doing harm either physically or psychologically on self or others. Socialization and related processes may contribute to the development of sexuality in individuals. This may be quite influenced by the norms surrounding sexuality in the society. Those who were fortunate to have a childhood environment do not consider sex as sin, do not approach it with guilt or go through it as a traumatic experience will only have positive concepts about sexuality. Sexual right is the freedom to be enjoyed by an individual to decide without any compulsion when, where, how and with whom, sexual acts are to be performed or not.

D

Sex education is important at all ages, indeed, but it is more important than it is imparted during childhood and adolescence. Many parents feel that knowing too much may lead to sexual misbehavior on the part of the youngsters. But this is not true. Studies have shown that by offering sex education and correct scientific information, premature involvement in sex has been delayed as; discussing the subject satiates curiosity and removes the compulsive motive to experiment. On the other hand, ignorant children are more prone to sexual abuse and sex-related crimes. Sex education should be targeted at individuals in the highest risk group, i.e. pubertal, prepubertal and young adults. But before attempting to do so, we need to understand adolescent sexuality. Sexuality encompasses the whole range of thoughts, feelings, fantasies, emotions, desires and language besides action, sexual behavior is only a part of it. Thus, sexuality is an integrated part of every individual’s personality and includes men, women as well as children. There is an energy that drives us to seek out love, contact and warmth, closeness that is expressed in our way to feel and to awake feelings as well as contact with each other. Our sexuality is expressed in the way we dress, the way we walk and relate to people. It makes us feel alive and good about ourselves. Hence, sexual behavior is only a part of the whole sexuality of an individual.

• • • • • • • • •

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MKC Nair



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Tex book of Pedia rics

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We often tend to forget that sexuality has eight other dimensions apart from physical, yet we often focus only on the physical dimension. Dimensions of sexuality could be 892 related to Maslow’s hierarchy of needs theory as follows:

vip.persianss.ir

In the female, the principal response is vaginal. The lining of the vagina is normally moist. This results in part from fluid from the uterus and mucus secretion from the cervix, as well as from the vaginal wall. The cervical fluid varies in amount and consistency through the ovarian cycle, i.e. close

A t

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Genital Response in Girls



In the male, the principal response is erection of the penis, due to filling of the erectile tissue with blood. In addition to penile erection, the testes becomes somewhat enlarged and the walls of the scrotum becomes thicker and tighter.

B

Genital Response in Boys

th

ibliography 1. Bancroft JHJ. Human Sexuality and its Problems, 3rd edition. USA: Churchill Livingstone, Elsevier; 2009. 2. Nair MKC. Adolescent Sexual and Reproductive Health. Indian Pediatr. 2004;41:7-13. 3. Sexual Behavior among Adolescents and young people in India some emerging trends working paper Series 3. MAMTHA, New Delhi. RFSU, Supported by SIDA 2003. 4. Sexual Reproductive Health of Young People (10–19 years). Nair MKC, Parthasarathy A (Eds). New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2006.

The biological function of the genital response in the male and female is to enable entry of the penis into the vagina, with the consequent deposition of semen in the vagina.

Sex education focusses largely though not exclusively, on self-awareness, personal relationships, human sexual development, reproduction and sexual behavior. Human sexuality is a function of the total personality, which includes reproductive system and processes, attitudes toward being a man or woman, and relationships among members of the same sex and the opposite sex. It embraces the biological, psychological, sociocultural and ethical aspects of human sexual behavior. It helps people to understand their sexuality, learn to respect others as sexual beings, and to make responsible decisions about their behavior. Sex is considered to have an inseparable role in married life, and it makes the bond between the couple more strong and healthy. Sexual relationship involves respect, trust and caring of the partner, perceiving the needs of the partner and feeling free to communicate desires and feelings.



R

Genital esponse

Teaching an dolescent about exuality





R

R

• Procreative: Rewarding for those who want to have children • e-creative: Re-creative for mere sexual pleasure • elational: Relational ensures a rewarding partner relationship. Sex is not just a means of procreation. Sex after all is the art of enhancing love. Human sexual arousal is a primitive physiological response that can’t be consciously willed. Every partner is different and even the same partner has different preferences from time to time. Good sex involves finding out what the partner wants to happen before, during and after love making.



R

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F

unctions of exual elation

to ovulation; there is marked increase in volume and has watery consistency. This facilitates entry of the sperm from the vagina into the uterus. Without sexual stimulation, the vagina is not sufficiently lubricated for comfortable entry of an erect penis. It is generally assumed that the sole function of the clitoris is to provide sexual pleasure for the woman as it contains large number of nerve endings.

dolescen Heal

swimming, bicycling, horse-riding, use of tampons during menses (not recommended) and insertion of fingers or other objects into the vagina for self-stimulation will lead to stretching or rupture of hymen well before the first intercourse.

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ommon Health Problems in dolescents

ntroduction

Adolescence is the period of least organic diseases in human life span. Mental health and social health issues become important. The significant amount of growth and developmental maturation in this period makes the adolescents vulnerable to growth and nutritional disorders. The development of sexual instinct with yet to complete self-protective maturation leads to unwanted pregnancy and STI. Tendency to explore and adaptation of risktaking behavior increases the incidence of accidents or unintentional injuries. Problem of social adaptation leads to intentional injuries like suicide attempts and homicide. Abuse of substance like smoking, consumption of alcohol, etc. also starts at this age. Many controllable chronic diseases of adult life might be detected at this age like juvenile diabetes mellitus, bronchial asthma and epilepsy. Acute infections of any system, although not specific for adolescents, commonly affect this population as well. The author will discuss in this section those health problems prevalent in adolescents excluding issues described in other sections like nutrition, sexuality, gynecology, mental health and counseling. The patient profile, for the year 2010, of the adolescent health clinic, Medical College, Kolkata is presented in Table 15.7.1 to get an example of Indian scenario of the adolescent health problems received at a teaching hospital.

A

cne

tiopathogenesis

Treatment for Mild cne Small papular lesions without cutaneous inflammatory erythema and tenderness. It is treated with topical agents like the following: • Topical antibiotics, e.g. clindamycin (1% solution, lotion, gel, foam; once or twice daily application), erythromycin (2% gel or liquid once daily) or sodium sulfacetamide (Sulfacet-R) • Benzoyl peroxide agents—comedolytic and bactericidal (2.5%, 5%, 10% gel or wash once or twice daily). Side effects are irritation and pigmentary changes. Combinations of topical antibiotic and benzoyl peroxide are available, e.g. benzaclin, benzamycin • Topical retinoids prevents follicular hyperkeratosis. It is the mainstay for the treatment of comedonal acne. Gels are better on oily skin but may cause irritation due to alcohol base. Use lowest strength preparations initially, increasing concentration if comedones persist. Application on dry skin may avoid irritation and erythema. Small amount (pea size) is sufficient to cover the entire face and apply only once at night. Preparations available are: (1) topical tretinoin, e.g. Retin-A, avita (0.025%, 0.05%, 0.1% cream, also as gel or liquid), Retin-A Micro (0.04%, 0.1% gel); (2) adapalene, e.g. differin (0.1% gel or cream). Combinations of benzoyl peroxide + topical antibiotic and tretinoin are beneficial by synergistic action, e.g. benzaclin + Retin-A but they should be applied separately at different time of the day since benzoyl peroxide may deactivate tretinoin • Other topical agents are: – Salicylic acid: Comedolytic, found in many over the counter creams, washes, solutions – Azelaic acid: Comedolytic, anti-inflammatory and used twice daily for postinflammatory hyperpigmen tation, e.g. azelex, finacea (20% cream).

linical eatures F

C

Basic lesion of acne is comedone, which may be blackhead (open type) or whitehead (closed type). Subsequently, it may 894 turn into papules, pustules or cysts. Acnes are distributed in areas having largest number of sebaceous glands like face,

­

­

Abnormal keratinization at the lower infundibulum of the hair follicle causes plugging of the follicular duct. This leads to impaction and distention of the duct giving rise to open or closed comedones. At puberty, sebum secretion is increased by androgenic stimulation. Propionibacterium acnes hydrolyze sebum and secretes proinflammatory and chemotactic factors to attract neutrophils, which release lysosomal enzymes leading to rupture of the follicles causing inflammatory papules and pustules.

–

–

E

Acne is a nodular cutaneous lesion consisting of multilobular sebaceous gland that drains its products into the follicular canal. More than 80% of adolescents and young adults are affected.

chest, back and shoulder. It may be secondarily infected by itching. Resolution occurs with depigmentation and indented or hypertrophic scar. A

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Sukanta Chatterjee



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Moderate Acne Moderate acne is inflammatory or nodular acne. It is treated with oral antibiotics to decrease inflammation and suppress P. acne organisms: (1) tetracycline (250–500 mg orally twice daily), (2) erythromycin (250–500 mg orally twice daily), (3) doxycycline (100 mg orally once or twice daily) and (4) minocycline (50–100 mg orally twice daily). All of them carry a risk of photosensitivity except erythromycin. Antibiotics should be used for a minimum of 5–8 weeks before progress is evaluated. All antibiotics carry a risk of

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vulvovaginal candidiasis and risk of decreased efficacy of birth control pill. Oral contraceptives, e.g. Ortho Tri-cyclen may also be used.

A

E

reast nlargement ­

Breast enlargement as a small mass is often a presenting problem in preadolescents and in boys also during adole scence. Girls and boys have the potential of full breast development by appropriate stimulation. Circulating estradiol along with that produced in the breast tissue by aromatase enzyme activity stimulates proliferation and differentiation of parenchymal epithelium. Fibrocystic changes and fibroadenoma are most common masses. In girls, it might start as a unilateral swelling at onset of puberty (thelarche) around 7 years of age. In boys, benign breast enlargement or puberty gynecomastia is common and may last for 6 months to 2 years but when it persists after achieving Tanner Stage V, surgical opinion is recommended. Obesity and hereditary factor may be responsible for the gynecomastia due to increased aromatase activity. Differential diagnosis includes normal variant, recreational drug abuse, testicular malignancy, chronic renal failure and Klinefelter’s syndrome.

Treatment

I

D

efinition: Involuntary voiding of urine at night after 4–6 years is called nocturnal enuresis • ncidence: Bedwetting is seen in 5% of 10 years old. Male-to-female ratio is 3:2 with a spontaneous resolution of 15% per year • tiology: It may be genetic, 15% in nonenuretic families, 44% and 77% when one or both parents, respectively, are enuretic. Constipation, urinary tract infection (UTI), pin worms may contribute. Urinary tract anatomical anomaly is unlikely in absence of day-time incontinence • iagnosis: Family history, primary or secondary and presence of other medical conditions are noted like distended bladder or colon. Urinalysis and culturesensitivity are helpful investigations with renal ultrasonography and voiding cystourethrogram in case 895 of obstructive manifestations or previous UTI E

•

octurnal nuresis E

N

Normal variant does not require any treatment except reassurance and follow-up. Breast mass should not be squeezed. Specific etiology as mentioned above needs to be managed appropriately.

D

h

u

 

 

B

 

 

Diet and climate have little evidence to influence acne. Cleansing of skin is recommended. Greasy cosmetics and hair preparations should be avoided. Manipulation and squeezing of facial lesions leads to rupture of intact lesions and provokes a localized inflammatory reaction.

t

Prevention

th

This may be treated with isotretinoin (1 mg/kg/day orally, given as a 4–5 months course). Most important side effects involve teratogenicity.

 

 

Severe Nodulocystic Acne

dolescen Heal

Table 15.7.1 Patient profile of adolescent health clinic, Medical College, Kolkata, 2010 Health problems encountered Percentage (n = 933) Adjustment and behavioral problem 23.7 Depression (31.22) Anxiety disorder (25.79) Personality disorder (14.93) Obsessive compulsive disorder (9.95) Psychosomatic (8.14) Addiction (4.97) Mental retardation (2.71) Anorexia nervosa (0.9) Slow learner (0.9) Psychosexual problem (0.45) Anemia 7.07 Leucorrhea 6.21 Viral fever 5.14 Diarrhea 4.5 Common cold 4.5 UTI 3.85 Eye problems 3.85 Caries teeth 3.43 Pharyngitis 3.43 Acne 3.43 Enteric fever 3.1 Dysmenorrhea 2.36 Malaria fever 2.36 Sinusitis 2.14 Bronchial asthma 1.82 Colitis 1.5 Allergic dermatitis 1.5 Scholastic problem 1.5 Stunted growth 1.5 Epilepsy 1.29 Infective hepatitis 1.29 Irregular menstruation 0.96 Obesity 0.85 Primary amenorrhea 0.85 Headache 0.85 Nocturnal enuresis 0.75 Migraine 0.64 Rheumatic fever 0.64 Congenital heart disease 0.6 Anxiety due to nightfall 0.53 Rheumatoid arthritis 0.43 Nephrotic syndrome 0.42 Vertigo 0.32 HIV 0.1 Abbreviations: UTI, rinary tract infection; HIV, uman immunodeficiency virus.

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Desmopressin (nasal spray or 0.2 mg tablet)—one spray in each nostril or one tablet at bedtime initially and may

1. Ammini AC. Gynecomastia. In: Desai MP, Menon PSN, Bhatia V (Eds). Pediatric Endocrine Disorders, 2nd edition. Chennai, India: Orient Longman Pvt. Ltd.; 2008. pp. 242-6. 2. Carlsen AR. Enuresis. In: Alario AJ, Brinkrant J (Eds). Practical Guide to the Care of the Pediatric Patients, 2nd edition. Philadelphia: Mosby, Elsevier; 2008. pp. 668-71. 3. Joseph G, Morelli. Acne. In: Kliegman RM, Behrman RE, Jenson HB, Stanton BF (Eds). Nelson Textbook of Pediatrics, 18th edition. Philadelphia: Saunders: Elsevier; 2008. pp. 2759-64. 4. Nair MKC, Pejaver RK. Adolescent Care 2000 and Beyond. Bengaluru, India: Prism Books Private Limited; 2000.

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rugs

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•

ibliography



•

•



•

No punishment since bedwetting is not under conscious control It is common and adolescents often get better on their own Involve the adolescent in working toward a cure, praise for success, encouragement for lack of control and attach responsibility like change of bed clothes Record keeping by calendar or star chart for success and lapse with agreed-on rewards for success Bedwetting alarm is good with 65–100% cure after 4–6 months.



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•

E

S

•

upportive ducation

be increased to two spray each nostril or three tablets. If successful, continue for 3–6 months then taper. Success rate is 75% with high relapse Imipramine (50–75 mg at bedtime) has high success rate but with possibility of relapse on discontinuation. Side effects are anxiety, dry mouth and sleep disturbance.



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• Treatment: Combined approach with supportive edu cation, behavior modifications and pharmacotherapy.

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efinition

-

The Rotterdam criteria defines polycystic ovaries syndrome (PCOS) when two of the three primary features are present: unexplained clinical or biochemical signs of hyper­ androgenism, oligoanovulation and/or a polycystic ovary.

Prevalence

T

Prevalence of PCOS in Indian adolescents is 9.13%. The pathogenesis is unknown; however, both genetic and environmental factors play a role, resulting in disordered gonadotropins release, dysregulated steroidogenesis, ovar­ ian and adrenal hyperandrogenism and hyperinsulinism. It is important to appreciate that PCOS is a syndrome, not a disease, reflecting multiple potential etiologies and variable clinical presentations. Adolescent girls with PCOS may present with hirsutism, menstrual irregularities, obesity, acne and/or signs of insulin resistance (IR) such as acanthosis nigricans. There may be no evidence of clinical and biochemical hyperandrogenism; ovarian volume and morphology may be of limited use. Hyperandrogenism and IR are more severe in obese adolescent PCOS. Adolescents who have irregular menstrual cycles have higher serum androgens than those who have regular menstrual cycles.

reatment

-

-

Treatment of PCOS is symptomatic; early intervention, counseling, lifestyle changes and weight management may be preferable as first line in adolescents, because it targets both menstrual dysfunction and long term associated morbidity. The use of combined oral contraceptives (COCs) is recommended as first line treatment for adolescents who

a

-

-

-

Dysmenorrhea (33–67.2%) is common and premenstrual syndrome (PMS) affects daily routine in 50–60% girls. If dysmenorrhea occurs early with menarche, Müllerian anomalies must be suspected. For primary dysmenorrhea, analgesics with fixed dose combination of aceclofenac and drotaverine is a suitable, effective and well tolerated treatment option. Menstrual cycles are often irregular in the first months after menarche. Most cases of abnormal uterine bleeding (AUB) in adolescents are caused by anovulatory cycles during the first 12–18 months after menarche, which is related to immaturity of the hypothalamic pituitary ovarian axis. Other common causes include pregnancy, infection, the use of hormonal contraceptives, stress (psychogenic or exercise induced), bleeding disorders and endocrine disorders (e.g. hypothyroidism, PCOS). Once pregnancy has been excluded, it is helpful to determine whether the bleeding is cyclic (regular) or acyclic (irregular) in nature. The differential diagnosis varies accordingly. Blood dyscrasias and structural anomalies (e.g. polyps, fibroids) are common with cyclic bleeding. Bleeding disorders should be considered in all adolescents with AUB who present with extremely heavy first menses, bleeding requiring blood transfusion, and patients with refractory menorrhagia and concomitant anemia. Sexually transmitted infections and pelvic inflammatory disease (PID) should be considered in all sexually active (or sexually abused) adolescents who complain of irregular, breakthrough or postcoital bleeding. Investigations should be done to establish the cause. If there is no obvious cause, the diagnosis is dysfunctional uterine bleeding (DUB) and is due to anovulation. Mild DUB can usually be managed with iron supplementation and observation. Hormonal therapy is usually necessary for moderate or severe DUB. Combined OCPs or progesterone alone can be given. Red blood cell transfusion may be necessary for patients who are hemodynamically unstable, have extremely low hemoglobin concentrations or have symptomatic anemia. Peripheral blood should be obtained 897 -

D

O

Polycystic varies yndrome

Menstrual isorders D

India has the largest population of adolescents in the world with 243 million individuals aged 10–19 years and girls below 19 years of age comprising one quarter of India’s rapidly growing population. Adolescent gynecology is an emerging specialty, involving pediatrics, endocrinology, gynecology, pediatric surgery, dermatology, psychiatry, public health medicine and genetics. The relatively common complaints in adolescents are dysmenorrhea, pelvic mass/ pain, genital irritation and amenorrhea with underlying uncommon etiologies such as Müllerian anomalies, ovarian tumors, foreign body, labial hypertrophy, dermopathies, genital ulcers and imperforate hymen. Common problems observed in an adolescent gynecology clinic are discussed here.

suffer from the menstrual and cutaneous symptoms of PCOS. Other therapeutic options for menstrual irregularities include progestin alone and the low dose oral contraceptives containing estrogen and progesterone. The COCs containing drospirenone have a better outcome than with desogestrel containing pills. Adding spironolactone or cyproterone is sometimes required, if the hirsutism is severe. Metformin can be used in obese adolescents with PCOS as an adjunct to weight control measures and to treat coexistent insulin resistant metabolic abnormalities. -

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Adolescent Gynecology

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Vulvovaginitis mainly nonspecific is the most common gynecological problem (95–98%). Perineal pain, interlabial masses, UTI and daytime incontinence are commonly seen. Improving hygiene, avoiding irritants and keeping vulva dry are the basic principles of treatment.

Adolescent ndometriosis Endometriosis is a progressive disease that can cause chronic pelvic pain and infertility. The most immediate issue is to relieve pain. Ultrasound will usually diagnose the condition when there are chocolate cysts. Usually, medical management is preferred in an adolescent but laparoscopy may be required in the case of large chocolate cysts.

Adolescent ontraception There is an unmet need of contraception and misinformation requiring urgent intervention. Both married and unmarried adolescents may be in need for contraception, and depen­ ding on requirement may be counseled regarding use of COC pill and condoms. Dual protection against pregnancy and STI is important. Given the transience of many adolescent relationships and the high probability of multiple, sequential sexual partners prior to marriage, a condom is the single best protective option for many adolescents. But it may be best to combine with an oral contraceptive pill, if possible. Emergency contraception as an emergency backup should also be available to young women.

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Adolescent girls face considerable health risks during pregnancy and childbirth, accounting for 15% of the global burden of disease for maternal conditions and 13% of all maternal deaths. Risk of medical complications like high blood pressure (BP), iron deficiency anemia and eclampsia is greater among adolescent mothers. An underdeveloped pelvis can lead to obstructed labor and grave complications like vesicovaginal fistula, infant mortality or maternal death. Teenage mothers also have a high risk of genital tract infection, preterm labor and intrauterine growth restricted babies. Early booking, adequate antenatal care and delivery by trained people should improve the obstetric and perinatal outcome in teenage pregnancies. Pregnancy may be unwanted resulting in unsafe abortion. Girls from troubled family backgrounds stand 11 times more risk of unmarried teenage pregnancy than those from happy family circumstances, according to a new study in Kerala. As much as 64.5% of the unmarried pregnant girls or young -

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In India, 26% girls are married before 15 years, and 54% before 18 years. Multiple partners, new partners, inconsistent use of condoms are well known risk factors for acquiring STI among adolescents. Sexually transmitted diseases increase the rate of transmission of HIV and 50% of all HIV positive new infections are in the age group of 10–25 years. The evaluation and treatment of STI in adolescents raises a number of unique issues, including consent for diagnosis and treatment, confidentiality, parental notification and mandatory reporting of sexual abuse. Sexual history should be taken, with appropriate counseling regarding risk taking behaviors. Sexually active adolescent should be screened for gonorrhea and Chlamydia. Symptomatic genital herpes and primary syphilis are important diagnostic considerations. Pelvic inflammatory disease is a common sequel of 898 genital gonorrhea and Chlamydia infections. Microscopic examination of vaginal fluid mixed with saline and with

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The common causes are hypothalamic amenorrhea, PCOS, hyperprolactinemia, Müllerian agenesis and ovarian failure. A careful medical history and clinical examination, distinction between primary and secondary amenorrhea, together with the presence or absence of secondary sexual characteristics is essential. Presence or absence of uterus and ovaries is evaluated with transabdominal sonography. Other investigations include measurement of follicle stimulating, prolactin and androgen levels if acne or hirsutism is present. If Turner’s syndrome or androgen insensitivity is suspected, a karyotype is done. The analysis of 48 patients of primary amenorrhea in a tertiary hospital over 3 years showed 54.2% Müllerian anomalies, 22.9% hypogonadotropic hypogonadism, 16.6% hypergonadotropic hypogonadism and 6.3% genital tuberculosis. Surgical vaginoplasty is required for complete or partial Müllerian agenesis. Patients with Müllerian agenesis are counseled regarding opportunities for adoption or surrogacy. The administration of hormone treatment is remarkably beneficial for young women with primary or very premature ovarian failure resulting in restoration of menstrual cycles and the prevention of short and long term hormonal imbalance consequences.

Vulvovaginitis and Urologic ssues

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Primary Amenorrhea

potassium hydroxide, and Gram stain is useful for diagnosis of trichomoniasis, bacterial vaginosis and Candidiasis. Culture is used widely for the diagnosis of gonorrhea, hlamydia and genital herpes. For treatment of STI, syndromic approach with single dose, observed therapy is preferable.

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from the patient for evaluation of bleeding disorders, including von Willebrand disease, before the blood is transfused. Puberty menorrhagia can be severe, sometimes requiring blood transfusion. Anovulation or DUB is the most common cause but bleeding disorders, other medical and organic conditions must be ruled out. The treatment includes hematinics, tranexamic acid and hormones. Tranexamic acid in 2 g/day dosage is an effective and safe option to control bleeding, while waiting for complete evaluation. But hormones are the mainstay of treatment in DUB.

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1. Bhattacharya SM, Jha A. Prevalence and risk of metabolic syndrome in adolescent Indian girls with polycystic ovary syndrome using the 2009 “joint interim criteria”. J Obstet Gynaecol Res. 2011;37(10):1303 7. doi: 10.1111/j.1447 0756.2010.01516.x. Epub 2011. 2. Iyengar K, Iyengar SD. Reproductive health on the ground meeting of women’s needs in Southern Rajasthan, India. Udaipur: Action Research Training for Health; 2000. 3. Levitt Dayal M, Motihar R, Kanani S, et al. Adolescent girls in India choose a better future: an impact assessment of an educational programme. In: Bott S, Jejeebhoy S, Shah I, Puri C (Eds). Towards adulthood: exploring the sexual and reproductive health of adolescents in South Asia. Geneva: World Health Organization; 2003. pp. 187 9. 4. Mukhopadhyay P, Chaudhuri RN, Paul B. Hospital based perinatal outcomes and complications in teenage pregnancy in India. J Health Popul Nutr. 2010;28(5):494 500. 5. Nidhi R, Padmalatha V, Nagarathna R, et al. Prevalence of polycystic ovarian syndrome in Indian adolescents. J Pediatr Adolesc Gynecol. 2011;24(4):223 7. Epub 2011. 6. Rotterdam ESHRE/ASRM Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long term health risks related to polycystic ovary syndrome. Fertil Steril. 2004;81(1):19 25. 7. Sagili H, Pramya N, Prabhu K, et al. Are teenage pregnancies at high risk? A comparison study in a developing country. Arch Gynecol Obstet. 2012;285(3):573 7. Epub 2011. 8. Sharma A, Taneja DK, Sharma P, et al. Problems related to menstruation and their effect on daily routine of students of a medical college in Delhi, India. Asia Pac J Public Health. 2008;20(3):234 41. Epub 2008. 9. Sharma P, Malhotra C, Taneja DK, et al. Problems related to menstruation amongst adolescent girls. Indian J Pediatr. 2008;75(2):125 9. 10. Sheelamoni A, Nair MKC. Pregnancy among unmarried adolescents and young adults. PhD Thesis awarded by University of Kerala, 2008.

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A high degree of suspicion of sexual abuse to be kept in mind in all cases of genital tract trauma in young girls.



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In absence of functioning uterus, the usual age for vaginal reconstruction is 16–20 years or 6 months before the marriage is fixed. First operation has the best chance of success • Normal sexual development depends on normal karyotype, presence or absence of genes for testicular determination and appropriate endocrinal milieu • Management of menorrhagia aims to find cause and institute appropriate treatment. Some adolescents require medical intervention for PMS • Hirsutism is a common disorder causing considerable psychological embarrassment. It may signify benign conditions like idiopathic hirsutism or PCOS and malig­ nant neoplasms of ovaries or adrenals • Polycystic ovaries syndrome may first manifest as persistent menstrual disorder, obesity and/or hirsutism. • Suspect endometriosis if progressively severe dysme­ norrhea is occurring for increasing number of days • Breast problems are common in young girls. One to five percent have developmental defects and 5–10% present with benign breast disorders • Amenorrhea demands evaluation if there is no men­ struation up to 15 years of age with normal puberty; up to 13 years in case of delayed pubertal development and cessation of menstruation for three cycle lengths or 6 months. In cases of normal uterus but delayed pu­ berty, bone age assessment rules out constitutional delay • Tuberculosis in India is very common and the aim is to diagnose and treat early to avoid long term sequelae.

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Malnutrition is a major health problem and 50% of adolescent girls are anemic in India. Imaging is an important adjuvant in diagnosis of adolescent gynecologic disorders.



Practice Guidelines

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women covered by the study came from “problem families”. The problems included divorced or separated parents, polygamous families, parents with marital disharmony, mentally challenged parents, old and debilitated parents and single parent with little other support.

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dolescent riendly chool nitiatives

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Children and adolescents are the wealth of nation and future citizens of our country; hence, it is imperative that they be brought up in a healthy, stimulating and safe environment. Such an environment will positively contribute to their physical, mental, cognitive, emotional, spiritual and social development. Since children and adolescents spend a considerable period of time in schools and colleges, these places should definitely provide such a positive environment. There are certain issues, which particularly pertain to adolescents as compared to their younger counterparts that include emotional problems, high-risk behavior, sexual matters, unwanted peer influence and mental health issues. A school that addresses all these issues may be considered an adolescent friendly school. The following may be adopted by the schools to make it an adolescent friendly school.

afe and Healthy nvironment

Schools/colleges and their neighborhood should be safe and healthy free from environmental and sound pollution. Silent zone should be maintained near schools as per government rules. Since children and adolescents are particularly vulnerable to initiate use of tobacco, alcohol and drugs at this age, their nonavailability near schools should be strictly ensured. Children with signs of depression, emotional problems and low self-esteem should be closely monitored since they are at high-risk for taking up tobacco and drug use.

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Health heck-up and Monitoring, Lifestyle isease Prevention

ment problems with peers, parents and sometimes teachers. Scholastic expectations from parents, examination stress, learning disabilities (LD), attention-deficit disorders, all may require professional assessment, remedial measures and counseling and these services should be made available in the schools/colleges. E

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Teenagers experience stress on various situations related to education, and psychological/emotional, physical and environmental/social problems. As part of a normal 900 developmental process also adolescents experience adjust

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Academic institutions with canteen should have clean kitchen and a clean place wherein children can bring in homemade food and eat. Outside vendors should not be allowed in the campus. Fastfood, fried items, oily food and aerated drinks should be discouraged in the canteen. Advertisements of aerated drinks should be prohibited in the canteen and neighborhood. Ensure that child labor is prohibited in the canteen and other workplaces. F

Considering the risk-taking behavior peculiar to this age group, strict monitoring of those using two-wheelers should be supervised for over speeding and careless and rash driving. Use of helmet should be made compulsory. Safety measures for other modes of transport should also be enforced.

Adolescence is a period, particularly prone to obesity. The hormonal changes, erratic dietary habits, lack of exercise and sedentary habits make an adolescent highly susceptible to obesity. Decreasing caloric intake and increasing physical activity are the basis for prevention and management. Four games period per week must be made compulsory in schools and colleges. There should be adequate playground area (10 acres land for high schools). Provision of health club with equipments like treadmill will motivate adolescents to a healthy lifestyle. C

A good health depends on a proper diet, a positive attitude and exercise. The major killer disease, the coronary artery disease and its risk factors like hypertension, diabetes, dyslipidemia and obesity have their origin in childhood. All children before admission to school/college should have weight, height, BP check and a general medical examination once in a year. Nutritional advice should be given to all children and adolescents by a professional on a regular basis. Discourage eating excess snacks, confectionaries, fastfood, soft drinks and fun-drinks. Routine dental check-up and eye check-up should be compulsory. Lapsed immunization, if any, should be completed, and adolescent immunization schedule should be followed. Psychological, emotional and social problems, if any, should be evaluated and necessary referrals made.

acilities for Personal Hygiene

Since children and adolescents spend about 5–6 hours in the schools, there should be adequate facilities for personal hygiene. Provision for adequate hygienic drinking water is a must to prevent waterborne diseases and to prevent UTI. Water requirement per person is more because of the excess physical activity peculiar to this age group.

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1. Agarwal RK. Promoting adolescent friendly reproductive and sexual health services. Indian Pediatr. 2008;45(1):881-2. 2. Bansal CP. Adolescent friendly school initiative program under IAP Vision—2007 module. 3. Nair MKC, George B, Sharma PS, et al. Nutrition, health and psychological status of teenage girls. Journal of the teenage care and premarital counseling—teens. UNICEF and Child Development Centre, Thiruvananthapuram, Kerala, India. 2003;3:8-9, 22-3. 4. Nair MKC. Perspectives in adolescent care: IAP. J Pract Pediatr. 1998;6(1):7-10. 5. Verma M, Chhatwal J. Common health problems in adoles cents. IAP Textbook of Pediatrics, 3rd edition. 943-50.



Regular classes on family life education consisting of classes on adolescent nutrition, personal hygiene, menstrual

ibliography

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amily Life ducation

Life skill training should be conducted in school/college on a yearly basis or more often to prevent substance abuse, smoking, alcoholism, sexual contact and adolescent pregnancy. It should also enable children and adolescents to deal actively with various demands of life.

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Apart from all the benefits of the television (TV), the ill-effects of media cannot be overlooked. Many studies have shown constant watching of violence scenes on TV and fantasy violence make children more aggressive in their behavior to others. Media is certainly the one factor contributing to early sexual behavior. Since teenagers tend to follow the behavior they observe in the media without seeing the known consequences, they may end up pregnant with HIV or with other sexually transmitted diseases. Considering all these, counseling on the appropriate use of TV and other media should be a part of the school/college program.

Life kill Training—Teenage lubs



Media Literacy

Adolescent health card developed at Child Development Center, Trivandrum, may be issued to all children and adolescents on admission to school/college and relevant data like weight, height, BP, immunization status, BMI to be recorded. Health check-up as prescribed could be conducted by the school.



Many adolescents require help and guidance to select a career of their interest and choice. A career guidance program will go a long way in building a secure future for him/her and the family.

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hygiene for girls, emotional support, awareness on one’s own sexuality, HIV/AIDS and substance abuse should be conducted in schools/colleges. Classes may be conducted once a month by a specialist.

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There should be minimum one urinal for 60 students and one latrine for every 100 students. Schools and colleges with more number of girls should have a proportionately higher number. There should be adequate supply of water in the toilets for maintaining genital hygiene and for washing hands. Sanitary napkins may be made available through school store or office. One may also consider napkin vending machines and facility for disposing sanitary napkins should be made available. Toilets should be kept neat and clean so that children will not hesitate to make use of the facility.

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Section

16 Rheumatology



16.1 16.2 16.3 16.4 16.5 16.6 16.7

















Section Editor : Surjit Singh Approach to a Child with Arthritis: Raju P Khubchandani Juvenile Idiopathic Arthritis: Raju P Khubchandani Systemic Lupus Erythematosus: Noel Narayanan Approach to Vasculitis in Children: Surjit Singh Kawasaki Disease: Noel Narayanan Other Rheumatological Disorders of Childhood: Surjit Singh Allergic Disorders in Children: K Nagaraju

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disorders remain amongst the most ill-understood of the childhood diseases in our country and are very frequently misdiagnosed and wrongly treated. A high index of suspicion with a detailed history and physical examination goes a long way in diagnosing these conditions at an early stage. Early diagnosis is the key to prevent significant morbidity.

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The term “rheumatological disorders” refers to diseases that affect the major connective tissues of the body (e.g. skin, bone, blood vessels, cartilage and basement membrane). These are amongst the most common chronic diseases of children. Contrary to common belief, these are by no means uncommon conditions. As a broad generalization, approximately 15–20% of all rheumatological diseases seen in adults have their onset in childhood. These

Approach to a Child with Arthritis Raju P Khubchandani Table 16.1.1 Common causes of articular involvement in children

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Avascular necrosis and other orthopedic conditions, dislocations, slipped capital epiphysis

 

General Statements and Principles

Reactive, e.g. Reiters arthritis, toxic synovitis of hip Trauma Hematological conditions, e.g. leukemias, coagulopathies, hemoglobino­ pathies Rickets and other deficiencies, e.g. scurvy

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Infections and post infectious disorders: •  bacterial septic arthritis, infective endocarditis, tuberculosis, Lyme, brucella •  viral: rubella, parvovirus, hepatitis viruses •  post streptococcal arthritis, rheumatic fever Tumors benign, e.g. hemangioma, osteoid osteoma, malignant, e.g. bone tumors, neuroblastoma Idiopathic juvenile idiopathic arthritis Drugs, e.g. pyrazinamide, thiazides, MMR vaccine Ehler Danlos and other hypermobility syndromes and inherited metabolic disorders, e.g. mucopolysaccharidosis, Wilson

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Table 16.1.1 shows that the causes of articular disorders in children are wide and varied. There is clearly much more to pediatric rheumatology than rheumatic fever and tuberculosis, two of the most over-diagnosed conditions in our setting • Arthritis too can be an emergency. It is imperative to identify those conditions whose early recognition is likely to influence management options and eventual outcome (e.g. acute bacterial arthritis) • Not all musculoskeletal or limb pains necessarily indicate arthritis. Limb pains may arise from disease in bone or neurovascular structures. On the other hand, the absence of pain does not preclude arthritis since children below the age of about 5 years seldom vocalize pain. Infants may present with mere irritability while toddlers may exhibit limb preference or a barely discernible limp • Several systemic diseases present with arthritis as a lead symptom (e.g. leukemia) and many rheumatologic diseases may have significant extra articular manifest ations [e.g. systemic onset juvenile idiopathic arthritis (JIA)] • Several rheumatological conditions evolve over time (e.g. lupus, JIA) and therefore it is not always possible to give a diagnostic label to the child at first presentation. Instead several diagnoses are established on follow-up • Several rheumatological conditions are essentially clinical diagnoses and/or diagnoses of exclusion. Investigations only help to rule out mimics or assess disease activity. Examples include JIA and Kawasaki disease (KD). The rheumatology consult often begins even as the patient enters the clinic with observation of the gait and level of pain virtually written on the child’s face. After some years of experience it is often possible to narrow down to a preconsult intuitive diagnosis even at this early stage of the meeting. The Ask, Look and Perform approach (Tables 16.1.2 and 16.1.3) works extremely well with the first two

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•  Systemic connective tissue disorders and vasculitides •  Lupus, dermatomyositis, scleroderma, mixed connective tissue disease •  Henoch-Schönlein purpura, Kawasaki, polyarteritis and other vascu litides

components being often effected simultaneously while the child is comfortably seated on the couch or in the parents lap.



Musculoskeletal Examination Needless to say musculoskeletal examination is the most crucial part of the evaluation of the child with arthritis. The reader is advised to be familiarized with pGALS (pediatric Gait Arms Legs and Spine)—a simple 3 minute video which illustrates the method of basic evaluation of the 903 musculoskeletal system in children.

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What

Why (the list is illustrative and not complete)

Age

Several age specific diseases, e.g. OJIA, KD (2–5 years), Lupus and ERA (adolescent)

Sex

Several diseases with sex preference, e.g. oJIA, Lupus (females) ankylosing spondylitis, ERA (males)

Length of history

Hours: trauma, hemophilia; Days: septic or reactive arthritis, Weeks: vasculitides, connective tissue disorders, indolent infections, Months: juvenile idiopathic arthritis, mechanical disorders, e.g. hypermobility, Years: pain syndromes, e.g. reflex sympathetic dystrophy, genetic disorders

Onset

Explosive and sudden: septic arthritis, transient synovitis of hip, gradual and insidious: connective tissue disorders

Time of worst symptoms

Morning stiffness or pain after rest (gelling): inflammatory disease, evening pains after physical activity improving with rest: mechanical pain

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Table 16.1.2 Approach to a child with arthritis

attern

Solitary: infections or tumors, Additive: reactive, migratory: rheumatic fever, intermittent: lupus, sickle, hemophilia

Constitutional Presence usually suggests inflammatory pathology with the exception of most types of JIA. Absence is typical of nonfeatures, e.g. fever, fatigue inflammatory or mechanical disorders malaise Associated symptoms

Table 16.1.4

Antecedent events or dugs

Trauma, recent viral or bacterial infections or recent dysentery recent immunization (MMR) reactive arthritis, drugs (pyrazinamide)

Known previous conditions

For example sickle cell disease or hemophilia, structural heart disease (infective endocarditis and septic emboli, Down syndrome, perthes disease)

Consanguinity

Autosomal recessive conditions sickle, periodic fever syndromes, bone dysplasias

Family history

Similar disease-genetic syndromes, spine/eye/joint disease: HLA B27-related arthropathies, psoriasis: psoriatic arthritis

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Abbreviations: JIA, Juvenile idiopathic arthritis; KD, Kawasaki disease; JIA, Oligoarticular juvenile idiopathic arthritis; MMR, Measles, mumps and rubella; ERA, Enthesitis related arthritis; HLA, Human leukocytic antigen.

 

Table 16.1.3 Look and perform approach What

Why (the list is illustrative and not complete)

General look

Toxic-septic arthritis, highly irritable-KD, comfortable when seated: JIA, la belle indifference: chronic pain syndromes

Gait and movements

May give a clue to the joints involved especially in uncooperative infants and toddlers

Deformities and limb length discrepancies

Juvenile idiopathic arthritis and hereditary dysplasias

Striking inspection features

Red hot single swollen joint-septic arthritis. Alopecia-lupus, rashes: JIA, lupus, dermatomyositis, Henoch-Schönlein purpura, KD, High myopia, hypermetropia, dysmorphic facies: syndromes Short or tall stature: syndromes, obesity: mechanical disorders, e.g. slipped capital femoral epiphysis. Also see Table 16.1.2

Detailed general and systemic examination

See Table 16.1.2

Musculoskeletal examination

See text below

Abbreviations: JIA, Juvenile idiopathic arthritis; KD, Kawasaki disease.

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• Articular versus periarticular involvement: Pain on active and passive movement, swelling, instability, locking crepitus or deformities suggests joint disorders. Periarticular pain occurs on active movement only and that too in certain planes (Table 16.1.4) • Inflammatory versus mechanical disease: Warmth, erythema, swelling and tenderness (the cardinal signs of inflammation) characterize inflammatory disease while mechanical diseases lack these features and often affect the overuse joints (ankle, knee, shoulder) • Disease active or burnt out: This may change thera 904 peutic approaches. Although it may be difficult, it is vital

to decide whether limited joint range and persistent deformity indicate old, burnt out, inactive arthritis or whether there is ongoing inflammation present. Intraarticular effusion should always be taken to indicate active inflammation. The next most sensitive indicator of active arthritis is pain at the end of range of joint movement • Pointers to chronicity: Pigmentation over joints, presence of deformity, contractures and deformities are indicators • (Site/s) Joint or joints involved specific to certain disease?: There are certain joints typically involved

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Table 16.1.4 Extra-articular features that may be associated with arthritis Why

Non purulent conjunctivitis Uveitis (acute anterior, painful, red eye) Uveitis (insidious anterior, presents as visual loss) Uveitis (posterior)

KD ERA OJIA Sarcoidosis

Mouth

Painful cracked, bleeding lips and strawberry tongue Mouth ulcer Red gums at tooth line

KD SLE, BS, ERA, DMS, Methotrexate DMS

Head and neck

Alopecia/hair loss

SLE

Skin

soriasis Periorbital rash (heliotrope) Malar rash (photosensitive)

soriatic arthritis DMS SLE

Hands

Raynaud’s phenomenon Nail pitting, onycholysis Nail fold infarct Subcutaneous calcinosis Digit infarction Gottron’s papules eriungual desquamation

DMS, SD soriatic Arthritis CTD DMS, SD AN DMS KD

Trunk and arms

Macular rash Erythema marginatum Subcutaneous nodules Urticaria

SOJIA, SLE, KD, Parvovirus rubella, ARF ARF, RF+ve-JIA CTD: Systemic vasculitides

Lower limbs and feet

Livedo reticularis urpura Erythema nodosum

asculitides HSP, SLE Sarcoid, IBD, TB, systemic vasculitides, CTD

Muscles

Wasting/contractures Tender swollen Proximal muscle weakness

JIA DMS DMS

Hematological

Lymphadenopathy etechiae allor

OJIA, SLE, Malignancy, TB, KD SLE, Malignancy SOJIA, SLE, Malignancy, SCD

Gastrointestinal

Dysphagia Abdominal pain Diarrhea Malabsorption Hepatic dysfunction Organomegaly

DMS, SD PAN, SLE Reactive arthritis, I D SD Wilson’s, SLE, hepatitis (B/C), SCD OJIA, SLE, malignancy, SCD

Respiratory

Upper airway disease Pleural effusion/pleuritis

Wegener’s granulomatosis SLE, SOJIA, ARF

Cardiovascular

ericarditis Myocarditis alvular disease Hypertension

SLE, SOJIA, ARF Polymyositis, ARF, SOJIA, Amyloidosis ARF, JAS, SLE, APS, Hypermobility PAN, SLE

Genitourinary

Urethritis Genital ulcers roteinuria Renal failure/hematuria

Reiter’s, Reactive arthritis BS   SLE, drug, amyloidosis SLE, NSAIDs, amyloidosis, systemic vasculitides

Neurological

Fits, coma, psychosis Chorea Neuropathies Headache

SLE SLE, ARF AN SLE

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Abbreviations: DMS, Dermatomyositis; SLE, Systemic lupus erythematosus; CTD, Connective tissue disease; IBD, Inflammatory bowel disease; ARF, Acute rheumatic fever; PAN, Polyarteritis nodosa; PsA, Psoriatic arthritis; SD, Scleroderma; KD, Kawasaki disease; ERA, Enthesitis-related arthritis; NSAIDs, Nonsteroidal anti-inflammatory drugs; HSP, Henoch-Schönlein purpura; SCD, Specific carbohydrate diet; BS, Behçet’s syndrome.

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Source: This table has been reproduced from Indian Journal of Pediatrics. 2002;69(10):875-80 with the kind permission of the editors.

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the presence of subcutaneous nodules (rheumatoid nodules or nodules in rheumatic fever) may offer a clue.

Pattern Recognition

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This final stage of clinical evaluation is easily the most important as the clinician attempts to collate the history and physical findings as if fitting several pieces of a jigsaw puzzle. For example: • A pattern of scattered, asymmetric large and small oligoarticular/limited polyarthritis (especially distal inter phalangeal joints) suggests juvenile psoriatic arthritis • Onset of polyarthritis in a teenage girl should suggest the possibility of systemic lupus erythematosus (SLE) or polyarticular JIA • Isolated hip involvement, may be caused by toxic synovitis, Perthes disease, slipped capital femoral epiphysis or less likely by chronic inflammatory arthritis • An older child or young adolescent male with low back pain may have ankylosing spondylitis but mechanical causes, infections or malignancy are more likely • Beware the toddler with oligoarticular involvement and fever. He may have leukemia.

ibliography 1. Khubchandani RP, D’ Souzas S. Initial evaluation of a child with arthritis–an algorithmic approach. Indian J Pediatr. 2002;69(10):875-80.



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in some conditions, e.g. psoriasis and the distal interphalangeal joint, reactive arthritis and the large joints of the lower limb, temporomandibular joint involvement in polyarticular juvenile arthritis (Single four or more?) umber of joints involved: While the causes of polyarticular disease (greater than four joints) are plenty, oligoarticular involvement is seen only in a few conditions such as oligoarticular juvenile idiopathic arthritis (oJIA), psoriasis, sarcoid, leukemia (Size) Large/small joints or combination: Purely large joint involvement characterizes certain diseases such as rheumatic fever and the combination of large and small joint disease can change the diagnostic thought Symmetry of involvement: While polyarticular juvenile arthritis, connective tissue diseases and vasculitides present with symmetric arthritis, oligoarticular juvenile arthritis, enthesitis-related arthritis (ERA) and infections are asymmetric in their presentation. Beware the remarkable symmetry of hereditary dysplasias Spine involvement (Axial disease): The presence of cervical spine involvement is seen frequently in polyarticular and systemic onset juvenile arthritis and sacroiliitis is an important feature of the spondyloarthropathies. On the other hand some rheumatologic conditions seldom affect the spine, e.g. Lupus and vasculitis Surrounding structures, e.g. enthesitis, skin nodules: Enthesitis-related arthritis is a specific diagnostic entity (see chapter on Juvenile Idiopathic Arthritis) and

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Adolescent He lt

16.2

Juvenile Idiopathic Arthritis

tiopathogenesis





The pathogenesis of JIA is extremely complex and involves interplay of genetic predisposition and inflammatory mechanisms. The major players in the pathogenesis are T cells, macrophages and B cells. Cytokines are glycoproteins secreted from inflammatory cells such as activated T cells and macrophages. They are essentially of two varieties, proinflammatory (IL-1, IL-6, TNF-alpha, IL-8) or anti-inflammatory (IL-4, IL-10, IL-1 receptor antagonist). Cytokines are instrumental in regulating the magnitude, nature and duration of the inflammatory response in arthritis. The inflammation resulting from the various interactions are responsible for the development of synovitis. This complex set of interactions elaborate the release of various metalloproteinase and other enzymes which cause the damage to the synovium and the adjacent tissues. The cytokines involved in the pathogenesis of JIA as a whole and in different subsets are still being investigated. The group of disorders under the term JIA (with the exception of the systemic onset variety) are considered as disorders of adaptive immunity occurring as a result of yet unidentified environmental factors in genetically predisposed individuals. Familial clustering, the presence of autoantibodies such as rheumatoid factor and antinuclear antibodies (ANA) in distinct subgroups are seen and a small but definite proportion of patients develop second rheumatologic/immunologic conditions. In contrast the view emerging now is that the systemic onset variety [Systemic juvenile idiopathic arthritis (sJIA)] is an autoinflammatory syndrome, i.e. it is a disorder with abnormalities in the innate immunity (cytokines like IL-1, IL-6 and IL-18, and neutrophils and monocytes/macrophages rather than lymphocytes play a major role in the pathogenesis of sJIA), distinguishing sJIA from other subtypes.

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linical Features

Some of the varieties of JIA are very age and sex specific. While sJIA may involve any age or sex the oJIA and polyarticular juvenile idiopathic arthritis (pJIA)-particularly the former, dominantly affect females. Oligoarticular juvenile idiopathic arthritis is a disorder afflicting the 2–5 year age group while pJIA is usually seen in children over 10 years. Enthesitisrelated arthritis is a disease of the adolescent male. Clinical manifestations in JIA are variable. The onset is usually insidious with a history of trauma which often precipitates the doctor visit. Patients with pJIA or sJIA may experience constitutional features such as fatigue or anorexia but these symptoms are rare in oJIA. Fever and extra-articular features are usually absent or minimal in varieties other than sJIA in which lymphadenopathy, hepatosplenomegaly, classic evanescent rash and serositis are seen. Children with rheumatoid factor positive disease may have subcutaneous “rheumatoid nodules” on the forearm or legs. The arthritis leads to joint pain and the child’s age will affect how they communicate pain and dysfunction, e.g. infants and toddlers may become irritable or simply use affected joints in a different way. They may stop using an affected limb (e.g. refusal to weight bear). Older children express pain on movement and report it to be aching in quality, of mild to moderate severity, appreciated by examination of the affected joints. Other common symptoms at presentation include morning stiffness and “gelling” after inactivity. Parents will often report their child to be “slow to get moving” in the morning or after a daytime nap with improvement after a period of time. On examination affected joints are usually warm and swollen with reduced range of motion, but not erythe matous. Large joints are more commonly affected, with smaller joints affected in pJIA. Examination of a child with arthritis should always include the temporomandibular joints and cervical spine, as arthritis in these joints is often underappreciated. The reader is advised to get familiarized with musculoskeletal examination in the pediatric age group. The pGALS is a simple 3 minute procedure and a video clipping can be viewed on the internet. ­

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It is estimated that JIA affects up to 1 in 1,000 children worldwide and is the most common cause of autoimmune musculoskeletal disease in children. There is no particular geographic or racial predilection.

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Prevalence

The updated classification scheme for JIA was presented by the International League of Associations for Rheumatology in 2001. It is based on mode of onset (presence of systemic findings), the number of joints affected and their progression, and the presence or absence of specific serologic findings (Table 16.2.1).



Juvenile idiopathic arthritis (JIA), previously known as Juvenile rheumatoid arthritis or Juvenile chronic arthritis, is a group of diseases with arthritis of unknown cause (implying that other diseases have been excluded) characterized by age of onset below 16 years and duration of at least 6 weeks.

lassification



Introduction

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Systemic arthritis (10–20%)

Fever of at least 2 weeks duration (daily for at least 3 days) and arthritis in one or more joints, plus one of the following: •  Erythematous rash •  Generalized lymph node enlargement •  Hepatomegaly and/or splenomegaly •  Serositis

Oligoarthritis (50–60%)

Arthritis affecting ≤ four joints during the first 6 months of the disease. If after 6 months more than four joints are involved the term extended oligoarthritis is used

Polyarthritis (20–30%) RF Negative

Arthritis affecting ≥ five joints during the first 6 months of the disease with rheumatoid factor negative

Polyarthritis (5–10%) RF Positive

Arthritis affecting ≥ five joints during the first 6 months of disease with rheumatoid factor positive on two occasions at least 3 months apart

Psoriatic arthritis (2–15%)

Arthritis and psoriasis or arthritis and at least two of the following: •  Psoriasis in a first degree relative •  Dactylitis •  Nail pitting or onycholysis

Enthesitis-related arthritis (1–7%)

Arthritis and enthesitis** or arthritis or enthesitis with at least two of the following: •  Presence/history of sacroiliac joint tenderness and/or inflammatory lumbosacral pain and HLA-B27 positive •  Onset of arthritis in a male over 6 years of age •  Acute (symptomatic) anterior uveitis •  History of ankylosing spondylitis, enthesitis-related arthritis, sacroiliitis with inflammatory bowel disease or acute anterior uveitis in a first degree relative

Undifferentiated arthritis

Arthritis that fulfills criteria in no category or in two or more of the above categories



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Table 16.2.1 Category, observed frequency* and diagnostic criteria





Management Children with JIA are best managed in a specialist multi disciplinary set up. While drug therapy is a crucial part of ­

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The diagnosis of JIA is essentially clinical, and exclusion and investigations are largely performed to rule out mimics (Table 16.2.2). A complete blood count may demonstrate anemia of chronic inflammation and the C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) may show mild to modest elevations which may be used to guide therapy. In sJIA anemia, polymorphonuclear leukocytosis and thrombocytosis are classically seen. Rheumatoid factor (RF) should be performed in patients with polyarthritis as its presence helps to classify (Table 16.2.1) and prognosticate about severe erosive disease. The presence of a positive ANA identifies risk for the development of asymptomatic uveitis, particularly in those with oJIA, but should be performed in all children with JIA. Human leukocytic antigen (HLA) B27 should be tested in children who present with signs and symptoms consistent with ERA (Table 16.2.1) and can indicate susceptibility to the development of axial arthritis in future years. Plain X-rays may demonstrate effusions but erosions are rarely seen in childhood. Bedside ultrasonography is being increasingly used to evaluate joints at diagnosis and followup as a complement to clinical evaluation.

management, the role of the physiotherapist, occupational therapist, child psychologist and social worker is immense in supporting the physician to achieve maximum possible success. There is currently no cure for JIA. The primary goals of medical therapy are to eliminate active disease, to normalize joint function, to preserve normal growth and to prevent long-term joint damage. The drugs used more commonly in the present day management of JIA are shown in Table 16.2.3. Detailed pharmacology and usage is beyond the scope of this article. The present day paradigm of care is toward early and aggressive management to capitalize on the window of opportunity that exists before erosive disease and deformity sets in. Thus in contrast to earlier days where NSAIDs formed the initial therapy with drugs being sequentially added to nonresponders, the approach today is to introduce disease-modifying anti-rheumatic drugs (DMARDs) early in the course of the disease using steroids as a bridge till they begin to take effect. TNF α and IL 1 or IL 6 inhibitors which come under the heading of biologicals are being increasingly used in the West, sometimes as first-line agents but their prohibitive cost prevents their routine use in our setting. Autologous stem cell transplant has been used for the most refractory cases. The next few lines give the salient outline of care of the various sub types of JIA.

iagnosis and Investigations



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Abbreviations: RF, Rheumatoid factor; HLA, Human leukocytic antigen. *The relative frequencies of the various subtypes stated above are based on Western literature. Scantily published Indian data and the author’s experience shows that the oJIA is not as common as in the West and the majority of cases seen in India are the sJIA variety. ** Enthesitis is inflammation at the site where tendon, muscle or fascia inserts on bone.

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Oligoarticular disease

Polyarticular disease

Systemic onset disease

•  •  •  •  • 

•  •  •  •  •  • 

•  Infections with leukemoid reactions/exanthems •  Systemic lupus erythematosus •  Kawasaki disease

Rheumatic fever Skeletal dysplasias Pain amplification syndromes Hypermobility syndromes Vitamin D deficiency Vasculitides

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Chronic infections, e.g. tuberculosis Reactive arthritis Benign and malignant tumors Acute leukemia Inflammatory bowel disease

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Table 16.2.2 Common mimics of juvenile idiopathic arthritis

 

Table 16.2.3 Drugs used commonly in the present day treatment of juvenile idiopathic arthritis Nonsteroidal anti-inflammatories Steroids

Disease modifying anti-rheumatologic drugs Biologicals*

•  Ibuprofen •  Naproxen •  Indomethacin

•  Methotrexate •  Sulfasalazine •  Leflunomide

•  •  •  • 

Etanercept Infliximab Abatacept Tocilizumab





•  Intra-articular-triamcinolone acetonide •  Topical ocular preparations •  Oral prednisolone •  Intravenous methylprednisolone

*Molecules currently approved by US FDA in management of different forms of JIA.

 

• Uveitis: Anterior uveitis which is often asymptomatic and therefore treacherous may lead to the “painless blind eye”. The child with oJIA is most prone followed by those with pJIA and then sJIA. Antinuclear antibodies positivity identifies those at higher risk and ophthalmic monitoring periodically is mandatory. Guidelines exist for risk stratification and periodicity of monitoring which ranges from 3 monthly to annually. Affected cases are treated with topical steroids with resistant cases needing systemic methotrexate. In contrast the HLA B27 positive child with ERA may develop symptomatic anterior uveitis—the “acute painful red eye”, which may promptly be treated with topical steroids. Routine monitoring is not indicated. • Growth issues and deformities: Growth failure and short stature is seen particularly in sJIA, not only from chronic inflammation but also from the high or prolonged doses of steroids consumed. Local deformities may lead to significant loss of hand

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omplications

function or locomotion, consequent handicap and even loss of vocation. Bony overgrowth caused by hyperemia of the affected joints (classically the knee) can lead to limb length discrepancy. Complications of cervical spine involvement include bony ankylosis and atlantoaxial subluxation making neck extension and intubation difficult. Temporomandibular joint involvement may cause significant micrognathia and consequent malocclusion. • Macrophage activation syndrome: This dreaded lifethreatening complication of sJIA is characterized by a change in the fever pattern with hectic spikes, a sick looking child with neurological alteration, abnormal liver function, coagulopathy, hypertriglyceridemia and hyperferritinemia. Prompt recognition and treatment with intravenous steroids with or without cyclosporine can be life saving. • Iatrogenic issues: The drugs used in the management of JIA can have complications with long-term use. The nephropathy and gastropathy with prolonged NSAID usage or the osteoporosis, propensity to infections, growth retardation and subcapsular cataracts due to steroid usage are examples. Careful monitoring of all drugs is paramount. Since most of the drugs are immunosuppressive a careful watch for infections and attending to immunizations are important.

utcome and Prognosis

In general, children diagnosed in this century are doing better than those toward the end of the last. This has been largely possible owing to the improved therapeutic armamentarium. Since JIA is not one disease, the outcome and prognosis varies with the subtype. Children with oJIA have the best 909

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ligoarticular: Nonsteroidal anti-inflammatory drugs are used initially but repeated intra-articular steroids in affected joints are the mainstay of therapy • Polyarticular: Treatment is started with NSAIDs and DMARDs (methotrexate) and if needed a low bridging dose of steroids. As methotrexate takes effect steroids and NSAIDs are withdrawn. Flares in individual joints are managed with intra-articular injections • ystemic onset: The systemic features are treated with NSAIDs and oral or intravenous steroids based on severity. The articular features are managed depending on the number of joints involved as cited above. S

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ibliography 1. Beukelman T, Patkar NM, Saag KG, et al. 2011-American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: initiation and safety monitoring of therapeutic agents for the treatment of arthritis and systemic features. Arthritis Care Res (Hoboken). 2011;63:465-82. 2. Prakken B, Albani S, Martini A. Juvenile idiopathic arthritis. Lancet. 2011;377(9783):2138-49. 3. Ravelli A, Martini A. Juvenile idiopathic arthritis. Lancet. 2007;369(9563):767-78.





• Juvenile idiopathic arthritis is the most common chronic inflammatory arthropathy of childhood and the etiology is as yet unknown • The International League of Associations for Rheumatology classification of 2001 recognizes seven subgroups of disease • The diagnosis of JIA is based mainly on clinical considerations and is one of exclusion • Investigations mainly help to rule out mimics or follow-up disease activity • Tests such as ANA, rheumatoid factor or HLA B27 are not diagnostic tests and should not be recommended as an



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“arthritis panel”. They are correctly used for classification or risk stratification • Multidisciplinary care is crucial for affected children • Significant advances in pharmacology coupled with a changed paradigm of care with an early aggressive approach have vastly improved the lives of these children • Uveitis, deformities, iatrogenic issues and the dreaded macrophage activation syndrome are complications which need to be watched for.



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outcomes, as do children who are pJIA RF negative. The sJIA group, follow an as yet unpredictable variable course with one group of children having monocyclic disease, a second group with a polycyclic course and a third with a chronic continuous course.

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16.3

Noel Narayanan

Exact etiology of SLE is not known. Several factors genetic, environmental, hormonal, B- and T-cell interactions and role of dendritic cell and abnormal apoptosis all are said to contribute to development of immune dysregulation. As a result autoantibodies are formed against DNA and other nuclear antigens, ribosomes, various tissue antigens, RBCs, WBCs and platelets. Several triggering factors like sunlight, viral infection and drugs can perpetuate the immune dysregulation. Damage to cells and tissues result from pathogenic autoantibodies and immune complexes. Antinuclear antibodies are present in almost all patients, though not specific for SLE, and a negative result for ANA makes the diagnosis unlikely. Antibodies directed against double-stranded DNA (anti-ds-DNA) are the hallmark for SLE and is commonly raised in active lupus nephritis. Antibodies to histones are seen in drug-induced lupus. C

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tiopathogenesis

Table 16.3.1 Revised criteria for diagnosis of systemic lupus erythematosus (American College of Rheumatology)  

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In children less than 18 years of age the approximate incidence is estimated to be 10–20 per 100,000 children. This can vary according to location and ethnicity. In India the exact incidence is unknown. A prevalence rate of 3 per 100,000 has been reported; much lower than reported from the west. Females out number males by a ratio of approximately 4:1 and this ratio is higher, 8:1, after puberty. Systemic lupus erythematosus is uncommon in the first decade and 20% of all cases occur in the second decade. Familial incidence of SLE is seen in 12–15% cases.

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pidemiology

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Systemic lupus erythematosus is the prototype of an autoimmune disease, where an immune dysregulation leads to formation of excess autoantibodies directed against selfantigen. Subsequent development of immune complexes and their deposition causes inflammatory damage of various organs chiefly the skin, kidneys, blood vessels and nervous system. Rogenius in 13th century first coined the term lupus meaning wolf bite, but it was William Osler who first recognized the systemic nature of the disease.

seen in the majority of cases. Diagnosis is easy in a patient presenting with the typical malar rash and multisystem involvement. Systemic lupus erythematosus may rarely manifest at the onset as idiopathic thrombocytopenic purpura (ITP) or hemolytic anemia. Eleven criteria are used for classification of SLE in adults and presence of four or more of the above 11 criteria, strongly suggest SLE (Table 16.3.1). These criteria can serve as guidelines for pediatric patients also. Characteristic butterfly rash is distributed over the cheeks and nasal bridge and spares the nasolabial folds. Other mucocutaneous lesions include purpura, alopecia, photosensitive rash, palatal and various vasculitic ulcers (Figs 16.3.1 to 16.3.3). Arthritis is polyarticular, non-deforming and can involve both large and small joints; hepatosplenomegaly and lymphadenopathy are often present. Renal involvement occurs in 60–80% of patients and is an important cause of mortality and morbidity. Renal manifestations can vary from asymptomatic microscopic hematuria to edema, hypertension or rapidly progressive glomerulonephritis. Renal biopsy is indicated to determine the severity of kidney disease and based on light microscopy findings, WHO has classified lupus nephritis from class I, which is normal to class VI showing advanced sclerosing nephritis. Forty percent of patients may show neurological mani festations. Both central and peripheral nervous system may be involved and manifestations include seizures, stroke, psychosis, transverse myelitis or peripheral neuropathy. Cardiac manifestations include myocarditis, valvular thickening, verrucous endocarditis (Libman-sacks disease),

Introduction

1. Malar rash 2. Nasolabial/oral ulceration 3. Photosensitive rash 4. Discoid rash 5. Arthritis 6. Serositis, pleuritis, pericarditis 7. Renal disorder Proteinuria >500 mg/24 hours or cellular cast in urine 8. Hematologic disorder Hemolytic anemia, thrombocytopenia, leukopenia, lymphopenia

linical Features ­

Systemic lupus erythematosus being a multisystem dis order may present in many different ways. It can present acutely or over a long period of time and the course may be intermittent or persistent. Diagnosis may be missed initially unless a high index of suspicion exists. Fever, arthritis and various skin rashes form the classical triad of SLE and are

9. Neurologic disorder: seizures, psychosis 10. Immunologic abnormalities: positive anti-ds-DNA, anti-Sm, anti-phospholipid antibody 11. Antinuclear antibody in raised titers Any four or more of the above 11 criteria should be present either serially or simultaneously.

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aboratory Investigations

Diagnosis of SLE is based on a combination of clinical and laboratory criteria. C-reactive protein is normal in SLE unless some complication like infection occurs. Antinuclear antibodies is universal but anti-ds-DNA and anti-Sm are more specific for SLE. Other autoantibodies such as anti-Ro, La and ribonucleoprotein (RNP) may occur. Patients presenting with thrombotic episodes should be tested for anti-phospholipid antibodies. Complement C3 and C4 are reduced in active disease and can be used to detect disease flare. Initial laboratory investigations include: • Hemoglobin, WBC total and differential count, platelets, ESR and CRP • Urea, creatinine, liver function tests and lipid profile • Mantoux test and chest radiograph • Urine routine and microscopy • Specific tests: ANA, anti-ds-DNA, C3 and C4. Other investigations like echocardiography, ECG and imaging studies are indicated based on the presence of various target organ involvement. Kidney biopsy and histological grading correlates very well with severity of renal disease and the type of treatment to be administered.



 

Figure 16.3.1 Alopecia, photosensitive rash

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Drugs like procainamide, hydralazine and anticon vulsants can cause a lupus like disease and antibodies to histones are positive in these patients. Neonatal lupus is a well-recognized entity seen in newborns of certain mothers, often with mild SLE. Newborn babies present with skin rashes and multisystem involvement which are often self-limiting except congenital heart block which may lead to cardiac failure and death.

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Figure 16.3.2 Palatal ulcer

omplications

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Complications can be of two types, one due to the disease itself and second as a consequence of drugs like steroids and immunosuppressants used for treatment. There is high-risk for end organ damage and failure of various vital organs like kidneys, CNS and heart. Steroids and other immunosuppressive drugs can cause many adverse effects including severe infection and infertility. Avascular necrosis of the femoral head, thrombosis and pulmonary hemorrhage are other complications. Pregnancy increases the risk for renal disease, thrombophlebitis and disease flare and newborn may be affected with neonatal lupus. remature atherosclerosis and malignancy can occur as long-term complications.

Systemic lupus erythematosus is a lifelong disease and patients must be indefinitely monitored preferably by an experienced physician for prompt recognition and mana gement of disease flare and complications. Before treatment is initiated identify organ system involvement and its severity. ­

 

Figure 16.3.3 Vasculitic ulcer on elbow

reatment

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conduction defect and coronary artery disease. Pulmonary infiltrates and hemorrhage can occur rarely.

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Prognosis of SLE is grim with more than half of the patients developing organ damage over time. Early detection of disease flare and complications has resulted in improved management of these children. Thus, the 5-year survival in recent years has improved to almost 95%. Major causes of death are infection, renal failure, CNS and cardiac complications and rarely pulmonary hemorrhage.

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1. Hari P, Bagga A, Mahajan P, et al. Outcome of lupus nephritis in Indian children. Lupus. 2009;18(4):348-54. 2. Hiraki LT, Benseler SM, Tyrrell PN, et al. Clinical and laboratory characteristic and long-term outcome of pediatric systemic lupus erythematosus. J Pediatr. 2008;152(4):550-6. 3. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40(9):1725. 4. Klein-Gitelman SM, Myones BL, Windle ML (2011). www. emedicine. Medscape. com/article/1008066: overview. Updated January 20, 2011. Accessed 13 June 2011. 5. Kumar A. Indian guidelines on the management of SLE. J Indian Rheumatol Assoc. 2002;10:80-96. 6. Marks SD, Tullus K. Modern therapeutic strategies for paediatric systemic lupus erythematosis and lupus nephritis. Acta paediatr. 2010;99(7):967-74. 7. Mondal R, Nandi M, Ganguli S, et al. Childhood lupus: experience from eastern India. Indian J Pediatr. 2010;77(8):889-91.



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will be required. Education of the family and the patients regarding disease and its complications play a vital role for the success of treatment.

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Mild disease without systemic involvement can be managed with analgesics and NSAIDs like naproxen. Hydroxychloroquine 5 mg/kg/day is useful for skin lesions and musculoskeletal problems. Avoid precipitating factors like sun exposure, viral infections and certain drugs. Serositis can be managed with low-dose steroid 0.3–0.5 mg/kg/day for 4–6 weeks followed by slow tapering. Severe disease affecting kidneys, blood, CNS or lung will require high-dose prednisolone 1–2 mg/kg/day in divided doses until disease activity is fully controlled (usually 4–6 weeks) and then slowly tapered to a small maintenance dose on alternate days for 4–6 months or longer. Acutely ill and toxic patients may be treated with IV pulse methylprednisolone 30 mg/kg/day for 3 days and then switched to oral daily dose and tapered to alternate day steroid. Patients with class III and class IV renal disease and severe systemic involvement of other vital organs should receive intravenous pulses of cyclophosphamide in addition to high-dose steroid. Mycophenolate mofetil has become an alternative therapy for lupus nephritis. Recently Rituximab, an anti-CD19 monoclonal antibody has been found useful in treatment of kidney diseases resistant to other forms of treatment and also for treatment of cytopenias. Clinical trials using autologous stem cell transplantation are in progress for treatment of severe persistent disease. Patients on long-term steroid treatment are at risk for osteopenia and its complications. Therefore diet, calcium and vitamin D supplementation are important. Azathioprin may have a steroid sparing effect. Infections are a common and serious complication and any fever should be promptly investigated and treated. Raised CRP is useful in detecting infection since it is not increased in disease activity. Regular monitoring of disease activity and modification of therapy

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pproach to Vasculitis in hildren Surjit Singh

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This usually involves the aorta and its major branches. Four major patterns of involvement are recognized: Type 1: aortic arch; Type II: descending aorta; Type III: aortic arch and descending aorta; Type IV: aorta and pulmonary artery involvement. The classification criteria for childhood Takayasu arteritis are given in Table 16.4.1. In our country many children with Takayasu arteritis may have a clinical association with tuberculosis and are frequently Mantoux positive. Takayasu arteritis must be excluded in children with renovascular hypertension. Diagnosis can be confirmed by angiography. Treatment is based on long-term immunosuppression with prednisolone and oral weekly methotrexate. With angioplasty and appropriate stent placement, the long-term prognosis is now reasonable and 5 year survival rates above 90% have been reported from several centers. Hypertension has to be managed carefully.

 

Table 16.4.1 Diagnostic criteria for vasculitis in children

Takayasu rteritis



Vasculitic disorders are not uncommon in children but are frequently missed in clinical practice. These should be thought of whenever a child presents with a multisystemic disorder. These conditions can be classified according to the size of the vessel involved: • Large vessel vasculitis (e.g. Takayasu arteritis) • Medium vessel vasculitis (e.g. Kawasaki disease, polyarteritis nodosa) • Small vessel vasculitis (e.g. Henoch-Schönlein purpura, Wegener’s granulomatosis). Of these, Henoch-Schönlein purpura and KD are, by far, the most common conditions seen in pediatric practice. The classification criteria for the common types of childhood vasculitis are given in Table 16.4.1. Kawasaki disease is discussed in next section. Other common vasculitides are detailed below:

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16.4



Polyarteritis Nodosa Polyarteritis nodosa (PAN) is distinctly uncommon in children and can be a very difficult condition to diagnose in pediatric practice as the clinical manifestations can be extremely variable. Usual clinical features include fever, rash (typically livedo reticularis), hypertension, abdominal pain, joint pains and myalgia. Neurological involvement can take the form of seizures, encephalopathy and peripheral neuropathy. The latter can be very difficult to evaluate in young children. Clinical diagnosis is facilitated by angiography when aneurysms are demonstrable in the renal arteries or celiac axis. On histopathology there is fibrinoid necrosis in medium sized arteries typically with segmental involvement. The diagnostic criteria for childhood PAN have been recently revised and are given in Table 16.4.1. Treatment consists of long-term immunosuppression with prednisolone and cyclophosphamide.

 

 

 

 

 

 

 

 

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1. Takayasu Arteritis Angiographic abnormalities (conventional, CT or MR) of the aorta or its main branches plus at least one of the following four features:   •  Decreased peripheral artery pulse(s) and/or claudication of extremities   •  Blood pressure difference greater than 10 mm Hg   •  Bruits over aorta and/or its major branches   •  Hypertension (based on childhood normative data) 2.  Polyarteritis Nodosa   A childhood illness characterized by the presence of either a biopsy showing small and mid-size artery necrotizing vasculitis or angiographic abnormalities# (aneurysms or occlusions) plus at least two of the following:   •  Skin involvement   •  Myalgia or muscle tenderness   •  Systemic hypertension (based on childhood normative data)   •  Abnormal urine analysis and/or impaired renal function   •  Mononeuropathy or polyneuropathy   •  Testicular pain or tenderness   •  Signs or symptoms suggesting vasculitis of any other major organ systems (gastrointestinal, cardiac, pulmonary or central nervous system) # Should include conventional angiography if magnetic resonance angiography is negative 3. Wegener’s granulomatosis   Three of the following six features should be present:   •  Abnormal urinalysis   •  Granulomatous inflammation on biopsy   •  Nasal sinus inflammation   •  Subglottic, tracheal or endobronchial stenosis   •  Abnormal chest X-ray or CT scan   •  Positive C-ANCA staining

See Chapter 10.5.

Wegener’s Granulomatosis Wegener’s granulomatosis (WG) is an uncommon disorder in pediatric practice in which there is involvement of the respiratory tract and kidneys. The condition usually has an insidious onset and constitutional symptoms (e.g. fever/ malaise), which are quite common. Laboratory diagnosis is based on detection of anti-neutrophil cytoplasmic antibodies (ANCAs), especially C-ANCA, which are virtually pathognomonic of WG. The diagnostic criteria for childhood WG

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1. Cassidy JT, Petty RE. Textbook of Pediatric Rheumatology, 5th edition. Philadelphia: Elsevier Saunders; 2005. 2. Indian Journal of Pediatrics. 2002;69:27-34. 3. Singh S, Kawasaki T. Kawasaki disease - an Indian perspective. Indian Pediatrics. 2009;46(7):563-71. 4. Jain S, Sharma N, Singh S, et al. Takayasu arteritis in children and young Indians. Int J Cardiol. 2000;75(Suppl 1):153-7. 5. Kakkar N, Vasishta RK, Banerjee AK, et al. Pulmonary capillary hemangiomatosis as a cause of pulmonary hypertension in Takayasu’s aortoarteritis. Respiration. 1997;64(5):381-3.



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The disease is characterized by multiple relapses. Major morbidity is because of the ocular and neurological manifestations. The pathergy test (i.e. cutaneous pustular reaction following needle pricks) is virtually pathognomonic in a clinical setting of the disease. Human leukocytic antigen B5 and B51 haplotypes have been associated with this syndrome. Drug therapy involves use of colchicine and thalidomide.

Heal

Behçet’s disease is an unusual vasculitic disorder characterized by the following clinical manifestations: • Major features: Aphthous stomatitis, genital ulceration, cutaneous manifestations and ocular disease. • Minor features: Gastrointestinal disease, thrombo phlebitis, arthritis, family history and neurological involvement.



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6. Mahajan N, Bisht D, Dhawan V, et al. Transcriptional expression and gelatinolytic activity of matrix metalloproteinases in Henoch-Schönlein purpura. Acta Paediatr. 2010;99(8):124852. 7. Mahajan V, Singh S, Khullar M, et al. Serum and urine nitric oxide levels in children with Henoch-Schönlein purpura during activity and remission: a study from North India. Rheumatol Int. 2009;29(9):1069-72. 8. Ozen S, Ruperto N, Dillon MJ, et al. EULAR/PReS endorsed consensus criteria for the classification of childhood vasculitides. Ann Rheum Dis. 2006;65(7):936-41. 9. Singh S, Aulakh R, Bhalla AK, et al. Is Kawasaki disease incidence rising in Chandigarh, North India? Arch Dis Child. 2011;96(2):137-40. 10. Singh S, Aulakh R. Kawasaki disease and Henoch-Schönlein purpura: changing trends at a tertiary care hospital in north India (1993-2008). Rheumatol Int. 2010;30(6):771-4. 11. Singh S, Bali HK, Salaria M, et al. Takayasu’s arteritis in young children: a potentially treatable condition. Indian Pediatr. 1999;36:291-6. 12. Singh S, Bansal A, Gupta A, et al. Kawasaki disease: a decade of experience from North India. Int Heart J. 2005;46:679-89. 13. Singh S, Das R. Clinical approach to vasculitides. Indian J Pediatr. 2002;69:881-8. 14. Singh S, Devidayal, Joshi K, et al. Severe Henoch-Schönlein nephritis: resolution with azathioprine and steroids. Rheumatol Int. 2002;22:133-7. 15. Singh S, Gupta MK, Bansal A, et al. A comparison of the clinical profile of Kawasaki disease in children from Northern India above and below 5 years of age. Clin Exp Rheumatol. 2007;25(4):654-7. 16. Singh S, Kawasaki T. Kawasaki disease - an Indian perspective. Indian Pediatr. 2009;46(7):563-71.

dolesce

are given in Table 16.4.1. With steroids and cyclophosphamide, the long-term outlook is excellent.

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awasaki isease

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ntroduction

Kawasaki disease (KD) has emerged as the most common cause of acquired-heart disease in children in the developed nations. The etiology remains obscure though several compelling evidences support the role of both infection and immunologic dysfunction in genetically predisposed children. Recent studies have identified the importance of a gene that regulates T-cell activation as a critical factor, which determines KD susceptibility and severity. Siblings of affected children are at tenfold higher risk of developing KD compared with the general population. The basic pathology is a necrotizing inflammatory vasculitis with a striking predilection for the coronary arteries. All three layers of blood vessels are involved with destruction of the internal elastic lamina causing weakness and aneurysm formation and intimal proliferation leading to stenosis. The disease is seen worldwide, across all races, and in recent years increased incidence has been reported from India and other countries like China and Japan.

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16.5

 

Table 16.5.1 Diagnostic criteria

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1. Fever lasting 5 days or more 2. Presence of at least four of the following five principal criteria: a. Bilateral non-purulent conjunctivitis b. Redness of the mucosa of oropharynx, strawberry tongue and dry fissured lips c. Changes in extremities, such as edema and erythema of hands and feet and later periungual desquamation which may also involve palms and soles d. Polymorphous non-vesicular rash e. Cervical lymphadenopathy of at least 1.5 cm in size usually unilateral 3. Illness not explained by another known disease

 

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Kawasaki disease affects predominantly children below 5 years of age and boys are affected more frequently than girls. The diagnosis is essentially clinical and is based on presence of fever of five or more days duration, accompanied by four of the five principal clinical criteria given in Table 16.5.1 and Figure 16.5.1. The fever is usually high, persistent and does not respond well to antipyretics. Many cases are self-limiting with acute symptoms lasting an average of 12 days. Untreated, in some children the disease can run a protracted course and sometime cause severe cardiovascular sequelae. Patients who do not fulfill the essential four clinical criteria are referred to as incomplete KD. This is more common in young infants, often difficult to diagnose and carries a greater risk for

coronary artery disease. An algorithm showing approach to diagnosis of incomplete KD is shown in Flow chart 16.5.1. Three distinct phases of KD occur. Acute phase lasts up to 2 weeks, when most severe clinical manifestations including fever are present. The subacute phase begins with resolution of fever and goes on up to 4 weeks, and during this phase thrombocytosis and the classical peri ungual desquamation are evident (Fig. 16.5.2). The final convalescent phase lasts up to 8 weeks. Not all symptoms may develop simultaneously and therefore these patients should be assessed repeatedly. Cardiac involvement occurs mostly during the acute and subacute phase and new lesions beyond 8 weeks are unlikely. A pancarditis may be evident and coronary arteries are involved in 20–25% untreated children leading to aneurysm formation (Fig. 16.5.3). Giant aneurysms can occur rarely, with a vessel diameter greater than 8 mm, and these carry a grave risk for thrombosis, rupture or myocardial infarction. Children who develop coronary artery abnormalities will require long-term follow-up. Involvement of other arteries occurs infrequently. Other common findings include extreme irritability, arthritis, diarrhea and vomiting, aseptic meningitis, hydrops of gallbladder and erythema and induration at Bacillus Calmette-Guérin scar. Perineal accentuation of the rash with desquamation is frequently seen. About 2% cases may recur. There are no confirmatory laboratory tests and the clinician must carefully exclude other diseases that mimic KD (Table 16.5.2).

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Figure 16.5.1 Characteristic desquamation of hands

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Flow chart 16.5.1 Approach to incomplete Kawasaki disease (KD)

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Figure 16.5.3 Dry fissured lips and strawberry tongue (Courtesy: Dr A Santhosh Kumar) Table 16.5.2 Differential diagnosis of Kawasaki disease •  •  •  •  •  •  •  •  •  • 

Source: Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Pediatrics. 2004;114(6):1708-33.

Measles Scarlet fever Drug reactions Stevens-Johnson syndrome Other febrile viral exanthems Toxic shock syndrome Staphylococcal scalded skin-syndrome Bacteremia and sepsis Juvenile rheumatoid arthritis Leptospirosis

aboratory Tests

In the acute phase a normocytic normochromic anemia and polymorphonuclear leukocytosis are frequently seen. Thrombocytosis is evident after the first week of illness and may be an outstanding feature. Acute-phase reactants, ESR and CRP, are typically elevated to high levels. Erythrocyte sedimentation rate may rise further after intravenous immunoglobulin (IVIG), though CRP is unaltered. It may take

Treatment The child has to rest at home until all clinical signs disappear. Intravenous immunoglobulin along with aspirin is the 917 standard treatment for KD. These should be administered as soon as diagnosis is made, positively within 10 days of onset ­

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Figure 16.5.2 Irritability, oral and eye changes (Courtesy: Dr A Santhosh Kumar)

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6–8 weeks for these values to return to normal. Proteinuria and sterile pyuria can occur. Mild increase in transaminases may be seen though jaundice is rare. Anti-streptolysin O (ASO) titer, ANA and serological tests for various infections are negative. Chest skiagram is usually normal. Rarely ECG abnormalities in the form of decreased voltage, ST-T changes and conduction defects are seen. Echocardiography will detect coronary artery involve ment in the form of increased echogenicity, coronary ectasia, aneurysm formation and also evidence of carditis. This should be done preferably by a pediatric cardiologist on admission, again during subacute phase and at the end of 6–8 weeks. A vessel diameter greater than 3 mm is abnormal for a child below 5 years. Other abnormalities like valvular leak, pericardial effusion and left ventricular dysfunction seen in the initial stages will usually subside without any sequelae. In chronic phase, selected group of children with coronary artery disease may require specialized investigations like stress test, perfusion scan, cardiac catheterization, CT or MRI imaging and coronary angiography.

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and the risk of coronary artery disease can be significantly reduced to less than 5%. Similarly, the overall mortality can be reduced from 2% to less than 0.3%. Worst prognosis is in children with the so-called “giant aneurysms”. Approximately one-half of all aneurysms will regress within 5–18 months. Remainder may progress to stenosis, occlusion and myocardial infarction at a relatively young age. There are some reports indicating a tendency for premature atherogenesis in coronary arteries affected by KD. These children should be monitored periodically for risk factors for atherosclerosis like hypertension, hyperlipidemia and counseled on avoidance of smoking and obesity. Current evidence does not support a higher risk of accelerated atherogenesis in long-term survivors of low-risk KD without coronary disease in the initial phase, though there are reports of endothelial dysfunction and dyslipidemia which could increase future risk for atherosclerosis.



















Kawasaki disease is usually a self-limiting disease, although without treatment about 25% children can develop serious coronary artery disease. With early recognition and adequate treatment, full recovery can be expected in majority of cases

1. Burns JC. Kawasaki disease update. Indian J Pediatr. 2009;76(1):71-6. 2. Gupta-Malhotra M, Gruber D, Abraham SS, et al. Atherosclerosis in survivors of Kawasaki disease. J Pediatr. 2009;155(4):572-7. 3. Narayanan SN, Ahamed MZ, Safia M. Cardiovascular involvement in Kawasaki disease. Indian Pediatr. 2005;42(9):918-22. 4. Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Pediatrics. 2004;114(6):1708-33. 5. Onouchi Y, Gunji T, Burns JC, et al. ITPKC functional polymorphism associated with Kawsaki disease susceptibility and formation of coronary artery aneurysm. Nat Genet. 2007;40(1):35-42. 6. Rowley AH, Shulman ST. Recent advances in the understanding and management of Kawasaki disease. Curr Infect Dis Rep. 2010;12(2):96-102. 7. Rowley AH. Incomplete (atypical) Kawasaki disease. Pediatr Infect Dis J. 2002;53:153-57. 8. Singh S, Kawasaki T. Kawasaki disease-an Indian perspective. Indian Pediatr. 2009;46(7):563-71.



Prognosis

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of illness. Ideally, a single dose of IVIG 2 g/kg is administered over 10–12 hours. This will result in rapid defervescence and resolution of clinical signs in 90% of cases and is a supportive evidence for the diagnosis of KD. However, ESR may take longer time to settle. Around 10–15% children may not respond to one dose of IVIG or show only a partial response and remain febrile with persistent inflammation after 36 hours of IV gamma. There is potential risk for coronary artery disease in these children and therapy with IVIG (2 g/kg) should be repeated. After a second dose, 80% will respond and become afebrile. Infliximab a TNF alpha inhibitor also has been found to be equally effective in these nonresponders. Those patients who are resistant to a second dose IVIG may be treated with IV methylprednisolone 30 mg/kg/day for 1–3 days with alleviation of acute signs and symptoms but not coronary artery disease. Aspirin is given in a dose of 80–100 mg/kg daily in four divided doses during the acute phase and then continued in a smaller anti-thrombotic dose of 3–5 mg/ kg daily. At the end of 8 weeks aspirin is discontinued, if cardiac evaluation does not indicate any coronary artery involvement. Otherwise, aspirin should be continued until full regression of coronary arteries occurs, occasionally lifelong. Addition of clopidogrel or rarely warfarin should be considered for children with large multiple aneurysms. Consideration should also be given for full treatment of children with incomplete KD and those presenting beyond 10 days if evidence of coronary involvement occurs or the fever persists along with elevated acute phase reactants. Long-term follow-up of patients with abnormal coronary arteries is required with ECG, lipid profile and cardiac catheterization. Selected patients with severe coronary artery stenosis may need coronary angioplasty, stenting or bypass surgery.

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Juvenile ermatomyositis Juvenile dermatomyositis (JDM) is a multisystem disease characterized by nonsuppurative inflammation of striated muscle and skin and a systemic vasculopathy. Unlike adults, pure polymyositis (i.e. in absence of dermatological changes) is uncommon in children. The diagnosis can be made on the basis of criteria provided by Bohan and Peter: • Characteristic heliotrope discoloration over the upper eyelids • Symmetrical proximal muscle weakness • Elevated levels of muscle enzymes (aspartate amino transferase, alanine aminotransferase, creatine kinase, aldolase) • Electromyographic evidence of myopathy • Muscle biopsy showing myonecrosis, myophagocytosis, and perifascicular atrophy.





A “definite” diagnosis of JDM can be made if a child fulfills the first criterion along with any three of the remaining four; it is considered “probable” if two of the four criteria are met and “possible” if only one of the four criteria is met in addition to the first criterion. Other typical dermatological changes include Gottron’s papules (collodion patches) over the dorsal aspects of metacarpophalangeal and interphalangeal joints of fingers (toes usually not involved), edema over eyelids, photosensitivity, a truncal rash and calcinosis. From the clinical point of view a child with characteristic dermatological findings along with proximal muscle weakness can be confidently diagnosed as having JDM and started on treatment irrespective of the biopsy findings. Magnetic resonance imaging (MRI) shows characteristic hyperintense signals on T2-weighted images suggestive of muscle edema and inflammation while the T1-weighted images may show fibrosis, atrophy and fatty infiltration. Typical findings on MRI may preclude the need for a muscle biopsy. Treatment involves use of intravenous boluses of parenteral steroids (methylprednisolone 30 mg/kg/day or dexamethasone 5 mg/kg/day) for 3–5 days followed by oral prednisolone (1.5–2 mg/kg/day). Steroids are then gradually tapered depending on the clinical response. Oral weekly methotrexate (15–25 mg/m2/week) is now increasingly being used as first-line therapy in combination with prednisolone. The usual duration of therapy is 18–24 months. Rapid tapering of steroids may result in disease relapse. The long-term prognosis is excellent. S

cleroderma The term scleroderma refers to “hardening of the skin”. It can be classified as follows: • Systemic scleroderma (e.g. diffuse cutaneous, limited cutaneous) • Overlap syndromes • Localized scleroderma (e.g. morphea, linear scleroderma, eosinophilic fasciitis) • Chemically induced scleroderma (e.g. associated with polyvinyl chloride, pentazocine, bleomycin) • Pseudosclerodermas (e.g. phenylketonuria, scleroderma, progeria and porphyria cutanea tarda). Diffuse cutaneous systemic scleroderma is usually associated with widespread visceral involvement including the gastrointestinal tract, heart, lungs and kidneys. It is believed that fetomaternal graft-versus-host reactions are involved in the pathogenesis of this condition. Onset of disease is insidious and may be difficult to recognize in the initial stages. The child presents with skin tightening (edema, atrophy and acrosclerosis), Raynaud’s phenomenon (i.e. blanching, cyanosis and erythema), soft-tissue contractures, arthralgias and myalgias, dysphagia (regurgitation, reflux, and 919 aspiration), dyspnea (interstitial fibrosis, low diffusing capacity)

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yme isease Lyme disease is characterized by recurrent episodes of fever, a characteristic macular annular rash (“erythema migrans”), joint symptoms (usually an asymmetric migratory arthritis of large joints typically with accompanying myositis) and involvement of the central nervous system (headache, aseptic meningitis, cranial nerve palsies). Ocular involvement in the form of uveitis and optic neuritis can also occur. Unlike adults, carditis is rare in children. In view of the multisystem involvement, the clinical presentation can be very variable and one has to have a high index of suspicion. It has not been reported very frequently from our country but there is no reason to believe that it would be rare in India. It is caused by a tick (Ixodes spp.) borne spirochete (Borrelia burgdorferi). The diagnosis can be confirmed by direct tests such as culture (technically difficult, results may take many weeks), polymerase chain reaction (specificity low) and histochemistry on synovial tissue (interpretation requires experience) or by indirect serological tests such as enzyme-linked immunosorbent assay (ELISA) (low specificity) or Western blotting (high specificity). According to the criteria given by the Centers for Disease Control and Prevention a definitive diagnosis of Lyme disease can be made when there is erythema migrans (> 5 cm diameter) or any one of the typical clinical features (arthritis, meningitis, radiculoneuritis, mononeuritis, carditis) in the presence of specific antibodies. These criteria have, however, not been validated in children. It may be noted that all serological tests may be negative in the first few weeks of the illness and the treating physician may get virtually no help from the laboratory. Early disease can be treated with oral amoxicillin (50 mg/kg/day) while for disseminated disease or late cases parenteral ceftriaxone (100 mg/kg/day) is the drug of choice. Duration of therapy is 4 weeks. Children treated late or incompletely can have a smouldering chronic course often resistant to any forms of therapy and resulting in considerable morbidity.

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920 Intravenous immunoglobulin is a powerful therapeutic tool

and can be lifesaving therapy for several clinical conditions.

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The antiphospholipid antibody (APLA) syndrome is a common accompaniment of systemic lupus erythematosus but can be seen in association with other rheumatological disorders as well. It was first described by Hughes and co-workers from London in the early eighties. The syndrome can, at times, arise de novo when it is known as primary APLA syndrome. It is a common cause of hypercoagulable states in children and can manifest with arterial and venous thrombosis, livedo reticularis and thrombocytopenia. The presentation can sometimes be catastrophic and may result in fatality. Laboratory diagnosis is based on the detection of anticardiolipin antibodies (IgM and IgG) and the lupus anticoagulant test. Treatment is with longterm oral anticoagulation.

1. Ahluwalia J, Singh S, Garewal G. Antiphospholipid antibodies in children with systemic lupus erythematosus: a prospective study in northern India. Rheumatol Int. 2005;25(7):530-5. 2. Burnouf T, Radosevich M. Reducing the risk of infection from plasma products: specific preventative strategies. Blood Rev. 2000;14(2):94-110. 3. Cassidy JT, Petty RE. Textbook of Pediatric Rheumatology, 5th edition. Philadelphia: Elsevier Saunders; 2005. Mahajan V, Singh S. Pediatric rheumatological disorders. In: Syngle A, Deodhar SD (Eds). Rheumatology: Principles and Practice. . New Delhi: Jaypee Publishers; 2010.pp.325-33. 4. Parslow TG, Sittes DP, Terr AI, et al. Medical Immunology, 10th edition. New York: Lange Medical Books/McGraw-Hill Medical Publishing Division, 2001. 5. Singh S, Ahluwalia J, Naseem S, et al. Antiphospholipid antibodies in children with systemic lupus erythematosus— 18 years of clinical experience. Arthritis Rheumatism. 2010;62 Supp: S2. 6. Singh S, Bansal A. Twelve years experience of juvenile dermato myositis in North India. Rheumatol Int. 2006;26(6):510-5. 7. Singh S, Gupta MK, Ahluwalia J, et al. Neuropsychiatric manifestations and antiphospholipid antibodies in pediatric onset lupus: 14 years of experience from a tertiary care center of North India. Rheumatol Int. 2009;29(12):1455-61.

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Antiphospholipid Antibody yndrome

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Mixed connective tissue disease is a multisystemic overlap syndrome characterized by features of rheumatoid arthritis, systemic scleroderma, SLE and dermatomyositis occurring in conjunction with high titers of anti-RNP antibodies (specific for U1 RNP). Nephritis is usually less common and less severe than in SLE. Many children show good response to lowdose glucocorticoids and NSAIDs. Oral weekly methotrexate is also a useful therapeutic option. Treatment must be individualized and should focus on the particular disease component which is predominating in a given child.



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It is prepared by fractionation of pooled plasma obtained from remunerated healthy donors and consists of normal intact polyspecific IgG. These donors are subjected to strict screening procedures and the quality of the end product essentially depends on the quality of this screening. Each batch of IVIG represents a donor pool of 4,000–10,000 individuals. Such large donor pools serve to ensure that the antibody repertoire is complete and representative of the population at large. Intravenous immunoglobulin preparations presently being marketed contain 90–95% monomeric IgG with only small amounts of IgA and IgM. The efficacy of IVIG depends essentially on the IgG subclass distribution of the given preparation. However, some IVIG preparations do not contain the IgG3 subclass in adequate quantities. Intravenous immunoglobulin is the preferred treatment for several childhood conditions like KD, autoimmune demyelinating polyradiculoneuropathy, and ITP. The recommended dose is 2 g/kg given as a single infusion or 1 g/kg given over two consecutive days. For ITP, however, doses much lower than the aforementioned (e.g. 0.5–0.8 g/ kg) have also been found to be equally effective. Intravenous immunoglobulin is also used as physio logical replacement therapy in children with hypogamma globulinemia, where the therapy has to continue lifelong. The recommended dose is 0.4–0.6 g/kg every 3–4 weeks. Intravenous immunoglobulin has also been used in children with autoimmune hematological disorders (e.g. neutropenia, thrombocytopenia), severe myasthenia gravis, and patients with life-threatening lupus. Intravenous immunoglobulin should be administered under careful supervision as there is a real risk of anaphylactic as well as anaphylactoid reactions. The infusion must be started very slowly and the child monitored for any side-effects.



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and characteristic subcutaneous calcifications. In addition, many children have abnormalities of nail fold capillaries which can be seen as capillary dropouts and dilated loops with a magnifying glass or the +40 lens of the ophthalmoscope. Onset of hypertension and proteinuria usually indicate renal involvement and should be a cause for serious concern. Systemic scleroderma is rare in children but can result in severe disability. Investigations show presence of ANA (with the characteristic nucleolar pattern on immuno fluorescence) and antibodies to Scl-70 (DNA-topoisomerase1) or centromere. No form of drug therapy has been found to be curative. Penicillamine and colchicine can produce beneficial results in some patients, especially if used early in the course of disease. Pulse dexamethasone therapy has also been shown to be effective. Monthly pulses of intravenous cyclophosphamide (followed by maintenance daily azathioprine or weekly methotrexate) can be life-saving in patients with interstitial lung disease. Nifedipine is useful for management of Raynaud’s phenomenon while enalapril can result in control of blood pressure and stabilization of renal function. The latter is also the drug of choice for scleroderma renal crises. With appropriate management, 10-year survival rates of up to 90% have been reported in children. Scleredema is a benign, self-limiting condition characte rized by non-pitting indurated edema over face, neck, shoulders and chest but always excluding the hands and feet.

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The term allergy means “altered state of reactivity”. The term “atopy” refers to an individual being prone to develop allergies because of a genetic state of hyper responsiveness to allergens. Common atopic diseases are allergic rhinitis, allergic asthma, atopic dermatitis and food allergies. This chapter discusses in brief regarding allergic rhinitis. Bronchial asthma is being dealt in the chapter on respiratory disorders.

Allergic disorders are nowadays believed to be “genetic conditions that are triggered by environmental factors”. Genes which are being currently evaluated as candidates for atopic diseases include 5q23-35 encoding Th2 cytokines and 11q13 which encodes the IgE receptor (FceR1-B). Other genes of interest include SPINK 5, ADAM 33 (20p), GPRA (7p) and DPP10 (2q). Family history of allergy is single most important factor predisposing a child to development of allergic disease. A parent with atopy roughly doubles a patient’s chance of being atopic. Risk of atopy is increased from 25% in the general population to about 75% when both parents are atopic. About 85% children have similar allergy like their parents.

he Atopic March

The atopic march refers to the characteristic evolution of allergic manifestations in a child with atopic tendencies with progression of age. According to this theory, eczema precedes rhinitis and asthma in atopic individuals and may be a predictor of future respiratory allergy. However, unlike respiratory allergies, which tend to persist into adulthood, atopic eczema generally improves with age. T

Mechanisms of Allergic issue Inflammation The sequence of events in IgE-mediated allergic reactions involves three phases after exposure to the antigen. The early phase involves release of preformed mediators following mast cell degranulation. This leads to local hyperemia, plasma protein leakage and tissue swelling and is clinically manifested by itching, sneezing, wheeze and cramps depending on the organ of exposure. This is followed by the late phase 6–12 hours later due to the release of chemotactic factors. There is an initial neutrophilic response which is rapidly replaced by an eosinophilic response. In chronic allergic disorders, a third phase of tissue inflammation persists for days to years. This is believed to be due to the Th2-type cytokines which delay apoptosis thereby prolonging the activity of allergic effector cells.

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A detailed history and thorough physical examination remain the cornerstone of diagnosing atopic disorders. In no other branch of medicine history proves so rewarding or investigations extremely futile as allergic disorders (Tables 16.7.1 and 16.7.2). The following histories are absolutely necessary while evaluating a child suspected to have allergy:

Table 16.7.1 Signs of allergy/atopy  

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Although, it often is remarked that everyone is allergic to something, in truth, only about 25–30% of the population is allergic to anything. Various studies have quoted the prevalence of allergic rhinitis in children at 20% and in adults at 30%. Children with risk factors like family history go on to develop asthma and persistent rhinitis. Of the rest, half would still go on to develop persistent symptoms. About 75% of asthmatics have associated-allergic rhinitis, whereas 30–35% of allergic rhinitis patients have associated-hyper reactive airway disease.

Face

Allergic shiners, allergic salute, allergic mannerisms, Dennies lines, allergic line, allergic gape, long face syndrome

Eyes

Conjunctivitis, long silky eyelashes

Nose

Pale nasal mucosa, hypertrophied turbinates, Nasal polyps hypernasality

Ears

Serous otitis media (glue ear)

Mouth

Cobblestone pharynx, throat clearing sounds (allergic cluck), dry lips

Neck

Lymphadenopathy

Skin

Flexural ulcers, urticarial rashes, dry skin, Dermographism

Chest

Wheezing, accessory muscle use

Table 16.7.2 Clinical tips for diagnosis of allergic disorders  

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Persistent symptoms in a well-thriving child Pattern of exacerbations and remissions with diurnal and seasonal variations Family history of allergic disorders Clinical: Pale nasal mucosa with inferior turbinate hypertrophy Allergic salute, allergic shiners, flexural lesions and nasal crease Eosinophilia in peripheral smear and increased IgE.

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AC in the bedroom, if yes, how frequently is it cleaned? Allergic salute and allergic cluck Individual events Response to medication. The following clinical pointers should not be overlooked (Figs 16.7.1 and 16.7.2): However, the following investigations favor an allergic etiology:

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Family history of allergy Number of episodes, frequency, duration and severity Seasonal variations Potential triggers, if any Pets at home Stuffed animals the child goes to sleep with Type of bed and furniture Smoking in family

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Figures 16.7.1A to E Pointers to allergic disorders in children. (A) Dennie-Morgan folds (creases in lower eyelid due to Müeller’s muscle spasm); (B) Allergic mannerisms exhibited by the child: child may exhibit facial grimaces like nose wrinkling and mouth wrinkling which relieves nasal itching and block in AR; (C) Examination of the nose; (D) Allergic shiners and allergic gape: allergic shiners are bluish-black discolorations under lower eyelids which are termed “allergic shiners”, caused by venous stasis in areolar tissues of lower orbito-palpebral grooves from pressure on veins by edematous allergic mucous membranes of nasal and paranasal cavities and (E) Long face syndrome

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Figures 16.7.2A and B (A) Allergic nasal crease: dark line between cartilaginous and bony septum due to constant edematous turbinate to relieve itching and free from septum pressing over the cartilaginous portion of the septum and (B) Allergic salute

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reatment

The management of allergic disorders includes avoidance of offending allergens, pharmacotherapy and when indicated immunotherapy. Avoidance of allergen is the single most important step in the treatment of allergic disorders. The most important environmental measures include avoiding furred pets in bedroom, prevention of water stagnation, use of air

Table 16.7.3 Allergen-control measures for house dust mite  

•

conditioners, regular washing and sun drying of beddings and professional extermination (Table 16.7.3). Use of specialized high-efficiency particulate air filtered air cleaners reduces airborne allergens. First-line pharmacotherapy includes second generation antihistamines (Table 16.7.4), bronchodilators, mast cell stabilizers and adrenergic agents used as decongestants. Combining H1 and H3 antihistamine blockade provide the novel approach for the treatment of allergic rhinitis especially nasal congestion without the hypertensive liability of current adrenergic agonists. The second-line agents include inhaled and intranasal steroids (Table 16.7.5). Systemic glucocorticosteroids are useful during exacerbations. Newer agents used in the treatment of allergic disorders include olopatadine, lodoxamide and omalizumab. Recombinant soluble IL-4 receptor antagonists and monoclonal antibody against IL-5 are agents presently being used in research settings. If these modalities fail after an adequate trial period, it may be prudent to try allergen immunotherapy provided the provoking allergen is known. It is fundamental and imperative that a patient understand the premise of treatment plan before accepting and adhering to avoidance steps and medication regimens. Terminology such as controller and preventer may help the patient accept and understand the difference between and need for bronchodilators and anti-inflammatory agents. Delivery systems for use in the nose and lungs must be demonstrated and, in turn, the patient’s technique is to be observed in each visit. Montelukast was found to improve nasal and bronchial symptoms. Montelukast is effective in allergic rhinitis associated with other comorbid conditions like asthma, urticaria, etc. The addition of an antihistamine to

•

Peripheral eosinophilia (> 375/mm3) Nasal eosinophilia (> 4% in nasal smear of young children) Total IgE is rarely helpful in children, as roughly 75% of atopic individuals have IgE levels greater than 100 U/ ml (normal 0–100 U/ml). Total IgE is however elevated in other conditions like parasitic infections, allergic bronchopulmonary mycosis. Allergy skin test is the most important ancillary test to confirm the diagnosis of allergy. The skin test results must be interpreted in light of the history to determine the importance of a positive test In vitro tests for specific IgE antibodies (radioaller gosorbent test and ELISAs). These tests are more expensive and less sensitive than skin tests However, the clinical utility of these tests is limited and history with examination remains the diagnostic criteria for diagnosis of allergic disorders Radiographic imaging (Water’s view) of sinuses may be useful in establishing the presence or absence of sinus infection in allergic rhinitis patient. Computed tomography is considered gold standard for seeing all of the paranasal sinuses, but cost and radiation exposure are the concerns Spirometry for establishing reversible airway obstruction and peak nasal inspiratory flow meter to detect the severity of nasal obstruction Elevated tryptase levels can help in anaphylaxis Newer modalities like eosinophil cationic protein, exhaled nitric oxide, assays for histamine-releasing factor are useful tools to identify eosinophilic inflammation. ­

• •

•  •  •  •  •  • 

Washing all walls and floors Removing carpets from bedrooms Replacing carpets with hard flooring Washing bedding on a hot cycle (55–60°C) Applying tannic acid Using vacuum cleaners for bedding

923

vip.persianss.ir

Drug

Age wise dose

Conditions requiring dose adjustment

Clinically relevant drug– drug interactions

extbook of Ped

Cetirizine

6 months to < 2 years: 0.25 mg/kg 2–5 years: 2.5 mg OD 6–11 years: 5 mg OD > 12 years: 10 mg OD

Renal and hepatic impairment

Unlikely

Levocetirizine

6 months to 5 years: 1.25 mg OD 6–11 years: 2.5 mg OD > 12 years: 5 mg OD

Renal and hepatic impairment

Unlikely

Fexofenadine

6 months to 2 years: 15 mg BD 2–12 years: 30 mg BD > 12 years: 120 mg or 180 mg OD

Renal impairment

Unlikely

Loratadine

1–2 years: 2.5 mg OD 2–12 years: 5 mg OD > 12 years: 10 mg OD

Hepatic impairment

Unlikely

Desloratadine

6–11 months: 1 mg OD 12 months to 5 years: 1.25 mg OD 6–11 years: 2.5 mg OD > 12 years: 5 mg OD

Renal and hepatic impairment

Unlikely

T

ia

i

 

tr cs

Table 16.7.4 Second generation antihistamines and the dose

 

Table 16.7.5 Intranasal steroids and the dose Drug

Age wise dosing

Indication

Budesonide Each spray (64 mcg)

6 to < 12 years: 1 spray/nostril BD > 12 years: 2 sprays/nostril BD

Allergic rhinitis

Fluticasone propionate Each spray (50 mcg)

4–11 years: 1 spray/nostril OD > 12 years: 2 sprays/nostril OD

Allergic rhinitis

Fluticasone furoate Each spray (27.5 mcg)

2–11 years: 1 spray/nostril OD ≥ 12 years: 2 sprays/nostril OD

Allergic rhinitis

Mometasone furoate Each spray (50 mcg)

2–11 years: 1 spray/nostril OD > 12 years: 2 sprays/nostril OD

Allergic rhinitis and nasal polyps

Ciclesonide Each spray (50 mcg)

> 6 years: 2 sprays/nostril OD

Allergic rhinitis

Triamcinolone Each spray (50 ugs)

> 2 years: 1 spray/nostril OD

Allergic rhinitis

econgestants



Intranasal decongestants are used in the treatment of nasal obstruction, in both allergic and non-allergic rhinitis and are effective in the short term. A prolonged use (> 10 days) of intranasal vasoconstrictors may lead to tachyphylaxis, a rebound swelling of the nasal mucosa and to “drug-induced rhinitis” (rhinitis medicamentosa). Allergen-specific immunotherapy is the practice of administering gradually increasing quantities of an allergen extract to an allergic subject to ameliorate the symptoms associated with the subsequent exposure to the causative allergen. There is good evidence that immunotherapy using inhalant allergens are clinically effective to treat respiratory allergies. It induces clinical and immunologic tolerance 924 thereby preventing the progression and improving the quality of life. It also prevents progression to asthma from allergic rhinitis. Sublingual immunotherapy has gradually replaced the injection immunotherapy because of its safety profile.

Allergen-derived T-cell peptide epitope offer the possibilities of modulating the immune response to allergen with only minimal side effects. Recombinant allergens are designed to simultaneously retain the immunogenic/tolerogenic properties of the mild type allergens and to exhibit a strongly reduced allergenic activity and less risk of anaphylactic side effects. The recent, recombinant, humanized, monoclonal anti-IgE antibody (omalizumab) forms complexes with free IgE, blocking its interaction with mast cells and basophils and lowering free IgE levels in the circulation. However, this treatment modality is expensive and is not routinely recommended in our set up. Management of allergic rhinitis is summarized in Flow chart 16.7.1.

Atopic ermatitis Atopic Dermatitis in infancy is a predictor for risk of development of allergic disorders in later life. This has to be actively diagnosed by the pediatrician. Lesions are limited to the face and extensor regions in infants while the typical flexural lesions are present in the older child. Skin is usually dry in most of the patients. Most children outgrow their vip.persianss.ir D

D

montelukast does not appear to have added benefits and FDA has not approved this combination.





1. Bousquet J, Clark TJ, Hurd S, et al. GINA guidelines on asthma and beyond. Allergy. 2007;62(2):102-12.



















2. Braunstahl GB. United Airways Concept: What Does it Teach Us about Systemic Inflammation in Airways Disease? The Proceedings of the American Thoracic Society. 2009;6:652-4. 3. Brozek JL, Bousquet J, Baena-Cagnani CE, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines: 2010 revision. J Allergy Clin Immunol. 2010;126(3):466-76. 4. Brunetti L, Francavilla R, Miniello VL, et al. High prevalence of autoimmune urticaria in children with chronic urticaria. J Allergy Clin Immunol. 2004;114(4):922-7. 5. Jauregui I, Mullol J, Dávila I, et al. Allergic rhinitis and school performance. J Investig Allergol Clin Immunol. 2009;19 Suppl 1:32-9. 6. Jirapongsananuruk O, Vichyanond P. Nasal cytology in the diagnosis of allergic rhinitis in children. Ann Allergy Asthma Immunol. 1998;80(2):165-70. 7. Leung DYM. Allergy and the immunologic basis of atopic disease. In: Kliegman RM, Behrman RE, Jenson HB, Stanton BF (Eds). Nelson text book of Pediatrics, 18th edition. Philadelphia: Saunders; 2007.pp.1360-5. 8. Management of allergic rhinitis and its impact on asthma: A Pocket Guide. Available from URL: www.whiar.org/docs/ ARIA_PG_08_View_WM.pdf. Accessed 29, July 2011. 9. Own by Dr. Approach to the allergic patient. In: Lieberman P, Anderson JA. Allergic diseases: diagnosis and treatment (Eds), 3rd edition. New Jersey, Totowa: Humana Press. 2007.pp.27-37. 10. Weinberg EG. The atopic march current allergy and clinical immunology. 2005;18:4-5. 11. Wolf BL. Approach to the allergic patient. In: Lieberman P, Anderson JA (Eds), 3rd edition. Allergic diseases: diagnosis and treatment. New Jersey, Totowa: Humana Press; 2007.pp.15-25.

925





ibliography

B



Urticaria/Angioedema Most acute urticarias in children are post viral or related to food. Common food triggers of allergy include egg, sea food, nuts and chocolate. They usually respond well to antihistamines. Persistent symptoms require investigations to identify the triggering allergen. Chronic urticarias, more than 6 weeks include physical urticaria, aquagenic urticaria, cholinergic urticaria and pressure-induced urticaria. Recent data suggest that perhaps 25% of chronic idiopathic urticaria do have an underlying autoimmune etiology. Urticarial vasculitis should be looked for when clinically indicated. When urticaria is associated with angioedema, abdominal pain, Raynaud’s phenomenon or eye pain (scleritis), the diagnosis of urticarial vasculitis should be pursued. Low complement forms of vasculitis are usually associated with autoimmune disorders like SLE.



lesions by 3 years of age. The aim of treatment is to maintain the epithelial integrity and to avoid contact with allergens. Emollients are used first. For difficult lesions, soft topical steroids like hydrocortisone are used. Newer drugs like tacrolimus and pimecrolimus (disease modifying agents) are used in severe cases. UV therapy holds good promise but carries a theoretical risk of future cutaneous malignancies.



h

a

 

Adolescent He lt

Flow chart 16.7.1 Management of allergic rhinitis: algorithm

vip.persianss.ir

Section

17 Intensive Care and Emergencies



17.1 17.2 17.3 17.4 17.5 17.6 17.7 17.8 17.9 17.10























Section Editor : Sunit Singhi The Need, Scope and Organization of Pediatric Intensive Care Units: Krishan Chugh Common Poisonings in Childhood: S Balasubramanian Cardiopulmonary Resuscitation: Late Yogesh C Govil Shock: M Jayashree Respiratory Failure: Uday B Nadkarni Fluids, Electrolytes and Acid-base Disorders: Sunit Singhi Assisted Ventilation in Children: Suchitra Ranjit Monitoring in the Pediatric Intensive Care Unit: Bala Ramachandran Neurocritical Care: Soonu Udani Transport of Critically Ill Child: Praveen Khilnani

vip.persianss.ir







ntensive

I

The Need, Scope and Organization of Pediatric Intensive Care Units

17.1

are and mer



encies







g



E

Pediatric intensive care is a branch of medical science which provides care to the critically ill children, many of whom have compromised respiration and circulation, with some of their organs already showing signs of dysfunction or at risk of functional failure. Three types of patients are admitted to the pediatric intensive care unit (PICU): 1. Those who have critical dysfunction of vital organs. 2. Those who have a high chance of critical dysfunction of vital organs in the immediate period ahead. 3. Those who require extra nursing care. An analysis of age and sex distribution of children admitted in PICU shows that majority of the children are infants and males predominate; a trend similar to that seen in western countries (Table 17.1.1). Pediatric intensive care provides comprehensive care to the critically ill child, often integrating a number of other pediatric subspecialties such as cardiology, pulmonary

medicine and surgery (Table 17.1.2). The field of pediatric intensive care encompasses practical management issues of resuscitation, monitoring, concentration of resources and bedside titration of therapy. The management of critically ill children in PICU is extremely expensive as it needs large number of skilled and trained personnel, sophisticated medical equipment and costly medicines. Our economic limitations make it imperative on us to concentrate the medical equipment and the trained personnel to a predesignated area, i.e. PICU. Admitting all seriously ill children into this designated area (PICU) ensure that there is optimum utilization of resources. In the developed countries, in a majority of centers critical care to children in the PICUs is being provided by trained certified pediatric intensivists. The pediatric intensivist must be capable of independent judgment and decisions at times of crises without consultation/collaboration. He/she must have a thorough understanding of pathophysiology of life support, i.e. appropriate treatment of organ systems failure. He/she must have skills for providing basic and advanced life support to the critically ill.

Introduction

C

Krishan Chugh

 

Table 17.1.1 Age distribution of pediatric intensive care unit patients (2003, N = 439)

(2009, N = 794)

Age group

N

(%)

Age group

N

(%)

< 1 month

14

3.2

< 1 month

10

1.25

1–6 months

107

24.3

1–12 months

236

29.7

7–12 months

44

10.0

1–3 years

123

15

1–4 years

125

28.47

3–5 years

106

13.3

5–8 years

65

14.8

5–10 years

149

18.7

9–12 years

47

10.7

10–15 years

137

17

> 12 years

37

8.43

> 15 years

33

4.3

Source: Sir Ganga Ram Hospital, New Delhi.

 

Table 17.1.2 Pediatric intensive care unit patients—distribution by primary system of involvement System

Vellore (%)

AIIMS (%)

SGRH (%)

PGIMER (2007–2010) (%)

Respiratory

26.2

13.5

17.31

25

CNS

23.4

36.0

23.69

30.5

CVS

9.5

7.8

5.92

9

GIT

7.3

13.8

11.39

2.9

Renal

2.2

7.0

4.1

2.9

Hematology

4.5

6.3

4.1

3.8

Infections

9.5

14.8

10.25

13

Poisoning

9.3

10.2

0.91

5.3

Miscellaneous

5.1

—

5.47

Abbreviations: GIT, Gastrointestinal tract; CNS, Central nervous system; CVS, Cycling vomiting syndrome.

927

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ediatrics

P of

k oo e

t

T x b

Continuing medical education of all members of the team is a mandatory. The trainees, residents, subspecialty residents and nurses all have to keep up with the latest knowledge. The pediatric intensivist has to provide this knowledge to them and encourage them to acquire it from other sources also. The director of PICU and his whole team are faced with another issue of acquiring and trying newer technologies and treatment modalities in the critically ill children. Some of these may be without adequate scientific evidence to support their use, but there is a pressure by the industry, colleagues and parents to “try” these as the available treatment options are not succeeding. In such circumstances, two principles must be remembered “do not harm to your patient” and follow “standard treatment protocols” or “consensus guidelines”.

Organization of a Pediatric Intensive Care Unit Consensus guidelines for setting up PICUs in India have been published brought by Intensive Care Chapter of the

Indian Academy of Pediatrics and Pediatric Section of the Indian Society of Critical Care Medicine in 2002.

Levels of Pediatric Intensive Care Unit Care and Admission and Discharge Criteria Levels of Pediatric Intensive Care Unit Care Two levels of PICU care are identified, level 3 and level 2 as per Indian guidelines, which corresponds with level 1 and level 2 of the guidelines by the American Academy of Pediatrics (AAP) and Society of Critical Care Medicine (SCCM). Level 3 (tertiary) PICU can be organized with level 2 (step down/ high dependency) service in nearby but separate area. In small private set-ups, level 3 and level 2 care can be provided in one unit, if required facilities and equipment as well as personnel as described below are available.

Level 3 Care (Tertiary Level Pediatric Intensive Care Unit) • •

Defined admission, discharge policies At least four to six ventilator beds

 

Table 17.1.3 Pediatric intensive care unit—unit design •  Proximity to lift with easy access to emergency department and operation theater, recovery room, children wards, laboratory and radiology department

Bed strength

•  For the total pediatric ward, beds up to 25, a PICU of six to eight beds is ideal; 1–2% of hospital beds, at the most 6% is what is recommended

Space

•  The patient care area should have approximately 20 sq m space available per patient with 3–3.5 meters separating each patient. The total area needed is about three times the size that is needed for beds alone. The area around the bed should allow enough space for performing routine ICU procedures. The doctor duty room/office should be close to PICU

Design/Lay out

•  Patient care area may have an open ward design or multiple enclosed room design. Whatever the design, the layout should allow good visualization of all patients from central station •  A central station for observation, record keeping and charting, preparation of medications and other functions is necessary •  For a 6–8 bed unit, a big room serving 4–6 patients, and two smaller rooms (25–30 sq m) serving 1–2 patients are adequate

Power supply

•  Uninterrupted power supply •  At least 16 electrical outlets and two each for oxygen and compressed air •  Minimum of three vacuum outlets is required •  Electrical outlets should be placed at the head of the bed and 36 inches (1 meter) above ground

Temperature control

•  Adjustable between 22°C and 26°C •  Centrally air conditioned and should have central heating for temperature control •  There should be at least six air-exchanges per hour; at least two of outdoor air

Illumination

•  The level of lighting for patient rooms not exceed 30 fc (foot candles), with the ability to dim the level to as low as 6.5 fc at night

Noise

•  The World Health Organization recommendation is that ambient noise should not exceed 35 dB

Beds

•  Beds should have ability to maneuver head end foot end as well as availability of two or more air/water mattresses to prevent bed sores •  Emergency alarm button to activate code system and intercom at each bed side

Crash cart

•  Emergency drugs and portable monitor/defibrillator •  Zones for medication preparation and cabinets for the storage of medications and supplies

Storage

•  For storage of large patient care equipment items not in active use •  Refrigerator—for drugs and blood components

Biomedical waste disposal

•  As per standard applicable pollution control guidelines

Conference room

•  A small library facility with ready access to important intensive care books, journals and policy manuals

928

















Location

vip.persianss.ir

•

24 hour access to blood bank, pharmacy, pathology, operating theater, and tertiary level of imaging services • Educational and research activities • Quality review/audit process in place. The recommendations for the design, services to be provided and the staffing required in the PICU are summarized below in Tables 17.1.3 to 17.1.5.

ntensive



are

C

• •

More than 100 ventilated patients per annum Pediatric intensivist heading the unit One pediatrician with postgraduate training and experience in critical care present in PICU at all times One to one nursing on ventilated patients High level of monitoring possible in all patients

I

• • •

 

and

Table 17.1.4 Services that should be available Monitoring

Temperature

•  Including core temperature

Cerebral functions

•  Intracranial pressure •  EEG •  Evoked potential •  Cerebral blood flow •  Bispectral index

mer

•  Respiratory rate •  Oxygen saturation •  Blood gases •  Inspired oxygen and end-tidal CO2 monitoring of ventilated children

encies

Respiratory functions

g

•  Heart rate and rhythm •  ECG •  Blood pressure (invasive and noninvasive) •  CVP and pulmonary artery pressure •  Cardiac output

E

Cardiac and hemodynamic indices

Therapeutic or diagnostic modalities Emergency resuscitation Respiratory support

•  Tracheostomy •  Mechanical ventilation •  Tube thoracostomy, thoracocentesis •  Bronchoscopy

Cardiac support

•  Defibrillation •  Temporary cardiac pacing

Infusion pumps and pressure infusion devices Dialysis

•  Peritoneal/Hemodialysis, CVVH

Desirable

•  Left heart support •  Intra-aortic balloon assist •  Extracorporeal membrane oxygenation •  Hyperbaric oxygen

Support services necessary for PICU Radio--diagnosis and imaging facility

•  24 hours coverage for portable X-rays of chest and abdomen •  Ultrasound •  CT- scan •  Echocardiography •  Angiography •  Lung scan

Laboratory services

•  24 hours a day of following facilities •  Hemogram •  Blood glucose, urea, creatinine and electrolytes •  Prothrombin time, PTT and platelet counts •  CSF, urine analysis •  Arterial blood gas Other desirable facilities/microbiology •  Blood chemistry (Ca, P, Mg, LFT) •  Toxicology and drug level measurements (digoxin, theophylline, aminoglycosides, etc.)

Abbreviations: CVVH, Continuous veno-venous hemofiltration; CVP, Central venous pressure; PTT, Partial thromboplastin time.

929

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ediatrics

 

Table 17.1.5 Staff requirements Physician staff

House-staff (resident)

•  Round the clock postgraduate level pediatrician •  Should have good airway and PALS and active PALS certification

Nurses

•  Performs continuous, vigilant, compassionate care

of

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e

t

T x b



•  A pediatrician trained and experienced in care of critically ill children including advanced skills in monitoring and life support techniques •  Establishes policies and protocols with the help of a group of experts •  Implements policies and protocols including admission and discharge criteria •  Quality assurance and improvement •  Fulfills equipment needs •  Teaching and training of medical, nursing and ancillary staff •  Maintains PICU statistics •  Member of infection control committee

P

Medical director/intensivist in charge

•  A ventilated patient needs one pediatric/ICU trained nurse by the bed side



•  Unventilated/relatively stable patients may require only one nurse per two to three patients •  Should have basic understanding of commonly encountered clinical conditions and should be trained in resuscitation techniques, respiratory care, electronic monitoring, PICU equipment and usage Ancillary staff

•  Physiotherapist (1) •  Dietitian (1) •  Respiratory technician (1) •  Radiographer (1) •  Biomedical engineer (1) •  Secretarial/clerical staff •  Cleaning staff •  Social worker (desirable) (1)

Abbreviations: PALS, Pediatric advanced life support; PICU, Pediatric intensive care unit.

Legal and Ethical Issues

Cost Issues Critical care medicine consumes a disproportionately large fraction of healthcare resources. Though the costs are somewhat lower in our country, an audit of the activities 930 of the PICU on a regular basis is an essential component of ensuring cost-effective, quality care. In a PICU, more so in the developing countries, a balance has to be maintained between quality of care on one hand and cost-effectiveness

 

Figure 17.1.1 Pediatric intensive care unit management

­



and efficiency on the other hand. Modern day pediatric intensive care involves giving ventilatory support (Table 17.1.6) and continuous vaso active support to many children. Continuing these measures during transport, e.g. to the CT scan center, inside the center and back to the PICU can be hazardous and requires sophisticated technology. If a decision to actually transport the child is made, quality care before, during and immediately after transport should be ensured. In its relatively short history, pediatric critical care has accomplished much for gravely ill-infants and children in the advanced countries. The field is evolving in our country too. Limitations of resources have put greater responsibility on us to work out strategies to give maximum cost benefit ratio. With ever increasing technological advances and





Occasionally, legal problems can arise in the PICUs. The best way to minimize them is to take an informed consent from the parents for all forms of treatment and maintain a clear, complete and honest communication with them throughout the child’s stay in the PICU (Fig. 17.1.1). Ethical issues crop up in the PICU almost every day. Both, parents and professionals, have to work together in a therapeutic alliance to set the goals of treatment in any individual case. However, it should be left to the professionals to make decisions about which treatment modalities are necessary to advance these goals. Institutional policies have been advocated to help, prevent or resolve ethical conflicts in critical care. It is the responsibility of all members of PICU team to help the parents cope up with a critical situation. They should try to understand the problems of the family, show empathy and objectivity, keep them fully informed about their child’s condition but never lose professionalism. Help of a social worker or a psychologist may be needed.

vip.persianss.ir

I

 

ntensive

Table 17.1.6 Profile of pediatric intensive care unit admissions Sir Ganga Ram Hospital, New Delhi 2003, N = 439

PGIMER

2009, N = 794*

2007–2010

N

(%)

N

(%)

Yes

119

27.1

192

24

55.7%

No

320

72.9

602

76

44.3%

Survivors

395

90

743

90

82.2%

Nonsurvivors

44

10

51

7

17.7%

are

C

Ventilation required

and

Survivors/Nonsurvivors

mer

E

*Source: Sir Ganga Ram Hospital, New Delhi

encies

g

 

Table 17.1.7 Duration of stay of pediatric intensive care unit patients Sir Ganga Ram Hospital, New Delhi (2003, N = 439)

PGIMER (2009, N = 794)

2007–2010

N

(%)

Duration of stay

N

(%)

< 1 day

40

9.11

< 1 day

168

21

3.1%

1–5 days

311

70.85

2–4 days

468

59

55.2%

6–10 days

47

10.7

5–7 days

75

9

20%

11–15 days

16

3.64

8–14 days

47

6

9.4%

16–20 days

10

2.28

15–21 days

14

2

4.6%

> 21 days

15

3.42.

> 21 days

22

3

8.6%



(PSI) and Acute Physiologic and Chronic Health Evaluation (APACHE) score. The paradigm of total quality management (TQM) has supplanted the older narrower paradigm called quality assurance and quality improvement in some centers. TQM is a team-based continuous process of examining and improving all structures and processes in the PICU. Computerized data and information systems are key tools in the TQM process. B







1. Guidelines for intensive care unit design. Guidelines/Practice Parameters Committee of the American College of Critical Care Medicine, Society of Critical Care Medicine. Critical Care Medicine Med. 1995;23(3):582-8. 2. Khilnani P, Indian society of critical care medicine (pediatric section): Indian Academy of Pediatrics (Intensive care Chapter), Consensus guideline for pediatric intensive care unit in India. Indian Pediatr. 2002;39(1):43-50. 3. Moss MM, Simone S. Physical Design and Personnel organization of the PICU. In: Nichols DG, Ackerman AD, Argent AC, (Eds). Roger’s Textbook of Pediatric intensive Care, 4th edition. Baltimore. Williams and Wilkins; 2008.pp.46-56. 4. Rosenberg DI, Moss MM, American Academy of Pediatrics Section on Critical Care. Guidelines and levels of care for pediatric intensive care units. Pediatrics. 2004;114(4):1114-25. 5. Rudy EB, Davidson LJ, Daly B, et al. Care activities and outcomes of patients cared for by acute care nurse practitioners, physician assistants, and resident physicians: a comparison. Am J Crit Care. 1998;7(4):267-81. 6. Tenner PA, Dibrell H, Taylor RP. Improved survival with hospitalists in a pediatric intensive care unit. Crit Care Med. 2003;31(3):847-52.







To ensure optimum outcome in patients being treated in a PICU, all efforts have to be put into maintain the quality of care. Several quality management techniques have been devised and tested. Traditional approaches include: lying down and following ICU policies and protocols, quality assurance programs and morbidity and mortality reviews. However, recently more effective methods of assessing quality have been introduced. These include “quality improvement” techniques, evidence based standards and critical care clinical practice guidelines. All along, the mandatory practice standards laid by the governmental health authorities of the region have to be followed to avoid getting into legal problems. A comparison of morbidity and mortality parameters among different PICUs is inevitable when evaluating the quality of care being provided in a given PICU. To do this, one must take into account the severity of illness of children treated in that PICU, which can be assessed with the help of several systems, e.g. Pediatric risk of mortality score (PRISM), Severity of organ failure (SOFA), physiologic stability index

ibliography



Ensuring Quality of Care



better understanding of critical illnesses in the future, we need to continue to strive towards decreasing morbidity and duration of PICU stay (Table 17.1.7) and mortality and helping families of the critically ill children to cope with the potentially overwhelming stress. There is a great scope for the services of pediatric intensive care to expand and to reach out to more and more critically ill children in centers across the country.

931





Duration of stay

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C

C



ommon Poisonings in hildhood

D

D

C

A

General pproach to a Poisoned hild

D

The general approach to the diagnosis and management of the poisoned patient can be described using a twopronged model as shown in Flow chart 17.2.1. In practice, the two prongs occur simultaneously. The left-sided prong begins with basic emergency medical, which should address the ABCs (airway, breathing, circulation). Focused therapy involves antidote administration when appropriate or aggressive supportive care tailored to the poison in question. Finally, when treating any poisoned patient it is prudent to consider early consultation with a toxicology service or regional poison center for further guidance (for example: AIIMS, National Poison Centre, New Delhi).

etoxification

Detoxification involves enhanced elimination of exposed toxin from body, avoidance of further systemic absorption and enhanced elimination of systemically absorbed toxin. The various methods of decontamination should be considered in poisoned child. The exact method used should be based on each individual clinical situation. Once a poisoning has been identified, various methods of enhanced elimination should be considered. There are four modalities to remove a poison from the gastrointestinal tract (GIT): 1. Syrup of ipecac 2. Gastric lavage 3. Activated charcoal 4. Whole bowel irrigation.

A collection of symptoms associated with certain classes of poisons is known as a toxic syndrome, or toxidrome. In patients, who have unknown overdoses, a toxidrome can assist in making a diagnosis and is also useful for anticipating other symptoms that may occur. Cholinergic, anticholinergic, sympathomimetic, and narcotic agents all have characteristic toxidromes. For example, the traditional description of the anticholinergic toxidrome, is ‘‘hot as a hare, dry as a bone, red as a beet, blind as a bat, mad as a hatter’’. Toxidromes are most clinically useful when the patient has been exposed to a single drug. When multiple

The clinician should consider poisonings as important differential diagnosis in any child with atypical manifestations or constellation of multiple symptoms not fitting into any diagnosis or not responding in predicted manner; should be suspected of poisoning. Altered mental status, gastrointestinal complaints, cardiovascular compromise, seizures, and temperature-related disorders can all be toxinrelated. Some are subtle, such as the flu-like symptoms seen with carbon monoxide poisoning, whereas cardiotoxins, such as digitalis, may mimic intrinsic heart disease.





Toxidromes

ifferential iagnosis of the Poisoned Patient



Poisoning represents one of the most common medical emergencies. Hospital based data shows that poisonings constitute 0.33–7.6% of total hospital admissions in children. Poisoning can be intentional or unintentional. Unintentional or accidental exposure makes up 80–90% in infants to preschool children, whereas older children or adolescents have much higher rates of intentional or suicidal poisonings. Children under five years are most at risk due to their exploratory behavior, finger-mouth activity, pica, temperament that leans toward hyperactivity. Most commonly they ingest the agents which are more culpable because of ease of access, attractiveness, taste, color, etc. Pathophysiologically, poisoning represent an acute onset broad spectrum multiorgan chemical trauma. Fortunately a diagnosis often can be made in most of the cases from a witness to the event and/or based on clinical features of particular toxin. The scope of toxic substances involved in poisonings is broad, and require wide range of knowledge. Table 17.2.1 lists some of the common toxic agents and their clinical manifestations that help pediatrician in making initial diagnosis in emergency during critical window period. Clinical symptoms may be the only clues to diagnosis when the cause of toxicity is unknown at the time of initial assessment and management. There are certain compounds considered as nontoxic or minimally toxic when ingested or exposed in small quantity. Some of these are listed in Table 17.2.2. However, it should be appreciated that all substances are poisonous and nothing is without poison. The potential for toxicity of these compounds is dependent on dose and duration of exposure.

drugs have been ingested, conflicting clinical effects may be present or may negate. Table 17.2.3 lists the common toxidromes.



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Table 17.2.1 Common toxic substances and their clinical manifestations Poison

Bitter almonds

Cyanide

Acetone

Isopropyl alcohol, methanol, paraldehyde, salicylates

Alcohol

Ethanol

Oil of wintergreen

Methyl salicylate

Garlic

Organophosphates, arsenic, thallium

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Odors

Miosis

Narcotics, OPC, mushrooms (muscarinic), clonidine, phenothiazines, barbiturates (late)

Mydriasis

Atropine, alcohol, cocaine, amphetamines, antihistamines, cyclic antidepressants, cyanide, carbon monoxide

Nystagmus

Phenytoin, barbiturates, ethanol, carbon monoxide

Lacrimation

OPC, irritant gas/vapors

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Skin Dry, hot skin

Anticholinergics, botulism

Diaphoresis

OPC, Mushrooms (muscarinic), aspirin, cocaine

Erythema

Anticholinergics, Boric acid, mercury

Oral cavity Salivation

OPC, corrosives, salicylates

Dry mouth

Anticholinergics, antihistamines, amphetamines

Burns

Corrosives, oxalate containing plants

Gastrointestinal Cramps

OPC, arsenic

Diarrhea

Antibiotics, iron, boric acid

Constipation

Narcotics, botulism, codeine, lead

Hematemesis

Corrosives, iron, salicylates and aminophylline

Cardiovascular Tachycardia

Atropine, aspirin, amphetamines, cocaine, cyclic antidepressants, theophylline

Bradycardia

Digitalis, narcotics, mushrooms, clonidine, OPC, beta blockers, calcium channel blockers

Hypertension

Sympathomimetics, anticholinergics, MAO inhibitors

Hypotension

Phenothiazines, barbiturates, cyclic antidepressants, iron, beta blockers, calcium channel blockers

Respiratory Hypopnea/apnea

Alcohol, narcotics, barbiturates

Tachypnea

Amphetamines, aspirin, ethylene glycol, CO, cyanide

Pulmonary edema

Hydrocarbons, heroin, OPC

Neuromuscular Coma

Sedatives, narcotics, barbiturates, OPC, salicylates, cyanide, CO, lead, cyclic antidepressants

Hyperpyrexia

Anticholinergics, quinine, salicylates, phenothiazines, amphetamines, cocaine

Ataxia

Alcohol, antidepressants, barbiturates, anticholinergics, phenytoin, narcotics

Muscle fasciculation

OPC, theophylline

Paralysis

OPC, mercury, arsenic

Altered behavior

Anticholinergics, alcohol, camphor, amphetamines

Abbreviations: OPC, Organophosphate compound; CO, Carbon monoxide.

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Table 17.2.2 Products that are nontoxic when ingested in small quantities Abrasives Antacids (non salicylate containing) Antifungals (topical) Ballpoint ink pen Bath oil (unless aspirated) Body conditioners Calamine lotion Candles (beeswax/paraffin) Chalk (calcium carbonate) Children toy cosmetics Oral contraceptives (without iron) Corticosteroids, topical Crayons (marked as AP or CP, gel) Dehumidifying packets (silica) Fabric softeners Fertilizers (insecticides, herbicides) Diaper rash creams/ointments Fishbowl additives Glues and paste Golf ball (core may cause mechanical injury) Hand lotions and creams Ink (black/blue-nonpermanent) Indelible markers Lipstick Laxatives Lubricating oils (unless aspirated) Modeling compound (play-doh) Paints, water colors Plant food (no insecticides/herbicides) Rubber cement Silica gel Starch Toothpaste (with/without fluoride) Zinc oxide

Magazines Matches Newspaper (chronic ingestion leads to lead poisoning) Pencil lead (graphite, coloring) Polaroid picture coating fluid Shampoo Soap and soap products (non caustic) Sun screen lotion Warfarin rodenticides (< 0.5%) exclude superwarfarin

Antibiotics, topical Bathtub floating toys Bubble bath soap Caps (toy pistols/potassium chlorate) Clay (modeling) Cosmetics Deodorants, underarm Detergents, hand/dish washing Glow products Grease Incense Iodophil disinfectants (unless the individual is allergic) Lozenges (anesthetics) Markers, porous tip Mineral oil (unless aspirated) Paint, indoor latex, water-based Petroleum jelly (Vaseline) Putty Shaving creams and lotions Spackles Sweetening agents (saccharin, aspartame) Water color paints

 

Table 17.2.3 Common toxidromes Toxins

Toxidrome

Cholinergic (organophosphates, carbamates)

(Dumbbells) diarrhea, diaphoresis, urination, miosis, bradycardia, bronchial secretions, emesis, lacrimation, lethargic, salivation

Anticholinergics (antihistamines, cyclic antidepressants, atropine, phenothiazines, scopolamine)

Hyperthermia (hot as a hare), flushed (red as a beet), dry skin (dry as a bone), dilated pupils (blind as a bat), delirium, hallucinations (mad as a hatter), Tachycardia, urinary urgency and retention

Sympathomimetics (cocaine, ephedrine, pseudoephedrine)

Mydriasis, tachycardia, hypertension, hyperthermia, seizures

Opioids (heroin, morphine, codeine, methadone, fentanyl, hydrocodone)

Miosis, bradycardia, hypotension, hypoventilation, coma

Opioid withdrawal

Diarrhea, mydriasis, goose flesh, tachycardia, lacrimation, hypertension, yawning, cramps, hallucinations, seizures

 

Flow chart 17.2.1 General approach to a poisoned child

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Syrup of ipecac: • Induces vomiting by both central and peripheral mechanisms • Mean time of vomiting 15–30 minutes • Removes 30–40% of ingested toxin • Not indicated in less than 6 months age due to poorly developed gag reflex • Contraindicated in corrosives, hydrocarbons (HCs), sharp foreign bodies and low Glasgow coma scale (GCS). Gastric lavage: • Done in left lateral position • 15 mL/kg cycles • Contraindicated in HC poisoning • May delay treatment with activated charcoal.

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Focused therapy involves antidote administration when appropriate or aggressive supportive care tailored to the poison in question. Table 17.2.4 lists antidotes available for some common poisonings.

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Hydrocarbon Poisoning Classes of hydrocarbons – Aliphatic/straight chain: Acetone, butane, propane, isopropane

Whole bowel irrigation: • Polyethylene glycol • Useful in iron, sustained release theophylline, heroin body packers • 25–40 mL/kg/hour till rectal effluent is clear • Contraindicated in perforation and ileus.

(Note: Details of other methods of enhanced elimination are beyond the scope of the chapter, interested reader may refer further recommended readings given at the end of this chapter.)

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Activated charcoal: • Wood, coconut, petroleum heated to 900°C with steam and CO2 in activation process • 1–2 g/kg • Increased surface area to 1,600–1,800 m2/g • Multiple doses needed for digoxin, phenobarbitone, carbamazepine, dapsone • Ineffective in cautics, HCs, heavy metals, iron, ethanol, methanol, ethylene glycol • Contraindicated in ileus, intestinal obstruction.

 

Table 17.2.4 Antidotes Toxin

Antidote

Dose and route

Paracetamol

N-acetyl cysteine

140 mg/kg stat orally followed by 70 mg/kg Q 4h for 17 doses (in chronic poisoning only 12 doses). IV administration within 8–10 hours of ingestion, loading dose of 150 mg/kg infused over 15–60 minutes, followed by an initial maintenance dose of 50 mg/kg over 4 hour, followed by 100 mg/kg over 16 hour

Anticholinergics (atropine)

Physostigmine

0.02 mg/kg IV

Benzodiazepines

Flumazenil

0.01 mg/kg IV (maximum 3 mg)

Beta blockers

Glucagon

0.15 mg/kg IV stat followed by 0.1 mg/kg/hour

Calcium channel blockers

Calcium chloride 10%

0.1–0.2 mL/kg IV

Calcium channel blockers

Glucagon

0.15 mg/kg IV stat followed by 0.1 mg/kg/hour

Carbamates

Atropine

0.1 mg/kg/dose (repeated till atropinization)

Organophosphates

Atropine

0.05 mg/kg/dose (repeated till atropinization)

Pralidoxime

50 mg/kg IV stat followed by 25 mg/kg Q 4 h

Cyanide

Amyl nitrite inhalation 3% sodium nitrite

0.15–0.3 mL/kg IV infusion (maximum 300 mg)

Sodium thiosulfate

400 mg/kg (maximum 12.5 g)

Digoxin

Digibind (digoxin immune antibody fragment)

1 mL binds 0.6 mg digoxin

Methanol

10% ethanol

10 mL/kg IV stat followed by 1–2 mL/kg/hour

Ethylene glycol

10% ethanol

10 mL/kg IV stat followed by 1–2 mL/kg/hour

Fomepizole

15 mg/kg/dose IV

Iron

Desferrioxamine

5–15mg/kg/hour IV infusion

Isoniazid

Pyridoxine

1 g per gram ingested

Methemoglobinemia

Methylene blue

1–2 mg/kg/dose IV

Opioids

Naloxone

0.5–2 mg IV titrated to effect

Salicylates

Sodium bicarbonate

150 mEq + 40 mEq KCl in 1 liter of 5% dextrose infused to maintain a urine output of 1–2 mL/kg/hour and a urine pH of 7.5

Tricyclic antidepressants

Sodium bicarbonate

1–2 mEq/kg

Warfarin/super warfarin

Vitamin K1

0.5 mg/kg IV/SC/PO

FFP

15 mL/kg/dose till PT normalizes

Botulism

Botulinum antitoxin

Heparin

Protamine

Type 1 antiarrhythmics

Sodium bicarbonate

Abbreviation: FFP, Fresh frozen plasma; PT, Prothrombin time.

1–2 mEq/kg

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Flow chart 17.2.2 Classification of opioids



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Aromatic/cyclic structures: Benzene, toluene, xylene Toxic/halogenated: Carbon tetrachloride, tricholroe thylene – Petroleum distillates: Kerosene, gasoline, furniture polish Aspirational potential of a hydrocarbon is measured in Saybolt Universal Seconds (SUS) Clinical picture: Chemical pneumonitis, acute respiratory distress syndrome (ARDS) Fatal dose 10–15 mL Chest X-ray (CXR) to be done after 6–8 hours Usually gastric lavage is contraindicated, but due to low viscosity, good GIT absorption and high systemic toxicity, it is indicated in camphor, halogenated, aromatic, metal (heavy), pesticides (CHAMP) Symptomatic management of chemical pneumonitis.

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The classification of opioids has been given in Flow chart 17.2.2. • ndogenous opioids: Endorphin, enkephalin, dysmor phine • lassic triad: CNS depression, respiratory depression, miosis • linical features: – Cyclic vomiting syndrome: Bradycardia, orthostatic hypotension – Gastrointestinal tract: Ileus, constipation – Respiratory system: Bronchospasm (due to histamine release) – Renal: Urinary retention – Genital: Loss of libido. –

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Primarily hepatotoxicity, but, renal tubular damage and hypoglycemic coma can also occur Congestion of ethanol is cytoprotective (due to competition of P-450 site) Toxicity: Four stages: – Stage I: First day, nausea and vomiting present: Liver function test (LFT) and prothrombin time (PT) are normal – Stage II: Second day, upper abdominal pain, hepa tomegaly, jaundice. Elevated bilirubin, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT) and prothrombin time (PT) – Stage III: 2–4 days, maximum liver dysfunction. Acute renal failure. Liver biopsy shows centrilobular necrosis – Stage IV: 4 days to 2 weeks, resolution of hepatic dysfunction Lethal dose is more than 200 mg/kg or single dose of 7 g Diagnosis of hepatotoxicity is by Rumack-Matthew nomogram (not given in this chapter) Rumack-Matthew nomogram is not useful in poisoning with sustained release formulation, chronic poisoning and when paracetamol is ingested along with anticholinergics or opioids Specific antidote: N-acetyl cysteine (NAC) 140 mg/kg stat orally followed by 70 mg/kg Q 4 h for 17 doses (in chronic poisoning only 12 doses). Intravenous administration within 8–10 hours of ingestion, loading dose of 150 mg/ kg infused over 15–60 minutes, followed by an initial maintenance dose of 50 mg/kg over 4 hours, followed by 100 mg/kg over 16 hours Alternative antidotes: Methionine, cysteine ­

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atura stramonium: Entire plant including nectar is toxic Thorn apple ontains belladonna alkaloids: Scopolamine, hyoscy amine, atropine Mad as hatter, hot as hare, dry as bone, red as beet, blind as beet atal dose: 4 mg atal period: 24 hours ode of action: Antagonizes the muscarinic action of acetylcholine. Nicotinic receptors are much less sensitive Peripheral antimuscarinic effects: Dry mouth and skin flushing, excessive thirst, blurred vision, loss of accommodation reflex, hyperthermia, tachycardia, symmetrical pupillary dilatation, urinary retention entral antimuscarinic effects: CNS stimulation followed by depression, agitation, confusion, picking at clothes, auditory, visual, tactile hallucinations Treatment: Activated charcoal: 1–2 g/kg pecific antidote: Physostigmine 0.02 mg/kg up to 2 mg maximum. M

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• Withdrawal: Mydriasis, piloerection, myalgias, cramps, hyperthermia, muscle twitching • pecific antidote: Naloxone, 0.5–2 mg IV titrated to effect • ther antidotes: Nalorphine, levallorphan, naltrexone.

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Table 17.2.5 Early and late complications of corrosive poisoning Late (> 72 hours)

Esophageal perforation, mediastinitis

Esophageal stricture

Stomach perforation, peritonitis

Pyloric stenosis

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Contraindication to NAC: Coma, vomiting, hepatic failure/encephalopathy, pretreatment with activated charcoal Poor prognostic factors: pH less than 7.3 – Sr. creatinine more than 300 micro moles/L – Prothrombin time more than 100 seconds, ence phalopathy grade III to IV – Factor VIII to factor V ratio more than 30 Among all these factor VIII to factor V ratio more than 30 is the best prognostic indicator.

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Alkalis: esophagus: liquefaction necrosis Acids: stomach: coagulative necrosis. Fibrosis starts in 3 weeks, followed by strictures. Mortality 50%. In survivors 95% develop strictures The early and late complications of corrosive poisoning have been listed in Table 17.2.5.

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orrosive Poisoning

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A list of organophosphorus substances is given in Table 17.2.6. ode of action: Inhibition of acetylcholine esterase by irreversibly binding to it. Deactivate it by phosphorylation, leading to accumulation of acetylcholine. Excess acetylcholine leads to initial over stimulation followed by eventual exhaustion and disruption of post synaptic neural transmission odes of poisoning: Ingestion, inhalation, ocular exposure, dermal exposure (Flow chart 17.2.3) uscarinic: “Sludge”—salivation, lacrimation, urination, diarrhea, gastrointestinal upset, emesis icotinic: Effect on voluntary muscles—fasciculation, fatigue, paralysis entral nervous system: Anxiety, delirium, psychosis, seizures, tremors M

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Moth balls contain 100% naphthalene Toxic metabolite: Alpha naphthol has hemolytic effect Commonest presentation Pain abdomen, vomiting, diarrhea, jaundice, dark urine, pallor, seizure Massive intravascular hemolysis in certain North Indian communities G6PD deficiency patients are more prone Management: Syrup of Ipecac, gastric lavage, activated charcoal – May require exchange transfusion – Forced alkaline diuresis prevents acute renal failure by preventing – Precipitation of hemoglobin, in renal tubules – Methemoglobinemia may require methylene blue. –

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Acts as a metabolic poison Ferritin (iron storage protein) is abundant in the heart and liver and leads to tissue destruction Mechanisms of toxicity – Direct corrosive effect – Electron sink mechanism – Free radical damage – Concentration-dependent coagulation disorder Toxic dose – 20 mg/kg Sub toxic – 20–60 mg/kg Potentially lethal – > 60 mg/kg Lethal Five stages – I: GIT-local necrosis, hemorrhage, acidosis, drowsiness – II: Apparent recovery: Iron accumulation continues in mitochondria – III: Circulatory failure: Shock, coagulopathy, acute tubular necrosis, pulmonary hemorrhage – IV: Hepatic necrosis: Increased bilirubin, SGPT, SGOT, PT – V: Gastric scarring: Gastric outlet obstruction, intestinal obstruction Predisposes to infection with Yersinia enterocolitica, Listeria monocytogenes Serum level – Less than 50 mcg/dL: No toxicity – Greater than 50 mcg/dL: Toxicity manifests – Greater than 350 mcg/dL: Toxicity evident, lethal Initial management – Gastric lavage – Activated charcoal does not bind iron – Milk of magnesia 100 mL Specific antidote: Desferrioxamine, 1 g chelates 90 mg of iron. Winrose-color-urine when on treatment. Therapy to be continued till urine color is normal or serum iron <300 mcg/dL.

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Immediate upper GI scopy within 48 hours Not recommended now: neutralizing agents, vinegar for alkali, and sodium bicarbonate for acids (release CO2, can cause distension and rupture) First aid: 500 mL milk or water – Suck a piece of ice Oral prednisolone for 2–3 weeks Management – Repeat Barium studies after 3 weeks – Esophageal bougies: dilatation – Esophageal replacement with colon or jejunum.

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Organophosphorus

Organochlorine

Carbamates

Repellents

Synthetic pyrethroids

Pyrethrum

Chlorthion

DDT

Carbaryl

Benzyl benzoate

Resmethrin

Nicotine

Fenthion

BHC

Dimetilan

Indalone

Bioresmethrin

Mineral oils

Malathion

Chlordane

Pyrolan

Meta-diethyl toluamide

Pothrin

Rotenone

Parathion

Aldrin

Propoxur

Dimethyl phthalate

Derris

Methyl parathion

Dieldrin

Fenitrothion

Methoxychlor

Dioxathion

Heptachlor

Diazinon

Toxaphene

Dicapthon

Kepone

Chlorpyrifos

Mirex

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Table 17.2.6 Common organophosphorus substances

Ethyl hexanediol

Dichlorvos Trichlorfon Abate Dimethoate Gardena Flow chart 17.2.3 Clinical features of organophosphorus poisoning

 

 

Table 17.2.7 Enzymatic activity according to the severity of organophosphorus poisoning Grade of poisoning

Enzyme activity

Mild

> 20%

Moderate

10–20%

Severe

< 10%

 

Flow chart 17.2.4 Different types of insecticides

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ntermediate syndrome: – After 24–96 hours of “apparent” full recovery – Mainly respiratory muscle paralysis and proximal muscle weakness, neck flexors, decreased DTR, cranial nerve palsies – Lacks muscarinic symptoms – Lasts 4–18 days – Does not respond to atropine or oximes. Treatment is supportive, ventilation rganophosphate-induced polyneuropathy: – 2–3 weeks after exposure to large dose of organophosphate compound (OPC) – Distal muscle weakness – Sparing of neck muscles and cranial nerves – Recovery takes 12 months with residual neurological deficits iagnosis: – Plasma pseudocholinesterase and RBC acetylcho linesterase levels are decreased (Table 17.2.7) – Urinary alkaline phosphate and phenols increased pecific antidote: Atropine, only for muscarinic effects – Pralidoxime, both for muscarinic and nicotinic effects Primary cause of death: Respiratory failure –

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Worldwide mortality rate is 3–25% Aggressive and timely treatment—complete recovery within 10 days. The different types of insecticides have been listed in Flow chart 17.2.4.

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1. Bronstein AC, Spyker DA, Cantilena LR, et al. 2007 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 25th Annual Report. Clin Toxicol. 2008;46(10):927-1057. 2. Basu K, Mondal RK, Banerjee DP. Epidemiological aspects of acute childhood poisoning among patients attending a hospital at Kolkata. Indian J Public Health. 2005;49(1):25-6. 3. Fountain JS. On-line poisons information in New Zealand. Current Status and Future Challenges. Clin Toxicol. 2008;46(5):378. 4. Gupta S, Taneja V. Poisoned child: emergency room management. Indian J Pediatr. 2003; 70 Suppl 1:S2-8. 5. Home Safety Council. Safe home is in your hands. W V Med J. 2008;104(4):38-9. 6. Mason RW, Barnes AJ. Chemical and product type categorisation of product ingredients in poisons centre data processes. Clin Toxicol. 2008;46(5):370.



ibliography



• Poisoning is an important emergency. Eighty to ninety percent of these in infants and young children are accidental in nature • In any child with atypical manifestations or constellation of multiple symptoms not fitting into any diagnosis or not responding in predicted manner;, should be suspected of the poisonings • Most of poisonings are asymptomatic during emergency visit and they require just observation and monitoring but pediatrician should be aware that clinical manifestations may develop later due to systemic absorption or organ injury itself and careful assessment and anticipated problems • Broad knowledge of toxic substances and their clinical manifestations helps in making early diagnosis during initial critical window period in emergency • Specific antidotes are not available for most of the poisons and hence emergency management should focus primarily on initial life support therapy and decontamination of exposed/ ingested toxin from body and avoidance of further systemic absorption • Certain group of poisons manifest with constellation of symptoms and signs called “toxidromes” that helps in tailoring or narrow down treatment against suspected toxic substance and in deciding specific antidotal therapy if available



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• Emergency bed side investigations like arterial blood gas, electrolytes, renal function tests, blood sugar, electrocardiogram should be done in all children with suspected poisoning to aid initial life supportive therapy • Necessary samples should be collected for toxicological screening during initial management, e.g. blood, urine, gastric aspirate for drug or toxin level

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Basic life support (BLS) is the initial phase of CPR recognized as the “ABC” of CPR, where “A” indicates “Airway”, “B” indicates “Breathing” and “C” indicates “Circulation”. The traditional sequence of ‘“ABC’” comprises of opening of airway followed by delivery of rescue breaths and then performing chest compressions; however, the 2010 American Heart Association (AHA) guidelines recommend a “CAB” rather than “ABC” sequence reflecting the fact that the vast majority of victims who require CPR are adults with ventricular fibrillation (VF)/pulseless ventricular tachycardia (VT), in whom chest compressions are more important than ventilations and that beginning CPR with chest compressions rather than rescue breathing leads to a shorter delay to first compression. However, animal studies and a recent, large, prospective, nationwide American pediatric study have shown that resuscitation results for asphyxial arrests (vast

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nsure safety of rescuer and child: From nonrespirable atmosphere, danger of electrocution, traffic, falling masonry or a burning building, etc. heck the child’s responsiveness: The rescuer must quickly assess the consciousness level by gently pinching but not shaking the child and asking loudly, “Are you alright?” pen the airway: If the child does not respond, the rescuer should shout for help and proceed immediately to open the airway. Airway obstruction is common in the unconscious victim because of relaxation of muscles and passive posterior displacement of the tongue. Following methods can be used to open the airway: Head-tilt chin-lift ( ig. 17.3.1 ): One hand is placed on the child’s forehead and the head is gently tilted back into a neutral or slightly extended position. Fingertips of the other hand are simultaneously placed under the child’s chin and the chin is lifted taking care of not pushing the soft tissues under the chin jaw thrust (Fig. 17.3.1B). If there is still difficulty in opening the airway, jaw thrust method is tried. The first two fingers are placed behind each side of the child’s mandible and the jaw is pushed forward. If injury to the neck is suspected, airway should be opened by using chin lift or jaw thrust alone. If this is unsuccessful, add head tilt a small amount at a time until the airway is open. Establishing an open airway takes priority over concerns about the cervical spine. eeping the airway open, look, listen and feel for breathing: To determine whether the child is breathing or not, the rescuer looks for chest movements, listens F

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Pediatric advanced life support (PALS) comprises BLS with the use of other adjunctive equipment and special techniques to assess and support the pulmonary and circulatory function and may not be optimally performed outside the hospital unless trained personnel who continue to be trained periodically to maintain their expertise as a part of an organized system such as the emergency medical service (EMS) system are available.

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Cardiac arrest is the cessation of cardiac mechanical activity, determined by the inability to palpate a central pulse, unresponsiveness and apnea. Cardiac arrest can follow a multitude of pathophysiologic processes. The commonest underlying causes of cardiac arrest in children are respiratory failure (asphyxia) and circulatory shock (ischemia). Asphyxial cardiac arrests most commonly are the result of acute hypoxia or hypercarbia, whereas ischemic arrests usually follow shock from hypovolemia, sepsis and myocardial dysfunction. Asphyxial arrests are also common in young adults as in trauma, drowning or poisoning. Unlike older adults, cardiac arrests of primarily cardiac origin, for example, arrhythmias and pump failure constitute less than 10–15% of all cardiac arrests in children. Thus, a vast majority of childhood cardiac arrests are considered as preventable by early recognition and treatment of respiratory failure and shock. Cardiopulmonary resuscitation (CPR) is described as the performance of a series of assessments and interventions, the goal of which is to generate sufficient oxygen delivery to the coronary and cerebral circulation to maintain cellular viability, while other resuscitation interventions are undertaken based on the underlying pathophysiologic processes. The 2008 pediatric data from the National Registry of Cardiopulmonary Resuscitation (NRCPR), USA recorded an overall survival of 33% among in-hospital cardiac arrests. Children have better survival rates in comparison to those of adults; among children, infants have the best outcome.

majority of pediatric arrests) are better with a combination of ventilation and chest compression. The 2010 Resuscitation Guidelines for pediatric BLS of Resuscitation Council, UK continues to follow the traditional “ABC” sequence.

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Figures 17.3.1A and B (A) Opening the airway head-tilt chin-lift maneuver; (B) Opening the airway with the jaw thrust maneuver

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adolescents. An oxygen flow of 10–15 L/minute into the oxygen inlet and a reservoir attached to the air inlet of the bag is necessary to deliver a high oxygen concentration (60–95%). It is crucial to observe a good visible chest rise but excessive chest rise caused by excessive ventilation may have adverse effects such as increased intrathoracic pressure compromising venous return and cardiac output (CO), air trapping and barotrauma in patients with small airway obstruction and distention of stomach increasing the risk of regurgitation and aspiration. If bag-mask ventilation does not provide adequate ventilation or if prolonged ventilation is needed, endotracheal intubation is indicated. • ssess the child’s circulation (signs of life): Following opening of airway and provision of rescue breaths, the need to provide chest compression is determined by looking for signs of life. These include response to stimuli, spontaneous movement, coughing or normal breathing (not abnormal gasps or infrequent, irregular breaths). A pulse palpation (carotid pulse in children, brachial pulse A







for breath sounds by placing his or her ears close to the victim’s mouth and nose and feels for exhaled air on his or her cheeks, taking no more than 10 seconds. If the child is breathing or resumes breathing, the child should be turned on his or her side into the recovery position to help maintain a patent airway and to decrease the risk of aspiration while checking for continued breathing. If no spontaneous breathing is detected, any obvious airway obstruction is removed. Then two rescue breaths are provided by mouth-to-mouth and nose in an infant (Fig. 17.3.2A) and mouth-to-mouth in a child (Fig. 17.3.2B) making sure that the chest rises visibly. A self-inflating bag-valve device with a face mask has a clear advantage over mouth-to-mouth/nose rescue breathing; in that a higher inspired oxygen concentration is provided (Fig. 17.3.3), and is considered as essential CPR technique for healthcare providers. The self-inflating bag should have a volume of at least 450–500 mL for infants and young children and 1,000 mL for older children and

B  

Figures 17.3.2A and B (A) Rescue breathing in an infant—mouth-to-mouth and nose breathing; (B) Rescue breathing in a child—mouth-to-mouth breathing

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Figure 17.3.3 Use of a self-inflating bag-valve device with a face mask

 

Figure 17.3.4 Chest compression in an infant



I

in infants or femoral pulse in all age groups) may be performed but failure to detect the presence of a pulse within 10 seconds in an unresponsive victim should be taken as an indication to initiate chest compression. • f circulation is adequate: If there is a palpable pulse greater than or equal to 60 per minute but there is inadequate breathing, rescue breathing alone should be provided at a rate of about 12–20 breathe per minute (1 breath every 3–5 seconds) until spontaneous breathing resumes. During delivery of rescue breaths, the pulse is rechecked every 2 minutes. If there are no sign of life, unless one can be certain of palpating a definite pulse of greater than or equal to 60 per minute within 10 seconds, chest compression is started, combining it with rescue breathing. The child should be placed supine on a hard, flat surface to achieve optimal compressions. In infants, the chest compression is done either by a two-finger technique in which two fingers (either the second and third or the third and fourth fingers) are placed perpendicularly over the sternum just below the intermammary line (Fig. 17.3.4) or preferably, the two thumb-encircling hands technique. In this technique, the infant’s chest is encircled with both hands with both thumbs placed side-by-side at the same location as described above, and the fingers spread around the thorax. The area of compression in a child is located by placing the heel of the hand, one finger’s breadth above the xiphisternal notch, with the long axis of the heel parallel to the sternum (Fig. 17.3.5). Either one or two hands can be used depending on the strength of the rescuer, but use of two hands with the other hand kept on top of the heel of one hand generates higher compression pressure and is less fatiguing. Continuous effective chest compression is the cornerstone of excellent quality BLS as it provides the only source of coronary and cerebral perfusion. High-quality chest compressions have the following characteristics: • “Push hard”, i.e. the sternum should be pushed with sufficient force to depress the chest to at least one-third of the anteroposterior diameter of the chest, about 1.05” (4 cm) in infants and 2” (5 cm) in children

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Figure 17.3.5 Chest compression in a child

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ompression-to- entilation atio R

•

“Push fast”, i.e. the compression rate should be at least 100 per minute. “Allow full chest recoil” as incomplete recoil is associated with higher intrathoracic pressures and significantly decreased venous return and cardiac output. “Minimize interruptions” to maximize the beneficial effects of chest compression producing blood flow. V

•

Since the overall cardiac output is only 25–30% of normal at best during CPR, ventilation also needs to be 25–35% of normal to achieve adequate matching of ventilation and perfusion during CPR. Previously recommended high

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Foreign body airway obstruction or choking is characterized by the sudden onset of respiratory distress associated with coughing, gagging or stridor. If the cough is effective, the child should be encouraged to persist with it until the foreign body is expelled. Intervention is necessary only if the cough becomes ineffective, if breathing is inadequate or if the child loses consciousness. Up to five back blows (Fig. 17.3.6) are given to an infant or a small child if he or she is still conscious but has absent or ineffective coughing. Back-blows can also be given to a child positioned head down or in a forward leaning position. If back blows fail to dislodge the object and the victim is still conscious, up to five chest thrusts are performed in an infant at the same location as for chest compression after turning the infant as a unit in to supine position. The technique for chest thrusts should be sharper and more vigorous than compressions and is carried out more slowly (five thrusts in 15 seconds). Abdominal thrusts (Heimlich’s maneuver) (Fig. 17.3.7) are used up to five times in a conscious child with ineffective cough until the foreign body is expelled or the child loses consciousness. If the child loses consciousness, the child is put in supine position, the airway is opened and rescue breathing attempted. Abdominal thrusts are then performed by placing hands one on top of the other at a point between the umbilicus and xiphisternum. Abdominal thrusts are not used for infants. A summary of sequence of actions for basic life support is shown in Flow chart 17.3.1.

E





Although shockable rhythms ventricular fibrillation and pulseless ventricular tachycardia are the initial rhythms in only about 10% children with cardiac arrest, their early recognition and treatment is critical since the outcome is much better. There are two types of defibrillator devices: (1) Manual defibrillator, and (2) automated external defibrillator (AED). Although the BLS sequence includes only the use of AED, defibrillation as a whole will be discussed in this section. Since AEDs analyze the rhythm, determine if a shock is required and deliver the shock if needed automatically; they have been used effectively by lay rescuers in out-of-hospital arrests in developed countries. However, as AEDs deliver a fixed electrical energy, currently manual defibrillators are preferred over AEDs for infants unless an AED with dose attenuator is available. During CPR, soon after initiating chest compressions, the rhythm should be checked on the monitor. If a shockable rhythm is detected, the defibrillator is charged while another rescuer continues chest compression. Once the defibrillator is charged, chest compression is paused, it is quickly ensured that all rescuers are clear of the patient and the shock is then delivered. The recommended first energy dose ranges between 2 Joules per kg to 4 Joules per kg body weight. When using AED, adult shock energy can be used for a child over 8 years of age but pediatricattenuated adult shock energy should be preferred for a child below 8 years of age. Cardiopulmonary resuscitation should immediately be resumed without reassessing the rhythm or feeling the pulse. lectrode position: The right (sternal) chest pad or paddle is placed on the chest wall just below the right clavicle and the apical (left) pad is placed on the inferior-lateral left chest in the mid-axillary line. As there should be at least 1” between the pads, they may be placed on the lateral chest wall on the right and left sides (bi-axillary) or front and back of the chest in infants and small children if they cannot be adequately separated in the standard position. Pads for infants and children should be 4–5 cm and 8–12 cm in size, respectively. In general, the largest pad that can be placed on the chest wall maintaining a 1” distance should be used as small pads increase the risk of skin burn injury.

oreign ody irway bstruction



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efibrillation

Continued or recurrent VF/VT requires repeat shocks at doses of 4 J/kg or higher with a biphasic defibrillator every 2 minutes while chest compression is continued in the intervening period.

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ventilatory rates, in addition to the interruptions they cause to chest compressions, may also impair venous return. Thus, the 2010 guidelines recommend cycles of 30 compressions followed by two effective breaths for a single rescuer. A compression-to-ventilation ratio of 15:2 is recommended if there are two trained rescuers. Once endotracheal intubation has been done, chest compression at a rate of at least 100 per minute and ventilation at a rate of 8–10 breaths per minute (a breath every 6–8 seconds) are performed continuously and simultaneously without a pause by two providers.

 

Figure 17.3.6 Performing back blows in an infant

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Bag and mask ventilation remains the preferred technique for emergency ventilation during the initial steps of pediatric resuscitation. However, endotracheal intubation is the method of choice for guaranteeing the airway. Intubation protects the airway from aspiration and gastric contents, permits suctioning of the airway, optimizes ventilation and delivery of adequate oxygen, and enables administration of resuscitation medications through endotracheal route. Both cuffed and uncuffed tracheal tubes are acceptable for infants and children undergoing emergency intubation. A 3.0 mm internal diameter (ID) cuffed endotracheal tube may be used in infants weighing more than 3.5 kg and less than 1 year of age while 3.5 mm ID cuffed tube is recommended for children between 1 year and 2 years of age. After the age of two, the cuffed tracheal tube size is chosen by the formula: ID (mm) = (age in years/4) + 3.5. Cuffed tracheal tubes may have the advantage of decreased risk of aspiration and air leak without carrying an increased risk of subglottic stenosis, provided excessive cuff pressures (> 25 cm water) are avoided. Cricoid pressure during rapid sequence intubation (RSI) or emergency tracheal intubation (TI) is discouraged as no data shows that it prevents aspiration. It is necessary to confirm correct tracheal tube position using exhaled CO2 detection by a colorimetric detector or capnography. In case of failed endotracheal intubation and when bag-and-mask ventilation is ineffective, use of laryngeal

dvanced Life upport S

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Figure 17.3.7 Abdominal thrusts with victim standing or sitting

Advanced life support (ALS) entails advanced airway management including use of ancillary equipment to support ventilation and oxygenation, prompt recognition and treatment of life-threatening arrhythmias, the use of





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pharmacologic therapy and other procedures extending into the post-arrest setting.

 

Flow chart 17.3.1 Summary of pediatric basic life support

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It is recognized that there are no placebo-controlled studies on any single medication that has shown improved survival to hospital discharge outcome for pediatric cardiac arrests. Medication commonly used for CPR in children are vasopressors (adrenaline or vasopressin), antiarrhythmics (amiodarone or lidocaine), sodium bicarbonate and sometimes atropine. Adrenaline is the primary resuscitation medication. It is administered in a dose of 10 μg/kg (0.1 mL/kg of 1:10,000 solutions) IV or IO or 100 μg/kg (0.1 mL/kg of 1:1,000 solutions) by the endotracheal route. However, endotracheal route is the least satisfactory route. Higher dose adrenaline is not recommended as it can worsen the hemodynamic condition by causing increased myocardial oxygen demand, ventricular ectopy and myocardial necrosis. For persistent arrest, same dose of adrenaline may be repeated every 3–5 minutes. Although adult CPR guidelines recommend vasopressin as an alternative to replace the first or second dose of adrenaline in all cardiac arrests, there is insufficient evidence at present for or against its use in pediatric cardiac arrest. Consideration and correction of reversible causes of cardiac arrest must be undertaken as soon as possible, namely, hypovolemia, hypoxia, acidosis, hypoor hyperkalemia, hypoglycemia, hypothermia, cardiac tamponade, tension pneumothorax, etc. Sodium bicarbonate (1 mEq/kg diluted 1:1 with sterile water) should only be used in patients with prolonged cardiac arrest, hyperkalemia or arrhythmias associated with

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Termination of ardiopulmonary esuscitation The decision to terminate resuscitation efforts is frequently difficult. The presence of “fixed dilated pupils” has in the past been used as a sign of established brain damage. However, this sign is unreliable and should not be used to discontinue CPR. In the absence of recurring or refractory ventricular fibrillation or ventricular tachycardia, history of a toxic drug exposure or electrolyte imbalance or a primary hypothermic injury, continuation of CPR is considered futile beyond 15–20 minutes if there is no return of spontaneous circulation. At the same time, survival with good outcome is not uncommon despite greater than 15 minutes of CPR. There are no clear guidelines on this issue at this time.

Post-resuscitation are C

rug Therapy

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Good ventilation, oxygenation and high-quality chest compression may be sufficient to restore an adequate circulation. Those who do not respond well need medications to increase the rate of return of spontaneous circulation and terminate or limit the risk of recurrence of arrhythmia. Vascular access: Peripheral venous access may be quite satisfactory if it can be obtained rapidly and flushing of administered medication is done by appropriate fluid bolus. If after 90 seconds or three attempts, venous access attempts are unsuccessful, intraosseous (IO) route on the anterior aspect of tibia 1–3 cm below tibial tuberosity should be employed in infants and young children. In older children, the intraosseous cannula may be inserted into the distal tibia, anterior superior iliac spine, distal radius or distal ulna. If vascular or IO access cannot be rapidly achieved, some lipid soluble resuscitation medications may be administered directly into the endotracheal tube if it is already in place. Intracardiac administration of drugs is not practiced because of risks of coronary artery laceration, pneumothorax, cardiac tamponade and intractable arrhythmias.

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tricyclic antidepressant overdose. It is not routinely indicated in CPR as intracellular diffusion of generated CO2 may be more detrimental to myocardial function and catecholamine responsiveness as compared to that caused due to metabolic acidosis. In addition, administration of sodium bicarbonate presents a large, osmotically active sodium load to an already compromised circulation and brain. Also, leftward shift of the oxyhemoglobin dissociation curve caused by sodium bicarbonate may interfere with tissue oxygenation. Antiarrhythmic medication: Medications for arrhythmias are only indicated after unsuccessful attempts at defibrillation. The first administered medication for ventricular fibrillation or pulseless ventricular tachycardia is adrenaline. Antiarrhythmic agent amiodarone or lidocaine is used if adrenaline and subsequent attempts to defibrillate fail. Amiodarone is administered in a dose of 5 mg/kg IV as a rapid bolus after the third shock and may be repeated after the fifth shock. The major adverse effects of amiodarone are hypotension and bradycardia. If amiodarone is not available, lidocaine is used in a dose of 0.5–0.75 mg/kg every 5–10 minutes up to a maximum of 3 mg/kg. While atropine in a dose of 20 μg/kg (minimum 0.1 mg, maximum 1 mg in children and 2 mg in adolescents) is effective for bradycardia or cardiac arrest induced by increased vagal tone, for example, during airway manipulation, calcium is no longer recommended in the treatment of asystole as it may be harmful to the ischemic myocardium.

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mask airway may be used as “rescue airway”. Although it facilitates effective ventilation, it does not allow tracheal suctioning or provides reliable airway protection.

Post-resuscitation care is an important element of CPR as the risk of mortality remains high during the first 24 hours following successful resuscitation. A close clinical and laboratory monitoring to manage the post-cardiac arrest syndrome includes taking care of (i) post-cardiac arrest brain injury, (ii) post-cardiac arrest myocardial dysfunction and hypotensive shock, (iii) systemic ischemia/reperfusion response and (iv) identification of the unresolved cause of arrest and its recurrence. Detailed discussion of these issues is beyond the scope of this chapter; but a few recent advances are: there has been increasing evidence 945 of potential harm from exposure to high concentration

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1. Berg MD, Schexnayder SM, Chameides L, et al. Part 13: pediatric basic life support: 2010 American Heart Association









Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010;122(18 Suppl 3):S862-75. 2. Kleinman ME, de Caen AR, Chameides L, et al. Part 10: Pediatric basic and advanced life support.: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Circulation. 2010;122(16 Suppl 2):S466-S515. 3. Resuscitation Council, UK 2010 Resuscitation Guidelines. Pediatric advanced life support. Available at www.resus.org. uk/pages/pals.pdf. 4. Resuscitation Council, UK 2010 Resuscitation Guidelines. Pediatric basic life support. Available at www.resus.org.uk/ pages/pbls.pdf.



ibliography

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of oxygen after cardiac arrest, thus, currently it is recommended to titrate the administered oxygen to maintain oxygen saturation of hemoglobin between 94% and 98% during the post-resuscitation phase. Secondly, therapeutic hypothermia, by keeping the body temperature in the range of 32–34° may be considered for infants and children who remain comatose following resuscitation from cardiac arrest.

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tiologic Classification of hock

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Hypovolemia:

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•  Fluid and electrolyte loss:   –  Diarrhea, vomiting   –  Excessive sweating   –  Pathologic renal loss •  Blood loss:   –  External: laceration   –  Internal: ruptured viscera, GI bleed   –  Intracranial bleed (neonates) •  Plasma loss:   –  Burns   –  Leaky capillaries: sepsis, inflammation





The patient with shock has abnormalities of either: • The heart • The blood volume • The blood flow distribution. Accordingly shock can be classified into three groups: 1. Hypovolemic (decreased circulating blood volume) 2. Cardiogenic (impaired cardiac function) 3. Distributive (inappropriate distribution of blood flow). Several etiologies which fall into these broad groups are outlined in Table 17.4.1. The primary pathophysiological event in shock, regardless of etiology is tissue hypoperfusion, which leads to tissue hypoxia, acidosis and end organ dysfunction. The pathway to cardiovascular failure results from impairment of either cardiac output (CO), systemic vascular resistance (SVR) or both. Cardiac output is the product of heart rate and stroke volume while stroke volume is determined by left ventricular filling pressure and myocardial contractility. Systemic vascular resistance on the other hand represents the impedance to left ventricular ejection (after load) as well as the tone of the peripheral vasculature. After adequate volume resuscitation patients in hyperdynamic or warm shock are peripherally vasodilated with high cardiac output whilst patients in a hypodynamic or cold shock present with increased vascular tone and low cardiac output. Children with sepsis are more likely to have cardiac failure than vascular failure as seen in adults. When cardiac output is unable to meet the demands of the tissues, compensatory sympathetic activity produces selective vasoconstriction of the skin and splanchnic vessels to divert blood flow to vital organs, namely brain, heart and kidney. Three pathophysiological concepts that need under­ standing especially in septic shock are as follows:

Table 17.4.1 Causes of shock  

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Shock is a state of impaired tissue perfusion resulting in an imbalance between oxygen demand and supply. This widespread reduction in effective tissue perfusion causes insufficient or improper delivery and distribution of oxygen and nutrients, the end result of which is an altered cellular and subcellular function leading to anaerobic metabolism, accumulation of lactic acid and consequently cellular damage, multiple organ dysfunction and finally cardiovascular collapse. Clinically shock is characterized by signs of hemodynamic instability, tachycardia, hypotension and evidence of organ hypoperfusion.

yocardial dysfunction: It develops in nearly all patients with septic shock. This dysfunction peaks soon after the onset of sepsis and resolves within 7–10 days in survivors. Sepsis stimulates the release of inflammatory mediators that can compromise cardiac M

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  –  “Third space loss”: intestinal obstruction, peritonitis •  Endocrine:















  –  Nephrotic syndrome

  –  Diabetes mellitus   –  Diabetes insipidus   –  Adrenal insufficiency Cardiogenic: •  Myocardial insufficiency*   –  Congestive heart failure (Congenital, or acquired heart disease)   –  Cardiomyopathies: myocarditis   –  Arrhythmias   –  Hypothermia   –  Drugs, toxins •  Outflow obstruction:   –  Cardiac tamponade   –  Pneumopericardium   –  Tension pneumothorax   –  Pulmonary embolism •  Distributive:   –  Septic shock   –  Anaphylaxis   –  Drugs/toxin   –  Tissue injury   –  Prolonged hypoxia of ischemia *Myocardial depressant effect of hypoglycemia, acidosis, hypoxia

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Hypovolemic hock Hypovolemic shock is the leading form of shock in children worldwide. It is usually caused by hemorrhage or dehydration. Relative hypovolemia may occur secondary to “third spacing” of fluids (extravascular fluid shifts) as it may be observed in children with burns or with sepsis. Depending on the severity and rate of development of hypovolemia, the shock may appear abruptly or evolve gradually over several stages. Regardless of etiology the final common pathway to circulatory insufficiency is diminished intravascular volume.

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This volume reduction results in decreased systemic venous return and ventricular filling pressure (preload), thereby decreasing the stroke volume. Children with hypovolemia due to fluid and electrolyte losses have both intravascular and interstitial depletion. Clinical findings include sunken eyes, depressed anterior fontanel, dry mucous membrane, poor skin turgor, delayed capillary refill, and cool extremities. On the other hand patients with hypovolemia due to increased capillary permeability such as in burns or sepsis, have intravascular hypovolemia in the setting of interstitial euvolemia or hypervolemia. This clinically manifests as signs of decreased end organ perfusion such as altered mentation, decreased urine output, and cool, but often swollen extremities. The classical signs of dehydration based on interstitial fluid depletion are absent. Once again, hypotension is a late finding and may not occur until intravascular volume has decreased by about 25%. This is the time when the compensatory mechanisms fail, and profound reduction of cardiac output and fall of blood pressure occur. S

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Cardiogenic shock is commonly described as “pump failure”. The common causes are myocarditis, dysrhythmias, and drugs with a myocardial depressant action, acidosis, congenital heart lesions and sepsis. It can also result from obstruction to the outflow tract, e.g. coarctation of aorta or aortic stenosis or in states of increased afterload like hypertension. Cardiogenic shock will have low cardiac output, hypotension and clinical signs of inadequate tissue perfusion. Typically intravascular volume is adequate or even increased, but cardiac dysfunction limits cardiac output.

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The most common cause of distributive shock is sepsis. The common denominator in this shock is leakage of intravascular fluid through capillary bed into interstitial space known as “third spacing” of fluids because of endothelial damage. Sepsis is a systemic disease caused by microorganism or their products in the blood. The majority of cases of septic shock are caused by Gram negative bacilli but it may be caused by Gram positive, rickettsial, fungal and viral infections. Early septic shock is known as “warm shock” or hyperdynamic phase as it is characterized by warm extremities, low SVR, high or normal cardiac output CO, normal BP and increased pulse pressure. Low systemic vascular resistance increases skin blood flow and causes bounding peripheral pulses. Therefore despite high cardiac output, shock and metabolic acidosis develop because blood flow is inappropriately distributed. Adequate and early treatment at this stage may prevent progression. The latter phase of “cold shock” or hypodynamic phase is characterized by cold extremities, high systemic vascular resistance, low cardiac output, narrow pulse pressure and hypotension leading to hypoxia, acidosis and death.

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function. Dilatation of ventricles, reduced contractility and decreased ventricular compliance may be seen. Both systolic and diastolic dysfunctions are well described in septic shock. Diminished responsiveness of the myocardium to β1 agonists is secondary to down regulation of β1 receptors, uncoupling of receptors from adenylate cyclase or depressed generation of cAMP. The myocardium is dysfunctional despite an increase in cardiac output during the hyperdynamic phase of sepsis. • ean arterial pressure ( P): It is important to recognize that oxygen is not distributed uniformly to the body. Modulation of systemic vascular resistance in different vascular beds is one of the body’s primary compensatory mechanisms to shunt blood preferentially to vital organs such as the heart and brain. In this way, an increase in SVR may maintain a normal blood pressure even in the face of inadequate oxygen delivery. Maintenance of an adequate mean arterial pressure (MAP) is fundamental to ensure adequate perfusion and organ function. When mean arterial pressure falls below the autoregulatory range of an organ, blood flow decreases, resulting in tissue ischemia and organ failure. Because the kidney receives the second highest blood flow of any organ in the body, measurement of urine output (with the exception of patients with hyperosmolar states leading to osmotic diuresis) and creatinine clearance can be used as an indicator of adequate perfusion pressure. • xygen delivery versus consumption: Oxygen delivery is primarily dependent on cardiac output. Enhancing cardiac output by increasing preload and contractility or by decreasing afterload will thus increase oxygen delivery. Contrary to adults, oxygen delivery, not oxygen extraction, is the major determinant of oxygen consumption in children. Attainment of the therapeutic oxygen consumption goal of >200 mL/minute/m² has been found to be associated with improved outcome. In patients with septic shock the concept of pathological oxygen utilization is forwarded to explain dependence of oxygen consumption on oxygen delivery even at supernormal oxygen delivery. The goal in such patients is therefore to increase oxygen delivery and consumption until consumption is independent of delivery.

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In this stage, the blood pressure and cardiac output fall as they cannot be sustained by the intense peripheral vasoconstriction. A cascade of anaerobic tissue metabolism and multiorgan dysfunction sets in. Patient presents with poor pulses, peripheral cyanosis, cold extremities, hypotension and acidosis. Vital organ perfusion gets progressively compromised. Oliguria or anuria results from diminished renal perfusion. Diminished cerebral perfusion manifests in the form of lethargy, confusion and disorientation. Rapid aggressive intervention is required to halt the progression to irreversible stage. Table 17.4.2 summarizes the clinical features in shock syndrome.

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The compensatory cardiovascular responses of a child with decreased preload, impaired myocardial contractility, and alterations in vascular tone differ from those of an adult. Cardiac output is the product of heart rate and stroke volume. Stroke volume in turn is determined by preload, afterload and myocardial contractility. In children cardiac output is predominantly heart rate dependent owing to the lack of ventricular muscle mass. Therefore a child in shock maintains an adequate cardiac output by mounting a tachycardic response. Stroke volume is determined by ventricular filling (preload), the impedance to ventricular ejection (after load) and intrinsic pump function (myocardial contractility). Children maintain adequate cardiac output by mounting a tachycardic response. Children maximize systemic vascular resistance to maintain a normal blood pressure, in the face of significant decrease in the CO. This increase due to peripheral vasoconstriction mediated by the sympathetic nervous system results in diversion or redistribution of blood flow from less vital organs such as skin, skeletal muscles, kidneys, and splanchnic organs, to more vital organs like the brain, heart, lungs, and adrenal glands. Therefore, blood pressure will remain maintained till very late stages of shock and hence is a poor indicator of cardiovascular homeostasis in children. The evaluation of other hemodynamic variables like heart rate and end organ perfusion, including capillary refill, the quality of the peripheral pulses, mentation, urine output, and acid base status, is more reliable than blood pressure in determining the adequacy of hemodynamic status in a child. Presence of hypotension is not a must for diagnosis of shock in children -

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ifference between Pediatric and dult hock

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Early shock refers to preserved vital organ functions secondary to effective compensatory mechanisms. Blood pressure is maintained although signs of inadequate tissue and organ perfusion are observed. The early physical signs are that of an exaggerated sympathetic response to stress. Tachycardia and signs of decreased peripheral perfusion namely cold clammy skin, capillary refill time more than 2 seconds and difference between core and surface temperature of ≥ 2°C are the most important clinical pointers to early shock. Tachypnea may be seen without evidence of an underlying pulmonary disease. Blood pressure is maintained within normal range during the early stages. Septic shock in the early stages presents with fever, warm well perfused extremities, bounding pulses and wide pulse pressure. A capillary refill time of 3 seconds or more denotes impaired skin perfusion. It is a valuable sign during assessment and monitoring.

Irreversible stage of shock is a progressive reduction incardiac output, fall in blood pressure and worsening metabolic acidosis, and multiorgan failure. Delayed recognition or inadequate treatment can lead to terminal shock.



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Table 17.4.2 Clinical stages of shock and physical signs Clinical parameters

Stage I (compensated)

Stage II (decompensated)

Stage III (irreversible)

Heart rate

Tachycardia

Marked tachycardia

Severe tachycardia, bradycardia

Tachypnea

Tachypnea/apnea

Hypotension

Severe hypotension



Normal Normal



Respiration rate Blood pressure



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Shock refers to dynamic state ranging from early, compensated shock to irreversible, terminal shock. Shock can progress over a span of few hours or occur over minutes, e.g. in hemorrhagic shock. The progression can be arbitrarily divided into three stages: • Early compensated shock • Decompensated shock • Irreversible shock.

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Clinical eatures and tages of hock

Pulse pressure

Normal

Low

Markedly low

Skin

Cool

Mottled

Cold and cyanotic

Mental status

Anxious

Obtunded

Coma

Urine

Normal

Oliguria

Anuria

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Shock is a clinical diagnosis. Laboratory investigations are basically required to ascertain the etiology, and severity of organ dysfunction. The investigations that should be obtained in a patient with shock are shown in Table 17.4.3.

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An immediate intravenous (IV) access has to be established. In children where IV access is difficult due to collapsed veins an intraosseous (IO) line must be established instead. Obtaining rapid vascular access with at least two wide

 

Table 17.4.3 Investigations obtained in a patient with shock   –  Stool occult blood

  –  Chest X-ray

  –  Gastric pH

  –  Echocardiogram

  –  Liver function test

  –  Blood gases

  –  Pancreatic functions

•  Respiratory system

•  Metabolic

  –  Blood gases arterial and mixed venous

  –  Serum Na+/K+/Ca+Mg+2 Phosphorus

  –  Lung function tests

  –  Blood glucose

•  Renal system

•  Infection screen

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  –  Cultures-blood CSF   –  Urine

  –  Serum urea/creatinine

  –  Stool

•  Hematologic system

  –  Pus

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  –  Hematocrit, TLC, DLC

•  Toxicology screen

Following adequate intravascular volume repletion, continued presence of hypotension and/or poor perfusion warrants the consideration of vasoactive therapy, which

  –  Coagulation parameters   –  Platelet counts

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  –  Urine Na /Sp. Gravity/Sediments   –  Urine protein/sugar

+

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•  Gastrointestinal

  –  ECG



•  Cardiovascular system



ascular ccess A

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Supplemental oxygen should be administered to all patients in shock in view of the impaired oxygen delivery to the tissues. Intubation for airway stabilization is indicated in children with shock having altered sensorium, increased work of breathing or respiratory failure.

The objective of fluid administration in shock is to rapidly restore effective circulating volume so as to establish vital organ perfusion. Optimization of circulating volume with help of fluids is most important cornerstone of therapy in shock. Volume expansion should be achieved rapidly with a crystalloid solution, i.e. isotonic saline or Ringer’s lactate. Volume replacement should begin as 20 mL/kg IV while one is trying to assess the etiology. Response to fluid challenge includes an improvement in capillary refill, decreasing tachycardia, elevation of blood pressure and maintenance of an adequate urine output (1 mL/kg/hour). Subsequent choice of fluid may depend on the etiology, acid base and electrolyte status, oxygen delivery and coagulation parameters. The amount of fluid to be infused depends on the volume status, patient’s response and the ongoing losses in the patients. Patients in hypovolemic and septic shock may require up to 60 mL/kg in first 1–1.5 hours. Patients with septic shock may require up to 150–200 mL/kg within the first hour itself. Volume resuscitation beyond the first hour should be titrated to signs of improved perfusion, age, appropriate mean arterial pressure (MAP), a mixed venous oxygen saturation of >70% and cardiac index > 3.3 L/minute/m2 (ACCM practice guidelines, 2008). Colloids and blood products may be required in selective situations. Blood as volume expander should be given for traumatic hemorrhagic shock or bleeding due to coagulopathies. Even in these situations crystalloids are the first choice for volume expansion while blood is being arranged. Dextrose containing solution should be avoided during shock resuscitation unless there is documented hypoglycemia. This is because dextrose containing fluids cause hyperglycemia and osmotic diuresis which can further aggravate shock. The initial fluid for resuscitation should always be a crystalloid either isotonic saline or Ringer’s lactate.

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Two major priorities in treatment of septic shock are (1) rapid assessment of patient’s disease process and (2) achievement of cardiopulmonary stability. Irrespective of the etiology the initial resuscitation and stabilization of all forms of shock should be guided by the ABC’s. Stabilization of airway, provision of oxygen and establishment of vascular access are immediate goals followed by fluid resuscitation.

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bore peripheral venous lines is extremely crucial. Vascular access may be extremely difficult in children with shock as they have collapsed veins. Since time is extremely crucial, Pediatric Advanced Life Support (PALS) guidelines recommend placement of an intraosseous needle in infants and children for pushing fluids. If peripheral access is not readily obtained intraosseous access should be established quickly in children. Central venous access should be considered for children in fluid refractory shock as this access helps in infusion of vasoactive drugs and monitoring of central venous pressure. T

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Myocardial depression, ARDS, acute renal failure, and disseminated intravascular coagulation (DIC) are the most dreaded and life threatening complications of shock.

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When hould ne Consider Inotropic herapy? Patients with low cardiac output (myocardial failure) despite adequate fluid resuscitation will require inotropy. Clinically,

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When an appropriate fluid challenge fails to restore adequate blood pressure and organ perfusion in patients with high cardiac output and low systemic vascular resistance (warm shock), vasopressor agents should be started. Clinically these children will have tachycardia, flush capillary refill, low to low normal blood pressure (MAP) and wide pulse pressure. Since children with septic shock more often have associated myocardial dysfunction as opposed to adults, it is preferable to combine inotropy with a vasopressor. V

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Vasodilators are drug of choice in shock with increased afterload. In situations where myocardial failure is associated with increased afterload, inodilators like milrinone having dual action of inotropy and afterload reduction can be considered. However the prerequisite for using vasodilators is that patient should have adequate blood pressure or perfusion pressure. Prostaglandin E1, a potent vasodilator is indicated in newborns with ductus dependent lesion presenting in cardiogenic shock due to ductus closure. S

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The therapeutic end points of shock resuscitation are: • Capillary refill of <2 seconds • Normal pulses with no difference between central and peripheral pulses. • Warm extremities • Urine output >1 mL/kg/hour • Normal mental status • Decreased lactate • Mixed venous oxygen saturation >70%. •

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The clinician must determine whether there is evidence of low cardiac output with high cardiac filling pressure that requires inotropic support or if hypotension is accompanied by high cardiac output that requires presser support. Children with severe sepsis can present with low cardiac output and high systemic vascular resistance (SVR) (cold shock) or low cardiac output and low SVR (warm shock). Accordingly in the cold shock, inotropic support should be started in case of fluid refractory shock while a combination of inotrope together with a vasopressor is warranted in warm shock. Generally β adrenergic agents are chosen for support of cardiac contractility and α adrenergic agonists for maintenance of perfusion pressure to maintain flow distribution to the tissues. Adequate cardiac output is more important than blood pressure because adequate tissue oxygen delivery is the underlying goal. Adequate distribution of flow depends on an adequate pressure head.

When hould ne Use asopressors?

etabolic acidosis: Metabolic acidosis, poor tissue perfusion and resultant anaerobic metabolism leads to significant metabolic acidosis. Uncorrected acidosis can lead to further cellular damage and myocardial depression. Sodium bicarbonate as a rescue therapy for acidosis is indicated only in a desperate situation where 951 imminent myocardial failure secondary to severe and persistent acidosis (pH is below 6.9–7.0) is suspected. M



How to Choose the ppropriate rug?

it will manifest as tachycardia, low blood pressure (MAP), prolonged capillary refill, and narrow pulse pressure. After having achieved central venous pressure (CVP) > 10 cm H2O and MAP > 65 mm Hg, ScvO2 of <70% indicates insufficientcardiac output. The same may be improved with use of dobutamine (up to 20 µg/kg/minute). If used in the presence of low blood pressure, it is preferable to combine it with a vasopressor. Similarly a patient with fluid refractory dopamine resistant septic shock may need either dobutamine or low dose adrenaline (< 0.3 mg/kg/minute) for narrow pulse pressure and/or prolong capillary refill for improving cardiac output. Children with catecholamine resistant cold shock requiring inotropy can be treated with phosphodiesterase inhibitors like milrinone. Children with primary cardiogenic shock can be treated with inotropes at the first go.

Intens ve Care and mergen es

should be goal directed. Vasoactive drug therapy in the treatment of shock states aims to increase oxygen delivery or organ perfusion or both. Increasing mean arterial pressure (MAP) to a level that allows appropriate distribution of cardiac output for adequate organ perfusion and hence oxygen delivery is one of the key functions of vasopressors. Optimal preload is essential for all patients in shock before vasoactive therapy is contemplated. The vasoactive agents used to support circulatory function may be classified as inotropes, vasopressors, vasodilators, and inodilators. Inotropes increase myocardial contractility and often increase heart rate as well, e.g. dobutamine, mid dose dopamine 5–10 μg/kg/minute, low dose epinephrine (< 1 μg/kg/minute). Vasopressors increase systemic and pulmonary vascular resistance and are therefore useful in patients with low systemic vascular resistance. If myocardial function is adequate, vasopressors will typically increase systemic and pulmonary artery pressures, e.g. norepinephrine, high dose dopamine >10 μg/kg/minute, high dose epinephrine (> 1 μg/kg/minute). Vasodilators are designed to reduce systemic and pulmonary vascular resistance. Although vasodilators do not directly increase myocardial contractility, they reduce ventricular afterload, which often improves stroke volume and cardiac output. Vasodilators are the only class of agents that can increase cardiac output and simultaneously reduce myocardial oxygen demand, e.g. nitroglycerin, nitroprusside. Inodilators (inotropes + vasodilator) improve cardiac contractility and reduce afterload, e.g. phospho­ diesterase inhibitors like milrinone and amrinone.

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• Corticosteroids: The 2008 Surviving Sepsis Campaign guidelines recommend use of stress dose of steroids (hydrocortisone 50 mg/m2 per 24 hours) in children once they are diagnosed to have catecholamine resistant septic shock and in suspected or proven adrenal insufficiency. • ewer inodilators: Levosimendan and enoximone are two new inodilators being investigated for use in cardiogenic shock. They possess inotropy as well as coronary and systemic vasodilatory properties. They increase myocyte sensitivity to calcium and mediate vasodilatation through activation of adenosine triphosphate (ATP) dependent potassium channels in vascular smooth muscles. • asopressin: Vasopressors are used in the setting of warm shock having low SVR. Vasopressin is used 952 as a second line vasoconstrictor in patients with catecholamine resistant warm shock. However its experience in children is limited.

onitoring of hock

The objectives of monitoring a patient with shock are: • To assess the efficacy of the therapeutic interventions (e.g. response to fluid bolus or vasoactive therapy) • To recognize complications and correct them • To assess the degree of associated organ dysfunctions that will help in prognostication. Monitoring involves careful and repeated examination of the child’s physiological status, i.e. vital parameters like heart rate, pulse volume, respiratory rate, blood pressure, mean arterial pressure, temperature (skin and core) and capillary refill. In addition patients need continuous EKG monitoring and a strict intake/output record. Blood pressure by itself is not a reliable end point for resuscitation. Children normally have a lower BP than adults and can prevent reduction in blood pressure by vasoconstriction or by increasing heart rate. Mean arterial pressure is instead used as a surrogate of organ perfusion in shock. Mixed venous oxygen saturation (SVO2) is dependent on cardiac output, oxygen demand, hemoglobin and arterial oxygen saturation. The normal value is 70–75% in critically ill patients. If cardiac output CO becomes inadequate then SVO2 falls. Persistent low SVO2 even though other end points of resuscitation have been corrected suggests more oxygen extraction and inadequate resuscitation. Central venous oxygen saturation is being increasingly used as an alternative to SVO2 as it correlates well with mixed venous saturation and can be obtained from a central venous catheter. Regardless of the vasoactive drug therapy used, increasing cardiac output above physiologic levels is not recommended. Two recent prospective clinical trials in critically ill patients with sepsis have failed to demonstrate benefit from increasing oxygen level to supernormal levels. The goal of resuscitation should be to achieve adequate levels of oxygen delivery to avoid flow dependent tissue hypoxia. Invasive hemodynamic monitoring: The central venous pressure (CVP) is a measure of right ventricular function and the preload. A low CVP (< 5 cm H2O) indicates hypovolemia. Central venous pressure however can be a poor indicator of volume status in children with pulmonary hypertension, non compliant right ventricle, poor right ventricular function, tricuspid regurgitation, pericardial tamponade and high positive end expiratory pressure (PEEP). The multilumen pulmonary artery catheters (Swan Ganz Catheter) yield valuable information about pulmonary artery occlusion pressure (PAOP), pulmonary artery pressure, mixed venous saturation, cardiac output, vascular resistance, oxygen delivery and consumption (Flow chart 17.4.1).

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ctivated protein C: Severe sepsis and septic shock are associated with an imbalance between pro and anticoagulants leading to DIC. Activated protein C is an anticoagulant that helps regulate coagulation and inflammation and has been found to be deficient in patients with septic shock. Though recombinant human activated C (rhAPC) has been shown to decrease mortality in adults, its role in children is yet to be conclusively proven. Also it has been shown to increase the risk of bleeding and hence not currently recommended in children. A

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In all other situations bicarbonate must be avoided and all attempts must be taken to correct the shock. Overcorrection can be hazardous leading to paradoxic CNS acidosis, coma and death. Calcium: Acute hemodynamic deterioration in various types of shock can lead to decrease in the ionized Ca++ level. This hypocalcemia leads to tachycardia, hypotension, alteration in sensorium and motor nerve excitability. An intravenous infusion of 1–2 mL/kg of 10% calcium gluconate should be given when ionized Ca++ level falls below 2–4 mg/d . cute renal failure: Adequate fluid replacement is necessary to prevent development of renal failure. Dialysis will be indicated in case of hyperkalemia, refractory acidosis and fluid overload. The current trend is towards early renal replacement therapy especially in septic shock as this helps in removal of noxious triggers too. Hematologic support: Hematocrit needs to be maintained between 35% and 45% with the help of transfusions. Bleeding which complicates shock can be managed with fresh frozen plasma, vitamin K, and platelet concentrates. astrointestinal support: Prophylactic use of antacids and/or an H2 receptor antagonist is recommended to prevent stress bleeds. utritional support: Shock leads to excessive catabolism, hence nutritional support is one of the important pillars in the management. Nasogastric feeding should start as soon as patient can accept enteral feeds. espiratory support: Mechanical ventilation is indicated for acute respiratory failure, to improve oxygenation and to decrease work of breathing. ntibiotic therapy: Appropriate empiric antibiotics should be started in suspected septic shock. It should provide broad spectrum coverage depending upon site of infection and local epidemiologic data regarding sensitivity pattern. An aminoglycoside (gentamicin or amikacin) and a third generation cephalosporin (cefotaxime, ceftriaxone) should be used for suspected Gram negative sepsis. Combination of cloxacillin and an aminoglycoside should be used if staphylococcal sepsis is suspected.

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Prognosis Better outcome depends on early recognition and aggressive intervention in the stage of compensated shock. The mortality also depends on the etiology of shock; septic shock has mortality up to 50%. Hypothermia, decreased cardiac output, decreased O2, development of multiple organ dysfunctions are poor prognostic indicators in shock. B



1. American Heart Association (AHA). American Heart Association (AHA) guidelines for cardiopulmonary resuscitation (CPR) and emergency cardiovascular care (ECC) of pediatric and neonatal patients: pediatric advanced life support. Pediatrics. 2006;117(5):e1005 e1028. 2. Brierley J, Carcillo JA, Choong K, et al. Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine. Crit Care Med. 2009;37(2):666 88. 3. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign. International guidelines for management of severe sepsis and septic shock. 2008. Crit Care Med. 2008;36(1):296 327. -





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• Shock is a state of widespread tissue hypoperfusion resulting in an imbalance between oxygen supply and demand • Causes include hypovolemia, septic (distributive) and cardiogenic • The diagnosis is clinical based on a constellation of altered hemodynamic parameters like tachycardia, poor peripheral perfusion and evidence of organ hypoperfusion • Blood pressure is relatively preserved in early compensated shock due to sympathetic overactivity. Presence of hypotension is therefore not a must for diagnosis of shock • Decompensated or late shock occurs when compensatory mechanisms have failed and presents with hypotension • Immediate treatment in all forms of shock irrespective of etiology involves stabilization of the ABC’s (Airway, breathing, circulation) • Timely vascular access either peripheral intravenous or intraosseous is crucial for fluid therapy • All patients of hypovolemic and septic shock should receive a crystalloid bolus of 20 mL/kg as rapidly as possible • Subsequent requirement of fluids and vasoactive medications depend on therapeutic response and etiology of shock • Frequent monitoring of hemodynamic parameters by clinical, non-invasive and invasive methods is required to judge response to treatment and to recognize complications early • Vasoactive medications should be started only after patient is adequately volume depleted

• Immediate broad-spectrum antibiotics are indicated for suspected septic shock • Obstructive cardiogenic shock may require an urgent echocardiography and surgical correction

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Flow chart 17.4.1 Practice guidelines: an algorithmic approach

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8. Meyer S, Gortner L, McGuire W, et al. Vasopressin in catecholami­ ne refractory shock in children. Anaesthesia. 2008;63(3):228 34. 9. Nadel S, Goldstein B, Williams MD, et al. Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomized controlled trial. Lancet. 2007;369(9564):836 43. 10. Namachivayam P, Crossland DS, Burt WW, Shekerdemian LS, et al. Early experience with Levosimendan in children with ventiricular dysfunction. Pediatric Crit Care Med. 2006;7(5):445 8. 11. Singhi S, Khilnani P, Lodha R, et al. Guidelines for treatment of septic shock in resource limited environments. J Pediatric Infectious Dis. 2009;4:173 92.



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4. Han YY, Carcillo JA, Dragotta MA, et al. Early reversal of pediatric neonatal septic shock by community physicians is associated with improved outcome. Pediatrics. 2003;112(4):793 9. 5. Kleinman ME, Chameides L, Schexnayder SM, et al. Pediatric advanced life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiopulmonary Care. Pediatrics. 2010;126(5):e1361 99. 6. Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ ATS/SIS. International Sepsis Definitions Conference. Crit Care Med. 2003;31(4):1250 6. 7. McKiermnan CA, Lieberman SA. Circulatory shock in children: an overview. Pediatrics in Review. 2005;26(12):451 60.

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ypes of espiratory Failure

Causes irway/Lung ysfunction: • Central airway obstruction: Croup, foreign body, epiglot titis, retropharyngeal abscess, vascular ring, bacterial tracheitis. • Peripheral airway/parenchymal lung disease, bronchi olitis, acute severe asthma, pneumonia, drowning, lobar emphysema, acute respiratory distress syndrome (ARDS), cystic fibrosis, diaphragmatic hernia. espiratory pump dysfunction: May be associated with signs of decreased respiratory drive. ecreased C input: Head injury, meningitis, encephalitis, intracranial bleeding, ingestion of CNS depressant. Peripheral nerve/neuromuscular junction: Polio, GuillainBarré syndrome, spinal cord injury, botulism, organo phosphorus poisoning, myasthenia gravis. uscle weakness: Respiratory muscle fatigue, myopathies, muscular dystrophies. Early recognition of impending respiratory failure is of paramount importance and is based primarily on clinical features. A good history and thorough clinical examination would arrive at early diagnosis of respiratory failure and its cause.

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ype I: Oxygenation Failure/Lung Failure It is always caused by venous admixture and is always manifested by elevated alveolar-arterial oxygen pressure difference P (A-a) O2. Here PaO2 is <50 mm Hg and PaCO2 is low or normal with patient breathing

Clinical Features

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Basic mechanisms involved are: • Poor availability of oxygen • Alveolar hypoventilation • Ventilation/perfusion mismatch • Presence of a shunt (right to left) • Limitation of diffusion. Poor availability of oxygen: Low PO2 for inspired air as occurs in high altitude. lveolar hypoventilation: This results in abnormal increase in PCO2 leading to respiratory acidosis. Significant hypercapnia is always associated with hypoxemia unless the patient receives supplemental oxygen since increased alveolar CO2 dilutes available O2 in lungs. entilation/perfusion ( /Q) mismatch: Most common reason is hypoxemia. V/Q mismatch results when gas exchange in different regions of the lungs is poor due to poor ventilation in relation to their blood flow and vice versa. Hence alveolar PaO2 is low and alveolar PaCO2 is high. Presence of shunt: In a shunt situation, perfusion is maintained however there is no ventilation. Thus shunt can be considered as an extreme form of V/Q mismatching. This causes alveolar to arterial oxygen difference to increase. Limitation of diffusion: Diffusion impairment may occur as a result of increased distance between alveoli and their associated capillaries as in interstitial edema/fibrosis, alveolar proteinosis.

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Pathophysiology

tiology

Predisposing Factors The small size of the airways and the fewer alveoli in infants and children is primary difference compared to older patients. Children have large tongue that fills oropharynx and the larynx is cephalad. Infants and young children have a narrow subglottic area hence small amount of subglottic edema can cause significant narrowing. Infants and young children have relatively little cartilaginous support of the airways which makes thoracic cage soft and compliant, ribs are positioned horizontally. Intercostals musculature and diaphragm are not fully developed.

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Acute respiratory failure (ARF) can be defined as clinical state in which the respiratory system fails to meet the metabolic demands of the body for oxygenation and removal of carbon dioxide from the pulmonary circulation, thereby leading to arterial hypoxemia or hypercapnia or both.

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room air at sea level. Oxygenation failure is always a manifestation of pulmonary parenchymal disease. • ype II: Ventilatory Failure/Pump Failure – The physiologic basis for pure ventilator failure is decreased minute ventilation and increased dead space ventilation or combination of both. PaO2 is below the normal level and PaCO2 more than 50 mm Hg with patient breathing room air at sea level.



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Acute respiratory failure (ARF) remains an important cause of morbidity and mortality in children. It accounts for about 50% of Pediatric Intensive Care Unit (PICU) admissions and carries high mortality. Early recognition of respiratory failure and timely intervention would help to prevent cardiorespiratory failure in majority of pediatric patients.

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17.5

• Increased respiratory drive: Increased rate and depth of breathing, anxiety, breathlessness/dyspnea, retractions, 955 prominent accessory muscles of respiration, nasal flaring.

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Ensure adequate gas exchange and circulation (ABCs of CPR) Eliminate triggering factor causing acute respiratory failure (ARF) Oxygen should be delivered to maintain arterial oxygen saturation more than 95% since hypoxemia is more dangerous than hypercarbia. Maintain blood pH at normal or near normal levels If ventilation appears to be inadequate, breathing should be initiated with bag-mask system with added oxygen Patient should be transferred immediately to referral facility after stabilization.

M

Managing a case of respiratory failure is a challenging task, but if recognized early and treated promptly can prevent mortality and morbidity associated with it. It consists of ABC approach of CPR (cardiopulmonary resuscitation) which includes assessing and ensuring airway patency, breathing and circulation. It should commence within a half minute of cardiopulmonary arrest to avoid damage to vital organs. If CPR is instituted after 4 minutes have elapsed, there is a high possibility of hypoxic brain damage.

 

A

Table 17.5.1 Normal values of blood gases Age

PaO2

PaCO2

Newborn to 2 years

60–90 mm Hg

30–35 mm Hg

2 years and above

80–100 mm Hg

30–35 mm Hg

 

Table 17.5.2 Types of respiratory acid–base imbalance pH

PaCO2

HCO3

Uncompensated (acute)

↓

↑

Partially compensated (sub-acute)

↓

↑

N ↑

Compensated (chronic)

N

↑

↑

Uncompensated (acute)

↑

↓

N

Partially compensated (sub-acute)

↑

↓

Compensated (chronic)

N

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N ↓

Respiratory acidosis

Respiratory alkalosis

anagement



It provides information about oxygenation, ventilation and acid-base status: • pH less than 7.25, PaO2 less than 60 mm Hg and PaCO2 more than 50 mm Hg or increasing at the rate of more than 5 mm Hg per hour is important to assess the extent of respiratory failure. • Other monitoring modalities are pulse oximetry, capnometry/capnography, Ttranscutaneous O2/CO2 tension, lung volumes and airway graphic analysis (Tables 17.5.1 and 17.5.2).

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• •

Respiratory rate more than 50/minute (2 months to 1 year) and more than 40/minute (1–12 years) tate of consciousness: Lethargy, confusion, agitation may be signs of hypoxemia and hypercarbia Decreased/absent breath sounds, inspiratory retrac tions, flaring of alae nasi Use of accessory muscles, apnea Cyanosis: fairly late and unreliable sign as it is influenced by skin perfusion and hemoglobin concentration. ­

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This is extremely useful in detecting edema of epiglottis, presence of foreign body, pneumonia or pneumothorax. It also reveals extensive bronchopneumonia, collapse of lung, pleural effusion/empyema and lung abscess. It is essential to take posteroanterior and lateral views of X-ray chest to arrive at definitive diagnosis. G

iagnosis

adiological xamination

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ecreased respiratory drive: Decreased rate and depth of breathing, lethargy, confusion, snoring. • vidence of lung disease: Wheezing/crepitations;, retractions—suprasternal, intercostal, subcostal. • espiratory muscle weakness/fatigue: Irregular/shallow breathing, paradoxical see-saw respirations, grunting. • Upper airway obstruction: Stridor, drooling, absent breath sounds. D

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Maintaining airway patency is the first step in the management of respiratory failure. It includes proper positioning of the patient, avoiding neck flexion, splinting the chest and clearing oropharyngeal secretions.

Indications for Endotracheal Intubation • Cardiopulmonary failure/cardiopulmonary arrest • Severe respiratory distress/respiratory muscle fatigue • Loss of cough or gag reflex • Need of ventilator support due to apnea/hypoventilation or excessive secretions • Transportation of patient who has the potential for respiratory failure. Tracheostomy It is indicated in upper airway obstruction, excessive secretions causing blockage of ET tube, prolonged ventilation and vocal cord paralysis.

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1. 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2005;112(24 Suppl):IV11-203 2. Carroll L. Non-invasive ventilation for the treatment of acute lower respiratory tract diseases in children. Clinical Pediatric Emergency Medicine. 2009;10:90-6. 3. Essouri S, Durand P, Chevrett L, Hass V, et al. Physiological effects of non-invasive positive ventilation during acute moderate hypercapnic respiratory insufficiency in children. Intensive Care Med. 2008;34(12):2248-55. 4. Hemalatha R, Swetha GK, Seshacharyulu M, et al. Respiratory syncitial virus in children with acute respiratory infections. Indian J Pediatr. 2010;77(7):755-8. 5. Khilnani P. Mechanical ventilation in pediatrics. Indian J Pediatr. 1993;60(1):109-17. 6. Mathers LH, Frankel LR. Pediatric emergencies and resuscitation. In: Behrman RE, Kliegman RM, Stanton BF, Jensen HB (Eds). Nelson Textbook of Pediatrics. 18th edition. Philadelphia: WB Saunders; 2007. pp. 387-405. 7. Randolph AG. Management of acute lung injury and acute respiratory distress syndrome in children. Crit Care Med. 2009;37(8):2448-54. 8. Singh M, Kumar L. Management of respiratory failure. Indian J Pediatr. 1996;63(1):53-60. 9. Thomas NJ, Shaffer ML, Wilson DF, et al. Defining acute lung disease in children with the oxygen saturation index. Pediatr Crit Care Med. 2010;11(1):12-7. 10. Venkatraman ST. Mechanical ventilation and respiratory care. In: Fuhrman and Zimmerman (Eds). Pediatric Critical Care, 3rd edition. Philadelphia: Mosby Elsevier; 2006. pp.683-719. 11. Zimmerman JJ, Akhtar SR, Caldwell E, et al. Incidence and outcomes of pediatric acute lung injury. Pediatrics. 2009;124(1):87-95.



A number of novel therapies such as extracorporeal membrane oxygenation (ECMO), inhaled nitric oxide and perfluorocarbon liquid ventilation have been tried to in an attempt to improve outcome in children with acute respiratory failure which is refractory to traditional modalities. High frequency oscillation (HFO) ventilation is very useful option where conventional mechanical ventilation fails to improve the patient’s condition.High frequency oscillation also helps in decreasing iatrogenic morbidity such as barotrauma, volutrauma, etc. associated with conventional mechanical ventilation.



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Mechanical Ventilation An infant or child whose respiratory failure persists despite oxygenation and establishment of an adequate tracheal airway needs ventilation. It is defined as a technique that incorporates a commercially available ventilator to improve either oxygenation or ventilation or both with oxygen enriched air. This is instituted when all conservative modalities of treatment fail. The objective of mechanical ventilation is to support the critically ill patient by improving gas exchange in lungs, increase lung volume to prevent or treat atelectasis and to relieve the patient of work of breathing.

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Oxygen Therapy A good clinical rule is to administer sufficient oxygen to keep PaO2 in the range of 60–90 mm Hg unless higher values are warranted. Humidified oxygen may be administered through mask, nasal prongs, hood or tent. Limitation of simple mask is the attainment of only 35–55% concentration of oxygen at a flow rate of 6–10 liters/minute. Partial re-breathing and non-rebreathing masks can deliver 50–60% and 95% oxygen concentration respectively with a flow rate of 6-10 liters/minute. Nasal prongs are less restrictive and better tolerated and provide oxygen concentration of 25–45% with1–6 liters/minute of oxygen flow. Oxygen hoods can be used up to 12 months of age but require gas inflow rate of at least 10–15 liters/minute. It is necessary to monitor patients by pulse oximetry to keep the oxygen saturation more than 90%.

ey

• Acute respiratory failure (ARF) is an important cause of morbidity and mortality in children and accounts for about 50% of the admissions in pediatric intensive care unit • There are basic anatomical and functional differences in the airways of adults and children which account for high incidence of ARF in children • Respiratory failure can be either due to failure of oxygenation or pump failure • Acute respiratory failure is diagnosed on the basis of clinical features and arterial blood gas estimation • Early recognition of impending respiratory failure and appropriate timely intervention such as following ABCs of resuscitation improves ultimate outcome • Maintaining airway patency and oxygenation remains the mainstay of therapy if this fails then one must resort to mechanical ventilation • Although mechanical ventilation is life saving it is accompanied to trauma to airways • Amongst the newer modalities of managing ARF in children, high frequency oscillation (HFO) technique is time-tested technique and other options such as ECMO, liquid ventilation remain experimental in nature



B

After the airway is opened, one must determine if the child is breathing. Look for rise and fall of the chest and abdomen. Listen for exhaled air flow at the mouth. If spontaneous breathing is present, a patent airway must be maintained. If there is no breathing or ineffective breathing, patient should be placed in recovery position. Rescue breaths to be given by mouth to mouth breathing or bag and mask ventilation with added oxygen. If rescue breaths are ineffective and airway is obstructed then one must resort to interventions such as endotracheal intubation and tracheostomy.

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reathing

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luids, lectrolytes and cid-base isorders Sunit Singhi



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Renal mechanisms: Kidneys regulate water balance and the osmolality of body fluids by controlling excretion of solutes and free water under the influence of ADH and natriuretic peptides. Hypovolemia and hyperosmolality are potent stimulus for ADH secretion

Physiological requirements of fluids and electrolytes consist of the amount of water and electrolytes necessary to replace obligatory urinary and insensible water losses (ISWLs), and the water required for metabolic activity. For every 100 kcals metabolized, a child requires approximately 110–115 mL of water, 3 mEq of sodium and 2.5 mEq of potassium (Table 17.6.2). About 10–15 mL of water is produced in the body during oxidation of endogenous and exogenous carbohydrates, proteins and fats. Thus for all practical purposes 100 mL of fluid is sufficient to metabolize 100 kcals. Table 17.6.3 shows maintenance requirements of fluids and electrolytes on the basis of body weight and surface

The integrity of an organism depends on a stable water and electrolyte balance. Total body water (TBW) is about 75% body weight at birth, which gradually declines to 65% of body weight by one year of age. Almost all the reduction in TBW is contributed by loss of extracellular water (ECW) over time. Two principle compartments of TBW, the intracellular water (ICW) and the extracellular water spaces remain constant at 2:1 after infancy. The ECW compartment consists of the interstitial and intravascular spaces, which are separated in a 3:1 ratio. Thus, the intravascular space constitutes 1/12 of the total body water. Concentration of electrolytes in body fluids is shown in Table 17.6.1. Sodium and chloride are the principal electrolytes in the extracellular fluid while potassium and phosphates are the principal electrolytes in the intracellular fluid (ICF). Electrolyte concentration of plasma is somewhat different from that of interstitial fluid. A major determinant of movement of water between plasma and interstitial fluid, and interstitial fluid and intracellular fluid is osmolality. Water will flow from a region of low to high osmolality. Osmolality of the plasma can be calculated by the following formula.

Table 17.6.2 Physiological losses of fluids and electrolytes

Glucose (mg/d ) Blood urea nitrogen (BUN) (mg/d ) + 18 2.8 Thirst is activated when ECF water deficit is about 2.0%. It remains the major early defense mechanism against hypertonicity and dehydration.

Source

Losses per 100 kcals metabolized energy Water (m )

Na+ (mEq)

K+ (mEq)

–15

0

0

Insensible losses

Extracellular fluid

Interstitial fluid

Na+

9.0

140

147

K+

158

4.5

4.0

Ca+

3.0

5.0

2.5

Mg

30

2.0

1.0

Cl–

4.0

103

114

HCO3–

10.0

25

30

Proteins

65

15

0

Phosphates

95

2.0

2.0

Organic acids

4.0

6.0

7.5

Sulfates

22

-

1.0

Cations (mEq/l)

0.1

0.2

–10

0.1

0.2

Urinary losses

–55

3.0

2.0

Water for oxidation

+15

Total for maintenance

100 m

3.2 mEq

2.4 mEq

Table 17.6.3 Daily maintenance requirement of fluids and electrolytes (Holliday and Segar) Requirements By body weight By surface area Water Up to 10 kg 100 m /kg 1,500 m /m2 (range 1,200–1,800 m ) 11–20 kg 1,000 m + 50 m /kg for extra weight above 10 kg > 20 kg 1,500 m + 20 m /kg for extra weight above 20 kg Sodium 3–4 mEq/kg/day 40–60 mEq/m2 Potassium 2–3 mEq/kg/day 30–40 mEq/m2 Chloride 3–4 mEq/kg/day L

+

Skin

958

L

L

L

L

L

Anions (mEq/l)

L

Intracellular fluid

–30

Stool losses

L

Electrolytes

ungs

 

 

Table 17.6.1 Electrolyte composition of body fluids

L



l

l

 

Plasma osmolality = 2 × (Serum Na+ in mEq/L) +

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Modified maintenance fluid volume to be started based on BSA body surface area

Prematurity

100–300

500–1,500/m2

1,500 m /m2 + 500 m /m2

Radiant warmer

50–100

2

250–500/m

1,500 m /m2 + 250 m /m2

Phototherapy

25–50

125–250/m2

1,500 m /m2 + 125 m /m2

Hyperventilation

20–30

100–150/m

1,500 ml/m2 + 100 m /m2

Increased activity

5–25

25–125/m2

1,500 m /m2 + 25 m /m2

Hyperthermia

12 /0°C

60/0°C

1,500 m /m2 + 60 m /0°C

C

L

L

E

L

L

L

L

2

L

L

L

L

Volume change in mL

L

% Change

t

 

Conditions increase ISWL insensible water loss

n ensive are and mergencies

Table 17.6.4 Factors increasing insensible water loss

 

Table 17.6.5 Factors reducing insensible water loss Volume change in mL

Modified maintenance fluid volume to be started based on body surface area

Enclosed incubator

25–50

125–250/m2

1,500 m /m2–125 m /m2

Humidified air

15–30

75–150/m

2

1,500 m /m2–75 m /m2

Sedation

5–25

25–125/m2

1,500 m /m2–25 m /m2

Decreased activity

5–25

25–125/m

1,500 m /m2–25 m /m2

Hypothermia

5–15

25–75/m2

L L L

L L L

L

L

1,500 m /m2–25 m /m2

 

Table 17.6.6 Neonatal fluid requirements (ml/kg/day) Birth weight

Day 1

Day 2

Day 3

Day 4

Day 5

< 1,000 g

80–100

Advance fluids as per hydration status

1,000–1,500 g

80

100

120

140

150

> 1,500 g

60

80

100

120

140

D

Dehydration is net loss of body water. It is the most common imbalance of body water in infants and children. The most



D

D

ehydration

ssessment of ehydration and stimation of olume eficit V







Approximately 70% of usual maintenance requirements are given during the first 2 days. It is gradually increased to 100% by day 4–5. Low birth weight infants require relatively more water. Table 17.6.6 provides guidelines for fluid requirements in the neonate. Sodium supplementation is started when cumulative weight loss from birth reaches ≥6% of birth weight, after ensuring initial diuresis unless serum sodium falls to ≤130 mEq/L. Potassium supplementation usually not required till day three of life, and then to be started based on serum potassium level. Elemental calcium at the dose of 36–72 mg/kg/day (4–8 mL/kg/day of 10% calcium gluconate) would be initiated in all sick babies and babies <1,500 g from day one of life.

A

eonatal Period

common causes are diarrhea, vomiting and excessive urinary losses (diabetes insipidus, osmotic dieuresis, hyperglycemia, diuretic use). Dehydration may be hypotonic, isotonic or hypertonic. In isotonic form, there is a proportionate loss of water and solutes from ECF. In hypotonic dehydration, the depletion of solutes (sodium, chloride) in ECF is much more than water. This leads to movement of water from ECF to ICF, causing a further contraction of ECF and shock. In hypertonic dehydration, there is an excessive loss of water proportionate to the solutes. This leads to movement of water from cells into the ECF causing intracellular dehydration. The steps in the successful management of dehydration in infants and children include the following: • Assessment of degree of dehydration • Rapid restoration of intravascular volume • Correction of total fluid deficit (rehydration therapy) • Replacement of ongoing loses and nutritional support • Provision of maintenance fluids and electrolytes • Monitoring to prevent resurfacing of fluid deficit and dyselectrolytemia.

E

N





area in a healthy child. Clinical conditions that affect water loss from the body or the total caloric expenditure require modification of normal requirement and it is given in Tables 17.6.4 and 17.6.5. It is reasonable to use N/2 saline as maintenance fluid in all acutely ill hospitalized children. The fluid recommendations given in Tables 17.6.4 and 17.6.5 can only serve as a rough guideline to initiate modified volume of maintenance of intravenous fluid in specific conditions but subsequent titration needs to be done based on ongoing volume status assessment, urine output measurement, fluid balance (positive or negative), and myocardial function.

2

L

% Change

L

Conditions reduce insensible water loss

Clinical history and examination, remains the mainstay of assessment of dehydration (Table 17.6.7) though their 959 reliability has been questioned.

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Table 17.6.7 Severity of dehydration assessment

t

t

Characteristics Infants

Mild 1–5%

Moderate 6–9%

Severe ≥ 10% (> 15% shock)

Children

Mild 1–3%

Moderate 4–6%

Severe ≥ 7% (> 9% shock)

Pulse

Normal

Tachycardia

Tachycardia, weak pulse

Systolic BP

Normal

Normal-low

Orthostatic to shock

Urine output

Decreased

Decreased

Oliguria

Buccal mucosa

Slightly dry

Dry

Parched

Anterior fontanel

Normal

Sunken

Markedly sunken

Eyes

Normal

Sunken

Markedly sunken

Skin turgor/capillary refill

Normal

Decreased

Markedly decreased

Skin (< 12 months age)

Normal

Cool

Cool, mottling, acrocyanosis

Note: In a malnourished child, subcutaneous tissue is markedly reduced. Reliance on sunken eyebal, fontanel and loss of skin turgor in these children may lead to overestimation of dehydration. On the other hand, in chubby children dehydration may be underestimated. Thirst, dry mucosa, urine flow, metabolic acidosis, and circulatory status, therefore, are more reliable indicators of dehydration in these children.

 

Table 17.6.8 Recommended fluid therapy for intravenous rehydration Solution

Maintenance

5% dextrose in 0.45% saline with 20 mEq/ KCl over 24 hours

Isotonic dehydration

5% glucose in 0.45% saline with 20 mEq/ KCl given over 24 hours

Hypotonic dehydration

5% glucose in 0.9% saline with 20 mEq/ KCl given over 12 hours followed by 5% dextrose water in 0.45% saline with 20 mEq/ KCl given over the next 24 hours

Hypertonic dehydration

5% dextrose water in 0.2% saline containing 20 mEq/ KCl to be given over the number of days necessary to lower the Na+ concentration by 10 mEq/day L

L

L

L

L

Type of fluid therapy

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D

F

orrection of Total luid eficit: ntravenous ehydration Therapy

In severe dehydration and hypovolemia, after rapid volume restoration, intravenous rehydration therapy (Table 17.6.8) is initiated. If child can drink, he can be started on complete oral rehydration therapy after ensuring that child had passed urine and dehydration is isotonic.

O

S

R N

D

E

lectrolyte isturbances

Common electrolyte disorders in sick children include hyponatremia, hypernatremia, hypokalemia, hyperkalemia, hypocalcemia, and hypomagnesemia.

Hyponatremia Hyponatremia is defined as serum sodium concentration of less than 135 mEq/L. It can occur due to water retention, sodium loss or redistribution of sodium and water. Pseudohyponatremia refers to relatively low serum sodium due to the expansion of plasma volume in hyperglycemia and hyperlipidemia. Serum sodium concentration is decreased by 1.6 mEq/L for every 100 mg/d rise of glucose concentration above 100 mg/d . Hyponatremia is a common occurrence in hospitalized sick children. The common causes in our experience are acute diarrhea, acute infectious disease namely pneumonia, l

R

C

Rapid expansion of intravascular volume is required to restore perfusion. This can be achieved by infusing 20–40 mL/kg 0.9% saline or Ringer’s solution over a one hour period, followed by an additional 20–40 mL/kg if the circulation is not fully restored.

If diarrhea continues after rehydration has been achieved, the ongoing loss can be replaced according to the stool frequency. For a large watery stool in small infants (< 6 months) 50 mL/stool, larger infants (> 6 months) 100 mL/ stool and in older children 200 mL/stool should be replaced with close monitoring of the child.

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apid estoration of ntravascular olume R

R

Laboratory investigations: Blood urea, serum creatinine, serum sodium level and measured osmolality may help in further categorizing the pattern of fluid and electrolyte deficits and to guide the fluid therapy.

eplacement of ngoing Loses and utritional upport







Tachycardia, decreased skin turgor, sunken eyes and fontanel, lethargic or impaired mental status, and oliguria predict a more than 10% weight loss, though their reliability has been questioned. Signs and symptoms of shock are more conspicuous in hypotonic dehydration, while in hypertonic dehydration CNS signs are more prominent.

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Clinical Features

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Hyponatremia is often associated with state of extracellular hypo osmolality and a tendency for water to move into the cells. This movement of water in the brain, which is encased in a rigid cranium, is responsible for the most clinical manifestations of hyponatremia. These features include nausea, difficulty in concentrating, confusion, lethargy, agitation, headache, seizures, and in extreme case brainstem herniation, and death. Hyponatremia can be acute or chronic: Chronic hyponatremia occurs when serum sodium falls slowly over a period of 48 hours. A patient with chronic hyponatremia will be less symptomatic. Acute hyponatremia occurs when serum sodium falls rapidly, in less than 48 hours. The brain does not have the opportunity to adjust to the change, and brainstem herniation may occur.

Dilutional Hyponatremia Hyponatremia can occur in patients with congestive cardiac failure, nephrotic syndrome, or hepatic failure due to greater increase in the body water as compared to sodium content. The total body sodium in these patients is high and urinary sodium is often less than 5 mEq/L; there is relative excess of free water in conjunction with an underlying condition that impairs the ability to excrete free water.

Management of Hyponatremia Treatment of acute symptomatic hyponatremia (with seizures/impaired consciousness) and serum sodium less than 120 mEq/L should be treated with IV infusion of 3% saline, 10 mL/kg at a rate of 1 mL/minute, to correct the sodium deficit by about 5 mEq/L. Rest of the correction should be achieved slowly by administration of saline (0.9% or 0.45%). The deficit may be calculated as follows: Sodium deficit = 0.6 x body weight (kg) x (135 observed serum Na*) Further correction should then proceed at an overall rate no greater than 0.5 mEq/L/hour or 12 mEq/L/day. Rapid correction may result in demyelination syndrome and cerebral pontine myelinolysis. In asymptomatic hyponatremia, sodium deficit is calculated as above but the correction is achieved over a period of 48–72 hours. Management of syndrome of inappropriate antidiuretic hormone secretion: Initial aim is to correct the underlying cause. If serum sodium is below 120 mEq/L or is associated with CNS symptoms, 3% saline should be given along with furosemide (1–2 mg/kg IV). Isotonic saline or N/2 saline should never be given. Since blood volume is already expanded, fluid administration may lead to pulmonary edema and heart failure. Management of cerebral salt-wasting syndrome: Cerebral salt wasting syndrome has volume contraction and hyponatremia in the setting of polyuria and increased urine sodium losses. Treatment with high dose fludrocortisones (0.2–0.4 mg/day) has proven to be beneficial in some patients. Since SIADH and cerebral salt wasting syndrome (CSWS) both can occur in neurological illnesses, it is important to differentiate these two conditions (Table 17.6.9).

-

-

-

CSWS

ow

L

Sodium

L

SIADH

ow

Increased

Decreased

Serum osmolality

< 280 mOsm/

Decreased

Urine osmolality

> 500 mOsm/

Increased

Urine to serum osmolality ratio

>1

>1

Urine Na concentration

L

L

Urine output

L

Body water

ow

Increased

High Increased

Abbreviations: CSWS, Cerebral salt-wasting syndrome; SIADH, Syndrome of inappropriate secretion of antidiuretic hormone.

-



-

 

Table 17.6.9 Difference between syndrome of inappropriate antidiuresis (SIADH) and cerebral salt-wasting syndrome



-

Hyponatremia due to syndrome of inappropriate anti­ diuretic hormone secretion (SIADH) requires fluid restriction to about two thirds of the normal requirement. Furosemide (1–2 mg/kg) may be used in symptomatic patients with SIADH and in dilutional hyponatremia to remove excess water while administering hypertonic saline. The common causes are CNS disorders (infection, trauma, hypoxic ischemic encephalopathy, Guillain Barré syndrome, cerebral malformations, and intracranial hemorrhage), pulmonary infections, cystic fibrosis, abdominal and cardiothoracic surgical procedures. Syndrome of inappropriate antidiuretic hormone secretion has well defined diagnostic criteria and need to be differentiated (Table 17.6.9) from cerebral salt wasting syndrome (CSWS) before initiating management.





Hyponatremia due to Syndrome of Inappropriate Antidiuretic Hormone Secretion

E

This can occur due to excessive salt and water loss from gastrointestinal tract consequent to diarrhea and/or vomiting, or renal losses due to diuretic therapy, less commonly but often dramatically in congenital adrenal hyperplasia, adrenal insufficiency and cerebral salt wasting syndrome. In hyponatremia due to renal losses, urinary sodium is usually more than 20 mEq/L.



Hyponatremia with Dehydration/Hypovolemia

C

-

meningitis and sepsis, heart failure, renal diseases, and hepatic failure. Presence of hyponatremia generally indicates a serious illness and poor outcome.

Hypernatremia Hypernatremia is defined as serum sodium concentration of more than 145 mEq/L. It represents a deficit of water

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Treatment





If the child is in shock or severely dehydrated, he should receive a rapid intravenous infusion of Ringer’s lactate or saline (0.9%) to correct hypovolemia. The next step is to address the underlying cause. In patients with hypernatremia that has developed over a period of hours, rapid correction (1 mEq/L/hour) is safe and improves prognosis. Slow correction is advisable in patients with hypernatremia of longer duration. The targeted fall should be 0.5 mEq/L per hour and 10 mEq/L per day.The goal is to bring serum sodium to 145 mEq/L. Peritoneal dialysis is indicated if serum sodium is 180 mEq/L or more. If child develops convulsions during correction of hypernatremic dehydration, it is usually due to water intoxication. In such cases 3–5 mL/kg of 3% saline or 20% mannitol should be given intravenously to reduce cerebral edema.

Disorders of Potassium Homeostasis

-

-

-

Potassium mainly affects bioelectric processes, including muscle contraction, nerve conduction and myocardial pacing. It can cause muscular weakness, hypotonia, diminished reflexes and paralytic ileus. Cardiac effects include various arrhythmias and ECG changes at serum potassium below 2.5 mEq/L. These include prominent U wave, prolongation of QTc (> 0.425 seconds), T wave inversion and flattening or depression of ST segment, prolonged PR interval, sinoatrial block, and ventricular extra systole. Electrocardiography changes may not correlate with serum potassium level. Long standing hypokalemia decreases the concentrating capacity of kidneys (Hypokalemic nephropathy) Respiratory paralysis may occur in severe hypokalemia. -

Signs of dehydration are minimal in hypernatremia as ECF is relatively preserved, skin turgor is maintained and it may feel rather doughy. Intracellular dehydration and severe hyperosmolality may cause cerebral damage with widespread cerebral hemorrhages, thromboses or subdural effusion. Hence CNS symptoms are very prominent. Child is hyperirritable with high pitched shrill cry. Seizures may also occur. Subsequently, progressive CNS depression may set in, leading to coma, pronounced metabolic acidosis and deep rapid breathing.

Clinical Features

Treatment • •

Identify and treat the underlying cause Oral potassium supplementation (Syp Potklor 15 mL = 20 mEq/L) or IV replacement (Inj KCl 1 mL = 2 mEq). The concentration of potassium in IV fluid should not exceed 60 mEq/L • Rapid correction. Indication: Serum potassium <2.5 mEq/L, symptomatic, ECG changes. Around 100 mL of stock solution is made by adding 90 mL NS with 10 mL KCl. Infusing the stock solution @ 1.5 mL/ kg/hour will deliver 0.33 mEq/kg/hour of potassium. (10% KCl, 1 mL = 2 mEq) under cardiac monitoring. In severe life threatening hypokalemia, the infusion is given with an infusion pump at a rate of 0.35–0.5 mEq/kg/hour till the ECG changes revert back to normal. • Mg repletion if Mg deficiency is present • K+ sparing diuretics can be added. Potassium should be administered only when urinary flow is established.



Clinical Features

gastric aspiration), urinary losses (prolonged use of diuretics, renal tubular acidosis, hyperaldosteronism, steroid therapy) hypomagnesaemia, intracellular K+ shift (alkalosis, therapy with b agonists, insulin, and diabetic ketoacidosis), protein energy malnutrition, therapy with carbenicillin and in critically ill children.

-

t

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with respect to body’s sodium stores and can result from a net water loss (diarrhea, vomiting, diuresis and burns) or excessive sodium intake. It can, therefore, be associated with any state of hydration; dehydration, overhydration or normal hydration. Hypernatremia with dehydration is common with acute diarrheal disease when water loss is more than the electrolyte losses and occasionally in patients with diabetes insipidus. Hyperventilation, fever, and inadequate water intake are other factors contributory to hypernatremia. Sometimes it may be iatrogenic due to excessive replacement of sodium in oral or IV fluids.

Normal values: Preterm up to 48 hours: 3.0–6.0 mEq/L, term newborn: 3.7–5.9 mEq/L, Infant: 4.1–5.3 mEq/L, Child: 3.4– 4.7 mEq/L, Adult: 3.5–4.5 mEq/L. Average potassium concentration in body fluids: Sweat: 4.5 mEq/L, Stool water: 85–95 mEq/L. Potassium concentration falls with increasing stool volume. In severe cholera, stool potassium is <10 mEq/L, stomach: 10 mEq/L, biliary drainage, duodenal and ileal secretions: 5 mEq/L

Hyperkalemia

Hypokalemia

Clinical Features

Hypokalemia is defined as a serum potassium level below

Mild hyperkalemia is often asymptomatic. When severe, the effects are mainly seen on the cardiac and skeletal muscles.

962 4.0 mEq/L. It occurs due to GI losses (vomiting, diarrhea, and

Hyperkalemia is defined as a serum potassium level of more than 5.5 mEq/L. It usually occurs due to impaired renal excretion (oliguria, acute renal failure, adrenal insufficiency, and chronic renal failure), shift or release of K+ into ECF as seen in metabolic acidosis, sepsis, acute hemolysis, acute rhabdomyolysis, and tumor lysis syndrome and tissue necrosis.

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-



-

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Treatment

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l

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l

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Normal range of serum total calcium concentration is 8.5–10.2 mg/d (2.1–2.5 mmol/ ) and ionized calcium is 4.8–7.2 mg/d (1.1–1.8 mmol/ ). Although hypocalcemia is known to cause several signs and symptoms (Table 17.6.11), it is often a laboratory diagnosis because the clinical manifestations are minimal or absent. Sepsis is often associated with hypocalcemia, mild degree of hypocalcemia (ionized calcium > 0.8 mmol/ or 3.2 mg/ ) are usually asymptomatic. Symptomatic ionized hypocalcemia presents with neurological and cardiovascular features. One should treat hypocalcemia if symptomatic or if the ionized calcium concentration is <0.8 mmol/ . The dose is 0.5–1.0 mL/kg of calcium gluconate over 5–10 minutes

C

l

l

Hypomagnesemia and Hypermagnesemia

-

-

Hypocalcemia

t

Magnesium is essential for maintenance of several cellular functions through its role in activation of adenosine triphosphate (ATP). Normal serum Mg++ concentration range between 1.5 mEq/L and 1.9 mEq/L. Hypomagnesemia can develop in a wide variety of clinical conditions such as protein energy malnutrition, malabsorption, hypo albuminemia, sepsis, following prolonged gastrointestinal suctioning, diarrhea, blood transfusion, aminoglycoside therapy, osmotic diuresis, and use of diuretics, etc. Hypomagnesemia is associated with prolonged PR interval, widened QRS complex, ST segment depression and low amplitude T wave on ECG. It may potentiate dysrhythmia due to hypocalcemia and digitalis toxicity. Refractory hypokalemia is a prominent feature of hypomagnesemia. Hypermagnesemia produces tall peaked T waves and narrow QRS complexes.

The treatment modalities are shown below: • Stop oral/IV potassium supplementation • Check the drugs and stop those that can precipitate hyperkalemia • Treat the underlying cause • Hyperkalemia with ECG abnormality is an emergency. Use the measures outlined in Table 17.6.10 for acute reduction in serum potassium • Dialysis is recommended if above measures are unsuccessful. Continuous veno venous hemofiltration (CVVH), hemodialysis, peritoneal dialyses are the different options available in the order of efficacy.

l

Management

-

followed by a continuous infusion 0.1–0.2 mL/kg hour (equal to 0.5–2 mg/kg/hour) over 2–4 hours. Thereafter, rate of elemental calcium should be maintained at a rate of 0.3–0.5 mg/kg/hour. Calcium chloride 10% solution, contains 1.36 mEq/ml or 27 mg/m and calcium gluconate 10% solution, and has 0.45 mEq/m or 9 mg/m .

n ensive are and mergencies

Muscular weakness and paresthesias, shock, bradycardia or cardiac arrhythmias may occur. Early ECG changes include prolonged PR, tall T waves, shortened QT interval and wide QRS complexes of decreased amplitude. In severe cases absent P waves, first degree heart block, sine wave (bizarre QRS complex), ventricular fibrillation and cardiac arrest may occur.

Most patients with symptomatic magnesium depletion and normal renal function have an estimated deficit of 1–2 mEq/kg. About twice the estimated magnesium deficit is replaced at a rate of 1 mEq/kg for the first 24 hours and 0.5 mEq/kg/day for the next 3–5 days.

Fluid Therapy in Special Situations Parenteral fluid therapy may be required in a wide variety of clinical situations to provide normal or adjusted maintenance fluid needs or to replace abnormal deficits as shown in Table 17.6.12.

 

Table 17.6.10 Treatment options for acute reduction in serum potassium Dose

Onset of action

Inj. Calcium gluconate 10%

100 mg/kg/dose (1 m /kg/dose) IV over 5–10 minutes

1–3 minutes

30 minutes

Inj. NaHCO3

1–2 mEq/kg/dose IV over 5–10 minutes

10–30 minutes

2 hours

Glucose + insulin

0.5 g/kg (2 m /kg of 25% D) 0.1 u/kg regular insulin IV over 15–30 minutes

30 minutes

2–4 hours

Nebulized salbutamol

2.5 mg < 25 kg; 5 mg > 25 kg over 10 minutes

Sodium polysteyrene resins*

0.5–1 g/kg orally/rectally

60–120 minutes

4–6 hours

Furosemide (Restricted usage)

1–2 mg/kg IV/IM

15–30 minutes

4–6 hours

L

L

Drug

Duration of action

120 minutes

L

*Sodium polysteyrene sulfonate (SPS) resin: Mix each gram in 3–4 m of water and mix with 10% dextrose and give as retention enema—retained for 15–30 minutes.

 

Table 17.6.11 Signs and symptoms of hypocalcemia





•  Nervous system: Fasciculations, muscle spasm, Chvostek’s and Trousseau’s signs, tetany, seizures •  Pulmonary: Bronchospasm •  Cardiovascular: Arrhythmias, hypertension or hypotension, congestive heart failure •  Gastrointestinal: Dysphagia, abdominal pain, biliary colic

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Table 17.6.12 Clinical situations requiring parenteral fluid therapy

                       

 

 

 

 

 

 

t

 

 

 

 

 

 

 

 

t

•  Maintenance fluids – In a comatose or sick child who is unable to take orally. •  Adjusted maintenance fluids – Oliguria/Anuria – Severe community-acquired pneumonia – Syndrome of inappropriate secretion of ADH – Raised intracranial pressure – Postoperative patient – Cardiac failure – Edema •  Maintenance plus deficit replacement and replenishment of concurrent losses of fluids: – Continuous gastrointestinal fluid losses (vomiting, diarrhea, nasogastric tube drainage and colostomy, etc.) – Burns – Diabetic ketoacidosis – Salicylate intoxication – Pyloric stenosis

L

 

Table 17.6.13 Average electrolyte contents of various GI fluids (mmol/ ) GI fluids

H+

Na+

Cl–

HCO3–

Gastric

80

40

20

150

0

Small bowel

0

130

20

120

30

Pancreatic

0

135

15

100

50

A

liguria and nuria

-

Fluid therapy whether oral or IV should be limited to 300–400 mL/m2 (15–20 mL/kg or 30–40 mL/100 kcal) per day. Urinary water loss can be added to it every 4–6 hours. Non urinary fluid losses are replaced by 10% glucose 964 solution. Electrolytes are given only if these are being lost. Hyperkalemia or hypokalemia can occur and should be

luid verload O

F

treated as discussed above. Patients with acute volume overload may require renal supportive therapy [peritoneal dialysis or continuous renal replacement therapy (CRRT)].

-





-

Fluid overload is common in critically ill children and is thought to contribute to oxygenation failure by increasing extravascular lung water (EVLW). Maintenance fluid calculated by Holliday Segar formula may often overestimate the fluid requirement in acute illness state. Significant decrease in insensible water loss, altered neurohormonal response along with increased fluid administration contributes to fluid overload in this patient population. While timely administration of fluids is lifesaving, positive fluid balance after hemodynamic stabilization is detrimental to organ function and negatively influences important outcomes in critically ill patients. Fluid overload from intensive care unit admission is defined as a percentage equal to [fluid in (L) fluid out (L)/ [ICU admit weight (kg)] x 100. Management: If the child has >10% of cumulative fluid overload, low dose furosemide infusion (0.1–0.4 mg/kg/ hour) can be started for controlled diuresis. If the child remains unresponsive to diuretics and cumulative fluid overload increases beyond 20%, early initiation of renal replacement therapy should be strongly considered. Frequent (6–12 hourly) fluid balance calculation would help to make such decisions at the earliest. Though CRRT is the well studied modality of renal replacement therapy in critically ill children, sustained low efficiency dialysis -

l



Gastrointestinal losses: Losses through nasogastric tube, ileostomy, and pancreatic fistula needs to be replaced volume for volume with a solution containing appropriate electrolytes (Table 17.6.13). Increased intracranial pressure (ICP): Overhydration should be avoided, but fluid restriction as had been advocated in the past may be harmful. Close monitoring is required especially when osmotic diuretic such as mannitol is used. Diabetic ketoacidosis: It is a hyperosmolar state and for all practical purposes most children would have an estimated fluid deficit between 8% and 10%. These patients have moderately low sodium, normal potassium and total body depletion of phosphate. Hypokalemia is a frequent occurrence once insulin therapy is started. If in shock, patient needs fluids not insulin. Give one 20 mL/kg normal saline or Ringer’s lactate boluses in an hour till pulse volume returns to normal. Then give half of estimated deficit + insensible losses + ongoing losses as N/2 saline + 20 mEq/L KCl in the first 8 hours. It is followed up with half of estimated deficit + insensible losses as N/2 saline + 20 mEq/L of KCl for next 16 hours. Glucose is added when blood sugar drops down to 250 mg/d . Accurate and frequent monitoring is essential. O

K+

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Respiratory alkalosis

ow

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A

Anion gap = Na+ – [Cl– + HCO3]. Normal anion gap ranges from 8 mEq/L to 16 mEq/L (12 ± 4) but it is variable in different

PaCO

Compensation

ow

N/low

Fall in paC 2 Acidic urine

High

N/high

Rise in paC 2, Alkaline urine

N/low

High

Acidic urine

N/high

High

Alkaline urine

o

HCO3 L

L

High

alculate the nion ap

o

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–

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Respiratory acidosis

High L

Metabolic alkalosis

ow

Assess pH: High/low – Low pH: pH <7.38: acidemia – High pH: pH >7.42: alkalemia Determine the primary acid base disturbance (Table 17.6.14) Calculate the degree of compensation (Table 17.6.15) Calculate anion gap. –

•

-

 

Metabolic acidosis

pH

C

Identify the Disturbance





Primary disorder

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E

•

Information about patient’s immediate environment– —FiO2, barometric pressure Clinical information, including the history and physical examination with emphasis on patient’s respiratory rate and vital signs, degree of respiratory effort, mental status and state of tissue perfusion Additional lab data: Previous ABG reports, electrolytes, blood sugar, BUN, hemoglobin or hematocrit, chest X ray, pulmonary function tests (if available). -

A

-

•

•

Table 17.6.14 Identification of the primary disturbance

I

Comprehensive History and Clinical Examination

cid-base Physiology

Acid base balance is an essential part of fluid and electrolyte management. Acid is a substance that tends to dissociate or give a hydrogen ion (proton donor) whereas base is a substance that tends to bind or associate a hydrogen ion (proton acceptor). Normal pH of blood is 7.40 (range 7.35–7.45). As a rule of thumb, 1 mm Hg increase in paCO2 decreases pH by 0.01 and 1 mEq/L decrease in HCO3 decreases pH by 0.02. Disturbances in acid base balance can occur due to primary respiratory or metabolic events. In general, if acid base imbalance is predominantly metabolic in nature, changes in pH, HCO3– and paCO2 occur in the same direction (all are reduced or increased and the main alteration is in HCO3–). In contrast if the disturbance is predominantly

ssessment and dentification of the cid-base isorder D

A

D

N

Patients with clinical evidences of poor peripheral perfusion should receive volume expanders (saline, Ringer’s lactate) at a rapid rate. Monitoring of the central venous pressure and acid base values are mandatory to guide the initial therapy. Subsequent fluid and electrolyte therapy depends upon the status of serum electrolytes and complications such as cerebral edema.

n ensive are and mergencies

ear- rowning

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respiratory in origin, changes in HCO3– and arterial paCO2 are opposite to changes in pH and main alteration is in paCO2. The primary and compensatory changes always occur in the same direction.

or peritoneal dialysis can be considered as alternatives in resource limited setting. Early initiation of renal replacement therapy may improve the prognosis in these children.

Examples: 1: pH 7.3, HCO3 14 = Primary metabolic acidosis 2: pH 7.57, HCO3 42, PaCO2 47 = Primary metabolic alkalosis 3: pH 7.57, HCO3 18, PaCO2 18 = Primary respiratory alkalosis 4: pH 7.2, HCO3 28, PaCO2 58 = Primary respiratory acidosis

O

 

Table 17.6.15 Compensatory changes in Paco2 and HC 3 in response to acidosis and alkalosis Primary disorder

Compensatory change

Expected compensation

Metabolic acidosis Fall in HCO3

Fall in PaCO2

∆ PaCO2 = 1.2 x ∆ HCO3

Metabolic alkalosis Rise in HCO3

Rise in PaCO2

∆ PaCO2 = 0.7 x ∆ HCO3

Respiratory acidosis Rise in PaCO2

Rise in HCO3

Acute : ∆ HCO3 = 0.1 x ∆ PaCO2 Chronic : ∆ HCO3 = 0.3 x ∆ PaCO2

Respiratory alkalosis Fall in PaCO2

Fall in HCO3

Acute : ∆ HCO3 = 0.2 x ∆ PaCO2 Chronic : ∆ HCO3 = 0.5 x Δ PaCO2

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fatigue, muscle cramps, lethargy, hyporeflexia, muscular irritability. • evere metabolic alkalosis: (HCO3 > 45–50 mEq/L) arrhythmias, tetany, seizures, delirium, stupor. Child may develop hypoventilation which could result in hypoxemia, difficulty in weaning from ventilator, increased digoxin toxicity, worsening of hepatic encephalopathy.

Metabolic acidosis is a clinical disturbance characterized by decrease in plasma bicarbonate concentration and low PaCO2 resulting from compensatory hyperventilation.

anagement • hloride responsive: Treating the underlying cause is the primary therapy. Correct the hydration status with intravenous 0.9% saline infusion at 10 mL/kg over 10– 30 minutes and if there is coexisting hypokalemia, that needs to be corrected with KCl supplementation. In case of diuretic induced metabolic alkalosis, stop the loop diuretic and it can be replaced by K sparing diuretics. • hloride resistant metabolic alkalosis: Treat the underlying cause and give potassium supplementation or potassium sparing diuretic.

N

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M

auses • ormal anion gap acidosis: Diarrhea, renal tubular acidosis, ureterosigmoidostomy, early stage of acute renal failure. • ncreased anion gap acidosis: Diabetic ketoacidosis, lactic acidosis, inborn errors of metabolism, salicylate poisoning, methanol poisoning, uremia, starvation.

C

F



Metabolic Alkalosis Metabolic alkalosis is defined as HCO3 >28–30 mEq/L, usually with a rise in pH >7.45. F

M



C

linical eatures Symptoms are due to hypokalemia and decreased ionized calcium levels. • Mild metabolic alkalosis (HCO3 < 36) is asymptomatic. • oderate metabolic alkalosis: (HCO3 36–42 mEq/L) can cause paresthesia, weakness, orthostatic hypotension,

F

C

linical eatures Signs and symptoms are related to the degree of hypercapnia. Child develops headache with either irritability or depression due to increase in intracranial pressure (ICP). There is impairment of consciousness varying from drowsiness to deep coma. Muscular tremors can occur. Tachycardia, flushing of skin or perspiration may be present. Blood pressure may be low with signs of shock. Ventricular fibrillations may occur. anagement Treatment is directed at the underlying cause and improvement of alveolar gas exchange by assisted ventilation. Oxygen administration with high flow rates may help to wash out carbon dioxide. If hyperkalemia or ventricular fibrillation develops in a child with acute respiratory acidosis, sodium bicarbonate may be life saving. It should be administered after establishing ventilation. M

E

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In respiratory acidosis there is decreased elimination of carbon dioxide from the body due to poor ventilation, which leads to accumulation of carbon dioxide. Acute respiratory acidosis is characterized by a primary rise in paCO2 above 45 mm Hg that remains at this high value up to 6–12 hours. Sustained elevation of paCO2 beyond 12 hours is defined as chronic respiratory acidosis.

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anagement mergency measures: Prevent further production of H+ by ensuring a proper airway, adequate peripheral perfusion, oxygen delivery • Treat underlying disorder if possible • icarbonate therapy: Intravenous bicarbonate should be used very judiciously if the pH is <7.2 and/or HCO3 ≤5 mEq/L aiming to raise pH to 7.2. NaHCO3 needs to be diluted at 1:1 concentration for IV infusion and the amount of bicarbonate to be given = 0.3 x body weight x base deficit. Disadvantages of NaHCO3 therapy are hyperosmolality, hypernatremia, hypokalemia, decrease in ionized calcium, intracerebral acidosis, shift of oxygen dissociation curve resulting in worsening of tissue hypoxia and worsening of intracellular acidosis. • Hemodialysis or peritoneal dialysis can be done to treat metabolic acidosis if severe or if associated with renal failure (uremic acidosis), or in poisonings.

•

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Respiratory Acidosis

k

C

linical eatures Manifestations of acidosis are related to the degree of acidosis. Worsening acidosis may produce hypotension, lethargy, stupor and progresses to coma. pH <7.2 is associated with increased risk of cardiac arrhythmias. Increased work of breathing ( ussmaul’s breathing) may predispose to superimposed respiratory acidosis. Chronic acidemia results in osteopenia, muscle wasting, and growth retardation.

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laboratories. The patient may have high anion gap metabolic acidosis when the calculated anion gap is more than 16.

Respiratory Alkalosis It usually occurs due to hyperventilation; psychogenic or neurogenic. It may be one of the earliest signs of sepsis. Acute respiratory alkalosis last no longer than 6–12 hours. The compensatory response to this phase involves consumption of HCO3 by body buffers. In the chronic phase renal suppression of H+ ion excretion and chloride retention occurs.

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Table 17.6.16 Recognition of type of disturbance in acid-base balance l

HCO3 (mEq/ ) 21–26

< 21

Combined metabolic acidosis plus respiratory acidosis

Respiratory acidosis

Mixed* metabolic plus respiratory acidosis

35–45

Metabolic acidosis

Normal

Metabolic alkalosis

< 35

Mixed* metabolic acidosis plus respiratory alkalosis

Respiratory alkalosis

Combined respiratory alkalosis plus metabolic alkalosis

C

< 21 > 45

K

F

ey

essages

1. Understanding that the body water compartments and their electrolyte composition is essential for effective fluid management 2. Current clinical evidence supports the use of N/2 saline as maintenance fluid in all acutely ill hospitalized children 3. Clinical conditions that affect the amount of water loss or total caloric expenditure mandate the modification in the quantity of maintenance fluid 4. All children who are on parenteral fluid therapy require frequent Na, and urine output monitoring to titrate parenteral fluid and electrolyte administration 5. Signs and symptoms of shock are more conspicuous in hypotonic dehydration. Neurological signs are more prominent in hypertonic dehydration 6. Symptomatic hyponatremia requires immediate 3% saline administration at 5–10 m /kg targeting the safe margin 120 mEq/l 7. Serum biochemical parameters along with serum and urine osmolality would help to differentiate SIADH, DI and CSWS as the clinical differentiation is often difficult 8. Hypomagnesemia needs to be looked for whenever there is refractory hypokalemia 9. Sodium bicarbonate therapy may not be useful in correcting high anion gap acidosis where correcting the primary cause would correct the acidosis

C

linical eature Usually there is hyperventilation with features of tetany as alkalosis decreases blood levels of ionized calcium.

M

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*pH reflects which mixed disorder is primary and which is secondary because compensation is never complete.

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Treatment Breathing in a closed circuit would cause accumulation of carbon dioxide. The underlying condition should be treated. Sodium bicarbonate therapy is not indicated.

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1. Adler SM, Verbalis JG. Disorders of body water homeostasis in critical illness. Endocrinol Metab Clin N Am. 2006;35(4):873 94. 2. Adrogue HJ, Madias NE. Hypernatremia. New Eng J Med. 2000;342(20):1493 9. 3. Arieff AI, DeFronzo RA. Fluids, electrolytes and acid base disorders second edition, 1995. 4. Emmett M. Anion gap interpretation: the old and the new. Nat Clin Pract Nephrol. 2006;2(1):4 5.

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ibliography



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During intravenous infusion in early resuscitation phase (0–2 hours) pulse rate, blood pressure, capillary refill time and sensorium should be monitored continuously and urine output, hourly. Subsequently recording intake and output, body weight to detect renal compensatory mechanisms or consequences due to fluid excess or deficit are the most important concerns. A chart should be maintained to record the relevant parameters at regular intervals. Clinical parameters should be reviewed at least 6 hourly and laboratory tests every 12–24 hours to adjust intake of water and electrolytes accordingly. The young infant can concentrate urine to about 800 mOsm/ . During parenteral administration of fluids, it is best not to tax the kidneys to concentrate maximally, but provide enough fluids to achieve urine osmolality between 300 mOsm/ and 400 mOsm/ .



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Mixed acid base disturbances are conditions where more than one primary acid disturbance occurs. The four commonly encountered mixed acid base disorders are: (1) respiratory acidosis + metabolic acidosis, (2) respiratory acidosis + metabolic alkalosis, (3) respiratory alkalosis + metabolic acidosis and (4) respiratory alkalosis + metabolic alkalosis (Table 17.6.16). The most serious acid base disorders are of mixed type when respiratory and metabolic disturbances result in a pH change in the same direction.

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Mixed Acid-base Disorders

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12. Singhi S, Marudkar A. Hypokalemia in a pediatric intensive care unit. Indian Pediatr. 1996;33(1):9 14. 13. Singhi S, Prasad SV, Chugh KS. Hyponatremia in sick children: a marker of serious illness. Indian Pediatr. 1994;31(1): 19 25. 14. Singhi S, Singh J, Prasad R. Hypocalcaemia in a paediatric intensive care unit. J Trop Pediatr. 2003;49(5):298 302. 15. Singhi S. Hyponatremia in hospitalized critically ill children: current concepts. Indian J Pediatr. 2004;71(9):803 7. 16. Singhi SC, Singhi PD, Srinivas B, et al. Fluid restriction does not improve the outcome of acute meningitis. Pediatr Infect Dis J. 1995;14(6):495 503. 17. Verbalis JG. Disorders of body water homeostasis. Best Practice and Res Clinical Endocrinol and Metab. 2003;17(4):471 503. 18. Wakil A, Atkin SL. Serum sodium disorders: safe management. Clinical Medicine. 2010;10(1):79 82. 19. Williams AJ. ABC of oxygen: assessing and interpreting arterial blood gases and acid base balance. BMJ. 1998;317(7167):1213 6.







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5. Greenberg A. Hyperkalemia: treatment options. Semin Nephrol. 1998;18(1):46 57. 6. Holliday MA, Segar WE. The maintenance need for water in parenteral fluid therapy. Pediatrics. 1957;19(5):823 32. 7. Jayashree M, Singhi S. Diabetic ketoacidosis: predictors of outcome in a pediatric intensive care unit of a developing country. Pediatr Crit Care Med. 2004;5(5):427 33. 8. Khadra EA. Disorders of the acid base status. Pediatric nephrology in ICU. 2009;19 31. 9. Kurtz I, Nguyen MK. A simple quantitative approach to analyzing the generation of the dysnatremias. Clin Exp Nephrol. 2003;7(2):138 43. 10. Moritz ML, Ayus JC. Intravenous fluid management for the acutely ill child. Currrent Opinion in Pediatrics. 2011;23(2):186 93. 11. Singhi S, Jayashreee M. Free water excess is not the main cause for hyponatremia in critically ill children receiving conventional maintenance fluids. Indian Pediatr. 2009;46(7):577 83.

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This may be broadly classified as: • Controlled mechanical or mandatory ventilation (CMV) • ssist mode: Patient’s effort is assisted by the ventilator • pontaneous mode: Patient is predominantly breathing on his or her own with some support from the ventilator. S

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EE

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MV

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idal volume ( ): This is the volume of gas that flows in and out of the chest during quiet breathing. In adults, the normal tidal volume is 500 mL. In children the tidal volume is 6–10 mL/kg. Frequency/ventilatory rate: The rate that is initially set depends on the indications for ventilation and the physiologic norm for the patient’s age. inute ventilation ( ): This is the product of the tidal volume and the ventilatory rate and is expressed in liters/minute. Peak inspiratory pressure/pressure limit (PIP): This is the highest pressure during the inspiratory period. The peak inspiratory pressure level is usually kept as low as possible since it has been implicated as one of the causes of barotraumas. Positive end-expiratory pressure (P P): It is designed to keep alveoli from collapsing at the end of expiration. The technique is very useful when lungs are

T

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Controlled echanical entilation In this mode, all breaths are initiated, sustained and 969 terminated by the ventilator with the patient taking no V

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• Positive pressure ventilation (PP ): Positive pressure is applied directly to the airway which forces air down the airways and into the lungs. • egative pressure ventilation: Negative pressure applied externally to the chest cage which will change the pressure dynamics so that gas flows from the relatively positive atmosphere to the relatively negative air spaces. Negative pressure ventilators range from tank ventilators (iron lungs) to abdominal and thoracic cuirasses. Although these ventilators are more physiological and avoids many of the complications of endotracheal intubation and PPV, the apparatus is more cumbersome and, access to the patient is limited. Both techniques may be used in pediatric ventilation although PPV is more common by far.

­

Mechanical ventilation may deliver a volume of gas to the patient’s lungs in one of two ways.

stiff and noncompliant and has become the mainstay of treatment of acute respiratory distress syndrome and pulmonary edema. Normal level of PEEP (physiological PEEP) is 3–5 cm H2O. Higher PEEP (10–15 cm H2O or even greater) may be used with caution. Adverse effects of PEEP are ventilator-induced lung injury (VILI), fall in cardiac output, and increased intracranial tension. The optimal PEEP must be a balance between maintaining adequate oxygenation at safe levels of FiO2 while maintaining adequate tissue perfusion. Inspiratory time and I: ratios: The I:E ratio refers to the relationship between inspiratory time (I) and the expiratory time (E). The normal I:E ratio is usually 1:1.5 to 1:2. Adjustment of the inspiratory time is the primary method by which the I:E ratio is altered. FiO2: It stands for fractional inspired oxygen concen tration where 100% oxygen is represented as 1.0, oxygen in room air (21%) as 0.21 and so on. ean airway pressure ( P): It is a measure of average positive pressure generated in the lung throughout the respiratory cycle. It is not a ventilator setting. Mean airway pressure is critical factor in determining both oxygenation and the potential for barotraumas. It is determined by several factors including PIP, PEEP, inspiratory time, ventilator rate and flow rate. Many ventilators have the ability to continuously monitor and display MAP allowing the clinician to see the effects of ventilatory adjustments on this value. ensitivity/trigger: This refers to the ease with which a ventilator can sense the patients demand for a breath and is usually expressed as the amount of negative pressure (pressure trigger) or change in flow (flow trigger) that a patient must create in order for the ventilator to respond. Setting the sensitivity too high may increase the work of breathing (the patient must create a higher intrathoracic negative pressure in order to get assistance from the ventilator). Setting the sensitivity too low may lead to over-triggering and the potential for ventilator-patient dyssynchrony. E

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ssisted entilation V

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Ventilation may be defined as the movement of air in and out of the lungs. Respiration is defined as the process of gas exchange within the lungs (external) or at the tissue level (internal). It may be spontaneous (patient breathing for himself) or assisted. Assisted ventilation involves an external device connected directly to the patient which provides the movement of air in and out of the lung. This device may be a resuscitation bag or a mechanical ventilator.

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Intens ve Care and mergen es

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Pressure support ventilation (PSV): – Here all the patients sensed ventilatory efforts are supported (“boosted”) by the ventilator to various degrees determined by the operator (Table 21.6.1). The patient’s spontaneous inspiratory effort is sensed and gas flows until a preset pressure is reached which is actively sustained until the end of inspiration. – The patient controls the breathing rate and the inspiratory and expiratory times, i.e. (I-time and E-time) – Pressure support ventilation has been shown to decrease inspiratory work, abolish diaphragmatic fatigue and has emerged as an important weaning mode, both as a stand-alone mode or in conjunction with synchronized intermittent mandatory ventilation (SIMV). – Weaning is facilitated since the level of pressure support may be adjusted from full to partial to none in a gradual fashion. Continuous positive airway pressure (CPAP): – Continuous positive airway pressure is usually defined as positive pressure maintained in the airways throughout the respiratory cycle during spontaneous respiration. – Technical considerations of continuous positive airway pressure: Many devices have been developed to deliver CPAP. All work on the same principle, using a continuous gas flow, a reservoir bag, a valve to maintain positive pressure above atmospheric pressure and a humidification device (Fig. 21.6.1). Continuous positive airway pressure is most commonly applied to the patient’s airways via an endotracheal tube. Other modes of application include face mask, nasal prongs or nasopharyngeal tube. – Indications and applications of continuous positive airway pressure: The primary indications are in acute lung injury, e.g. ARDS and HMD. Other conditions in which CPAP is useful include apnea, tracheobronchomalacia and weaning from mechanical ventilation.

•

Whenever mechanical ventilation is initiated, the caregiver has to undertake a tremendous responsibility since the potential for disastrous consequences of this life support technique is enormous. Close monitoring of the patient’s condition is therefore essential. • utrition: A ventilated child with an endotracheal tube cannot be given direct oral feeds, since the tube interferes with normal swallowing. However, the majority of ventilated children may be fed enterally via a nasogastric tube. The few patients in whom enteral feeding is not possible because of ileus or abdominal pathology should receive parenteral nutrition. Whichever the route chosen,

•

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ssisted-control ventilation: This is essentially identical to the respective controlled modes except that the patient plays a significant role in initiating the breath. The patient performs only the triggering work, while the ventilator completes the remaining limiting and cycling work. Intermittent mandatory ventilation: Intermittent mandatory ventilation was developed as a method of partial ventilatory support to facilitate “liberation” from mechanical ventilation. – In this mode, the patient can breathe spontaneously while also receiving mandatory breaths. As the patient’s respiratory function improves, the number of mandatory machine breaths may be decreased, until the patient is breathing unassisted on CPAP. For the spontaneous breaths, the ventilator simply acts as a source of humidified gas flow. Unfortunately, there are two problems with this system: (1) it is possible for the patient and the ventilator to inspire in series, thus “stacking” one breath on top of another, leading to high airway pressures; (2) The workload of spontaneous breaths remained quite high—remember that the patient still has to inspire without assistance through an endotracheal tube and ventilator circuit—a difficult prospect with normal lungs, a serious burden with an acute lung injury. A variation of this mode, (Synchronized IMV = SIMV) allows the mechanical breaths to be given on patient demand. The issue of stacking breathes is solved by an inbuilt sensor that synchronizes the patient’s spontaneous breaths up to the set rate. However, most infant ventilators deliver IMV, not SIMV as developing appropriate sensitivity and rapid response times to an infant’s efforts is technically more difficult. The problem of the excessive effort of the spontaneous efforts was solved by introducing an assisted spontaneous breathing mode—“Pressure support (PS)” ventilation. Pressure support is described in more detail in the following section.

The combination of SIMV-PS remains a popular weaning mode in pediatrics.

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active role in the ventilatory cycle. In general, this mode is reserved for patients who have insufficient/absent ventilatory drive (either from the disease process or iatrogenically due to sedative and/or paralytic agents). • Controlled mechanical ventilation may be volume controlled where a preset tidal volume is delivered during a set inspiratory time at a set frequency and constant flow irrespective of the peak pressure generated. Here volume is guaranteed but pressure is variable depending on the lung mechanics. In pressure-controlled or pressure-limited time cycled CMV; the ventilator delivers a positive pressure up to a PIP above PEEP during a preset inspiratory time at a set frequency. Here, while the clinician has guarantee over the preset pressure, delivered volumes may be variable and depend on the mechanics of the patients lungs, airways and ventilator circuit.

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Tracheal mucosal damage Sinusitis/middle ear infection (nasal ET tubes) Laryngeal edema, subglottic stenosis.

Nosocomial Infections • •

Ventilator-associated pneumonias Ventilator-associated tracheoabronchitis.

Mechanical Operational Problems • • •

Mechanical failure Alarm failure Inadequate humidification.







1. Esteban E, Frutos F, Tobin MJ, et al. A comparison of four methods of weaning patients from mechanical ventilation. Spanish Lung Failure Collaborative Group. N Engl J Med. 1995;15;332(6):345-50. 2. Heffner JE. Airway management in the critically ill patient. Crit Care Clin. 1990;6(3):533-50. 3. Heulitt MJ, Wolf GK, Arnold JH. Mechanical ventilation. In: David G Nichols (Ed). Rogers Textbook of Pediatric Intensive Care, 4th edition. Philadelphia, PA: Lippincott, Williams and Wilkins; 2008.pp.508-31. 4. Martin LD, Bratton SL, Walker LK. Principles and practice of respiratory support and mechanical ventilation. In: Rogers Textbook of Pediatric Intensive Care, 3rd edition. Baltimore: William and Wilkins; Baltimore; 1996.p.265.



Bibliography

V

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Causes of eterioration in entilated Patients Acute Deterioration • D—Displaced tube in esophagus, or slipped down in right main bronchus • O—Obstructed tube

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Related to Endotracheal/Tracheostomy Tube



A

Related to Increased Airway Pressures and Lung Volume • entilator-induced lung injury: Ventilator-induced lung injury may be multifactorial ranging from barotrauma, volutrauma, atelectrauma and biotrauma. End results may be in the form of pulmonary interstitial pneumonia, pneumothorax, pneumopericardium, peneumoperitoneum, subcutaneous emphysema. • Pulmonary parenchymal damage, chronic lung disease. • Decreased cardiac filling and poor perfusion. • Other organ dysfunction, renal, hepatic, CNS.



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Numerous complications may contribute to patient morbidity and mortality.

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Laboratory Investigations rterial blood gas: Within 20–30 minutes of initiating ventilation, after altering ventilatory settings, and every 4–6 hours thereafter, unless there is a marked change in condition. Chronic patients need gases infrequently, generally in the event of change in condition. The goal should be to maintain PaO2 60–90 mm Hg, PCO2 35–45 mm Hg, pH 7.35–7.45. These goals may vary depending on the disease state (e.g. ARDS, intracranial hypertension, chronic respiratory disease). Others: Complete blood counts, electrolytes, and renal function tests daily, culture of lower respiratory tract secretions when ventilator-associated pneumonia is suspected.

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Complications of ssisted entilation

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Gradual Deterioration • Partial tube occlusion • Sepsis, pneumonia • Myocardial dysfunction, pulmonary edema • Biochemical-glucose, electrolyte disturbances, metabolic alkalosis.

onitoring of the entilated Patient

Clinical assessment may provide valuable information: • Assess frequency and strength of spontaneous breathing • Synchronization with the ventilator • Chest wall excursion and frequency of air entry/exit • Circulation: Pulse, BP, systemic perfusion • Abdominal distension, feed tolerance • Neurobehavioral activity • Readiness for weaning. Radiological assessment: Radiographs should be done at least once daily in the acute phase and whenever acute deterioration occurs. The following should be looked for: • Position of ET tube and nasogastric tube • Overall lung volume, evidence of hyperinflation • Air leak syndromes: Interstitial emphysema, pneumothorax, etc. • Presence of atelectasis, pneumonia, pulmonary edema • Heart size.

P—Pneumothorax, pneumopericardium E—Equipment failure, disconnection.

Intens ve Care and mergen es

an attempt to meet calorie and protein requirements must be made, however, excessive carbohydrates should be avoided as it may result in increased CO2 production. • Indications for sedation: Intubation and ventilation are uncomfortable, painful and fear provoking and most patients receiving this therapy will require some form of sedation. The current trend is to avoid muscle relaxants as far as possible. Prior to the use of medications to sedate the patient, it should be ensured that the ET tube is patent, in good position and well-secured and the ventilator settings are appropriate and no complications (see following section) have occurred.

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Monitoring in the Pediatric ntensive are Unit Bala Ramachandran

Monitoring is an integral part of intensive care, not only to follow the progress of the patient, but also to detect deterioration early so that appropriate interventions can be instituted. Despite the availability of a variety of technological measures, the most important “monitor” continues to be a vigilant bedside nurse and physician. Broadly speaking, monitoring can be invasive or noninvasive. The various systems that are commonly monitored include the cardiovascular, respiratory and neurological systems.

I

nvasive Monitoring

Invasive hemodynamic monitoring is one of the mainstays of therapy in the PICU. It is used for diagnosis, surveillance and titrating response. It is especially important in patients who are hemodynamically unstable because invasive pressures have been shown to be higher than non-invasive and invasive measurement allows continuous measurement, thereby allowing early detection of deterioration. The basic principle is that a catheter is inserted into a vessel and connected via a fluid filled non-compliant tubing system to a pressure transducer



CO

E

n U

This is one of the most important modalities of monitoring in the PICU. It uses a probe placed on the skin to measure the percentage of oxyhemoglobin. Pulse oximetry is invaluable in the care of seriously ill children. However, the user should be aware of its shortcomings. It may be inaccurate in patients with poor peripheral perfusion, such as hypotension or shock. Extremity movement, ambient light and abnormal hemoglobins, like carboxyhemoglobin, also alters it.

xhaled

2

Monitoring

This uses a sensor to measure the CO2 in the exhaled gas and displays it either as a number (capnometry) or graphically (capnography). In addition to the numerical value, the shape of the waveform gives useful information about the pulmonary status. Exhaled CO2 monitoring is extremely useful in that, as it can be used in conjunction with pulse oximetry, to non-invasively monitor both oxygenation and ventilation. This enables the number of blood gases required to be minimized, thereby reducing the cost of care.

Neurological Monitoring Various techniques are available to monitor the neurological status in the PICU. These include intracranial pressure (ICP), EEG, and bispectral index (BIS). Intracranial pressure monitoring is used in patients with head injuries and other conditions with elevated ICP. Various methods are available to monitor ICP. Most commonly, this is done with a fiberoptic intraparenchymal monitor. Alternatively, an intraventricular catheter connected to a

IB

B

O

Pulse ximetry

V d

ti e

This uses an oscillometric technique to measure the blood pressure. Care must be taken to ensure that the correct size cuff is used. In addition, the measurement may not be accurate in patients with shock.

G R



Most often, a multiparameter monitor is used to monitor the ECG, respiratory rate, pulse oximetry and non-invasive blood pressure. In addition, various options, such as invasive pressure, exhaled CO2, and temperature, are available. The important factors in selection of a particular monitor include the parameters, cost, durability, availability and cost of spare parts and after sales service.

Non-invasive lood Pressure (N P)

that converts the pressure into electrical signals, which are processed and displayed on the monitor. In addition to the actual pressure, valuable information can be obtained from the waveforms. One must be aware of the various factors that can affect the measurement. These include the position of the catheter, the presence of clots or air bubbles, and improper calibration or zeroing of the transducer. Invasive monitoring is used most often to measure the arterial blood pressure. The catheter is commonly inserted into either a peripheral or the femoral artery. Catheters should not be inserted into end arteries, like the brachial artery, since a thrombus can lead to limb loss. The same assembly is used to measure the central venous pressure. For this purpose, a catheter is inserted into a central vein, with its tip being positioned inside the thorax. The CVP is used for hemodynamic purposes. Again, the user should be aware of the various factors that can affect the CVP. A similar setup is used to non-invasively monitor the intra-abdominal pressure via an indwelling urinary catheter, allowing early detection of intra-abdominal hypertension. A variety of newer techniques, such as PiCCO® and LiDCO™, are available. These use proprietary algorithms to measure and calculate various hemodynamic parameters, like cardiac output, systemic vascular resistance, etc. Another system, called Pedia Sat, continuously measures the central venous oxygen saturation via a special CVC.

C

asic ntensive are Unit Monitoring I

B



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1. Evan JM, et al. Principles of invasive monitoring. In: Zimmerman J, Fuhrman B (Eds). Pediatric Critical Care., 3rd edition. Philadelphia: Mosby Inc. 2004. pp.251-64. 2. Khilnani P, Irazzuta J. Monitoring in pediatric intensive care unit. In: Khilnani P (Ed). A Practical Approach to Paediatric Intensive Care. New Delhi: Jaypee Brothers Medical Publishers; 2004.pp. 45-53.



Both the multiparameter monitor and the ventilator provide basic monitoring of the respiratory rate. Most modern ventilators now allow monitoring of pulmonary graphics. A

ibliography

erge cies

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ther Methods of Monitoring

The use of bedside echocardiography is rapidly gaining acceptance. The initial learning curve is steep but, once trained, the technique allows rapid, repeated, assessment of cardiac dysfunction, fluid accumulation in various serous cavities and pneumothorax.

espiratory Monitoring

G R

V d

ti e

n U

Int

detailed discussion of this topic is beyond the scope of this chapter.

e sive are a d

transducer assembly can measure the ICP. This system has the advantage of allowing drainage of CSF and therefore has a therapeutic role as well. Many patients in the PICU are admitted with seizures. In these, EEG monitoring is very useful since it allows immediate detection of seizure activity, especially non-convulsive status epilepticus. The incorporation of a video camera allows continuous recording, so that abnormal movements often confused with seizures can be differentiated from true seizure activity. Other forms of neurological monitoring include BIS (bispectral index), which measures the state of wakefulness with a forehead electrode, and cerebral function monitoring.

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Neurocritical are Soonu Udani



n U

Table 17.9.2 Localization by respiratory pattern  

Airway management is of paramount importance in comatose children as their protective reflexes are obtunded and they are more prone to aspiration. Even without direct trauma to the airway or respiratory system, disorders of breathing (Table 17.9.2) commonly accompany serious brain disorders. Abnormalities in respiratory rate and

G R

V d

ti e

A

A

ssessing Life-threatening irway Problems

breathing pattern may indicate pathology that originates in the lungs, acidosis or nervous system dysfunction. Hypoxia and specifically a PaO2 <60 mm Hg are associated with reflex vasodilatation and increased cerebral blood flow, which will increase intracranial pressure (ICP). Hence airway should be protected and adequate oxygenation should be ensured at the first suspicion of need. Indications for tracheal intubation are given in Table 17.9.3. Rapid sequence intubation (RSI) should be performed in comatose children with due attention to cervical spine stabilization (jaw thrust not head up-chin lift). Thiopental or propofol can be used as inducing agents as they have a cerebroprotective effect, with a rapid uptake and rapid washout. Fluid loading needs to be exercised with caution if there is poor perfusion or hypotension. Midazolam with Fentanyl is a useful alternative especially in hypotensive patients. For paralysis, a nondepolarizing neuromuscular blocking agent (NMBA) like rocuronium (0.6–1.2 mg/ kg) should be used. Lignocaine (1–2 mg/kg) should be administered 2–5 minutes before laryngoscopy. Correctly done, this is the safest method to prevent a surge in ICP and catecholamines during intubation. Assisted ventilation to maintain normoxia and normocarbia is then required along with continued sedation in such patients.

Children with neurological problems account for 25–35% of admissions to pediatric intensive care units (PICUs). The most common reason for hospitalization for an acute neurological problem is an altered level of consciousness or coma. The potential causes of coma are numerous and central nervous system infections are the most common in children with non-traumatic coma. Regardless of the etiology, initial management of the comatose child involves immediate attention to sustain life and prevent secondary brain injury from hypoxia, hypercarbia, hypotension and other insults. Table 17.9.1 gives a broad outline of the overall management and general care. Neuromuscular diseases will have issues mainly of ventilation where sensorium may be reasonably intact. Coma is a state of altered consciousness with loss of both wakefulness and awareness of self and surroundings characterized by a state of sustained, pathologic, unarousability, unresponsiveness and absence of sleep wake cycles, which must last for at least 1 hour.

Cheyne stokes

Bilateral cerebral hemispheres with intact brainstem, midbrain, upper pons. Metabolic (uremia, hypoxia, hypertensive)

Neurogenic hyperventilation Midbrain, pons, raised ICP, acidosis, hypoxia

•  Airway, breathing, and circulation assessment and stabilization

Apneustic

Mid or caudal pons, pontine infarction

•  Assessment of depth coma: GCS score

Cluster breathing

Low pons/high medulla

•  Identify and treat critical elevations in intracranial pressure

Ataxic breathing

Medulla, pontine/cerebellar hemorrhage

•  Blood pressure management depends on considerations regarding underlying coma etiology

Table 17.9.3 Indications for tracheal intubation

•  Initial investigations

•  Loss of pharyngeal reflexes—risk of aspiration

•  Neurologic assessment

•  Apnea

•  Empirical anti-infective therapy if indicated (discussed elsewhere)

•  Cervical spine injury

•  Give specific antidotes if toxic exposures are known (discussed elsewhere)

•  GCS < 10

•  Imaging

•  Anisocoria

•  Seizure control

•  Hypercarbia PaCO2 > 45 mm Hg





 

Table 17.9.1 Steps needed in the initial management

 

t

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Tex book of Pedia rics

17.9

•  Decrease in GCS by > 2 irrespective of previous GCS

•  Hypoventilation from neuromuscular disease

•  Nursing care

•  Need to control ventilation—even when the patient is hyperventilating—PaC 2 < 25 mm Hg

974

•  Further investigations and monitoring

o



•  Detailed history and examination

vip.persianss.ir

A drop in mean arterial pressure (MAP) will drop the cerebral perfusion pressure (CPP) and lead to secondary brain injury. CPP = MAP–ICP is an important equation that needs to be remembered while dealing with a child with serious cerebral dysfunction. Hence most therapies are focused on preventing rises in ICP and keeping MAP normal or high normal so that CPP stays in the range of 40 mm Hg in infants, 45–50 mm Hg in children, and >50 mm Hg in 12 years and above.

Int C E

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ti e

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n

Provide uniform ventilation with adequate and fixed tidal volume so as to have the least fluctuations in arterial carbon dioxide levels • PaO2 >60 mm Hg • PaCO2 32–36 mm Hg • Peak inspiratory pressure below 8 cm H2O as far as possible • Central neurogenic hyperventilation may need to be overcomed by sedation and paralysis to prevent the vasoconstricting effects of hypocapnia • Endotracheal suctioning is done only when required and should be preceded by lignocaine 1–2 mg/kg IV. 2 minutes prior to suction. The readers are directed to Chapter 6 (Neurology) for the detailed discussion on management of raised ICP. Unlike a comatose child, the child with neuromuscular illness (e.g. Guillain-Barré syndrome, Myasthenia gravis) will be awake after the initial period of adjustment. The chest wall has poor tone and is very compliant and VT needs to

V d

I

R

This is the primary task performed when a child is first seen. A precise record of repeated examinations and assessments is essential. For consistence and interobserver accuracy, the Glasgow coma scale with its pediatric modification is used (Table 17.9.4).

It is a fair assumption that any deeply comatose patient from whatever causes (Table 17.9.5) should be treated as having raised intracranial pressure ICP until proven otherwise. Table 17.9.6 outlines the initial measures to reduce ICP.

R

I

•

C

A



V

Principles of entilation in aised ntracranial Pressure

ssessing the Level of onsciousness

aised ntracranial Pressure

n

irculation



Common error: Deep coma, so no sedation required; Correct—all patients require proper RSI

n

n

C

Cerebral edema may cause herniation syndromes (Table 17.9.7) which often herald deterioration and death unless ICP is lowered rapidly by medical or surgical means. Initial and immediate management of critically raised ICP includes IV hyperosmolar therapy (mannitol or 3% saline) and temporary hyperventilation to achieve a PaCO2 of 32–36 mm Hg. Excessive or prolonged hyperventilation may compromise cerebral perfusion, resulting in further hypoxic-ischemic injury.

e sive are a d merge cies

[ ondepolarizing neuromuscular blocking agents should never be used in neuromuscular diseases— myasthenia, Guillain-Barré syndrome (GBS), snake bite]

 

Table 17.9.4 Level of consciousness—Glasgow coma scale: pediatric modification Eye opening

Spontaneous

Spontaneous

4

To sound

3

To pain

2

None

1

Age-appropriate verbalization, orients to sound, fixes and follows, social smile

5

Cries, but consolable

4

Disoriented

Irritable, uncooperative, aware of environment

3

Inappropriate words

Irritable, persistent cries, inconsistently consolable

Incomprehensible sounds

Inconsolable crying, unaware of environment or parents, restless, agitated

2

None

None

1

Obeys commands

Obeys commands, spontaneous movement

6

Localizes pain

Localizes pain

5

Withdraws

Withdraws

4

Abnormal flexion to pain

Abnormal flexion to pain

3

Abnormal extension

Abnormal extension

2

None

None

1

To command To pain None Verbal response

Oriented Confused

Motor response

Best total score Usually a score of less than 12 corresponds to “coma”. Children less than 2 years of age should receive full verbal score for crying after stimulation.

15

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Uncal

t

 

Table 17.9.7 Herniation syndromes

•  Intracranial hemorrhage

Unilateral fixed dilated pupil



 

Tex book of Pedia rics

Table 17.9.5 Causes of increased intracranial pressure in coma

Unilateral ptosis



•  Space-occupying lesions •  Diffuse axonal injury in trauma

Minimal deviation of eyes on oculocephalic/ oculovestibular testing

•  Edema of infarction or contusion

Hemiparesis





•  Infection/inflammation and resulting edema

Diencephalic

Small or midpoint pupils reactive to light

•  Post-hypoxic-ischemic (Post CPR, near drowning, inhalation injury)

Flexor response to pain and/or decorticate posturing





•  Hydrocephalus

Full deviation of eyes on oculocephalic/ oculovestibular testing



t





•  Hypertensive encephalopathy with posterior reversible edema syndrome (PRES)



Hypertonia and/or hyper-reflexia with extensor plantars

Table 17.9.6 Initial measures to reduce intracranial pressure

Cheyne-Stokes respiration



 

Midpoint pupils, fixed to light



Upper pontine

•  Maintain normoxia (> 60 mm Hg) and normocarbia (32–36 mm Hg)



Extensor response to pain and/or decerebrate posturing



•  Give normal maintenance isotonic IV fluids

Hyperventilation





•  Maintain normal blood sugar and serum electrolytes

Lower pontine





•  Osmotic diuretics like mannitol (0.5–1 g/kg intravenously), or hypertonic saline 3% (5 mL/kg loading then 0.1–1 mL/kg/hour on a sliding scale) 









V d

•  Use controlled hyperventilation if clinical signs of impending herniation appears

S

eizures

n U

eneral are C

G



Seizures are common, be it trauma, febrile, nonfebrile, metabolic coma or febrile status. Around 12–25% of these may have obvious convulsive seizures and the rate of subclinical or non-convulsive seizures or status epilepticus (NCSE) may be as high as 33–53% in some studies. These are detrimental in terms of brain metabolism and need urgent treatment and can only be diagnosed by monitoring EEG. In severe traumatic brain injury, prophylactic anticonvulsant therapy with phenytoin may be considered to reduce the incidence of early post-traumatic seizures. Status epilepticus management protocol recommended by the IAP Expert committee on Pediatric Epilepsy, Indian Academy of Pediatrics 2006 is given in Table 17.9.8.

All neurocritically ill children should be cared in extremely controlled and well-monitored conditions. Gentle handling





Medullary



ti e

be adequate to maintain splinting and prevent atelectasis. Neuromuscular blocking agents must never be used in them as the weakness will be potentiated. Sedation and analgesia must be tailored to the level of anxiety and adaptability of the child and parents. Family interaction must be kept to a maximum.

Minimal deviation of eyes on oculocephalic/ oculovestibular testing

G R



•  Minimize stimulation (suctioning and movement)





Midbrain

•  Elevate head end of the bed not more than 30°



•  Place head and neck in midline

Midpoint pupils, fixed to light No response on oculocephalic/oculovestibular testing No response to pain or flexion of legs only Flaccidity with extensor plantars Shallow or ataxic respiration Pupils dilated and fixed to light Slow, irregular, or gasping respiration Respiratory arrest with adequate cardiac output

and good protocolized nursing care is crucial. Following measures should be implemented: • Around 300° head up unless shock contraindicates • Hourly pupil and GCS check and recording • Eye care with lubricant and closure to prevent exposure keratitis • Feeding at intervals to prevent hunger, gastric ulceration • Bladder and bowel care with soft stools to prevent pain and constipation • Suctioning with premedication with intravenous and endotracheal lignocaine • Prevention and prompt treatment of fever • Prompt recognition of seizures to further prevent rises in ICP • Bed sore and other pain check as pain can cause discomfort and raise ICP • Watching for development of autonomic dysfunction: sweating, tachy/bradycardia, swings in BP and temperature (in spinal injury, GBS, status epilepticus) • Deep vein thrombosis prevention in older, heavier children • Steroids have no role in traumazor pyogenic meningitis.

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IV Lorazepam 0.1 mg/kg or IV Diazepam 0.2 mg/kg followed by IV phenytoin/fosphenytoin (PR DZP 0.5 mg/kg/IM MDZ 0.2 mg/kg if no IV access) Repeat LRZ/DZP once more SOS (5–10 minutes)

•  Core temperature > 35°C

IV Fosphenytoin 20 PE/kg/phenytoin 20 mg/kg (30 minutes)

•  Apnea (complete absence of documented respiratory effort at PaCO2 > 60 mm Hg

 

Table 17.9.9 Criteria for brain death

e sive are a d merge cies n

 

Table 17.9.8 Protocol for management of status epilepticus



•  Absence of reversible conditions causing coma (Hypo or hypernatremia, hypoglycemia, depressant drugs, etc.)



C



•  Flaccid tone and absence of spontaneous or induced movements

IV Valproate 1: 1diluted NS 20–40 mg/kg over 1–5 minutes or IV Phenobarbital 15–20 mg/kg (45–60 minutes) (Reassess airway again; consider tracheal intubation if the airway is compromised or the patient develops respiratory depression) Transfer to a PICU set-up as now the child has refractory SE and will need intensive/aggressive monitoring in a tertiary PICU set up.

n

K



­















1. Edwards P, Arango M, Balica L, et al. Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid in adults with head injury-outcomes at 6 months. 2005;365(9475):1957-9. 2. Nicholas S, Abend NS, Kessler SK, Helfaer MA, Licht DJ. Chapter 53: Evaluation of the Comatose Child. In: David NG (Ed). Roger’s Textbook of Pediatric Intensive Care, 4th Eedition. Lippincott: Williams and and Wilkins Publishers; 2008.pp. 846-61. 3. Parent S, Mac-Thiong Jean-Marc, Roy-Beaudry M, et al. Spinal cord injury in the pediatric population: a systematic review of the literature. J Neurotrauma. 2011;28(8):1515-24. 4. Pearson-Shaver AL, Mehta R. Chpt 54 Coma and altered sensorium. In: Fuhrman BP, Zimmerman J(Eds). Pediatric Critical Care., 3rd edition. Mosby Elsevier Publishers; 2006.pp.855-65. 5. Wong CP, Forsyth RJ, Kelly TP, et al. Incidence, aetiology, and outcome of non-traumatic coma: a population based study. Arch Dis Child. 2001;84(3):193-9.



ibliography



B







I

F

Prognosis



essages

• A GCS in children of <12 should be treated as raised ICP until proven otherwise • Spinal tap should be deferred until the patient is stable • ABCs should be a priority at all times: Hypoxia, hypercarbia and hypotension alone or in combination have devastating effects causing secondary brain injury • Isotonic maintenance fluids with glucose check at pre sentation • Fever, pain, seizures also contribute to secondary brain injury • Stepwise management of ICP is crucial to outcome • Appropriate investigations and treatment as per etiology

irst-line nvestigations

Brain Death Criteria It often falls upon the intensivist to declare death and deal with the bereaved family. No ambiguity should exist in thought or speech when this announcement is made to the family of a child on life support. There is no turning back once this declaration is made (Table 17.9.9). These guidelines may vary slightly but remain the same in principle.

ey

M

•  All of the above are repeated after 24 hours

Abbreviations: LRZ, Lorazepam; DZP, Diazepam; MDZ, Midazolam.

In dealing with emergencies, it is best to leave prognostication for a later date and only deal with the condition of the child as it is seen, while explaining that things change from hour to hour for the first few days.

E

•  Isoelectric electroencephalogram

Midazolam infusion (loading dose of 0.2 mg/kg followed by 0.1 mg/ kg/hour titrate every 15 minutes upwards by 0.05 mg/kg/hour till control; maximum dose not clear though up to 1 mg/kg/hour reasonably safe) Propofol infusion or Pentothal infusion (Affordability, availability, monitoring facilities crucial in decision) General anesthesia if maximum doses of midazolam/propofol/pentothal have not worked.

Lumbar puncture is performed in every febrile patient with coma unless contraindicated. The contraindications include clinical features of raised ICP, focal signs, thrombocytopenia, local infection and shock. CT scan should be performed in all children with coma except those with a known cause of coma such as hypoglycemia and postictal state. CT head is abnormal in approximately 50% of cases and initial normal CT scan does not rule out an evolving lesion or raised intracranial pressure.

n



•  Loss of all brainstem reflexes including mid position or fully dilated non-reacting pupils, no gag, cough or sucking reflex, absent corneal and oculovestibular reflexes

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Transport of ritically ll hild Praveen Khilnani Table 17.10.1 Essential components of a successful critical care transport program

Goals of Transport

•  Institutional endorsement and financial support for round the clock services











Following four are essential goals of transporting a sick child: 1. To reach the referring facility as quickly as possible with trained personnel and equipment. 2. To stabilize the patient’s condition preventing further deterioration. 3. To move the patient to a facility capable of providing more extensive care or additional services that will enhance patient outcome. 4. To continue to deliver critical care equal to the receiving tertiary care facility while recognizing the limitations inherent in traveling. Essential components of a successful transport system are listed in Table 17.10.1.



•  Dedicated team proficient at providing neonatal and/or pediatric critical care during transport 

•  Sufficient volume of critically ill and injured patients to enable team to maintain skills and expertise •  Communications/dispatch capabilities •  Prospectively written clinical and operational guidelines •  Quality and performance improvement activities

Transport team: Equipment and personnel. Essential and desirable equipment is listed in Table 17.10.2. Team composition depends on the patient’s needs: Dedicated pool of qualified doctors, nurses, paramedics and/or respiratory therapists are required. A team member’s degree is less important than his or her ability to provide the level of care required considering critical care during transport conditions is significantly different from an ICU or emergency department setting. Physician versus nonphysician transport team: Many dedicated teams include a physician: There is little published evidence that this configuration results in improved outcome compared with non physician teams.

Qualifications and Training

–

–

–

• Team leader qualifications: – Educational and experiential background – Clinical and technical competence – Leadership skills – Critical thinking skills – Communication and interpersonal skills – Appreciation of public and community relations • esirable qualifications of transporting personnel: – The transporting physician should ideally have received training in intensive care and transport medicine, pediatric advanced life support (PALS)/ neonatal resuscitation program (NRP) certification as applicable. – In addition, involvement in previous critical care transports and at least 2 years of experience in anesthesia, intensive care or other equivalent specialty is desirable. – Proficiency in performing essential procedures such as Bag mask ventilation, Intravenous access/Intraos­ seous infusion, intubation, mechanical ventilation, chest tube insertion.



-

– –



The former one is more frequently used. Both have their own relative benefits and shortcomings, however either can be used. Safety of the patient and team must always be the over riding factor in the initial transport mode determination. Optimal mode would depend upon nature of illness and urgency of the transport. Evaluation of the current patient status and care required before and during transport is essential. In addition logistics 978 such as local resources, availability for transport, weather considerations, and ground traffic accessibility and cost involved are also important.

–





Two modes are commonly used: 1. Road/ground/surface ambulance 2. Air (helicopter/fixed wing aircraft).

D

–

Mode of Transport

–

–

-

I S



I

ntrahospital: Transport of a patient from one location to another within the hospital, e.g. Transporting a sick patient for imaging like CT scan/MRI/operating room 2. nterhospital: Transport of a patient between hospitals. 3. cene run: Transport of a patient from a non medical site to the nearest available or designated hospital.

•  Ground and/or air ambulance capabilities

-

Types of Transport 1.

 

Initial resuscitation and stabilization of a critically ill child and continued care during the transport are very important determinants of outcome. Majority of emergency phy­ sicians have no pediatric training and most transports aim at shifting the child as soon as possible to the nearby tertiary center, rather than providing the initial care. Most transports are being performed by private vehicles, autos, taxis due to nonavailability of basic ambulances owing to lack of organized transport services. Fortunately most private tertiary hospitals and many major medical college affiliated hospitals now have good transport programs.



t

t

Tex book of Pedia rics

17.10

vip.persianss.ir

I

–

•  End tidal CO2 monitor if intubated (desirable) •  Infusion pumps, portable suction

–

•  Adequate oxygen

C

–

•  Pulse oximeter

Recording of investigations and categorization of patient into subsets like: intensive, time critical, ill and unstable, ill and stable, unwell or well. – Team leader/organizer needs to allocate the tasks to particular team members as per the needs of the patient. – Effective communication between the referring physician or transport members and the tertiary center physician. – Airway, breathing and circulation should be assessed and personnel should be able to intervene rapidly if need arises. – Adequate humidification and oxygen must be supplied. – Equipment to monitor heart rate and blood pressure and to provide thermal support is very essential (as children frequently become hypothermic). In essence airway must be secured, breathing must be assured, monitor and pulse oximeter hooked up with at least two reliable sites of intravenous access. All tubes and lines must be well secured and sedative/ muscle relaxant syringes must be loaded, labeled and kept ready for intubated patients. • Transport phase – Transport team must call the accepting institution regarding expected time of arrival (ETA) patient’s condition and equipment needs. Any anticipated need for CT/other investigations, need for blood, additional medications, procedural set ups, consul­ tations (surgical or other), need for operation theater arrangements must be communicated in advance. – Safe movement of patient in and out of vehicle. – Ongoing monitoring of major organ systems during transport. – Prompt recognition and treatment of problems en route. – A transport care record should be maintained which should include the initial evaluation of the referring physician. – Treatment given during transport and any change in condition of the patient and condition of patient at the time of admission to the tertiary center apart from medications given en route must also be documented. – Safety of the patient as well as the personnel and adherence to the standard universal precautions including gloves, masks and hand washing or use of alcohol base hand rubs. – Use of restraints/stretcher belt for the patient should be always be practiced. Most transport teams allow one family member to ride in front seat of the ambulance if possible. – Special considerations for air transport especially if uncompressed aircraft/helicopter: Use 100% oxygen and pneumothorax must be drained if already there. If there is gastrointestinal distention/obstruction, a large bore nasogastric tube should be in place. As a general rule all drains should be kept open during 979 air transport. Tertiary hospital responsibility starts when transport team takes over the medical care at the referring institution. t

 

•  Portable cardiorespiratory monitor

–

n ensive are and

Table 17.10.2 Essential transport equipment

•  Nebulizer •  Portable ventilator (desirable) •  IV poles, pumps, , fixed seat (1), removable stretcher, storage

–

•  Pediatric sized equipment

Em

–

•  Transport incubator

– – – – –

–

–

R

R

Transport Team esponsibilities

–

Retrieving team may choose to stabilize the child on site before transporting: (stay and play) rather than take away an unstable patient (scoop and run). • Stabilization phase – Detailed history taking and examination especially of vital signs, and written informed consent.



–

–

–

-

Referring physician’s responsibilities include early institution of goal directed therapy in the pretertiary hospital setting. This has clearly shown to improve outcomes. After initial resuscitation and stabilization, following issues need to be addressed: • Should the child be referred to another facility? • If so, which facility? • Has a physician accepted the patient to be transferred? • Has essential information been provided by the referring institution? Information provided should be reasonably complete and accurate: • Referring MD’s name, institution, and phone number • Patient’s name, age, weight, vital signs • Brief history and clinical findings and reports (laboratory or radiology) • Any diagnostic or therapeutic interventions performed. • Current clinical status • Proper communication is essential: – Doctor to doctor – Nurse to nurse • Ensure that a bed is available • Medical advice for stabilization may be obtained when one calls.

–

– –

R

eferring Hospital esponsibilities



S

kills needed: Nurse and technician: Pediatric intensive care unit work experience. Pediatric advanced life support/neonatal advanced life support certification. – Bag mask ventilation, IV insertion/IO infusion, administration of O2, nebulization, IV fluids and medications. – –

–

•



–

g

er encies

•  Defibrillator and emergency medications

vip.persianss.ir

1. Ajizian SJ, Nakagawa TA. Interfacility transport of the critically ill pediatric patient. Chest. 2007;132(4):1361 7. 2. Brink LW, Neuman B, Wynn J. Air transport. Pediatr Clin North Am. 1993;40(2):439 56. 3. Duke T. Transport of seriously ill children: a neglected global issue. Intensive Care Med. 2003;29(9):1414 6. 4. Johnson CM, Gonyea MT. Transport of the critically ill child. Mayo Clin Proc. 1993;68(10):982 7. 5. Khilnani P, Chhabra R. Transport of critically ill children: how to utilize resources in the developing world. Indian J Pediatr. 2008;75(6):591 8. 6. Orr RA, Felmet KA, Han Y, et al. Pediatric specialized transport teams are associated with improved outcomes. 2009;124(1):40 8. 7. Pon S, Notterman DA. The organization of a pediatric critical care transport program. Pediatr Clin North Am. 1993;40(2):241 61. 8. Pristas LR, Rausch T. Transport considerations for the critically ill child. Crit Care Nurs Q. 1997;20(1):72 80. 9. Reynolds M, Thomsen C, Black L, et al. The nuts and bolts of organizing and initiating a pediatric transport team. The Sutter Memorial experience. Crit Care Clin. 1992;8(3):465 80. 10. Turner DA, Kleinman ME. The use of vasoactive agents via peripheral intravenous access during transport of critically ill infants and children. Pediatr Emerg Care. 2010; 26(8):563 6. 11. Venkataraman ST, Orr RA. Intrahospital transport of critically ill patients. Crit Care Clin. 1992;8(3):525 31. 12. Venkataraman ST, Rubenstein JS, Orr RA. Interhospital transport. A pediatric perspective. Crit Care Clin. 1992;8(3):515 23.

B

-

  If in doubt, intubate!





  Stabilize cervical spine

 Secure all IV lines well



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 Do not sedate for “agitation” (unintubated)

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 Do not give unrealistic expectation of referred hospital





 Move patient safely in and out of vehicle

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 Repeated reassessment





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 Recognize tube dislodgement: ETCO2 helps  Keep the patient warm



  End tidal CO2 monitoring with capnograph



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  Secure endotracheal tube



  Do not transfer with an unstable airway

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Table 17.10.3 Dos and don’ts of transport





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After obtaining history, assess appropriateness of trans­ port and dispatch team. • Document all information exchanged and record the timing of transport activation. • Advise and assist referring physician in initial stabilization of patient. • Maintain communication and provide additional recommendations as needed until transport team arrives at the receiving institution. Pediatric transport teams are a unique service for critically ill children. Safe and timely transport saves lives. Transport can be safely and effectively performed if conducted by specially trained team, strongly supported by established protocols. The approach must be evidence based and goal directed. Legal issues can be avoided by proper



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communication, consents and adequate documentation of patient condition before transport, during transport and at the time of handover to the receiving institution. Some dos and don’ts are listed in Table 17.10.3.



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 Do sedate if intubated

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18 Pediatric Subspecialities





















18.1. 18.2. 18.3. 18.4. 18.5. 18.6. 18.7. 18.8. 18.9.



Section Editor : P Ramachandran Common Behavioral Problems: Manju Mehta Common Surgical Problems: Ketan Parikh Common Orthopedic Conditions: Prakash P Kotwal Common Eye Problems: Upreet Dhaliwal Common Problems of Ear, Nose and Throat: Divya Prabhat Skin Diseases in Children: Jayakar Thomas Common Dental Problems: PK Baskar Pediatric Radiology: Arun Kumar Gupta Environment and Child Health: H Paramesh

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Common Behavioral Problems

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Parents often complain to the pediatrician that their child is very stubborn, does not listen to their commands, is very demanding and is aggressive. School authorities may refer the child for recurrent abdominal pain. These are some examples of behavioral problems. It is important to identify these problems in the initial stages as they can be managed optimally to help the child grow normally and have balanced mental health.

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Certain behaviors are normal for a particular age, e.g. thumb sucking or enuresis in 2 years old child is normal but abnormal for 10 years old child. F

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If a particular behavior occurs once in a while it is normal but if it occurs very often it is a matter of concern, e.g. a child has abdominal pain every morning before going to school.

Definition

Severity

Behavioral problems in children are reported by parents and school teachers in the developmental period. These children are also termed as maladjusted or having emotional disturbance. They may manifest behaviors that deviate from normal behavior expected from a child of same age. These problems are related to inappropriate behaviors and feelings, unsatisfactory interpersonal relationships, school learning problem, unhappiness, physical symptoms or fears related to school or personal problems. They range from mild, shortlived periods of unacceptable behavior, to more severe problems such as hyperactivity, conduct disorders and refusal to go to school. Behavioral problems may occasionally occur in any child but require to be managed by the specialist when they become frequent and disrupt school and/or family life. Children who are not able to process their behavior or lack problem-solving skills can have trouble adjusting to a normal life and require medical and educational intervention.

Even a single episode of high intensity or severity requires professional attention, e.g. violent behavior, fainting, muteness, etc.

Some behavior is persistent and has negative impact on growth of the child, e.g. poor concentration or hyperactivity causes decline in academic performance. One way to identify a problem in child is if his behavior does not match the expectations within the family. If that behavior inhibits his ability to work in the classroom or interact with peers, or if he is constantly talking and disrupting other classmates and not focusing on his work, then you have an issue. Behavioral problems can be global as well as culturally specific and ever evolving. This affects their acceptance in the family as well as society further influencing treatmentseeking behavior, e.g. self injury may warrant acceptance as abnormal behavior but not shyness. Though International Classification of Diseases and Related health Problems (10th edition) (ICD-10) and Diagnostic and Statistical Manual of Mental Disorders (IVth edition, Text Revision) (DSM-IV-TR) are used for classification of mental disorders in children, behavioral problems are classified as externalizing and internalizing. Externalizing behavior problems include problems related to acting out like conduct problems, antisocial behavior, aggressiveness, attention and hyperactivity problems. Internalizing disor ders include problems like anxiety, phobia, depression, somatic complaints, somatoform disorders and obsessive and compulsive disorders. Autism spectrum disorders, childhood onset psychosis are not included under behavior problems, they are mental disorders. Behavioral and emotional problems can also manifest as comorbidity with chronic physical problems like epilepsy, diabetics, nephrotic syndrome, etc. It also manifests with developmental problems like mental retardation, speech disorders and specific learning disability.

Prevalence

Effect on Development



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Behavioral and Emotional Problems— Classification Behavioral problems have a wide spectrum ranging from normal behavior, maladjustment to serious behavioral and emotional disorders. Some behavior problems occur during the development period, are transient and resolve on their own, whereas some become more complicated and need professional intervention. Criteria to label a child to be 982 having a problem are as follows.



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Behavioral problems are very common in children, but serious disorders have been reported between 10% and 15% in different studies. With the changing sociocultural scenario behavior and emotional problems are on increase. These problems are seen in both genders, but certain problems like attention deficit hyperactivity disorder (ADHD) are more commonly seen in boys.

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Conduct disorder is defined by DSM-IV as repetitive and persistent pattern of behavior, in which the basic rights of others or major age appropriate societal norms or rules are violated. The persistent antisocial behavior of children and adolescents significantly, impairs their ability to function in the social or academic area. Such children are arrested as they get in conflict with law such as theft, attempt to

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In childhood some habits are very persistent and cause concern to parents. These are tension-discharging pheno mena such as head banging, body rocking, temper tantrums, breath holding spells, thumb sucking, nail-biting, teeth grinding (bruxism) and tics. The details are given in Table 18.1.1.

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Conduct Disorder

Behavioral Problems

Temper tantrum

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Provide emotional security Disobedient, attention attracting behavior The problem increases when child is Firm consistent parenting, early social skill on part of child to get demands met, recovering from an illness, fatigue or when training, and professional intervention when severe the child is hungry especially in social situations Breath holding spells

Thumb sucking

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Table 18.1.1 Habit disorders Problem Meaning Reason Treatment behavior Head banging Rhythmic rocking and head banging in Sensory stimulation or pleasure for the Environment should be created in a way early life child who is otherwise uncared for or that child cannot get injured deprived of human touch or interaction Activities should be provided to the child, which can be comprehended by him and can engage him

Normal in infancy

This occurs in children when parents fail Role of iron supplementation to discipline a child or get manipulated by the child Iron deficiency May start later after birth of a sibling or Record situation when thumb sucking is when in stress done

Abnormal in preschool and above years Occupy child in activity engaging their hands Anxiety management skills

Nail-biting Tics

Common in girls and boys in middle and late childhood Repetitive movement of muscle groups that have no apparent useful function

It is often associated with anxiety and nervousness Represent discharges of tension originating in emotional and physical states

Behavioral reinforcement Keeping the child busy and teaching anxiety management Combination of pharmacological and nonpharmacological treatment is effective

Mostly muscles of face, neck, shoulders, Must be differentiated from involuntary trunk and hands are involved, e.g. lip movements smacking and grimacing, tongue thrusting, eye blinking, throat clearing Unaccompanied by loss of consciousness

Helping the child to find ways to express that resentment may relieve the problem

It may create problems in dental occlusion Stress mannerism Release of tension originating in unex pressed anger or resentment

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Teeth grinding or bruxism

Not seen during sleep and can be controlled voluntarily for short periods of time Voluntary grinding of teeth Calcium deficiency

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• • • •

Parents who had conduct disorder, antisocial personality disorder or substance abuse disorders High testosterone levels Abusive, chaotic and neglectful family environments Exposure to marital conflict and physical aggression, maternal depression, large family size combined with lower socioeconomic status and early loss of either parent due to divorce.





Children with conduct disorders are often school dropouts, have specific learning disability. They may be abusing illegal substances. Management of child with conduct disorder is described below: • • • •

Childhood conduct disorder often persists into adolescence, and predicts antisocial behavior and alcohol

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Pharmacological management for reducing aggression These include individual therapy, based on alliance building and behavioral principles Family therapy designed to improve communication among family members and to elicit underlying conflicts is somewhat effective Correctional schools can address the educational needs of juvenile delinquents.

or substance abuse in adulthood. In general, risk factors for poor prognosis are childhood onset (< 10 years of age), high level aggression, low intelligence, early court involvement and peer rejection.

Oppositional Defiant Disorder



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Oppositional defiant disorder is characterized by extreme demanding and aggressive behavior. Adolescent appro priate behaviors like increased peer group interaction, striving for independence and experimentation with risky behavior become exaggerated, severe and disruptive. Oppositional defiant disorder is seen more often in boys. It involves temper tantrums, continuous arguing, defiance of rules, continual blaming of others and frequent use of obscene language. Adolescent has very good relationship with peers outside his immediate family. Treatment approaches are commonly employed including behavior therapy, family therapy and parent management training. A

Substance buse Substance abuse and alcohol are increasing like an epidemic in children and adolescents. The substances abused are inhalants—thinner, white fluid, cough syrups, smokeless tobacco (pan masala, gutka), opioids, charas and ganja. Twenty percent of children and adolescents start experimenting with alcohol and drugs by 11 years of age. There are other psychosocial factors, which lead to addiction namely, change in lifestyle, low frustration, tolerance, easy availability of drugs and peer pressure. The clinical manifestation of substance use in children is—decline in academic performance, change in behavior, irritability, decreased interaction with family members, lying and stealing and changes in eating and sleeping behavior. These children can be assessed on detailed case history, mental status examination, tobacco and standardized psychological rating scales such as cut down, annoyed, guilty and eye opener (CAGE), teen addiction severity index and Fagerstrom’s test for nicotine dependence, cognitive behavior therapy and family therapy can help to control craving and developing coping strategies.

Enuresis Enuresis (bed-wetting) is a very common problem in both boys and girls in developmental period. It is the involuntary voiding of urine not occasioned by a physical condition. The severity is determined by frequency of urination, and the quantity is not a diagnostic consideration. The child should have a mental age of at least 4 years (ICD-10) or 5 years (DSM-IV-TR). While a majority of patients have nocturnal bed-wetting, a diurnal (but during sleep) variety and a combined variety have also been described. Enuresis is classified as persistent (primary) and regressive (secondary). In primary, the child has never been dry at night. About 75% belong to this category, and is probably the result of inadequate or inappropriate toilet training (e.g. parents do not want to wake up the child in the middle of the sleep). The regressive type is







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murder, sexual offences. The milder form is telling lies, running away from school or stealing. The rate is much higher among boys than girls. There is evidence for two clusters of symptoms in conduct disorder: (1) aggressiveness and (2) delinquency. Aggression may be directed toward people (e.g. peers) or animals (cruelty toward animals) or objects (destruction of property). Delinquency, on the other hand, includes antisocial behaviors such as lying, stealing, running away and truancy that do not primarily involve physical attack on others. The onset of these symptoms may be preceded by the presence of a difficult temperament and high level of physical aggression in preschool years. While evaluating a child for conduct disorder, one must consider whether the reported behavior is appropriate developmentally for the age of presentation. Defiance and temper tantrums are often used by children between 1.5 years and 3 years of age when frustrated. This often resolves with time. Similarly, 2–4 years old often use lying as a method of playing with language. By observing the reactions of parents and caregivers, preschoolers learn about expectations for honesty in communication. Almost all children steal something at some point in their lives. It becomes a problem when it happens more than once or twice. Thus, certain behaviors become a symptom only when they occur at a greater frequency or persist beyond a developmentally appropriate age. Unlike the previous behaviors, however, truancy, runaway behavior, destruction of property (e.g. through fire-setting) and repeated aggression against animals or others are never developmentally appropriate. Factors contributing to the development of conduct disorders are as follows:

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Masturbation in children is a type of self abuse. Children resort to this type of abuse as a means of self pleasure. When children are lonely and insecure, they seek pleasure by self stimulation. Though, this is a common problem in older children; yet sometimes a mother of 2–3 years old boy may report that the child rubs his genitalia against the bed repeatedly. Some children engage in this activity even in classroom. Masturbation can be one of the most embarrassing aspects of growing up, and parents feel very disturbed. Parents need to be counseled that masturbation has no physical or mental side effects until taken to an extreme. But the child definitely goes through the fear of being caught with his pants down and brought to shame. And this fear leads to an extreme state of anxiety that would require proper counseling and therapy. I

Gender dentity Disorder ­

Gender identity disorder (GID) manifests through a presence of strong and persistent cross-gender identi fication manifested by a desire to be of other sex, wearing clothes of other gender, e.g. girls dressing in boys’ clothes, showing preference in games and play of other sex. There is discomfort in one’s own gender role. Both biological (hormones) and psychological factors can precipitate this behavior. In this problem, families with girl children

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Encopresis refers to a condition of overt psychogenic soiling at inappropriate places at any age when bowel control should have been established. Encopresis is very embarrassing for the child as it leads to rejection by peer group; it also indicates a more serious emotional disturbance than enuresis. This condition was less common (around 1% of school age children), but now the problem is on increase due to early morning school timings. Some children try to postpone going to the toilet due to laziness, and then control is lost at the wrong place. Management is primarily with behavioral techniques.

Victims of sexual abuse can present with many problems like shock, mutism, and fearfulness and depressed mood. At times, some victims show high sexual arousal after once being sexually abused. Such sexually aroused children become problematic for their family members as they look at their younger siblings as a source of gratification of their increased sexual arousal. As a result, the problem of incest is commonly reported. For the management of such children, the same therapeutic approach is applied as in the posttraumatic stress disorder. Psychoeducational programs of both short-term and long-term types help effectively to the individual and the family members.

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Encopresis (Soiling)

Sexual buse

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often precipitated by stressful environmental events, such as birth of a sibling, marital conflict in parent or death of a family member. Bed-wetting in this case is transitory and prognosis is better. Methods to control enuresis are given in Table 18.1.2.

may reinforce younger child to behave like a boy. In assessment, normal cross dressing in young age should be differentiated with persistent maladaptive behavior. In case family and child insist in corrective sex change operation, comprehensive psychological assessment is required.

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Table 18.1.2 Methods to control enuresis •  Reward the child for dry night •  Once bed-wetting occurs, older children should be asked to wash their own clothes and soiled bed sheets •  Children should not be given any fluids after dinner •  Waking the child 1–2 hours after sleep to void urine again may help •  Punishment and humiliation by parents or siblings should be discouraged •  Stress and anxiety management for the child •  Tricyclic antidepressants

Pica This disorder involves repeated or chronic ingestion of nonnutrient substances—plaster, charcoal, clay, toothpaste, paint and mud; the age of onset is usually 1–2 years. Although, tasting or mouthing of objects is normal in infants and toddlers; pica after the 2nd year of life needs investigation. It is associated with mental retardation, iron deficiency, high frequency of maternal and paternal deprivation, family disorganization, poor supervision and low socioeconomic status. Children with pica are at increased risk for lead poisoning and parasitic infestations. Pica can be treated with a combination of education and guidance, family counseling, and behavior modification and oral iron where appropriate.

Rumination Disorder The main characteristic of this disorder is weight loss or failure to gain at the expected level because of repeated regurgitation of food without nausea or associated gastrointestinal illness. This rare condition occurs more commonly in boys and usually appears between 3 months and 14 months of age. It is potentially fatal in up to onefourth of affected children. Behavioral treatment is directed toward positively reinforcing correct eating behavior and negatively reinforcing rumination. Parent counseling and family therapy are often necessary.

Sleep Disorders A substantial portion of children struggles around bedtime due to difficulty in falling asleep. Many use special methods to help them fall asleep. Infants who show difficulty in establishing regular night time sleep patterns may also show general fussiness and irritability. In some household, night time is very hectic due to socializing, which causes lack of interest to sleep in children. Sleep difficulty may be a reflection of parental strife or underlying anxiety disorder 985 such as separation anxiety disorder. If there is conflict in

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Emotional Disorders nxiety Disorders

Anxiety fearfulness and worrying are regularly experienced as a part of normal development. When they become disabling to the point that they negatively affect social interactions and development, they are pathologic and warrant intervention. Separation anxiety disorder, overanxious (generalized anxiety) disorder, obsessivecompulsive disorder (OCD), phobias and post-traumatic stress disorder are all defined by occurrence of either diffuse or specific anxiety related to predictable situations. Of these, the former two are more specific in their onset at any age. The prevalence of anxiety disorders has been reported to be 6.8%. About one-third of these children were overanxious, and another third had specific fears or phobias.

Separation Anxiety Disorder The main characteristic of a child with separation anxiety disorder is excessive anxiety concerning separation from home or a primary caretaker. The antecedents of 986 developmentally normal anxiety, initially presents at 7–8



months of age as infants begin to differentiate from their primary caregivers. The prevalence of this disorder has been estimated to be between 3% and 4%. There is a female predominance of 3:1. Children with separation anxiety disorder show intense anxiety to the point of panic when they are separated from their primary caretaker. They can have difficulties playing outside of home, staying with babysitters, going to school or even being alone in a part of their home. Physical symptoms (e.g. headache, pain abdomen, etc.) can occur when separation is about to occur (e.g. when going to school) or does occur. Sleep disruption can occur with the child, requiring someone to stay with them till they fall asleep. They may also refuse to sleep alone. Children can worry about getting lost and never being reunited with parents. Fears about harm to the family may become exaggerated (e.g. fears of kidnappers/monsters coming into house). Mothers of children with separation anxiety disorder very commonly have a history of psychiatric illness, especially an anxiety or a depressive disorder. Then, children can be managed by behavior therapy and family therapy.



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parents, alcoholism, too many demands from parents on the child to excel, it can lead to sleep problems. Children with ADHD also are reported to have sleep problems like difficulty in falling asleep, restless leg syndrome and parasomnias. Different types of parasomnias have also been described: • Nightmares are common phenomena occurring in the rapid eye movement (REM) phase of sleep. These occur more often in girls with affective or anxiety disorders • Night terrors occur in the stage 4 of non-REM sleep. The child usually wakes with a scream, is confused, shows signs of intense autonomic activity (labored breathing, dilated pupils, sweating, tachycardia), and appears frightened. The patient often does not recall the incident on waking up the next morning. They may be related to a specific developmental conflict or to a precipitating event • Sleepwalking or somnambulism occurs in stages 3 or 4 non-REM sleep. There may be an associated history of enuresis or family history of sleepwalking. It is usually benign but temporal lobe epilepsy should be ruled out • Narcolepsy is characterized by frequent daytime naps, cataplexy, sleep paralysis and/or hypnagogic hallucinations. Polysomnographic studies, showing early onset of REM sleep following sleep onset, are required for definite diagnosis. Some children talk in sleep about the things happened during the day. This is considered normal if it occurs occasionally, and does not have impact on child’s functional ability during the daytime. There are standardized rating scales to assess sleep disorders. For management, underlying cause should be assessed. Both pharmacotherapy and psychological interventions can be given.

Overanxious Disorder Children with this disorder have unrealistic worries about future events, the appropriateness of past behavior and concerns about competence. They frequently present with somatic complaints (e.g. sweating, palpitation, chest pain, difficulty in breathing, nausea, etc.) are markedly selfconscious, need large amounts of reassurance, and have trouble relaxing. These children may be managed with self-control measures like relaxation techniques—yoga and biofeedback.

Examination Anxiety Many children before examination experience feeling of apprehension and anxiety. The anxiety begins with preparation period, and becomes intense near examination. Children with this type of anxiety develop poor appetites, recurring abdominal pain, headache and sleep disturbance. Mild cases of examination anxiety can be managed by psychological intervention. In severe cases, pharmacological treatment is required.

Phobias Children with phobias are anxious only under specific conditions. They try to avoid specific objects or situations that automatically lead to anxiety (e.g. animals, closed or open spaces, heights, etc.). School phobias are commonly seen in children; in this, the child develops irrational fear to some aspects of school situations. The child is not able to attend school in spite of deep interest in studies. Though anxiety is prominent, some children also have depressive feelings. Other complaints may be abdominal pain, vomiting, anorexia, headache and giddiness. The symptoms are usually intense or present during the school-going hours.

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Children with OCD present with repetitive thoughts (obsessions) or repetitive rituals or movements (compu lsions). Obsessions have been defined as intrusive thoughts, fears or images, which become imposed on the conscious mind repeatedly. The fear that some bad event might happen causes anxiety in the child. Compulsions are concerned with fears of contamination. The most common compulsions are “hand-washing” continuous checking of school words, mathematics or writing and repeated touching. The other fears are death of parent, sexual fears, moral worries about doing the right thing. This condition is treated with specialized behavioral techniques, e.g. thought stopping, graded exposure and response prevention. Often, drug treatment and behavior therapy are combined.

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Why a particular child behaves in an abnormal way will depend upon his biological and environmental factors, which include family, school and society in which he lives. Some behavioral problems can occur, whatever the family or home situation is. In some cases, however, stressful external events, such as moving home or divorce, may produce periods of problem behavior. Table 18.1.3 summarizes these factors.

ssessment of Behavioral and Emotional Disorders A

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Obsessive-Compulsive Disorder

Causes of Childhood and dolescent Disorders

Examination of the child consists of interviewing the child as well as his/her family. Often, a child’s understanding of what troubles him/her may be at variance with the reports of his/her parents and teachers. Also, many behavior problems are situation-specific. For example, a child may have severe temper tantrums, only when he/she is with his/her mother or a child who is obedient at school may be destructive in the home. Therefore, as a general rule, information should be gathered from multiple sources (e.g. parents, peers and teachers, etc.). Child’s behavior and cooperation may vary from time to time. A child may have his/her good days and bad days. A comprehensive assessment would therefore, require observing the child serially over several sessions. Assessment for behavior problems is carried out in the following steps:



Amongst somatic complaints, recurrent abdominal pain is very common in young children, 80% of these have nonorganic cause for pain. The pain can occur before going to school, before examination or under other stressor. These children are generally anxious, have poor coping skills and may have unrealistic high expectation in school performance. Parents also are very anxious and reinforce illness behavior in the child. Behavioral assessment helps in understanding cause and parent’s anxiety can be reduced.

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Somatoform disorder or conversion disorder is the most common disorder seen in child psychiatric clinics. It is the disturbance of voluntary motor or sensory system. Often, the symptoms are means to get primary and secondary gains. These patients commonly seek first consultation with the pediatrician as the symptoms are primarily physical, like pseudoseizures, aches and pains, hyperventilation, headache, vomiting and paralysis. The symptoms are variable, fluctuating and usually, do not follow any organic pathway. It occurs in both boys and girls, generally above the age of 8 years. A variety of methods have been recommended for symptom removal such as reassurance, suggestions, behavioral modification (operant conditioning and aversive therapy), hypnosis, use of placebo, and use of sedatives. Parent counseling is very important to decrease anxiety in parents and to modify their reinforcing behavior. A simple antecedent-behavior-consequence (ABC) chart may be maintained by the parents to understand the cause of the symptoms.

Depression has been on rise in children and adolescents; it presents with sadness, mood disturbance in children. It affects the child’s ability to participate in relationship with parents and peers. The child is not able to enjoy activities which he did earlier. It has impact on school performance also. Depressed school-aged children present with sad facial expressions, easy tears, irritability, social withdrawal, vegetative symptoms, anxiety and behavioral disturbances. They have lack of interest in activities liked earlier there is decline in school performance and decrease in interaction with family members and friends. Delusions are uncommon in psychotically depressed prepubertal children. There is 2–4% increase in prevalence of depression with age. The prevalence of depressive disorders in childhood has been estimated to be 0.15–2.0%. Girls report significantly more depressive symptoms than boys. Depressive symptoms vary, according to the age and developmental level.

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Depression

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Generally, the cause of school phobia is disturbed family relationships. The first step in treatment is to help the child to attend school. Behavioral techniques (like graded exposure) are very effective in the management of school phobias. Parents should be given insight into the mechanism involved. Drugs may be considered when anxiety and depression are severe.

Case History and Mental Status Examination A detailed case history is taken from the time of conception to the present. This includes beginning of problem behavior, development of the child, family history, family environment, child’s temperament, school performance and interpersonal 987 relationship.

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Cognitive ssessment

Behavioral ssessment of a Child Child’s behavior is systematically observed and recorded, according to antecedents (situations), feeling, thought, behavior and consequences. Parent can be involved in this recording. Older children can do this on their own.

Prevention Majority of behavioral problems in children arise from a complex interaction between child and environmental characteristics, related to situational family stresses psycho education to parents and members of extended family if staying together can help in reducing anxiety in parents, and to modify family environment. Pediatrician can help parents cope with troublesome behaviors through education and brief intervention techniques such as behavior modification. In addition, the pediatrician can help to promote “competence” by teaching parents how to interact with their children in more affectionate and cognitively stimulating ways. By providing parenting skills, high expectations from the child can be lowered, his needs and uniqueness can be appreciated. In this current situation, parents want the child to be perfect, strong, smart and quick. He may be humiliated for not living up to the expectations of the parents. Thus, parents should create an environment in the family to make the child comfortable and anxiety free. Providing parents with knowledge and helping the child to develop emotional regulation will help in preventing behavioral problems. Parents’ own anxiety should be under control. The expectations from the child should be proportionate to the child’s cognitive and physical ability. ­

On a standardized objective test, child’s cognitive abilities are assessed. These include attention, concentration, verbal and performance intelligence, social maturity, adaptive behavior and memory. Attention and concentration can be assessed on digit span test, color/letter cancellation test. Verbal and performance tests of intelligence, Wechsler’s intelligence scale for children (WISC), Malin’s intelligence scale for Indian children (MISIC) should be used to assess intelligence. In children less than 5 years of age, social maturity level referred as social quotient (SQ) can be assessed using Vineland social maturity scale. The diagnoses of mental subnormality, specific learning disorders and developmental language disorders can be diagnosed on the basis of these tests.

(1) Child behavior checklist (CBCL) and (2) Conner’s Rating Scale for assessment of ADHD, parent and teacher versions, examples of self-report instruments are Child Depression Inventory (CDI) and Perceived Competence Scale (PCS). There are Indian’s standardized rating scales and norms available for the assessment. Some of the Indian rating scales are—developmental psychopathology checklist for children (Kapur 1995).

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The mental status examination refers to child’s current abilities to understand his actions and interaction with the environment. The child is observed in a structured situation and standard questions are asked to assess his feeling and thoughts. Both case history and mental status examination are important in making diagnosis of the child.

Culture Media Terrorism Violence Neighborhood Ethnicity

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Table 18.1.3 Causes of behavior and emotional problems Biological Psychosocial Family School Stress Attitudes of parents Genetic disposition Self-esteem Over protection Fragile-X syndrome Achievement Rejection Down syndrome Peer group Child abuse Brain damage Discipline Discipline Intelligence Social skills Anxiety Temperament Antisocial Role model Illness Expectation Physical handicap Time spent with child Fatigue Conflict Malnutrition Parents Family members Alcoholism

Projective Technique Projective tests are unstructured stimulus material on which child’s unconscious conflicts and thoughts are elicited. These tests are very useful in understanding the psychodynamic aspect of child’s behavior and his interactions with family members. Some of the examples of these types of tests are Draw-A-Person Test, House-TreePerson Test, in which a child is asked to draw a plain sheet of paper with his imagination. In Children’s Apperception Test, child has to make a story on the pictures given to him. They are very useful in understanding the psychopathology and planning treatment.

Rating Scales and Questionnaires Rating scales and questionnaires are objective methods to assess psychopathology and personality of the child. Parents 988 or teachers rate the rating scales. Self-rating scales are used for adolescents. Two well-known checklists for children are:

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• Availability of parents in developing years of the child, consistent discipline style, understanding uniqueness of the child and ability in parent to control their negative emotions will help the child to have positive mental health



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Practice Points/Tips Management should begin with an explanation to the parents of the diagnosis, its probable cause, the way in which the child can be helped and the likely outcome. It is important to reassure parents, as they play an important role in management of their children. Coping strategies and skill building can be done in play manner. As much as possible, sick role should not be given to the child. Certain elements of standard pharmacological treatment require modification when treating disorders in the context of the developing body and brain. The potential for longterm adverse effects in children of psychotropic drugs on the development of brain and body is of critical concern. Indeed, there are at least two instances of age-related effects of drugs on biological development: (1) the slowing of body growth by psychostimulants (like methylphenidate) and (2) the hepatotoxicity induced by valproate. Due to these fears, the clinician will need to carefully consider if pharmacological treatments are required at all.

1. Alsaker FD. Annotation: the impact of puberty. J Child Psychol Psychiatry. 1996;37(3):249-58. 2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition – Text Revision (DSM-IV-TR). Washington, DC: American Psychiatric Publi shing, Inc.; 2000. 3. Bailey A, Philips W, Rutter M. Autism: towards an integration of clinical, genetic, neuropsychological, and neurobiological perspectives. J Child Psychol Psychiatry. 1996;37(1):89-126. 4. Conners CK. Conner’s Rating Scales—revised technical manual. Toronto: Multi Health Systems; 1997. 5. Dhalla S, Kopec JA. The CAGE questionnaire for alcohol misuse: a review of reliability and validity studies. Clin Invest Med. 2007;30(1):33-41. 6. Fagerström KO. Measuring degree of physical dependence to tobacco smoking with reference to individualization of treatment. Addict Behav. 1978;3(3-4):235-41. 7. Harter S. The perceived competence scale for children. Child Dev. 1982;53(1):87-97. 8. Kaminer Y. The Teen Addiction Severity Index around the globe: the Tower of Babel revisited. Subst Abus. 2008;29(3): 89-94. 9. Kapur M. Psychological management of childhood problems. In: Kapur M (Ed). Mental Health of Indian Children. New Delhi: Sage Publications; 1995. 10. Kelly D, Aylward G. Attention deficits in school-aged children and adolescents. Current issues and practice. Pediatric Clin. North Am. 1992;39(3):487-512. 11. Levine MD. Neurodevelopmental dysfunction in the schoolaged child. In: Behrman RE, Kliegman RM, Arvin AM (Eds). Textbook of Pediatrics. Bangaluru, India: Prism Publications; 1996. pp. 100-7. 12. Machover K. Drawing of the human figure: a method of personality investigation. In: Anderson HH, Anderson GL (Eds). An Introduction to Projective Techniques. New York: Prentice Hall; 1951. 13. Mehta M, Pandav CS, Pande P, et al. Mental health problems in rural primary children. Indian J Social Psychiatry. 1991;7: 32-9. 14. Peterson BS. Neuroimaging in child and adolescent neuropsychiatric disorders. J Am Ascad Child Adolesc Psychiatry. 1995;34(12):1560-76.

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Bibliography

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National Institute for Health and Clinical Excellence (NICE), World Health Organization (WHO), American Academy of Child and Adolescent Psychiatry and Indian Psychiatric Society, child psychiatry section have developed detailed practice guidelines. Details can be seen on www.iacap. org. According to these guidelines, the ultimate judgment regarding treatment must be made by the clinician, depending on the clinical evidence provided by the patient and his parents. The treatment will be carried out, according to the options available and resources available. They have developed pocket cards for each disorder, which include key points, diagnosis and evaluation procedure, criteria for diagnosis and treatment algorithm.

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ommon urgical Problems Ketan Parikh

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It is the persistence of patency of the processus vaginalis through which the abdominal contents descend into the inguinoscrotal region. During the process of testicular descent, a tongue of peritoneal fold, the “processus vaginalis” envelops the testis antenatally. Normally, its communication with the peritoneal cavity should seal off by birth. The persistence of this communication in a variable portion of its extent is termed “patent processus vaginalis” (PPV)—(Fig. 18.2.1) and may lead to hernia/hydrocele or an encysted hydrocele of the cord.

however, an intermittent hernia may be missed during imaging, especially in a sedated child • iagnostic laparoscopy to identify a patent processus vaginalis: Recommended only in select situations (Fig. 18.2.2).

Complications •

An inguinal hernia has a high chance of complication in the form of irreducibility, obstruction and strangulation – Higher chance of complication in premature babies, (as high as 50% in the first 3 months); hence, they should be operated early – On strangulation, the edematous and congested sac presses onto the testicular vessels causing a variable degree of testicular hypoxia and resultant testicular dysfunction – In most children, the contents of a hernia are bowel or ovary (in females) and thus strangulation can lead to intestinal gangrene and potentially fatal peritonitis or ovarian gangrene (Figs 18.2.3 and 18.2.4) – The overall surgical complication rate of an obstructed hernia is 10 times more than an unob­ structed hernia • pneic spells: Prematures with hernia are known to suffer apneic spells. –

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Figure 18.2.1 Diagrammatic representation of intestines (yellow) passing through patent processus vaginalis (PPV)

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Treatment Surgery (herniotomy) should be advised as soon as the hernia is diagnosed. Traditionally, performed through a small incision in the ipsilateral groin, the communication with the peritoneum is exposed, divided and ligated. In recent years, herniotomy is also being done by the laparoscopic

Figure 18.2.2 A patent processus vaginalis (PPV) as seen during laparoscopy  

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ncidence: Three to four percent of children are affected but up to 30% in premature babies. Male:female ratio (6:1) Presentation: Any time after birth but the most common around 1 year and thus “congenital” a misnomer in most cases swelling in the groin or the scrotum: – Bilateral in a small number of cases – Often a history of increase in the size of swelling on crying or after activity – The swelling is reducible unless incarcerated Palpation of the root of the scrotum after reduction gives a characteristic “silk glove” feeling nvestigations: No diagnostic investigations routinely recommended Ultrasonography (inguinal region): Ultrasonography (USG) may help to differentiate from a hydrocele; I

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Figure 18.2.4 Gangrenous ovary in a strangulated hernia

approach. Laparoscopy can also detect a contralateral PPV, which can be tackled simultaneously.

of this postnatal descent is complete by the 1st month in a term “neonate”. The exact cause of nondescent is not always known.





Unlike an inguinal hernia, a hydrocele has a high chance of resolution in the first 6 months of life. Since the contents are only fluid, a hydrocele is not prone to complications and thus surgery can be deferred till after infancy.

Treatment

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The scrotum on the side of nondescent will be empty and less developed than the contralateral normal side The testis may be palpable in the inguinal region.



Various locations of UDT have been described, but clinically the most relevant is to differentiate a palpable gonad from an impalpable one. Careful clinical examination can identify an extra abdominal gonad in most cases. Inability to palpate the testis along the path of descent would indicate either of these possibilities: •

etractile testis: After a normal descent, the testis may get pulled up due to the hyperactive cremasteric reflex and may temporarily become intrainguinal. It may become palpable by examining the child in a squatting position or by milking the testis down the inguinal canal. The scrotum is well formed and the testis can definitely be located in the scrotum in sleep. An ultrasound examination may misdiagnose these cases as UDT • n ectopic testis is one, which has got diverted from the normal path of descent. Such a testis may be palpable in the superficial inguinal pouch, prepubic or perineal locations. All these cases need surgical repositioning into the scrotal sac • nonpalpable testis could be: – A high intra abdominal UDT – An atrophied testis due to a vascular accident such as torsion – Intersex anomaly: Wherein the nonpalpable gonad is either dysgenetic/streak or ovotestis/ovary – True nondevelopment of ipsilateral testis. –

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• An inguinal hernia in a child needs to be operated at whichever age it is identified with minimal delay to avoid preventable complications • The parents must be warned to identify complications when first consulted for a swelling in the groin

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linically: An inguinoscrotal or a scrotal swelling: • May be restricted to the inguinal region (encysted hydrocele of the cord) • Diurnal variation in the size of swelling possible • Usually, not easily reducible because of inverted ink bottle effect.

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Structurally, a hydrocele is a PPV where the peritoneal cavity communication is very narrow, permitting only peritoneal fluid into the sac.

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Figure 18.2.3 Acute right groin swelling in a female child—strangulated hernia

Although the incidence of UDT is almost 3% in the term “neonate”, it drops to only 0.8% at about 6 months. Most

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Undescended testes (UDT) are the failure of testis to complete its normal descent into the scrotum.

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Intra abdominal temperature, which is higher than the scrotal temperature, affects germ cell maturation and the fertility potential of the UDT. Ultramicroscopic changes in the seminiferous tubules have been conclusively documented beyond the age of 1 year in an UDT • Prone to trauma: In the inguinal region, the testis can get damaged due to blunt trauma • Prone to torsion: The UDT is significantly more prone to torsion and may present as an acute abdomen or as an enlarged tender mass in the groin • Prone to tumor: Undescended testes are approximately 50 times more prone to malignant change. The propensity may be decreased by early orchidopexy • An accompanying inguinal hernia on the ipsilateral side could develop its own complications as discussed above.

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ning), whereas they may pick up testicular tissue, the sen­ sitivity and specificity do not justify their routine use • iagnostic laparoscopy: It is the only reliable investi­ gation in UDT.

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The testis is extremely unlikely to descend after 6 months of age Efficacy of hormonal treatment has not been proved Only surgical treatment has withstood the test of time universally Desirable to complete therapy by the age of 1 year. Since there may be a need for a two staged procedure in selected cases, a patient with UDT should undergo his first pediatric surgical assessment by 6 months of age and surgery between the ages of 6 months and 1 year. Earlier surgery is indicated in case of: Presence of an ipsilateral hernia: Since the hernia needs surgery as early as possible, the orchidopexy should be combined with this surgery ny other complication: Since UDT has a high chance of undergoing torsion, the parents of a child with UDT need to be warned that in the event of an acute inflammation in the inguinal region, an urgent surgery may be warranted to derotate the torsion and bring the testis down into the scrotum.



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ictum: An acute scrotum should be considered to be testicular torsion unless proved otherwise. This is because the resultant ipsilateral testicular hypoxia may lead to the production of autoantibodies to the proteins in the seminiferous tubules and thus, affect the functioning of the contralateral testis even before the affected testis will undergo necrosis.

nvestigation

Doppler examination of the scrotal region or a radionuclide scan to see the blood flow to the scrotum is recommended but does not have adequate sensitivity or specificity, and may also lead to precious loss of time.

Treatment An acute scrotum is one of the most urgent situations in pediatric surgery because of the possibility of vascular damage to the affected testis and the possible immunological effects on the functioning of the contralateral testis. Thus,

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In a nonpalpable testis, laparoscopy has emerged as an important modality to locate the testis or confirm its atrophy or absence. It can also be used to mobilize the retroperitoneal 992 vessels in UDT. Additionally, it helps to effectively stage the procedure in case of a high intra abdominal testis with a short vascular supply.

Figure 18.2.5 Left testicular torsion  

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urgent scrotal exploration is advised in any acute scrotum when torsion cannot be excluded. On exploration, the torsion is corrected if possible and the testis fixed to the scrotum to prevent further episodes of torsion. If the testis has already undergone necrosis (Fig. 18.2.6), orchidectomy should be done to minimize the immune mediated damage to the contralateral testis. In either case, the contralateral testis should also be exposed and fixed to prevent torsion on that side.

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Phimosis is the inability to retract the preputial skin over the glans. Physiological phimosis (seen in infants) is due to the inadequate separation of the inner preputial skin from the glans penis, and does not warrant any active treatment (not even massage). Forceful retraction or massage may lead to tears on the prepuce, which heal with fibrosis and convert the physiological phimosis to pathological. Pathological phimosis is due to a fibrotic cicatrix of the preputial aperture and thus requires treatment (Fig. 18.2.7).

 

Figure 18.2.7 Pathological phimosis: fibrotic cicatrix at the tip

ymptomatology

Treatment In infancy, application of a mild topical steroid with gentle retraction of the prepuce may help in mild phimosis. In case of definite pathological phimosis, surgical treatment (circumcision or preputioplasty) is usually indicated. Circumcision done in the neonatal age may cause ammo­ niacal dermatitis of the glans.

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Poor stream, straining at micturition, burning micturition or recurrent attacks of balanoposthitis. Paraphimosis is an emergency, which occurs due to the forceful retraction of the phimotic prepuce over the coronal sulcus, which then cannot be repositioned leading to edema of the preputial skin and in prolonged cases may also lead to vascular compromise of the prepuce or even the glans penis.

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years, preputioplasty which ensures easy retractability (Figs 18.2.8A to D) but preserves the preputial covering and thus, the sensitivity of the epithelium of the glans is rapidly becoming popular.

The earlier aggressive advocacy for circumcision in infants has been diluted by the American Association of Pediatricians. • Circumcision (which involves amputation of a significant portion of the preputial skin) has been the traditional surgical treatment of phimosis. In recent

• Phimosis is physiological in most infants • Forceful retraction or massage of prepuce can convert a physiological phimosis into pathological phimosis • Preputioplasty as an alternative surgery for phimosis is gaining wider acceptance all over the world

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Hypospadias is a condition wherein the urinary opening is abnormally placed on the ventral aspect of the penis. It is classified depending on the position of the urinary opening in increasing order of severity (Fig. 18.2.9). In almost all these patients, the prepuce is deficient ventrally, and the preputial skin gets concentrated onto the dorsum of the penis forming a cape like hood (dorsal hood). In many cases, there is also an accompanying ventral curvature of the penis (chordee) (Fig. 18.2.10). Additionally, there may be a meatal stenosis leading to a very thin (needle point) stream of urine and straining. A multifactorial genetic inheritance pattern has been documented in a few cases. The more severe varieties may 993

 

Figure 18.2.6 Testicular gangrene following a torsion of the testis

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Figures 18.2.8A to D Preputioplasty: an alternative surgery for phimosis, which preserves the preputial cover of glans and ensures free retractability (A); radial cuts of preputioplasty (B); the postoperative result ensuring easy retractability (C and D)

Figure 18.2.10 Chordee in case of hypospadias  

 

Figure 18.2.9 Diagrammatic representation of hypospadiac meatus: (A) Glanular; (B) Coronal; (C) Penile; (D) Penoscrotal; (E) Perineal

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also have penile shortening and a bifid scrotum. Some of these cases may also have disorders of sexual development (Fig. 18.2.11).

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Something coming out PR (Fig. 18.2.13) • Bleeding may be associated • Predisposing factors: Constipation, diarrhea, severe cough. • Treatment: – Of the predisposing factors – Submucosal injections—usually curative – Per rectal/abdominal or laparoscopic surgery required in very rare cases.

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The mouth and the lips are formed by a fusion of five processes of mesenchyme. Cleft lip and cleft palate result due to a variable failure of this fusion process (Fig. 18.2.14). In 12% of the cases, the condition is familial.

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left Palate eeding: Problems with sucking are dealt with by special teats or spoon feeding. However, in most cases,

Figure 18.2.12 Rectal polyp  

 

Figure 18.2.11 Hypospadias with right undescended testes (UDT)—a case of true hermaphroditism

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Rectal polyp is a benign adenomatous polyp, usually single. • Common in the age group of 3–6 years • Clinically presents as: – Bleeding per rectum (PR)—fresh blood in drops at the time of defecation – Something coming out PR (Fig. 18.2.12) • Polyp may be felt on digital examination • It needs to be removed surgically.

Umbilical Hernia Umbilical hernia is the protrusion of the intra abdominal contents through a weakness in the umbilical fascia into a skin lined sac. Idiopathic in most cases, it may rarely be associated with hypothyroidism, Trisomy 13 or 18 and the Beckwith Wiedemann syndrome. • A variable protrusion of the umbilicus, which increases on crying or straining • Palpable defect in the umbilical ring • Outcome: Most hernias close spontaneously by the age of 2–3 years

ectal Polyp

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Meatal stenosis, if present, should be corrected at the earliest because it can lead to obstructive uropathy. • Distal hypospadias without chordee are compatible with a normal urinary and sexual function. Treatment in these cases is predominantly for cosmetic and psychological satisfaction • Proximal hypospadias may affect fertility • Correction of chordee must precede the urethroplasty either in two stages or as a combined single surgery • Tissue used for the urethral reconstruction should be hair free skin or nonmucus secreting mucosa • Timing of the repair: All the stages of repair should be completed before the child is school going. Generally speaking, surgery for proximal hypospadias between 6 months and 1 year, and the more severe varieties between 12 months and 24 months • pispadias: In this much rare condition, the urethral opening is situated dorsally on the penis. The more proximal variety is associated with urinary incontinence.

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also allows proper moulding of the alveolus for better long term results Classically—at 10 weeks, 10 lbs weight and hemoglobin (Hb) of 10 g%; however, some centers repair the lip at birth Repair of the palate between 9 months and 12 months.

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Remnants or anomalies of the branchial apparatus lead to congenital anomalies egg: Branchial fistula, sinus or cyst in that order of frequency (Fig. 18.2.15). Usually, the external opening of the fistula lies in the lower third of the neck near the anterior border of the sternomastoid muscle. The tract penetrates deeper and traverses within the bifurcation of the common carotid artery toward the tonsillar fossa. • The opening is often seen later in infancy—intermittent small quantities of mucoid discharge • There may be a small skin tag or a tiny cartilaginous tag near the opening • Secondary infection may lead to abscess formation. Fistulogram is routinely not recommended.

 

Figure 18.2.13 Prolapse of rectum: arrow points to the lumen in the center of the prolapse to differentiate from a prolapsed polyp

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There is a high chance of secondary infection. In late cases, malignant transformation of the lining is also known.

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If infected, antibiotics and surgical excision in the noninflamed stage Surgery—dissection of the entire tract through the carotid bifurcation up to the tonsillar fossa. C

Thyroglossal yst The thyroid gland develops from the base of the tongue where it descends to take its formal position. During its course of descent, small groups of cells may get

 

Figure 18.2.14 Complete cleft of the lip and palate—unilateral



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the Indian mother learns to place nipple to the side of mouth and the child manages to suck on the breast • peech: Nasal twang is often seen even after successful repair • reathing: A special mention must be made of the child with a cleft palate and a short mandible—Pierre Robin syndrome—these babies have a tendency of tongue fall and choking • Recurrent upper respiratory tract infection (URI) and middle ear infection due to the free communication between the oral and nasal cavities.

Treatment •

Surgical correction of the lip—often advised early to protect parents from psychological trauma. Early repair

Figure 18.2.15 Obstructed branchial sinus: the blocked opening is seen in the center of the swelling  

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sequestrated, which gradually form a cyst—thyroglossal cyst.

About three times more common than branchial remnants in childhood • Asymptomatic mass in the midline of neck (Fig. 18.2.16) • Smooth, round, elastic and opaque • Moves with deglutition and protrusion of tongue • If infected—red and tender and if incised may form sinus • Ultrasonography may be used for diagnosis. Treatment: Surgery—excision of the entire tract with body of hyoid bone (Sistrunk’s operation) (Fig. 18.2.17).

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Figure 18.2.18 Laparoscopic view of a Meckel’s diverticulum

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This is the persistent proximal part of the vitellointestinal duct. The diverticulum is present on the antimesenteric border of the terminal ileum (Fig. 18.2.18).

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leeding: It is usually painless and profuse. It is due to peptic ulceration in the surrounding ileal mucosa due to acid secretion from heterotopic gastric mucosa seen in some cases • ntestinal obstruction: – As a lead point of an intussusception – A band from the diverticulum to the umbilicus may cause internal herniation or volvulus • iverticulitis: It produces symptoms and signs identical to appendicitis but the prognosis is worse as the diverticulum is more prone to perforation and peritonitis. D

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Figure 18.2.16 Thyroglossal cyst: swelling in the midline of neck

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bstructive Uropathies

 

Figure 18.2.17 Sistrunk’s surgery for thyroglossal cyst—note the excised hyoid bone along with the entire tract till the base of the tongue

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Obstructive uropathy is a set of conditions causing chronic, partial obstruction to the flow of urine anywhere distal to the renal calyces.

The pelviureteric junction (Fig. 18.2.19) The vesicoureteric junction

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Figure 18.2.19 Dilated pelvis of a hydronephrotic kidney

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Pelviureteric Junction bstruction Pathology The obstruction is either due to an adynamic segment or an external compression commonly by an aberrant renal artery. The partial obstruction gets exacerbated during any diuretic period.

Management Principles • • • •

Urgent antenatal consultation required, if oligohy­ dramnios Postnatal management: On the basis of the differential renal function, size and progress of hydronephrosis Spontaneous resolution known in infancy Definite indications for surgery—deteriorating renal function/pain/infection/palpable mass—Anderson Hynes pyeloplasty (open or laparoscopic). -

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linical eatures • Antenatal detection • Pain in the abdomen • Recurrent urinary tract infection (UTI) • Lump in the abdomen—kidney or palpable bladder • Rarely hematuria • Gastrointestinal symptoms like nausea, vomiting and anorexia, especially in an infant • Nonspecific symptoms such as failure to thrive, weakness and lethargy • Poor urinary stream/straining at micturition/retention of urine in case of urethral valves.

Figure 18.2.20 Micturating cystourethrogram (MCU) showing Grade 5 vesicoureteric reflux (VUR) on left side with trabeculated bladder, dilated posturethra with normal caliber distal urethra  

The urethra: Posterior and anterior urethral valves Obstruction to the flow of urine could lead to: Ballooning of calyces and thinning of the renal parenchyma. The renal function gradually deteriorates. High pressures in the antenatal period could cause renal dysplasia Infection further deteriorates renal function.

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Vesicoureteric reflux is due to the failure of the valvular action at the vesicoureteric junction, which allows a variable quantity of urine to reflux back into the ureter. Vesicoureteric reflux may be secondary to high pressures in the bladder in case of distal outflow obstruction.

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omplications Deterioration of renal function due to progressive renal dilatation Pyonephrosis and septicemia in case of infection.

Pathology • •

Features of obstructive uropathy Renal damage could be significant in presence of active infection.

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iagnostic and valuative maging • bdominal ultrasonography: It identifies the extent of pelvic and ureteric dilatation, bladder hypertrophy, urethral dilatation and postvoid residue besides any other anomalies • ntravenous pyelography ( VP)—replaced by T urography or M urography: Detailed anatomical delineation • A micturating cystourethrogram (MCUG) to look for vesicoureteric reflux (VUR) or urethral obstruction (Fig. 18.2.20) • sotope renogram: To assess differential function and scarring (preferably done with an open indwelling bladder catheter).

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Intestinal obstruction is the failure of aboral progression of intestinal contents. • ynamic obstruction: It is due to a physical occlusion of a portion of bowel, which may arise either: – From outside the wall of the bowel as in compression due to bands, etc. – From within the wall, e.g. atresia, etc. – From within the lumen like inspissated meconium, etc. • dynamic obstruction: It is due to absence of peristalsis in the whole or a segment of the bowel. Clinically, the presentation is dependent on the level of obstruction, the severity of obstruction, the acuteness of obstruction and the possibility of vascular compromise, if any. • Upper intestinal obstruction: Early onset of vomiting and failure to tolerate feeds. Abdominal distension, if present, is confined to the upper abdomen. The baby may pass some normal colored meconium or pale colored meconium. Early severe dehydration: – Duodenal atresia: The vomitus may be bilious or nonbilious. Antenatal hydramnios – Malrotation with midgut volvulus – – –

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Figure 18.2.21 Urethroscopic view of posturethral

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Nil by mouth (N M): When in doubt, keep the baby nil orally Keep baby warm—in the hospital and during transport Cover open wounds, e.g. exomphalos, meningo­ myelocele, etc. Pass nasogastric tube and always keep it open: (No. 6 or higher), especially in case of vomiting or breathless child [pass nasogastric tube (NGT) minimizes aerophagia and aspiration] Transport preferably in prone position Recording passage of urine and meconium with its color and informing surgeon upportive: Antibiotics, intravenous (IV) fluids, moni­ toring of vitals. E

Surgical Options



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They are thin curtain like membranes in the posterior urethra causing a partial obstruction to the flow of urine (Fig. 18.2.21). Poor urine stream in a male child should make one suspect PUV.

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• Obstructive uropathy or UTI may have insidious presentations • Need to identify the patients who will require urgent aggressive treatment • Obstruction may resolve or may be progressive • Long-term follow-up is essential.

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Treat primary cause of VUR, if possible, e.g. posterior urethral valves (PUV) or neurogenic bladder Surgery (definitive treatment): – Subureteral polytetrafluoroethylene injection (STING): Endoscopic injection of dextranomer hyaluronic acid (Deflux)® at the vesicoureteric junction – Ureteric reimplantation: Transvesical Extravesical Laparoscopic.

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mall intestinal obstruction: It is characterized by abdominal distension, failure to pass meconium and later vomiting (invariably bilious): – Jejunal or ileal atresia – Meconium ileus • arge intestinal obstruction: The earliest symptom is failure to pass meconium, other symptoms of intestinal obstruction follow. Abdominal distension is gross and generalized: – Hirschsprung’s disease – Anorectal malformations (ARM) – Meconium plug syndrome – Colonic atresias. K

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• Bilious vomiting or bilious gastric aspirate in a newborn is considered pathognomonic of intestinal obstruction • Higher the obstruction, more the dehydration

ntestinal tresia A

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Figure 18.2.23 An erect plain X-ray showing a double-bubble sign of a duodenal atresia

Intestinal atresia is an obstruction of the intestine due to a complete occlusion of the lumen (Fig. 18.2.22). C

linical features and diagnosis: These are dependent on the site of atresia.

Investigations

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• ouble-bubble sign: Duodenal atresia (Fig. 18.2.23) • Multiple fluid levels: Jejunal or ileal atresia (Fig. 18.2.24) • Treatment: Early surgery, after atleast partial correction of dehydration • n laparotomy: Resection and anastomosis or bypass of atretic segment (Fig. 18.2.25).

Prognosis • •

Fairly good in uncomplicated cases Deteriorates, if treated late, low birthweight or premature, or presence of sepsis or other anomalies  

Figure 18.2.24 An erect X-ray of abdomen showing fluid levels in the upper abdomen with a gasless lower abdomen suggesting a jejunal atresia

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Poor if multiple atresias or there is a large section of the bowel, which does not have a proper vascular supply (apple peel atresia).

ntestinal Malrotation

If the process of intestinal rotation is incomplete, then malrotation is said to have taken place.

Pathological Anatomy •

Figure 18.2.22 Atresia: showing complete block of the intestine  

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The duodenojejunal flexure is to the right of the midline and cecum adjacent on its left, and thus significantly narrowing the root of the mesentery; the ascending and transverse colon are mobile. Together these

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Clinical Features There is a sudden development of upper intestinal obstruction in an apparently normal child, who may have passed normal meconium earlier. If volvulus neonatorum sets in duodenal atresia with gangrene of the midgut (bleeding PR), there is progressive deterioration in the general condition with septicemia.

Diagnosis

 

Introduction The neonatal manifestation of mucoviscidosis—a condition affecting all the mucus secreting glands of the body, causing excessive viscidity of the mucus secretion. It is an autosomal recessive disease, which is common in western countries. In recent years, incidence is increasing in India.

Pathology The mucus secreted in the intestine is extremely sticky, like plasticine, leading to adherence of meconium to the intestinal mucosa, and thus choking up the lumen of the distal intestine, not allowing any contents to pass through.

Clinical Features • • •

Mid intestinal obstruction Baby may pass some white chalky meconium Viscid meconium may be palpable as a doughy substance in the lower abdomen.



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n erect -ray of abdomen: A large stomach bubble or a double bubble and may show few distal gas shadows. Multiple fluid levels are not seen in this variety of intestinal obstruction • arium studies: Duodenum lies to the right of midline; alternatively, a Ba enema would show the entire colon to the left of midline. Ultrasonography with Doppler can identify the abnormal lie of the superior mesenteric artery and bowel ischemia if any. A

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anomalies can lead to twisting of the intestine (volvulus neonatorum) Abnormal peritoneal bands [Ladd’s bands (Fig. 18.2.26)] run from right peritoneal wall to the cecum over the third part of the duodenum compressing the duodenum In case of volvulus neonatorum, the vascularity of entire midgut can suffer, leading to gangrene, if not corrected early.

Figure 18.2.26 Diagrammatic representation of the pathological anatomy in a malrotation: ileocecal region to the left with Ladd’s bands crossing from the right abdominal wall toward the ileocecal region compressing the duodenum (which is entirely on right side). Note the narrow root of mesentery—a cause for midgut volvulus

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Figure 18.2.25 Jejunal atresia: massively dilated jejunal loops (white arrow) and collapsed and small caliber distal small bowel (black arrow)

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• Resuscitation as required (high fluid requirement) • xploratory laparotomy: Ladd’s bands released and root of the mesentery widened to prevent further episodes of volvulus (Ladd’s procedure) • Gangrenous bowel, if any: Resection or exteriorization. Prognosis: Good, if surgery done before gangrene sets in.

Diagnosis X

• Plain -ray of the abdomen: Dilated bowel but no fluid levels • Gastrograffin or (conray/urograffin) enema: Micro­ colon (a thin narrow segment of distal relatively unused bowel).

Treatment The very high osmolarity of conray or gastrograffin enema causes dissolution of the inspissated mucus and may be curative. In case, the obstruction does not resolve after the use of conray, surgery will be required to relieve the 1001 obstruction.

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Hirschsprung’s disease is a common condition characterized by congenital aganglionosis of a variable length of the colon extending proximally from the anorectal junction.

Physiology Normal peristaltic activity involves a wave of relaxation preceding a wave of contraction. Parasympathetic inner­ vation is essential for this wave of relaxation.

Pathological natomy A

In Hirschsprung’s disease, the parasympathetic ganglia are absent from the Meissner and Auerbach’s plexuses of the affected bowel. The aganglionic bowel is normal in caliber but due to the absence of the peristaltic activity, the wave of relaxation is absent thus leading to a functional obstruction. The normally ganglion proximal bowel undergoes massive dilatation and hypertrophy.

Figure 18.2.27 Barium (Ba) enema (late view) in case of Hirschsprung’s disease: note the normal caliber anorectal portion with a massively dilated sigmoid  

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Hirschsprung’s isease

Etiology Usually sporadic but occasionally the disease runs in families. Male:female ratio is 4:1.

Clinical Features • • • •

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Conservative treatment involving repeated enemas/ suppositories, may help in overcoming an acute attack of intestinal obstruction and postpone the surgery. Definitive treatment is surgical. The principle of surgery is the removal of aganglionic segment of colon and ensuring that normal ganglionic bowel is anastomosed to the anal canal. This is usually done in stages. Various commonly performed surgeries include the modified Duhamel’s procedure, Swenson’s procedure and Soave’s procedure.

Recent Advances Surgery is being done in single stage for the neonates but its long term results are still being debated. The main procedures may be performed laparoscopically.

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A plain X ray of the abdomen shows features of intestinal obstruction—large dilated colon loops In newborns: Pelvic region—gasless due to empty lower colon arium enema [essential to do under screening or image intensifier television ( TV) control with limited quantity of a in saline]: A cone shaped colon at the junction of the ganglionic and aganglionic segments (Fig. 18.2.27) norectal manometry: Anorectal manometry may strongly suggest the diagnosis of Hirschsprung’s disease The final confirmation is only with a full thickness biopsy of the rectal wall, which will show absence of ganglion cells in the rectal muscle wall. -

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ifferential diagnosis: Absence of soiling distinguishes it from habitual constipation, which usually presents after the 1002 age of 6–12 months.

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Diagnosis

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Presentation—at birth or later Constipation dating back to early infancy or a delay in passage of the first meconium beyond 24 hours of life Intestinal obstruction—may be relieved by enemas Rarely, attacks of foul smelling diarrhea interspersed with constipation may confuse the picture In chronic cases, child fails to thrive and is malnourished bdominal distension: Usually marked, the transverse colon is often visible n rectal examination: The rectum is felt to be empty, and on withdrawal of the examining finger, there is an explosive passage of flatus and feces.

Treatment

Anorectal anomalies are wide spectrum of anomalies that affect the opening of the terminal anorectum and adjacent perineal structures.

Incidence Roughly 1 in 5,000 live births.

Pathological Anatomy The anus does not open normally at the usual site. The opening may be severely stenotic or absent. In the latter case, the rectum ends as a blind pouch. There may be a fistulous communication from the rectal pouch to perineum or the urinary tract in the male or the genital structures in a female. The usual muscles of continence are present in the normal positions but since the terminal gastrointestinal tract (GIT) may not pass through them, they may be poorly developed.

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Figure 18.2.29 Flat perineum as seen in a baby of high anorectal malformations (ARM)

 

Figure 18.2.28 Anorectal malformations (ARM): cutaneous fistula opening on scrotal raphe (low variety)

Associated Anomalies with this Group ER

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• V T association: Vertebral, anorectal, tracheoesoph­ ageal and renal • V T association: Vertebral, anorectal, cardiac, tra­ cheoesophageal, renal and limb • Genitourinary anomalies, especially VUR are probably the most common association.

Classification

Mainly directed at ascertaining the relationship of the anorectum with levator ani and the identification of a fistula if any.

 

Invertogram or a Lateral Prone Film Figure 18.2.30 assesses the level of air shadow in the blind rectal pouch with respect to bony landmarks. Since the swallowed air can take 24 hours to reach the rectum, this assessment is likely to be fallacious if done earlier. In patients with an open fistula, the same relationship can be ascertained by dye studies through the fistula.

Treatment •

ow anomalies: Since the rectum has already descended through the levator muscles, treated by a surgical exploration of the perineum at birth • ntermediate or high anomaly: An initial colostomy to relieve the intestinal obstruction. At a later stage, a L

Investigations

Figure 18.2.30 Invertogram in case of low anorectal malformations (ARM)

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The classification centers around the relation of the terminal anorectum and the levator ani muscle. • ow variety: The rectum passes through the levator funnel entirely. The continence muscles are well developed (Fig. 18.2.28) • ntermediate variety: Rectum enters the levator funnel but does not pass through it entirely. There is frequently a fistula to the posterior urethra in the male, or the vestibule in the female. The continence muscles are developed • High variety: The anorectum does not pass through the levator, which is poorly developed—externally manifested as a flat perineum (Fig. 18.2.29), and the fistula is to the urethra or bladder in male and there may be a cloacal anomaly in the female. Clinically, most varieties of ARM should be identified at birth itself or may present as low intestinal obstruction. In those with a wide external fistula, the presentation may be of recurrent constipation.

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definitive surgery—the most common being posterior sagittal anorectoplasty (PSARP). The colostomy is closed as the third stage of surgery.

Pathology

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Musculature of the pyloric antrum is significantly hypertrophied, thus the pylorus is thickened; pyloric canal is lengthened and narrowed. The olive shaped pylorus becomes hard to feel when contracted. This hypertrophied pylorus is clinically palpable as a “pyloric tumor” (Fig. 18.2.31). The stomach proximal to the obstruction is dilated and hypertrophied. Gastric mucosa in infancy produces a potent lipase, which hydrolyses milk to free fatty acids. The rancidity of the curdled milk gradually causes progressive mucosal edema and precipitates complete obstruction (Fig. 18.2.32), and thus symptoms often delayed till 3–6 weeks.

Clinical Features

 

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Facies is characteristic—alert, anxious and hungry look. Unlike a toxic or septicemic baby, these patients have a slow and shallow breathing due to alkalosis Visible peristalsis on inspection (left to right). Examination must be done with the child comfortably placed in the mother’s lap and in good light Palpation of the “tumor” (palpable in 70% cases) is the diagnostic sign. It should be looked for with the left hand, sitting on the patients’ left palpating below the right costal margin, underneath the liver border.

Specific Investigations • • •

Serum electrolytes: Hypokalemic, hypochloremic alkalosis Ultrasonography shows the “tumor” Contrast studies with Ba only if necessary—“string sign”, large stomach, delayed emptying, gastritis (Fig. 18.2.33). Differential diagnosis includes almost any condition leading to nonbilious vomiting in children, especially gastroenteritis, septicemia, meningitis, intracranial hemorr­ hage and gastroesophageal reflux (GER).

Usually, child is seen between 3 weeks and 6 weeks or any time between 1 week and 4 months. • Vomiting is the most important presenting symptom— progressive, forcible, projectile and nonbilious, may come from nose. In most cases, the baby is hungry again after the vomit. There may be altered blood • Constipation: Due to poor intake • Weight loss or failure to gain weight • Jaundice—occasionally seen due to nutritional deficiencies.

Figure 18.2.32 Diagrammatic representation of the hypertrophy of the pylorus along with the mucosal edema precipitating the complete obstruction of the pyloric outlet

Treatment

Figure 18.2.31 Laparoscopic view of the hypertrophied pylorus in a case of infantile hypertrophic pyloric stenosis (IHPS)  

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• Nonsurgical treatment with prokinetics: To be used only in case of strong contraindication to surgery as the treatment has erratic results and is too prolonged • urgical treatment: Treatment of choice – Preoperative: Correct dehydration and electrolyte imbalance by: Rheolytic thrombectomy (RT) aspirate and stomach wash with normal saline Administer 1/3 or 1/2 strength saline through NGT or IV – Operation: Fredet Ramsted’s pyloromyotomy—laparo­ scopic surgery possible – Results: In experienced hands, results are excellent.

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Table 18.2.1 Difference between exomphalos major and minor Exomphalos major Exomphalos minor Defect is more than 5 cm in Defect is less than 5 cm in diameter diameter Cord is attached to the base of sac Cord is attached to the tip of sac It may contain liver, stomach, etc. It contains only bowel Primary closure may not be possible Primary repair is easy

 

Figure 18.2.34 Exomphalos minor

 

Figure 18.2.33 String sign seen on Barium (Ba) meal examination in case of infantile hypertrophic pyloric stenosis (IHPS)

xomphalos or mphalocele O

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The diaphragm is formed from different embryonal components, viz. • The septum transversum • The pleuroperitoneal membranes • The dorsal esophageal mesentery and the body wall. Failure of fusion of any one of these components can result in a defect in the diaphragm, which allows the abdominal viscera to herniate into the chest cavity (Fig. 18.2.35). The most common variety is the Bochdalek hernia, which involves the posterolateral part of the diaphragm. It is more common on the left side (Fig. 18.2.36).

It is the herniation of the abdominal contents through open umbilical ring into the base of umbilical cord. The contents are not covered by skin but a thin, translucent and avascular membrane consisting of peritoneum and amniotic membrane sandwiching a thin layer of Wharton’s jelly. This sac, translucent at birth, gradually opacifies after a few hours. The contents range from a small length of bowel to almost the entire bowel, stomach, liver, spleen, pancreas and bladder. Table 18.2.1 lists the difference between an exomphalos major and an exomphalos minor (Fig. 18.2.34), as they are of prognostic significance.

Clinical Features

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Prenatal USG diagnosis, desirable and termination of pregnancy an option Incidence: 1:6,000 births Associated with many chromosomal defects and syn­ dromes like exomphalos macroglossia gigantism (EMG) syndrome Multiorgan defects are common.

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omplications: If left untreated—septicemia.

Treatment • • •

Primary—prevent heat loss and infection Attempt primary closure under general anesthesia (GA) If not possible—staged closure or silo method.

Pathophysiology Pathophysiological events leading to respiratory distress in congenital diaphragmatic hernia (CDH): • The shift of mediastinum during the antenatal period causes pressure on the contralateral developing lung affecting its development also. This pulmonary hypoplasia limits the gaseous exchange in the available lung tissue. • Pulmonary hypoplasia also affects the vascular component of the lung. Thus, there is an increased resistance in the pulmonary vasculature resulting in pulmonary hypertension. This may prevent closure of the ductus arteriosus, which may further lead to a persistent fetal circulation. • The presence of abdominal contents in the chest causes pressure on the lung—this restricts lung expansion, which can be compounded by the gaseous distension of the bowel in a crying baby. • The hypoplastic lung may not be able to handle normal inspiratory pressures and the resultant alveolar rupture may result in pneumothorax on the affected side or 1005 even on the other side.

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nvestigation A chest X ray is diagnostic. It shows loops of bowel in the chest cavity. There may be significant mediastinal shift or an associated pneumothorax. In right sided Bochdalek hernia, liver is the main constituent of the chest cavity In doubtful cases, an abdominal USG or CT scan of the chest is useful Hypoxia and acidosis should be estimated by arterial blood gas analysis. -

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Breath sounds on the involved side are absent, occasionally peristaltic sounds can be heard due to displacement of viscera to the chest. In most cases, the abdomen is scaphoid. Heart sounds and apical impulse are on the right side. Occasionally, patients present late with only recurrent lower respiratory tract infection (LRTI).

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Figure 18.2.35 Left-sided diaphragmatic hernia with marked mediastinal shift

Treatment Primary Management • •

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Tracheoesophageal istula F

If antenatally diagnosed, these patients must preferably be born in hospitals with adequate facilities for immediate advanced neonatal care and neonatal surgical facilities. Postnatally: In the severely affected baby, there is respiratory distress and cyanosis. The ipsilateral chest appears prominent with evidence of mediastinal shift.

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• Antenatally diagnosed CDH patients should be delivered in a center with advanced neonatal care • Clinically, a strong suspicion should be made on seeing a breathless child with a scaphoid abdomen since other causes of breathlessness cause abdominal distension due to aerophagia

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The severity of symptoms and signs depends mainly on the status of lung development. A severely hypoplastic lung may not be compatible with life, whereas at the other extreme, some cases of CDH may be relatively asymptomatic for years and may present much later in childhood due to repeated chest infections.

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Figure 18.2.36 Thoracoscopic view of diaphragmatic defect (white arrows) in a case of congenital diaphragmatic hernia (CDH). Black arrow shows the heart

An NGT passed immediately to deflate the stomach and reduce aerophagia Intubation with an endotracheal tube at the earliest for a breathless child. If intubation is not possible, oxygen may be administered by an oxygen hood. Bag and mask ventilation is avoided for fear of increasing aerophagia Ventilation ideally with a high frequency ventilator Acidosis correction In case of severe pulmonary hypertension, drugs to cause pulmonary vasodilatation Surgery is performed only after stabilizing the baby’s condition as much as possible. Through a laparotomy, the defect in the diaphragm is identified, the herniated viscera are reposited in the abdomen, and the defect is repaired. Thoracoscopic surgery is being deployed in an increasing number of patients who are stable enough to tolerate the same Very rarely, extracorporeal membrane oxygenation (ECMO) may be indicated in these patients.

The trachea and esophagus are formed by splitting of the primitive foregut around the 4th week of intrauterine life. An abnormality during this process causes this anomaly.

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Antenatally: There may be hydramnios, especially in pure atresia without fistula Frothing of saliva is the most characteristic feature due to air bubbling through the collected salivary secretions in the pharynx Vomiting—only if baby is inadvertently fed Abdominal distension is a prominent feature except in type A where the abdomen is scaphoid Cyanosis: Cyanosis may be due to—concomitant cardiac anomalies or pneumonitis Associated anomalies: Vertebral, anorectal, cardiac, tracheoesophageal, renal and limb defects A baby with an H fistula usually presents late, with choking during feeds, excessive vomiting, gross aerophagia and recurrent pneumonia Diagnostic clinical test in all except the H-type fistula: A stiff no. 10/12 rubber catheter or Ryle’s tube is passed into the pharynx of the baby through mouth, and a characteristic resistance is felt as the catheter gets arrested in the atretic “upper pouch”. A soft feeding tube or catheter may coil in the dilated upper pouch and miss the diagnosis. A lateral chest X ray with the catheter in place will give an idea of the gap between the upper and the lower pouches -

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Whereas, the exact etiology is unknown, associated anomalies occur as a part of the vertebral, anorectal, tracheoesophageal and renal anomalies (VATER) association and vertebral, anorectal, cardiac, tracheoesophageal, renal and limb (VACTERL) association. Incidence ranges from 1:3,000 to 1:4,500 live births. Five types of anomalies are recognizable (Figs 18.2.37A to E): 1. Esophageal atresia without tracheoesophageal fistula 2. Esophageal atresia with an upper pouch fistula 3. Esophageal atresia with lower end fistula (the most common) 4. Esophageal atresia with fistula at both ends of the esophagus 5. H type tracheoesophageal fistula (Fig. 18.2.38). In the most common variety (Figs 18.2.37C and 18.2.39), saliva collects in the upper pouch and may spill over in the trachea leading to aspiration pneumonia. Inspired air is partly shunted into the stomach through the fistula causing gaseous distension of the stomach. The gastric distention leads to reflux of the acidic contents of the stomach through the trachea into the lungs causing chemical pneumonia.

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Figures 18.2.37A to E Different types of esophageal atresia. (A) Esophageal atresia without tracheoesophageal fistula; (B) Esophageal atresia with an upper pouch fistula; (C) Esophageal atresia with lower end fistula (the most common); (D) Esophageal atresia with fistula at both ends of the esophagus; (E) H-type tracheoesophageal fistula

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Prognosis

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Depends on the weight, associated anomalies and the time elapsed before treatment can be started. If all factors are favorable, survival rates of over 80% can be achieved.

ntussusception

Intussusception indicates the telescoping of one part of the intestine into another—common around 8–10 months of age (Fig. 18.2.40).

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Pathology • •  

Figure 18.2.38 Bronchoscopic view of H-type tracheoesophageal fistula

 

Figure 18.2.39 Thoracoscopic view of lower esophagus arising from trachea in type “C” esophageal atresia case

The most common site—ileocecal region (Fig. 18.2.41) The most common lead point—a hypertrophied Peyer’s patch following a change in the bacterial flora during weaning or gastrointestinal infection or due to ingestion of infected respiratory secretions • Compression of the mesentery and venous congestion within the innermost layer of intussusception causes secretion of blood and mucus, characteristically labeled as red currant jelly stool. Further vascular compromise may lead to gangrene of a portion of the bowel.

 

Figure 18.2.40 Diagrammatic representation of intussusception and its parts

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Treatment The therapy for esophageal atresia must take into account the maturity and weight of the baby besides the presence if any of the lung infection and associated anomalies. Waterston’s criteria are a guide to treatment.

Surgical Priorities Disconnection of fistula Prevention of salivary pooling Establish esophageal continuity. Surgery is performed through a right thoracotomy. In selected cases, a staged approach is adopted.

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ecent advances: The surgery is being done by the thoracoscopic approach, which minimizes the morbidity of an open thoracotomy and facilitates earlier recovery.

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Figure 18.2.41 Laparoscopic view of an intussusception

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Table 18.2.2 Common pediatric surgical conditions and their basic management plan Conditions Management plan Congenital inguinal hernia Operate early even at 1 week of age, if necessary Fear of strangulation is highest in newborn period Tunica vaginal hydrocele/ No years of urgency. Operate after encysted hydrocele of cord 6 months of age but preferably before 2 years of age unless seen later Phimosis Usually after 2 years of age, rarely before 6 months of age. Preputioplasty—an alternative surgery Paraphimosis Reduce as soon as possible (ASAP), plan early surgery Emergency surgery if not reduced manually Undescended testis After 6 months of age and preferably before 1 year of age Earlier, if accompanied with hernia Cleft lip Usually around 3 months of age Cleft palate Usually between 9 months and 12 months of age Tongue-tie Preferably before 1 year of age Branchial cyst and sinus After 6 months of age Cystic hygroma After 3 months of age. Earlier if respiratory symptoms Thyroglossal cyst and sinus Usually after 6 months of age Torticollis After 1 year of age Umbilical hernia Usually after 2 years of age, any time earlier if history of (H/o) recurrent irreducibility. Emergency in case of obstruction Omphalocele Primary or delayed primary depending on the size Gastroschisis At birth Hypospadias Usually after 6 months of age, may be after 1 year of age if severe chordee

nvestigations Ultrasound of the abdomen can be diagnostic. Alternatively, a Barium enema—the coiled spring sign or the claw sign (Fig. 18.2.43).

Figure 18.2.42 Red currant jelly stools Courtesy: Dr A Vaidya

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If diagnosed within 24 hours of attack, hydrostatic reduction attempted by a pediatric surgeon (under USG or radiological control) with facilities for immediate surgery in case of complications • If hydrostatic reduction fails or is contraindicated— exploratory laparotomy: Operative reduction or if necessary, resection and anastomosis. The commonly seen pediatric surgical conditions and the treatment plan are summarized in Table 18.2.2. B



 

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Figure 18.2.43 Coil spring picture in a Barium (Ba) enema for intussusception

ibliography

1. Belman AB, King LR, Kramer SA, et al. Clinical Pediatric Urology, 4th edition. London, UK: Martin Dunitz Ltd; 2002. 2. Glick PL, Pearl R, Irish MS, et al. Pediatric Surgery Secrets. USA: Hanley and Belfus Medical Publishers, Elsevier; 2001. 3. Grosfeld JL, O’Neill JA, Coran AG, et al. Pediatric Surgery, 6th edition. Philadelphia: Mosby, Elsevier; 2006. 4. Gupta DK, Gupta D, Carachi R. Pediatric Surgical Oncology, 1st edition. United States: McGraw Hill; 2009.

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Classically a healthy, well nourished child, less than 1 year of age There may be a prior history of an upper respiratory tract infection (URTI/URI) Colic’s—pain occurs in short bursts with intermittent periods of remission Vomiting—bilious only in late cases Red currant jelly stools—usually with no fecal matter after one to two times (a differentiating feature from dysentery) (Fig. 18.2.42) On abdominal palpation—intussusception may be felt as banana shaped mass with its concavity toward the umbilicus. Occasionally, it can be felt PR In late cases—features of septicemia and peritonitis.



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9. Rodgers BM, McGahren ED. Mediastinum and pleura. In: Oldham KT, Colombani PM, Foglia RP, Skinner MA (Eds). Principles and Practice of Pediatric Surgery. Philadelphia, USA: Lippincott Williams and Wilkins; 2005. pp. 929 49. 10. Sinha CK, Davenport M (Eds). Handbook of Pediatric Surgery, 1st edition. New York, USA: Springer; 2010. 11. Smithers CJ, Fishman SJ. Vascular anomalies: lymphatic malformations. In: Holcomb GW III, Murphy JP, Ostlie DJ (Eds). Ashcraft’s Pediatric Surgery, 5th edition. Philadelphia: Saunders Elsevier; 2010. p. 989.

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5. Gupta DK, Gupta D, Sharma S, et al. Pediatric Surgery: Diagnosis and Management, 1st edition. United States: McGraw Hill; 2010. 6. Mattei P. Congenital diaphragmatic hernia. In: Mattei P (Ed). Fundamentals of Pediatric Surgery, 2nd edition. New York, USA: Springer; 2011. pp. 535 42. 7. Puri P, Höllwarth ME (Eds). Pediatric Surgery: Diagnosis and Management, 2nd edition. Berlin, Heidelberg, Germany: Springer Verlag; 2009. pp. 990 8. 8. Puri P. Newborn Surgery, 3rd edition. USA: Oxford University Press; 2003.

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Pediatric Sub

18.3

In rigid clubfoot or in cases where some residual deformity is left after conservative treatment, surgical treatment is resorted to which can be as follows: • Tendo-Achilles lengthening is done to correct the equinus deformity • Posteromedial soft tissue release is done to lengthen or release the tight/contracted soft tissue structures on the medial and posterior aspects of the foot and ankle • Bony operations are done after 4 years of age to correct the deformity. D

evelopmental ysplasia of the Hip

Figure 18.3.1 Congenital talipes equinovarus (clinical photograph)

Figure 18.3.2 Neglected clubfoot with callosities

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The deformity is corrected fully and maintained up to the skeletal maturity so that the deformity does not recur. The treatment should start as early as possible.

The term developmental dysplasia of the hip (DDH) is preferred to congenital dislocation of hip (CDH) as in many children the hip is normal at birth but develop subluxation or dislocation later. Its significance lies in its early diagnosis because neglect or delay in treatment can make the patient handicapped.

Principles of reatment

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Surgical Methods





Ideally, a routine screening of the newborn child for detection of congenital malformations should also include the following, apart from other anomalies: • Clubfoot • Congenital dislocation of hip • Spina bifida. It may be a unilateral or bilateral deformity. The foot, calf and heel are smaller in size. The foot cannot be dorsiflexed fully due to tightness of Achilles’ tendon. In neglected clubfoot when the child presents late, callosities are seen over the lateral border or the dorsum of the foot, as the child walks on it (Fig. 18.3.2).

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• Passive manipulation: In the newborn, the mother is taught to manipulate the child’s foot passively every day in an attempt to correct the deformity, till the child is about 6 weeks old • Plaster of Paris cast: The deformity is corrected by passive manipulation and maintained by a plaster of Paris (POP) cast. The cast is changed every 2 weeks till the deformity is fully corrected or requires surgery. Splint or special shoes are given after correction.

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Clubfoot or congenital talipes equinovarus (CTEV) is a deformity of the foot, in which the foot is turned inward (Fig. 18.3.1). Though a congenital deformity, it may be part of a systemic disease such as arthrogryposis multiplex congenita (AMC), muscular dystrophy or Meningocele, etc. The clubfoot deformity consists of equinus (plantar flexion) of the ankle joint, inversion of the foot at the subtalar joint and adduction of the forefoot at the midtarsal joint. There is also medial rotation (torsion) of the tibia. The incidence of this deformity is 1 in 1,000 live births.

Nonsurgical Methods

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The girls are affected 5–6 times more in comparison to boys. One or both hips may be affected. The diagnosis is difficult in the early cases, and therefore, the condition has to be looked for.

In the Newborn There may be asymmetrical skin folds on the inner aspect of thigh (Fig. 18.3.3). Abduction of the hip joint may be limited. The clinical tests—Barlow’s or Ortolani’s test may help in the diagnosis. These tests are meant to dislocate or reduce the hip, respectively (Figs 18.3.4A and B).

In Older Children

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The diagnosis may not be difficult as there is widening of the perineum, marked lumbar lordosis and a characteristic waddling gait.

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A radiograph will confirm the diagnosis. Arthrography helps to show the outline of the cartilaginous parts of the joint. Magnetic resonance imaging (MRI) may be equally useful.

reatment

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The treatment varies with the age of the patient. The prognosis is better when the treatment is started as early as possible, preferably in the 1st week of life. Reduction of the dislocation can be achieved by the following methods: • losed manipulation under general anesthesia and POP cast application • pen reduction of the hip joint by surgical operation.

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Figures 18.3.4A and B (A) Barlow’s and (B) Ortolani’s tests—line diagram

the ileum bone or a shelf operation. A varus derotation osteotomy is required to correct excessive anteversion of the neck of femur.

cute Osteomyelitis

Acute osteomyelitis is defined as acute infection of the bone marrow. The common organism responsible is Staphylococcus aureus. However, Streptomyces albus, Streptococcus and Escherichia coli are also known to cause it. Clostridium welchii are found in infections following a compound fracture. Salmonella is a rarely isolated organism but is frequently seen in patients with sickle-cell disease.

Pathogenesis Hematogenous osteomyelitis starts in the metaphysis of long bones. An abscess develops, which rapidly spreads to the medullary canal. The infection then comes under the periosteum lifting the latter from the bone, resulting in a subperiosteal abscess (Fig. 18.3.5) and cutting off the blood supply to the bone underneath. The bone becomes dead and develops into a sequestrum. In children, the periosteum can get lifted off easily resulting in a large diaphyseal sequestrum (Fig. 18.3.6). In situations where the metaphysis is intracapsular, e.g. upper end of the femur, the abscess may burst open from the metaphysis directly into the hip joint and cause septic arthritis. D





If the acetabulum is too shallow, the head of femur has a tendency to dislocate. The acetabular roof can be reconstructed to make it deep by doing an osteotomy of

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Early diagnosis is important and yet difficult since the radiograph may look normal in the initial period. The diagnosis is made essentially by clinical judgment. There may be a history of trauma to the affected part preceding the onset of symptoms. One may also find a primary focus of infection in the body, e.g. skin, throat, etc. The child presents with high fever, headache, rest lessness and dehydration; occasionally with signs of toxemia. The child resists movement of the limb and there is tenderness over the metaphysis.

 

Figure 18.3.3 Asymmetrical skin folds of thighs in developmental dysplasia of the hip

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Acute osteomyelitis, when treated inadequately, passes on to chronic osteomyelitis. Sometimes, the disease may become chronic due to poor host defense mechanism.

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is sent and empirically intravenous chemotherapy using ampicillin and cloxacillin should be started. One may also add gentamicin to broaden the spectrum. The antibiotic is subsequently changed according to the culture and sensitivity report. The limb is immobilized in a POP cast. If there is no response to this treatment within 24 hours, surgical drainage of the abscess is carried. Antibiotics are continued for a period of 6 weeks approximately.



The chronic osteomyelitis is characterized by persistence of discharging sinuses, which is fixed to the underlying bone. Pain may occasionally be present during an acute exacerbation. The adjacent joint may be stiff due to secondary arthritis. A radiograph may show a cavity in the bone containing a sequestrum, occasionally with a pathological fracture (Fig. 18.3.7). Chronic osteomyelitis should be differentiated from Ewing’s sarcoma and tuberculous osteomyelitis. T



 

Figure 18.3.5 Hematogenous (acute) osteomyelitis. Spread of pus from metaphysis to: (1) the medullary canal, (2) subperiosteal abscess. The pus has come out through the cortex and lifted the periosteum. The cortex underneath will lose its blood supply and become sequestrated, (3) directly into the joint (rarely), (4) the joint, since the metaphysis is intracapsular (note the attachment of the joint capsule) and (5) the muscular plane or outside through a sinus

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Acute osteomyelitis has to be differentiated from pyogenic and other noninfective arthritis.

reatment

The most important factor for a successful treatment is early diagnosis. At the first suspicion of acute osteomyelitis, the child should be admitted and investigated. A blood culture

• • • • • •

Antibiotics are given according to the pus culture and sensitivity reports Surgical operations are performed to remove the sequestrum (sequestrectomy) and to remove the infected granulation tissue (curettage) Amputation may be indicated very rarely, especially when the sinus undergoes a malignant change or the patient develops amyloidosis.

omplications Stiffness of the adjacent joints Pathological fracture Deformity due to malunion of a pathological fracture Shortening, when the growth plate is damaged A long-standing discharging sinus may rarely cause squamous cell carcinoma Secondary amyloidosis.



Osteomyelitis in human immunodeficiency virus disease: The destruction of bone is much more extensive with little or no reparative new bone formation. The bones usually involved are upper tibia and lower femur. The disease is often bilateral, and septic arthritis is common.

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The investigations are nonspecific and may not clinch the diagnosis. The investigations show: (1) raised local leukocyte count (up to 20,000) and a raised erythrocyte sedimentation rate (ESR), (2) blood culture may isolate the organism, (3) radiograph may show a periosteal reaction in the metaphysis, as late as 7–12 days and (4) a technetium99m bone scan may show an increased uptake.

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Figure 18.3.6 Chronic osteomyelitis. Large diaphyseal sequestrum involving radius (radiograph)

reatment

Pyogenic (septic) arthritis is caused by pyogenic organisms, mainly Staphylococcus aureus. However, Streptococci, Pneumococci, Gonococci, Meningococci and E. coli may 1013

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Acute septic arthritis of infancy (Tom Smith arthritis) is seen in infancy, and is generally secondary to a neighboring bone lesion. The child presents with the signs and symptoms of acute inflammation, occasionally toxemia. In infants, the femoral head is cartilaginous and gets destroyed completely by the infection thereby, affecting the future function of the limb. The treatment in the acute stage is early drainage under proper antibiotic cover. T

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Osteoarticular uberculosis

uberculous Osteomyelitis

 

Figure 18.3.7 Pathological fracture of humerus in chronic osteomyelitis

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Tuberculosis of the bones and joints is almost always secondary to a primary focus elsewhere in the body.

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Tuberculosis may affect any joint; however, the commonly affected joints are hip, knee and elbow. The shoulder, wrist and ankle joints are rarely affected. The tuberculous infection of the joint may be synovial or osseous.

Clinical Features The patient usually presents with pain and swelling of the affected joint with restriction of all movements of that particular joint. In advanced cases, there may be a discharging sinus and deformity of the joint.

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Knee is the commonly affected joint. However, hip, elbow and shoulder joints may also be affected. The child presents with the symptoms and signs of acute inflammation, occasionally toxemia. Examination of the joint fluid may help in the diagnosis. The blood examination may not be very helpful since a raised leukocyte count and ESR will be present in most inflammatory conditions.

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The organisms gain entry through: • Hematogenous route from a primary focus in the respiratory tract, genitourinary tract, intestinal tract, teeth, tonsils, etc. or umbilical cord sepsis in children • An infection in the bone, particularly when the metaphysis is intra-articular as in hip or shoulder • A puncture wound.

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infect the joint occasionally. In young children, Haemophilus influenzae has also been reported to be a common organism. Acute pyogenic arthritis may also occur in children in acute infectious diseases such as enteric fever, influenza, pneumonia, etc.

Tuberculous infection is seen in small bones, such as metacarpals, metatarsals, phalanges (Fig. 18.3.8), carpals calcaneus, etc. The long bones are rarely affected. Tuber culous osteomyelitis is a subacute infection, and therefore, presents as pain, swelling of the affected part and occasionally, a discharging sinus.

Tuberculous arthritis Acute rheumatism Acute pyogenic osteomyelitis.

reatment

Principles of Treatment Figure 18.3.8 Tuberculosis of phalanges  

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Early diagnosis, appropriate antibiotics and joint drainage can save the joint from complete destruction and disorga nization.

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Unilateral cases have to be differentiated from tuberculosis and transient synovitis. Bilateral cases have to be differentiated from cretinism, multiple epiphyseal dysplasia, mucopolysaccharidosis and sickle-cell disease. T

reatment



Pathologically, the condition is self-limiting. The aim of treatment is prevention of deformity of the femoral head and ensuring containment of the head within the acetabulum by surgical or nonsurgical methods. In the early stage of pain and muscle spasm, the child is put to bed rest with skin traction. When the muscle spasm is

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Though the classical presentation is that of a child with a painless limp, the child may present with a history of periodic attacks of limping with pain in the hip or referred pain to the knee. There are signs of local inflammation. In early stages, there will be limitation of movement with muscle spasm. Plain X-ray and bone scan are helpful in establishing the diagnosis. However, MRI is the gold standard investigation.

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• Pain: A few patients may present with constitutional symptoms such as fever, cough, loss of appetite and weight, but generally pain in the back is predominant symptom. It is usually the first indication of the disease, and is localized over the affected area of the spine. Occasionally, the patient may feel referred pain in the areas other than spine, e.g. “girdle pains” along the intercostal nerves, in tuberculosis of the dorsal spine • eformity: Deformity of the spine—kyphosis—results from destruction and collapse of the affected vertebra • bscess: It is called “cold” abscess because it presents away from the site of activity of the disease, and therefore, does not present with the usual signs of inflammation over it. Clinically, the abscess can be seen as: (1) psoas abscess, (2) abscess in the lumbar triangle, (3) abscess over the side of the chest wall and occasionally, (4) an abscess in the gluteal region • Paralysis: Paraplegia is often the presenting symptom in patients with tuberculosis of spine. This results from compression of the spinal cord due to abscess, granu lation tissues, bony sequestrum or due to mechanical pressure caused by angulation of the vertebral column. Quadriplegia will result from cord compression in the cervical spine.

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Clinical Features

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Tuberculosis of the spine commonly affects the thoraco lumbar spine; however, it is also seen in the other regions of the spinal column.

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Perthes’ disease is one of the most common osteochon droses. Also known as coxa plana, it is an avascular necrosis (AVN) of the head of femur resulting from interference with its blood supply. This results in deformation of the head and neck of femur (Fig. 18.3.9). It occurs between the ages of 3 years and 10 years, with 80% male preponderance. Usually unilateral, bilateral cases are relatively rare (10%).

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The treatment consists of following: • Antituberculous drugs—a three or four drug regime is started initially and then maintained on two drugs for a total period of about 12–18 months • Immobilization of the affected part in a plaster for about 4–6 weeks • Surgery—curettage of the bony lesion with or without bone grafting • The aim of treatment is to achieve a fixed or a mobile joint based on the condition of the joint. Surgical fusion (arthrodesis) achieves a painless fixed joint; whereas some sort of arthroplasty is done to get a mobile joint. T

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anterolateral decompression, radical operation or lami nectomy.

Treatment

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nti-tuberculous drugs: The drug therapy is given for a total period of 18 months • est to the part: Rest to the spine may be given by means of a POP jacket or a corset • rainage of the abscess: A cold abscess may require aspiration or drainage. The cord compression is relieved by various procedures like costotransversectomy, D

Figure 18.3.9 Perthes’ disease of the left hip  

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lesion is small. Amputation is indicated if limb salvage is not feasible • Radiotherapy and chemotherapy are indicated for local control of the disease after incomplete surgical removal of the tumor and to control the micrometastasis. A regular follow-up every 3 months is mandatory to detect any recurrence or spread of the tumor.



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Ewing’s tumor is an uncommon type of highly malignant bone tumor occurring in children (more common in males), in the age group of 10–20 years. It affects the diaphysis of long bones like femur, tibia and humerus (Fig. 18.3.11). It also occurs in flat bones like pelvis.

Clinical Features

Clinical Features

Pain is the initial and dominating symptom. After some weeks, a bone swelling appears and progressively increases in size. On examination, the swelling is fusiform; the skin is stretched, shiny with prominent veins. The swelling is warm to touch, and may also show pulsation if the tumor is very vascular. It has variegated consistency. The patient’s general health deteriorates with anemia, loss of weight and cachexia. The patient develops pulmonary symptoms due to secondaries. Therefore, in every patient X-ray of chest must be done routinely. Biopsy must also be done in every case to establish the diagnosis.

The patient presents with gradually increasing pain, followed by swelling. The swelling is firm to soft in consistency with indefinite margins. There is usually fever, anemia and leukocytosis, and therefore, the condition often simulates subacute osteomyelitis. The swelling rapidly increases in size with involvement of soft tissues and the general condition deteriorates. It is known to metastasize in other bones like skull, vertebrae and ribs, in addition to lungs, by spread through bloodstream.



Osteosarcoma is a highly malignant primary bone tumor that occurs between the ages of 10 years and 20 years. It is more common in males. It is commonly seen in metaphysis of distal end of femur (Fig. 18.3.10), proximal end of tibia and the proximal end of humerus.

Treatment

Treatment This tumor is radiosensitive and regression following therapy is remarkable. However, the local recurrence rate is high. Hence, currently after preoperative chemotherapy, surgical resection of the tumor-bearing bone is done with skeletal reconstruction followed by postoperative chemotherapy. This regimen has increased the survival rate from 5% to 50%. Amputation is indicated in locally advanced cases.

Broadly speaking, the treatment of osteosarcoma is usually a combination of the following: • Surgery: A limb saving surgery is done, after neoadjuvant chemotherapy, if the case is diagnosed early and the



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relieved, the child is allowed to walk with a weight-relieving caliper. Avoiding weight bearing stresses prevents femoral epiphyseal deformation. This caliper is continued till the head of femur shows revascularization. Surgery is done to improve containment of the femoral head in the acetabulum.

Figure 18.3.11 Ewing’s sarcoma  

Figure 18.3.10 Osteosarcoma of lower end of femur  

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Miscellaneous Problems ransient Synovitis of the Hip

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Also called observation hip, it is a sterile inflammation and effusion, of unknown etiology, of the hip joint affecting children between 4 years and 8 years of age. The importance of this condition lies in the fact that it may be preceding other conditions such as septic arthritis of the hip or Perthes’ disease. The child, therefore, is to be kept under observation.

Clinical Features

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The main complaints are pain in the groin and refusal to move the limb or walk. There is usually no fever. The movements of the hip are restricted, especially the internal rotation. However, the child is otherwise comfortable when resting in bed with a pillow under the knee.

Treatment

 

Figure 18.3.12 Genu valgum

The child is admitted for observation. Immobilization by skin traction to the limb may relieve muscle spasm and pain. The condition resolves spontaneously within a week’s time. K

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ow egs (Genu Varum) and nock- nees (Genu Valgum) Normal Development Many children have bow legs when they start walking. Then, they develop knock-knees between the ages of 3 years and 6 years. These deformities are physiological, and will get corrected spontaneously in the majority.

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Figure 18.3.13 Clinical photograph of genu varum of both knee joints

reatment



Genu valgum denotes a malalignment in the frontal (coronal) plane, in which the part distal to the site of deformity deviates away from the midline (Fig. 18.3.12). Unilateral genu valgum may be caused by disturbance in the epiphyseal growth at the lower femur or upper tibia due to trauma or osteomyelitis. Bilateral genu valgum can be caused by endocrine or metabolic disorders, rickets and epiphyseal dysplasia or can be idiopathic. Treatment: Genu valgum deformity can be ignored in the toddlers as it may get corrected spontaneously. However, if the distance between the two medial malleoli (intermalleolar distance) is more than 10 cm at the age of 10 years, it will need surgical correction, which can be achieved by osteotomy of the femur or tibia, depending upon the site of the deformity.

Genu varum or “bow legs” is the lateral curvature of leg involving either the tibia or femur or both (Fig. 18.3.13). Mild genu varum is physiological up to 3 years of age. The other causes are: rickets, post-traumatic or infective and idiopathic.

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Normally, the foot has longitudinal and transverse arches. The normal longitudinal arch is visible on the medial side of the foot (Fig. 18.3.14). When this arch is less developed, it is called as flat foot (Fig. 18.3.15).

Causes and Types of Flat Foot •

ongenital vertical talus: The talus bone is placed vertically in the foot, instead of being horizontal which C

Genu Varum

A mild deformity can be treated by modifications in the shoes. Moderate to severe deformity needs surgical correction.

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is normal. A radiograph will confirm the diagnosis. The treatment is difficult. Manipulation and serial plaster casts may be indicated in mild cases, whereas severe cases need surgery (Fig. 18.3.16).

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Figure 18.3.16 Congenital vertical talus



• Physiological or infantile flat foot: This is the most common type, in which the child has flat feet when he or she starts walking. But gradually, the arch develops within the next 2–3 years. In such a case, no specific treatment is required. However, an arch support inside the shoe and slight modification in the sole of the foot may be prescribed. In an older child, exercises for the intrinsic muscles of foot may be taught. In severe cases, triple arthrodesis, i.e. fusion of the selected tarsal joints is indicated after skeletal maturity.

 

Figure 18.3.14 Normal arch of the foot

Scoliosis

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Scoliosis is defined as lateral curvature of the spine. It can be congenital due to growth of only one-half of a vertebra (called as hemivertebra), idiopathic (the most common type) or paralytic. The treatment should be started as early as possible to prevent progression of the curve, and also to prevent cardiorespiratory complications as a result of severe deformity.

Torticollis results from contracture of the sternomastoid muscle on one side. Thickening of the muscle (sternomastoid tumor) occurs in infancy, replaced by fibrous tissue. The tight sternomastoid muscle exerts a pull on the head tilting it on the same side. If not treated early, it results in asymmetrical development of the face. Treatment is surgical release of the tight muscle.

 

Figure 18.3.15 Flat foot

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Refractive error is an optical defect in the eye that prevents light rays from focusing on the macula, thus preventing clear vision. Most children are hypermetropic at birth; however, the eyeball enlarges over time so that the eye becomes emmetropic; if the process of enlargement continues, older children will be myopic. Refractive errors are due to an abnormality in axial length, curvature or index of the optical media. Thus, longer length, steeper curvature and higher index will cause rays of parallel light to focus sooner, in front of the retina, producing

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Visual Problems

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Eye development is critical in the first few months of life; processes that interfere with development may seriously impact vision. It is recommended that children receive their first eye screening at birth, followed by an assessment at 6 months, and thereafter, at every visit to the pediatrician (Table 18.4.1). The following children should be referred for ophthalmic evaluation as early as possible: • Abnormal history (does not make eye contact, focus on and follow objects by 3 months of age and reach for objects by 6 months of age) • Abnormal appearance (redness of eyes or eyelids, watery or purulent discharge, white cornea, white pupil, asymmetric pupil size, swelling or drooping of eyelid, squint) • Evidence of discomfort (excessive rubbing of eyes, avoids bright light, keeps one or both eyes closed most of the time).

myopia. The reverse situation will cause hypermetropia; rays of parallel light are brought to a focus behind the retina. Accommodation (increasing the curvature of the lens) shifts the focus anteriorly so that a clear image is formed on the retina. Constant accommodation in hypermetropes causes headaches, eyestrain and excessive convergence (causing convergent squint). Astigmatism results when the refractive power of the eye is different in different meridia so that different foci are formed on the retina. Suspect refractive errors when children report difficulty in reading off the blackboard, eyestrain on near work and holding books close to the eyes. Check vision using Snellen’s chart; repeat using a pinhole. In refractive errors, vision improves with the pinhole since it prevents spherical aberrations by cutting off peripheral rays. A pinhole can easily be made by creating a hole (< 1 mm in diameter) in the center of an opaque disc of cardboard. Refractive errors are commonly treated using corrective lenses such as spectacles or contact lenses. Refractive surgery can also correct some refractive errors. A

ntroduction

mblyopia

Amblyopia (lazy eye) is a partial decrease of vision in the absence of anatomical/structural abnormality. It results when there is inadequate foveal stimulation and/or abnormal binocular interaction (different visual input from the two foveae) during the first 5 years of life when the visual system is still developing. When there is a difference in the quality of the images recorded by each eye, the brain disregards the blurred image; this results in the visual system developing more slowly for that eye. Amblyopia may be due to uncorrected refractive errors, strabismus, or due to visual deprivation (ptosis, surgical lid closure, bandaging, corneal opacity, cataract). In preverbal

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Table 18.4.1 Important milestones in the development of the pediatric eye At birth 1 month 2–3 months Visual acuity Can see up to 3 m Can see up to 4 m Can see up to 8m Fixation reflex Normal optokinetic nystagmus Convergence Starts reflex Binocularity Starts Pupillary reflex Color vision Menace reflex

Sluggish Well developed Black and white and shades of gray Present

6 months 6/12

1 year 6/9

3 years 6/6

Well developed Well developed Well developed

Full color

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Xerophthalmia is a bilateral, dry, lusterless condition of the conjunctiva and cornea due to vitamin A deficiency. It occurs in malnourished children since they already have low stores

 



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The child has redness, itching and foreign body sensation in the eye, swollen lids, and rarely, reduced vision (due to corneal involvement). The type of discharge helps in differentiating between viral (watery) and bacterial conjunctivitis (mucopurulent). Viral conjunctivitis due to adenovirus or picorna virus is very common, occurs in epidemics, and may cause preauricular lymphadenopathy. Etiological diagnosis is usually not necessary. Adenoviral conjunctivitis is highly contagious (epidemic keratoconjunctivitis). The pediatrician should advise frequent handwashing, separate towels, handkerchieves, etc. to reduce the risk of spreading infection. There is no specific treatment; however, symptoms can be reduced with instillation of artificial tears, topical antihistamines or applying cold compresses. Bacterial conjunctivitis resolves spontaneously without specific treatment; however, topical, empirical antibacterial therapy results in earlier microbiological remission. O







Photosensitive pigments in the cones allow us to see colors. There are three types of cones, each containing a different pigment, red (erythrolabe), green (chlorolabe) or blue (cyanolabe) that preferentially absorb only one part of the visible spectrum. Many millions of hues can be generated by stimulation of all three cones to varying degrees. Genes contain the coding instructions for the three pigments; if the instructions are wrong, the wrong pigments are produced and the abnormal cones will be sensitive to a different wavelength. A child that has difficulty in identifying colors by 3–4 years of age could be color blind. All children, especially boys, should have a routine color vision check once during a school health checkup. Color blindness is most common for red and green. Inherited as an X-linked defect, it is seen in 10% of males and 0.4% of females. Blue color blindness (5% of people) is due to a defect on chromosome-7. Color blindness may also be acquired in conditions that involve the cones or the visual pathway (chorioretinitis, diabetic retinopathy, optic neuritis, partial optic atrophy, migraine, stroke and cerebral trauma). Unlike congenital color blindness, the acquired forms may be unilateral, progressive or transient, and show no gender predisposition. Screening tests are used to detect if a color vision defect is present or not (Ishihara pseudoisochromatic plates). More sophisticated tests are required, if the objective is to exactly classify the type and degree of defect (Farnsworth-Munsell 100-Hue test or Lantern test). Persons with abnormal color vision cannot take up jobs dealing with public safety, and the driving of commercial vehicles, train engines or airplanes; children should be aware of this when they are considering future careers.

of vitamin A; it may be precipitated by exanthematous febrile illness or persistent diarrhea. Children may report night blindness. Bitot’s spots, conjunctival and corneal xerosis, corneal melting (keratomalacia) or corneal scars may be present. Treatment comprises replacement of vitamin A, treatment of the precipitating condition, general health of the child and ocular condition. Keratomalacia requires emergency management to prevent corneal perforation. Corneal transplantation is the only treatment once corneal scars form.

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olor lindness

Figure 18.4.1 Purulent conjunctivitis in a neonate (ophthalmia neonatorum)



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children, suspect poor vision in one eye when the child protests covering of one eye (the eye with better vision), shows fixation preference for one eye, has unilateral squint or eccentric fixation. The four “Os” of amblyopia treatment are as follows: 1. ptics: Optics treat all conditions that prevent a clear foveal image from forming. 2. cclusion: Occlusion occludes the better eye so that amblyopic eye is forced to work (conventional occlusion). It should be alternated between the two eyes to prevent the occluded eye from developing amblyopia. If older children resist occlusion, atropine is used to blur vision in the sound eye (penalization). 3. rthoptics: Foveal stimulation exercises. 4. peration: For strabismus, the endpoint of therapy is alternation of fixation or equal vision in the two eyes.

phthalmia Neonatorum

Conjunctivitis occurs due to infection acquired from the birth canal. There is watering and purulent discharge from both eyes in the 1st few days of life (Fig. 18.4.1). The infection may be chlamydial, gonococcal or due to Herpes simplex. If Gonococcal, the local symptoms and signs are severe;

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It is an allergic response to protein from endogenous infections (Staphylococcus, mycobacteria, herpes simplex, helminthiasis). The patient presents with one or more phlyctens (blisters) on the bulbar or palpebral conjunctiva, limbus or cornea. The blisters ulcerate and heal by scarring, and are recurrent unless the endogenous infection is treated. The patient complains of itching, foreign body sensation and redness of eye. Corneal lesions cause pain, photophobia and may affect vision. Treatment includes topical steroids, along with investigation and treatment of infective cause elsewhere in the body. When there is local staphylococcal infection (conjunctivitis, blepharitis), give topical antibiotics.

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The common acute infections are blepharitis, stye (hord eolum externum) and hordeolum internum. Hordeola are painful swellings; there is blockage of the glands associated with an eyelash follicle (externum; Fig. 18.4.2) or meibomian gland (internum), along with staphylococcal infection. Uncorrected refractive errors and reduced immunity may be responsible for recurrent lid infections. Treat refractive errors, and prescribe empirical local antibiotics. If a lid abscess forms, it must be drained under cover of systemic and topical antibiotics. Chalazion, also due to blockage of meibomian gland, is a painless granulomatous reaction to lipid content of the gland. Chalazion may resolve on its own. If it is large or does not resolve, intralesional steroid injection may help, or it may be incised and its contents curetted under regional anesthesia.

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The child presents with pain, redness of eye, blepharospasm and diminished vision. The cornea is opaque, and there is mucopurulent (bacterial or fungal ulcer) or watery discharge (viral ulcer). There may be a history of injury with vegetative material (plant leaf, twig, animal tail; fungal ulcer), fever (viral ulcer) or abuse of steroid eye drops. Apply a sterile eye pad and refer to an ophthalmologist urgently.

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rbital ellulitis

This is a serious condition; infection of the soft tissue of the orbit usually derives from the adjacent ethmoidal sinus, or from preseptal (eyelid) cellulitis. There is painful proptosis, lid edema, restricted ocular movements, and the cornea may develop exposure keratitis. Optic nerve function may be compromised. The condition mandates admission, and immediate local and systemic broad spectrum antibiotic therapy. If an orbital abscess forms, it has to be surgically drained.

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Typically seen in diphtheritic conjunctivitis, membranes may also form on the conjunctiva when the infective organism is highly virulent or the host immunity is low. Diphtheritic membranes are difficult to peel off; treatment is directed to both the local and systemic conditions; the child must be isolated. Membranes that do peel off should be removed (pseudomembranes) as this reduces the infective load in the eye, and appropriate specific antimicrobial treatment be given.

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Figure 18.4.2 Infective swelling in the upper eyelid in the region of the eyelashes (hordeolum externum)

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there are systemic features like fever, urethritis, arthritis, endocarditis, meningitis and septicemia. A conjunctival swab will help identify the organism, but treatment should begin at once. Wash eyes copiously and frequently. Apply atropine eye ointment if there is associated keratitis or uveitis (common in gonorrhea). If the discharge is copious and purulent, treat as for gonorrheal infection: Pen G (10,000 IU/ mL) eye drops every few minutes till discharge reduces, then 2 hourly. Give parenteral ceftriaxone stat. Use ciprofloxacin eye drops in Pen-sensitive babies. In chlamydial infection (the most common), instill tetracycline/erythromycin eye ointment and give oral erythromycin. If herpes simplex, give IV or intramuscular (IM) acyclovir. Pregnant women with suspected vaginal infections should be treated well before delivery. If infected women present in labor, instill 2.5% povidone-iodine or tetracycline/erythromycin ointment into their baby’s eyes soon after birth.

Spring Catarrh is an allergic conjunctivitis due to exogenous allergens like pollen, animal hair, etc. seen mainly in the 1st decade of life, more in boys. It has a seasonal recurrence (in the warm months, subsiding in winter); it usually subsides by puberty. The child has itching and ropy mucoid discharge in both eyes. In the bulbar form, there are gelatinous papillae around the limbus. In the palpebral form, there are large papillae in the palpebral conjunctiva, giving a

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These are painless, cystic masses usually found around the orbit at birth, near the medial or lateral part of the eyebrow. They represent surface ectoderm that got entrapped during bony fusion; thus, they overlie bony sutures. They are filled with sebaceous material including hair. They may leak after trauma; extruded sebaceous material produces inflammation and pain. Dermoids may be connected by a stalk to an intraorbital component. While periorbital der moids are superficial, and thus simpler to remove surgically, orbital ones require an orbital approach. R

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Squint (strabismus) is the condition when the axes of the two eyes are misaligned relative to each other. The misalignment may be horizontal or vertical resulting in esotropia (one eye is relatively convergent), exotropia (one eye is relatively divergent; Fig. 18.4.3) or hypertropia (one eye is directed upward relative to the other). In addition, deviations may be concomitant or incomitant. Concomitant deviations do not vary with the direction of gaze; incomitant deviations vary

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Anterior uveitis in children is seen in a variety of systemic conditions; hence, the pediatrician may be the first to see these patients. Infectious causes include tuberculosis, H. simplex, herpes zoster and mumps. Noninfectious causes are more common; the strongest association is with juvenile idiopathic arthritis (JIA), where the child has no ocular symptoms and may progress to band-shaped keratopathy, cataract and glaucoma. Other causes are spondyloarthropathies and sarcoidosis. A general medical history, physical examination and specific laboratory tests may elicit cause. Children with these conditions should be seen by an ophthalmologist even if they have no ocular complaints. A complete examination of the eye and ocular adnexa is essential, including the cornea (H. simplex keratitis), uvea (granulomatous or nongranulomatous uveitis), lacri mal glands and regional lymph nodes (sarcoidosis). A fundus examination is mandatory to detect cystoid macular edema in eyes with chronic uveitis and to rule out posterior uveitis. Topical cycloplegics, and topical or periocular corti costeroids are the mainstay of treatment.

with the direction of gaze, and are usually due to paralysis of an extraocular muscle. Squint may be constant, being present throughout the day, or it may appear intermittently. Most squints develop sometime in the first 3 years of life. Newborn babies may squint occasionally, until their binocular reflexes develop; thus, any squint that presents or persists after the age of 3 months must be investigated. In many cases, the cause is not known. In some, there is a strong family history (infantile esotropia). Squint may occur in uncorrected hypermetropia (excessive accommodation to see clearly causes excessive convergence, producing convergent squint); due to poor vision in one eye; or due to cerebral palsy, hydrocephalus or brain injury. In squint, the fovea of each eye is focusing on a different object; thus, two different images reach the brain leading to confusion. The brain ignores the image coming from the deviated eye, leading eventually to strabismic amblyopia in that eye. In addition, binocular vision cannot develop so the child loses depth perception. Intermittent squint permits each fovea to receive adequate stimulation some of the time; hence treatment, though mandatory, is not emergent. Constant squint, however, needs early and aggressive treatment. If a refractive error is present, children should wear the spectacles constantly. In many cases, no other treatment is required. As the child grows, spectacle power is adjusted appropriately. If any squint remains in spite of spectacle correction, it can be corrected by muscle surgery. A small number of children require surgery on the eye muscles to straighten the alignment. After surgery, it is usually necessary to continue spectacles, occlusion and exercise as advised by the ophthalmologist. A false impression of squint (pseudostrabismus) may result from a flat, wide bridge of nose, or due to epicanthal folds so that the eyes look closer together than they really are. This appearance gradually disappears as the baby’s nose bridge grows.

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cobble stone appearance. The two forms may coexist; the cornea may be involved too. Where known, the allergen should be avoided. Just before the warm months, to delay onset of symptoms, start topical antihistaminics and mast cell stabilizers. During symptomatic periods, give topical corticosteroids (low dose/full dose) and cold compresses. Topical immunosuppressant (cyclosporine A) may be required in recalcitrant cases.

 

Figure 18.4.3 Divergent squint (exotropia), left eye (picture used with permission from Clinical Methods in Pediatrics, 2nd edition)

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Bacterial overgrowth in congenital dacryocystitis may produce an acutely painful, erythematous swelling of the lacrimal sac. The inflamed sac may rupture through the overlying skin resulting in fistula formation. Infection may spread beyond the sac to produce preseptal cellulitis, or into the orbit (orbital cellulitis). More serious complications (cavernous sinus thrombosis, blindness and death) may supervene in immunocompromised individuals. The discharge should be cultured, and immediate broad spectrum systemic antimicrobial therapy started. If an abscess forms, it should be drained. The condition should be reassessed 2–3 weeks after the acute condition subsides. Scarring from the acute event may prevent successful syringing and probing; dacryocystorhinostomy is usually indicated.



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This is a result of incomplete canalization of the nasolacrimal duct, usually due to epithelial debris, membranes or valves in the duct. There is excessive unilateral or bilateral watering soon after birth. The lacrimal sac may distend with accumulated secretions to form a palpable, cystic mass below the medial canthal tendon (mucocele). Pressure over this mass causes mucopus to regurgitate through the puncta into the conjunctival sac (regurgitation test). The condition is amenable to conservative treatment with lacrimal sac massage several times a day for a few months, to push debris into the nose. Sustained pressure should be applied directly over the lacrimal sac, just under the medial canthal tendon, with the small finger of the parent’s hand. The parent should be advised to ensure closure of the eyelids so that the puncta are occluded at all times during massage. In this way, the lacrimal sac does not empty into the conjunctival sac during massage, ensuring an adequate hydrostatic pressure to push debris into the nose. Empirical antibiotic eye drops are prescribed to prevent infection. If there is no relief after a month or two, the ophthalmologist will perform syringing and probing (under general anesthesia) to mechanically push the debris into the nose. Probing may be repeated two or three times; if it fails, surgery in the form of dacryocystorhinostomy is indicated.



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children for ocular abnormalities. Cataract can be diagnosed by noting a poor red reflex in the eye, or a white reflex in the pupil. All such children should be urgently referred to an ophthalmologist. The cause of cataract, in about a third of the cases, is obscure; a quarter show autosomal-dominant inheritance. Bilateral cataracts can be due to infection during pregnancy (rubella, chicken pox, cytomegalovirus, herpes, syphilis and toxoplasmosis), galactosemia, diabetes, hypoglycemia, hypocalcemia, drugs (corticosteroids) and trisomy or myotonic dystrophy. Congenital unilateral cataract can be associated with ocular abnormalities like posterior lenticonus and persistent hyperplastic primary vitreous. Ocular trauma is an important cause of unilateral cataract in older children (Fig. 18.4.4); uveitis and retinoblastoma are other causes. Some types of cataracts are visually insignificant, and the child may only require refractive correction. Surgery is indicated if the cataract is large enough to block vision, and must be performed as soon as possible to prevent amblyopia. The convex power of the lens has to be replaced by spectacles, contact lenses or intraocular lenses. Intraocular lenses are not implanted in children less than 2 years of age since the eyeball is yet to grow and the refractive power will change. Contact lenses or spectacles are used full time. If they are older than 2 years at the time of surgery, intraocular lenses are preferred. All children will need additional spectacle correction for near work as they get older. They will need intensive follow-up to manage refractive changes, amblyopia, squint, possible complications of surgery like glaucoma or retinal detachment, and after-cataract (inflammatory pupillary membranes or thickening of the posterior capsule after cataract surgery). If an after-cataract does form, the visual axis has to be cleared using laser or surgery. If the cataract is a familial abnormality, all siblings and offsprings must be screened within 2 weeks of birth, and periodically thereafter for some years.

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Chapter 12 on “Malignancies in Children”—(Chapter 12.6 Retinoblastoma).

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Pediatric ataract Figure 18.4.4 Corneal opacity (arrow) and cataract after injury with bow and arrow  

Cataract is a visually disabling opacity in the lens. It can occur at birth or develop later. Pediatricians play a vital role in diagnosing cataract since they are in a position to screen

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Figure 18.4.5 Sutured laceration at lateral canthus after injury with a stick



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Primary developmental glaucoma (congenital glaucoma) results when elevated intraocular pressure occurs in the first 4 years of life. It is rare, its incidence being between 1:10,000 and 1:15,000 live births. It is bilateral in 75% of cases. The principal defect is a failure in cleavage of the anterior chamber angle during embryogenesis. The characteristic clinical picture is enlargement of the eyeball; the infant sclera is more elastic than in the adult and stretches in response to elevated intraocular pressure. The enlarged eye resembles that of the ox, and the condition is called buphthalmos (ox eye). The presenting triad is watering, photophobia and blepharospasm; these result from the large edematous cornea. In general, a horizontal corneal diameter greater than 12 mm is highly indicative of the disease. Optic disc cupping is seen early, increases rapidly and reverses to some extent with treatment. Glaucoma in childhood may be secondary to ocular developmental disorders like aniridia (congenital absence of iris), or ectopia lentis (subluxation of lens). It may also be associated with systemic syndromes (Sturge-Weber syndrome, neurofibromatosis). Children with these dis orders should be referred for periodic examination to an ophthalmologist. Examination under anesthesia is mandatory to rule out other conditions that mimic congenital glaucoma (megalocornea, keratitis, ophthalmia neonatorum, muco polysaccharidosis). Large corneal diameters (vertical and horizontal), optic disc cupping, characteristic corneal edema and elevated intraocular pressure clinch the diag nosis. The mainstay of treatment is surgical. Pressure must be medically controlled before surgery. Even after successful control of glaucoma, the child needs treatment for refractive error induced in the enlarged eye and for amblyopia. Follow-up must be life-long, since the effect of surgery tends to diminish over time.

 

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Superficial oreign ody The child complains of sudden onset of foreign body sen sation, with watering and redness. While conjunctivitis can also cause foreign body sensation, the pricking sensation of a foreign body is aggravated on eyeball movement in a particular direction, or on blinking. Corneal foreign bodies may be immediately visible; if it is not dislodged by irrigating with normal saline (under topical anesthesia), refer to an ophthalmologist. A foreign body on the bulbar or inferior palpebral conjunctiva may be removed using a sterile cotton swab stick; one in the superior palpebral conjunctiva can only be visualized and removed on everting the eyelid. If eversion is not possible, refer. After removal, topical antibiotics should be prescribed for a few days to prevent infection. Corneal abrasion induced by the foreign body or by the process of its removal will necessitate padding and bandage. ­

Ocular injuries are the major cause of morbidity in children. Most occur due to unsupervised play and are preventable. Usual modes of injury in children include stick, bow and arrow (Fig. 18.4.4), ball, stone, fist gulli-danda, fireworks, scissors, knives, needles and other sharps. The type of injury may be mechanical or chemical; mechanical trauma may result in concussion or a sharp, lacerating injury. The eyelids, orbits or eyeball may be involved (Figs 18.4.5 and 18.4.6). Very often, there is a clear cut history of injury; sometimes, particularly in preverbal children, no history is given. In suspected injury, like child abuse, even if there are no obvious ocular signs, refer for ophthalmic evaluation to rule out posterior segment trauma. Ocular injuries have potential to cause loss of vision; in addition, eyelid and orbital injuries may result in disfigurement, causing 1024 psychosocial morbidity as well.

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Chemical injuries must be urgently managed at first presentation by thoroughly washing out all chemicals using any available inert solution; tap water, saline, Ringer’s lactate may be used. Particulate material should be mechanically removed, and washing should continue for 15 minutes, before referral to an ophthalmic center. In mechanical trauma too, the child should be referred; however, if there is bleeding from the eyelid or eyeball, apply a sterile pad and bandage before transport. F

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Figure 18.4.6 Subconjunctival hemorrhage after injury with a pencil

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Retinitis pigmentosa is a group of inherited disorders characterized by retinal pigment dystrophy; there is pro gressive night blindness (nyctalopia) and loss of peripheral vision (tunnel vision). It is progressive, sometimes causing complete blindness. It can show all types of inheritance, with autosomal dominant being the most common. It may be associated with systemic disease, i.e. hearing loss (Usher syndrome). Worldwide prevalence of RP is approximately 1 in 5,000. It can present at infancy up to the 3rd or 4th decade of life. The characteristic triad seen in the retina includes bone spicules in the midperipheral retina, waxy optic disc pallor

1. Adams AJ, Verdon WA, Spivey BE. Color vision. In: Tasman W, Jaeger EA (Eds). Duane’s Foundations of Clinical Ophthalmology, 15th edition. Philadelphia, Pa: Lippincott Williams and Wilkins; 2009. 2. Braverman R. Diagnosis and treatment of refractive errors in the pediatric population. Curr Opin Ophthalmol. 2007;18(5):379-83. 3. Custer PL. Blepharoptosis. In: Yanoff M, Duker JS (Eds). Ophthalmology, 3rd edition. St. Louis, Mo: Mosby Elsevier; 2008. 4. Forbes BJ, Guo S. Update on the surgical management of pediatric cataracts. J Pediatr Ophthalmol Strabismus. 2006;43(3):143-51; quiz 165-6. 5. Goldstein HP, Scott AB. Ocular motility. In: Tasman W, Jaeger EA (Eds). Duane’s Ophthalmology, 15th edition. Philadelphia, Pa: Lippincott Williams and Wilkins; 2009. 6. Rubenstein JB, Virasch V. Conjunctivitis: infectious and noninfectious. In: Yanoff M, Duker JS (Eds). Ophthalmology, 3rd edition. St. Louis, Mo: Mosby Elsevier; 2008. 7. World Health Organization. (2003). Vitamin A supplemen tation. [online]. Available from www.who.int/vaccines/en/ vitamina.shtml [Accessed December 2012].

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Retinopathy of prematurity is a fibrovascular proliferation in the retina of premature infants. Vascularization of the fetal retina reaches the periphery by 32–40 weeks of gestation. Thus, eyes of premature babies may have avascular peripheral retina. In response to hyperoxic conditions in the nursery, vasoconstriction occurs to protect the immature retina. When babies are removed from oxygen rich environments, the resultant relative hypoxia triggers angiogenic factors, which promote neovascularization at the junction of vascular and avascular retina. All babies less than 1,500 g birthweight or less than 32 weeks of gestational age at birth are at risk; other risk factors include hypoxic episodes, supplemental oxygen, sepsis, respiratory distress, hypercarbia and concurrent illness. All such babies should have retinal screening exami nations to detect ROP. The first eye examination should be performed at 27–28 weeks of gestational age, or at the 4th week of life. Follow-up examinations should continue till the retina is fully vascularized or signs of ROP develop. Treatment is in the form of laser or cryotherapy to prevent retinal detachment. Surgery is indicated in the retinal detaches; however, visual prognosis is very grave at this stage. Treatment must, therefore, begin early in order to prevent retinal complications.

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Papilledema is swelling of the optic nerve head due to elevated intracranial pressure. It is usually bilateral, and may develop over hours or weeks. Elevated intracranial pressure raises the pressure in the subarachnoid space around the optic nerve, causing stasis of axoplasm flow, buildup of toxic material and swelling. Elevation of intracranial pressure in infancy, before the fontanelles close, may not result in manifest papilledema. Symptoms specific to papilledema include transient obscurations of vision, constriction of visual field and decreased color perception. Vision may be normal until late in unresolved papilledema, when optic atrophy sets in. Causes of papilledema include malignant hypertension, central nervous system (CNS) space occupying lesions, head injury, meningitis, encephalitis, venous sinus thrombosis, hydrocephalus, craniosynostosis and use of drugs like tetracycline and corticosteroids. Investigative modalities include neuroimaging (CT scan, MRI) and venography for cause, and perimetry and fluorescein angiography to esta blish the diagnosis. Early detection, identification of cause and treatment may be life saving.

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Optic atrophy is the endpoint of any disease process that causes retinal ganglion cell axons to degenerate. In children, it can be hereditary (Leber-optic atrophy) or induced by retinal [retinitis pigmentosa (RP), retinopathy of prematurity (ROP)], orbital (compression by tumor or inflammation, trau matic neuropathy) or intracranial conditions (optic neuritis in meningitis or encephalitis). A relative afferent pupillary defect may be the only objective sign of optic atrophy. If unexplained, optic atrophy is discovered during a routine check-up; the following investigations may assist in the diagnosis of cause: fundus examination, ultrasound of orbit, CT or MRI of orbit and brain, visual evoked response, visual fields and color vision. All cranial nerves must be examined to rule out associated nerve involvement and to locate the site of lesion. Since there is no treatment for the atrophy, it is important to detect and treat the underlying cause before atrophy sets in.



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and retinal arteriolar attenuation. Some patients develop cystoid macular edema, which reduces central vision as well. There is very little treatment available; vitamin A, vitamin E, docosahexaenoic acid, acetazolamide (for macular edema) and lutein/zeaxanthin have been tried. Refraction and low-vision aids may help. Cataract surgery is done if complicated cataract develops. Gene therapy and transplantation of retinal pigment cells or stem cells is under experimentation.

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ommon Problems of ar, Nose and Throat Divya Prabhat from acoustic signs passing from the cochlea nerve to the brainstem.

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Depending upon the site of diseases, the hearing loss or deafness is classified as follows: • onductive deafness: The disease affects the external or middle ear, i.e. involving the sound conducting mechanism of the ear • ensorineural deafness: The disease affects the perceiving apparatus, i.e. cochlear or VIII nerve or any area up to the brainstem.

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• Visual reinforcement audiometry (V ): Here, a young child is conditioned to press a button when a sound is heard • onditioned audiometry: The child is taught to build a tower of bricks each time he or she hears the (test) sound.

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These are done between the ages of 2–5 years, where the child is asked verbally to perform tasks. eyond 5 years, puretone audiometry is done, which requires the child’s response to different sounds.

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toacoustic emission ( ) tests: The outer hair cells function of the cochlea and can be performed in the neonate • mpedance audiometry: Where a low frequency sound is introduced into a sealed external canal. The impedance to sound would be much greater if the tympanic membrane is stiff (e.g. middle ear fluid) than when compliant. Various graphs obtained help us to diagnose Eustachian tube block, serous otitis media, ossicular discontinuity, otosclerosis, etc. • Brainstem auditory evoked responses ( ERA): Electrical signals are picked-up by surface electrodes resulting I

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Genetic – Waardenburg syndrome – Klippel-Feil syndrome – Pendred syndrome Nongenetic – Diseases during pregnancy - Toxemia - Diabetes - Nephritis - Measles and other viral infections – Drugs taken during pregnancy - Streptomycin - Quinine - Salicylates Perinatal – irth trauma—anoxia – Hemolytic disease—kernicterus – Prematurity Postnatal – Genetic - Otosclerosis - Familial perceptive deafness – Nongenetic – Infectious diseases, e.g. measles, mumps, etc. – Trauma – Otitis media – Ototoxic drugs. –

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• 7–18 months: Distraction tests are performed. The child may be distracted from behind by various sounds • 18–30 months: Child’s cooperation is sought. The child is given simple tasks to perform in response to certain sounds.

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Management Conductive deafness is fully corrected by either medical or surgical treatment. Sensorineural deafness is managed by using a hearing-aid, which amplifies the basic sound.

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Serous otitis media is characterized by the presence of nonpurulent fluid in the middle ear, also known as “glue ear”.

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Organisms reach the middle ear: • Via the Eustachian tube following nasopharyngitis, rhinitis, sinusitis, pharyngitis, etc. • Through a perforated tympanic membrane due to a previous disease, trauma or tympanotomy • Rarely by blood-borne infections.

Tubotympanic disease (safe type) occurs as a residual effect of an acute suppurative otitis media Atticoantral disease (unsafe type) is associated with a cholesteatoma, which is a three-dimensional epidermal and connective tissue structure in the form of a sac that has the capacity for progressive and independent growth at the expense of the underlying bone (Fig. 18.5.1). The characteristic of each type is given in Table 18.5.1. O

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cute uppurative titis Media

Acute suppurative otitis media (ASOM) is nearly always a sequel to an upper respiratory tract infection, which is seen commonly during childhood. In infants, the Eustachian tube is relatively short, wide and horizontal, thus allowing easy access of milk and vomitus in the middle ear. Thus, feeding while lying down, vomiting or forcible nose blowing in older children may lead to acute otitis media.

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Myringotomy may be done only in cases of severe earache with a bulging drum or when impending intracranial complications present with an inadequate drainage.

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Living foreign bodies are killed by borospirit drops and then syringed out • Nonliving foreign bodies are removed with wax hook. Forceps should never be used for removal as they push the foreign body dangerously further in. Impacted hygroscopic foreign bodies may be removed after using glycerin drops, which would shrink the foreign body • General anesthesia may be required for the above procedure in an uncooperative child or for impacted foreign bodies.

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The types of foreign bodies that are found in the external canal may be living (e.g. maggots or insects) or nonliving (e.g. stones, beads or hygroscopic foreign bodies like pea, bean, etc.). Symptoms include pain, irritation, noise and cough.

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Antibiotic therapy is the most important form of treatment and must be used in all stages of the disease Nasal decongestant drops are used to improve drainage of the exudate via the Eustachian tube Antihistaminics are given to decongest the middle ear, Eustachian tube and paranasal sinus mucosa Analgesics to relieve pain.

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Deafness—which is of mild conductive type Fullness—with sensation of fluid moving in the ear Air-bubbles or fluid may be seen on otoscopic exami nation.

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Children with sensorineural loss not benefitting with a hearing aid are candidates for a cochlear implant, which is done as early as 10 months of age.

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Ear discharge for culture and antibiotic sensitivity X-ray mastoid to detect the destruction of air cell partitions Hearing test to detect the hearing loss

Treatment

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Aural toilet is maintained by sucking out the ear discharge Borospirit eardrops are used only after a perforation occurs. Eardrops are not recommended before a

igure 18.5.1 Different types of perforation (shaded)  

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Unsafe ear Atticoantral Attic Common Scanty, purulent and foul smelling Sometimes Not affected Mixed hearing loss Sclerotic with destruction Common Mastoidectomy

Treatment

Types

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Grommet is a hollow tube of inert material, which is placed as a ventilating tube for the middle ear spaces.

pistaxis

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Sinusitis Foreign body Antrochoanal polyp Deviated nasal septum Rhinolith Unilateral choanal atresia Meningocele/encephalocele Rhinosporidiosis.

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Allergic rhinitis Ethmoidal polypi Adenoids Sinusitis Angiofibroma Diphtheria Septal abscess Atrophic rhinitis.

Nasal Polyps Nasal polyp is prolapsed edematous respiratory mucosa.

Epistaxis is bleeding from the nose.

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Ethmoidal polyp arises from the mucosa of the ethmoidal sinuses and by the effect of gravity occupies the anterior choanae. Clinical features of nasal polyps are given in Table 18.5.2.

Table 18.5.2 Clinical features of nasal polyps Antrochoanal Ethmoidal polyp Polyp Number Single Multiple Side Unilateral Bilateral Etiology Infective Allergic Source Maxillary sinus Ethmoid sinus Age Small children Young adults Type Triradiate polyp Single attachment Direction Grow toward posterior Toward anterior choanae choanae Recurrence Rare Common Operation Nasal sinus endoscopy Polypectomy endoscopy (FESS) Abbreviation: FESS, Functional endoscopic sinus surgery  

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Antrochoanal polyp arises from the maxillary sinus, enters the nasal cavity through the natural ostia of the sinus and also passes backwards into the posterior choanae.

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Valsalva’s inflation to improve Eustachian tube function Local decongestant nose drops as well as antihistaminics for the same Myringotomy may be required, if no response to medical line of treatment Grommet insertion when recurrence is seen after a myringotomy.

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Table 18.5.1 Clinical features of chronic otitis media Clinical features Safe ear Type of disease Tubotympanic Perforation site Central Granulations Absent Discharge Copious, mucoid and nonfoul smelling Bleeding Never Respiratory tract infection Increase in the amount of discharge Audiogram Conductive hearing loss X-ray mastoid Sclerotic Complications (fatal) Nil Treatment Tympanoplasty

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Vital parameters—for evaluation of shock Hemoglobin—anemia Coagulation tests—bleeding disorders Computed tomography scan—sinusitis, fractures, tumors iopsy—malignancy.

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ge: It affects children above 5 years of age, but infants are liable to suffer from acute ethmoiditis ex: It affects both equally Acute rhinitis causes spread of infection to the sinuses by the way of their natural ostia from the nasal cavities Pharyngeal infections, especially tonsillitis act as a focus of infection Dental infections Swimming and diving lead to water penetrating into the sinus Trauma may be due to: – Contusion of the sinuses – Compound fracture of one of the sinuses – Foreign bodies – arotrauma General health, if poor, precipitates sinusitis.

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Cardiovascular system – Rheumatic heart disease – Pulmonary hypertension – Infective endocarditis lood disorders – Christmas disease – Hemophilia – Purpura – Aplastic anemia Drugs – Salicylates – Quinine Renal failure Hepatic failure Septicemia. –

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Immediate – Pressure—by compression of the nose between the thumb and the first two fingers – Ice cold packs—applied on the bridge of the nose, which may stop the bleeding by reflex vasoconstriction – Trotter’s method—the patient is made to sit upright and incline forward with mouth open and pinched (self) nostrils, then asked to breathe out quietly spitting out all the blood from pharynx Assessment of blood loss and vital parameters checked. Treatment of shock and hypovolemia Measures to control bleeding: – Cautery – Cryosurgery – Packing – Anterior nasal packing – Posterior nasal packing – Foley’s catheter – Surgery—ligation of vessels General measures – Sedation: This reduces restlessness of the patient and allays anxiety – Hematinics and multivitamins to improve the hemoglobin – Antibiotics are required along with packing to prevent infections.

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Traumatic – reach in mucosal continuity - Fractures of nose - Operations, e.g. submucosal resection (SMR), polypectomy, etc. - Nose picking – arotrauma - Nose blowing - High altitudes Inflammatory – Acute - Nonspecific rhinitis, e.g. coryza - Specific rhinitis, e.g. diphtheria, adenoiditis, sinusitis, etc. – Chronic - Nonspecific, e.g. atrophic rhinitis - Specific, e.g. scleroma, rhinosporidiosis, chronic sinusitis, etc. - Midline nasal granuloma Neoplastic – enign - Angiomatous polyp - Papilloma - Nasopharyngeal angiofibroma – Malignant - Carcinoma - Sarcoma of the sinuses/nasopharynx – Miscellaneous - Foreign body - Rhinolith - Nasal parasites

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ymptoms Headache, malaise and fever Loss of normal vocal resonance Pain around the various sinuses Referred pain in the ear

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Flushing of the cheek with swelling in case of maxillary sinusitis and involving the upper eyelid in frontal sinusitis Tenderness is elicited at the canine fossa in maxillary sinusitis and above the medial canthus in frontal sinusitis Anterior rhinoscopy reveals redness and mucosal congestion. Pus may be seen trickling from the middle meatus area.

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acteriological examination is required, if the sinusitis does not respond to antibiotic treatment. – Radiology—Water’s and Caldwell’s view/CT scan - Mucosal thickening - Opacity of sinuses - An air-fluid level Nasal sinus endoscopy. -

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ymptoms Throat pain Fever Malaise and headache Neck swelling Earache (referred).

igns Tachycardia and fever Tonsils are enlarged and congested Pharynx is often inflamed Tender and enlarged jugulodigastric lymph nodes (bila teral).

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Chronic tonsillitis Quinsy (peritonsillar abscess) Parapharyngeal abscess Suppurative cervical lymphadenitis Acute otitis media.

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Rheumatic fever Acute glomerulonephritis Sydenham’s chorea Infective endocarditis.

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Prevention by improving general condition of the child. Lowering of resistance affects the mucosal blanket integrity as well as the ciliary action Medical – Antibiotics: Appropriate for the infectious agent – Local decongestants are used. – Analgesics and anti-inflammatory drugs – Antihistaminics – Steam inhalation: For clearing out the secretions Surgical After the acute phase is over: – Correction of a deviated septum: Septoplasty – Antral puncture – Nasal sinus endoscopy to restore the normal physio logical mucociliary clearance of the sinuses via its natural ostia.

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ed rest Plenty of fluids and soft solid foods Analgesics to reduce fever and throat pain Antibiotics Gargles Tonsillectomy for chronic tonsillitis.

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ue to nasal obstruction: Mouth breathing, nasal discharge and voice becomes nasal (rhinolalia clausa) • ue to ustachian tube blockage: Earache, deafness, secretory otitis media and later chronic suppurative otitis media • ue to mouth breathing: Dribbling of saliva, noisy breathing at night, high arched palate and chronic pharyngitis • General: Mental backwardness and lethargy. D

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Adenoids are enlarged hypertrophied nasopharyngeal tonsils.

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– Narrow maxillary arch – Crowded protruding teeth – Vacant facial expression X-ray lateral skull reveals the enlarged adenoids Nasal endoscopy to visualize the adenoids Examination under general anesthesia to visualize or palpate adenoids.

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Management Medical

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igure 18.5.2 Complete collapse of the lung (R) with mediastinal shift and emphysema of the lung (L). Foreign body (supari) was removed from the main bronchus (R) F

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Antibiotics Antihistaminics Local steroid nasal sprays Improvement of general condition.

Grommet insertion for treatment of deafness Nasal sinus endoscopy for sinusitis Adenoidectomy.

 

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Tracheobronchial oreign odies



These foreign bodies may lead to a life-threatening situation due to obstruction in the respiratory passage. The absence of a definite history of foreign body aspiration, changing clinical signs as the disease evolves, may mimic various other clinical conditions, and thus, making the diagnosis a difficult challenge in children.

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Radiograph of chest shows either an obstructive emphysema or collapse or mediastinal shift or the foreign body itself (metallic) or may even be normal (Figs 18.5.2 and 18.5.3). Virtual bronchoscopy scan may be required in some cases.

Types

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Foreign bodies are divided into various types, according to the air-flow pattern: • ypass of air: Foreign bodies like a button, ring or bead, which have an opening within itself, allow passage of air to either side. Therefore, the child is never breathless, and the radiograph shows no abnormal findings other than the foreign body

 

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igure 18.5.3 Radiopaque foreign body seen in the (R) bronchus (arrow)

ne-way airway obstruction: Metallic and other nonorganic foreign bodies lead to a unidirectional obstruction in the airway. Inspiration leads to passage of air distal to the foreign body. However, on expiration, it leads to entrapment of air distal to the foreign body. This airway pattern leads to obstructive emphysema, and therefore, the radiographic findings and breathlessness • Total airway obstruction: Vegetable foreign bodies like a pea or groundnut swell up in the bronchus due to their hygroscopic nature. The increase in size of foreign body causes impaction of the foreign body onto the bronchial wall. This leads to a collapse of the lung segment distal to the foreign body and compensatory emphysema of the other one. O

Tachycardia Tachypnea Indrawing of the chest Cyanosis.

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ronchoscopy for removal of the foreign body Tracheostomy (very rare) only as an absolute emergency.

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Dermatological problems are seen by pediatrician’s everyday and comprise of around one-quarter of a busy outpatient clinic. Most children and adolescents present with skin disorders that can be easily diagnosed and treated. This chapter presents a brief account of some such skin conditions.

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of the burrow, has a slightly scaly appearance, and at the distal end, there may be a tiny vesicle, adjacent to which is the female mite. Secondary pyogenic infection may complicate neglec ted scabies (Fig. 18.6.1). At times, this may mask the original disease; therefore, scabies should always be suspected in cases presenting with extensive pyoderma. The lesions of scabies show a characteristic distribution: webs and sides of the fingers, anterior and ulnar sides of the wrist, anterior axillary fold, anterior abdominal wall and around umbilicus, the waist, lower parts of the buttocks, inner thighs, ankles, cubital and popliteal fossae. The face and palms are never affected in adults. In infants, however, they may be involved. ­

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Definition/Description

Investigations/Dermatopathology

Scabies is a skin infestation by the mite, Sarcoptes scabiei, which is usually transmitted by skin-to-skin contact and causes generalized intractable pruritus, with frequent secondary bacterial infection.

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Epidemiology/Etiology Scabies affects all ages but is most common in young adults who often acquire it by sexual contact. In infants and young children, scabies presents with different clinical features. Epidemics of scabies occur in cycles every 15 years. Nosocomial outbreaks have also occurred. The causative agent is Sarcoptes scabiei var hominis. The fertilized female parasite is responsible for the infestation; it invades the stratum corneum and forms burrows where it deposits its eggs. The eggs then hatch and continue the life cycle. The average number of adult female mites on an individual suffering from the common form of scabies is about 12. The incubation period is 14 days.

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Look with lens for typical burrows on finger webs, flexor aspects of wrists and penis Look for “dark point” at the end of the burrow—this is the mite Open this part of the burrow slowly, and the mite will stick to the needle and can be easily transferred to the slide. If there is a nodule, biopsy may reveal portions of the body of the mite in the corneal layer.

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All individuals in the house are preferably treated simultaneously. Clothes and bed sheets should be washed or dry-cleaned. The antiscabetic preparation

Clinical Evaluation



Nocturnal, severe pruritus is commonly present. In children contracting the infection for the first time, pruritus develops 1 month after infestation. In subsequent infestations, itching develops within a few days (children already sensitized to the mite and its products). The eruption is usually polymorphic consisting of small pointed papules, papulopustules, scratching marks (excoriations), sometimes vesicles and urticarial lesions. The characteristic burrows are usually present in small numbers. The burrows are grayish brown, curved or S-shaped, slightly elevated ridges, about 5 mm in length. The point of entry of the mite, the most superficial part

 

Figure 18.6.1 Infected scabies of the hands. Note the vesicular lesions with pustules

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Pediculosis apitis Definition/Description Pediculosis capitis is an infestation of the scalp by the head louse, which feeds on the scalp and neck and deposits its eggs on the hair.

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ites of predilection: Head lice are nearly always confined to the scalp. The occipital and postauricular regions are favorite sites. Head lice may rarely infest the beard or other hairy sites. S

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Head lice deposit nits on the hair shaft as it emerges from the hair follicle. So with recent infestations, nits are seen near the scalp but with long-standing infestations; nits may be 10–15 cm from the scalp. As scalp hair grows 0.5 mm daily, the presence of nits 15 cm from the scalp surface indicates that the infestation is approximately 9 months old. New viable eggs have a creamy-yellow color; empty eggshells are white. Excoriations, crusts and secondary impetiginized lesions are commonly seen and may extend onto neck, forehead, face and ears, and mask the presence of lice and nits (Fig. 18.6.2). In extreme cases, the scalp becomes a confluent, purulent mass of matted hair, lice, nits, crusts and purulent discharge, so-called plica polonica. Papular urticaria may be seen on the neck as a reaction to louse bites.

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should be applied from neck to toes. Any of the following may be used: – Permethrin 2.5–5% dermal cream, single application washed off after 8–12 hours. A second application may be indicated a week later if symptoms do not improve – Sulfur precipitate ointment 3–5% applied daily after a hot bath for three to four successive nights Gamma benzene hexachloride is applied after a hot bath; the same clothing is retained for 48 hours and then a further bath is taken and the clothing and bed sheets are changed. It must not be prescribed to infants or pregnant women or children with history of seizures Benzyl benzoate emulsion 25–33% applied to the whole body except the head for three successive nights Crotamiton 10% has an antipruritic effect in addition to its scabicidal action. The patient should take a hot bath and dry himself/herself carefully on a towel. Crotamiton should then be applied daily for 2 days followed by a bath on the 3rd day An oral antihistamine may be prescribed for itching Children should also receive systemic antibiotics if there is secondary bacterial infection (honey-colored crusts or tender erythema surrounding the lesions) Oral ivermectin 3–6 mg as a single dose is found to be very effective as a scabicide and larvicide. It is best suited for treatment of groups of children, as in boarding schools.

Treatment One of the following preparations may be used: • Carbaryl 0.5% (lotion–shampoo) or malathion 0.5% (lotion–shampoo): The lotion is applied to the scalp for a 12 hours period followed by shampooing with shampoo containing the same pediculocide. Repeat after 10 days. Unlike carbaryl, malathion has been shown to possess a residual protective effect against reinfection that lasts for about 6 weeks • Pyrethroids, e.g. tetramethrin 0.3% combined with piperonyl butoxide 3% applied for 1 hour and better left overnight. Repeat on the second day

Epidemiology/Etiology



Pediculus humanus var capitis is the causative agent. Pediculosis capitis is more common among school children, especially girls, but all ages may be affected. It does not respect any social class. Unlike P. humanus corporis (the body louse), the head louse is not a vector of infectious diseases. Transmission occurs via shared hats, caps, brushes, combs and also by direct head-to-head contact. Epidemics may occur in schools.

Clinical Evaluation

Figure 18.6.2 Infected pediculosis capitis. Note lymph node behind the right ear  

Head lice may be identified with the naked eye or using a hand lens. The majority of patients have a population of less than ten head lice. Nits, the parasite’s eggs, appear as oval grayish-white egg capsules (1 mm long) firmly cemented to the hairs. They vary in number from only a few to thousands.

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Permethrin 1% rinse (a synthetic pyrethroid) applied to scalp and washed off after 10 minutes. It is a highly efficacious agent, and is much better than gamma benzene hexachloride Gamma benzene hexachloride is applied to the scalp and left for 12 hours, followed by shampooing. Treatment may need to be repeated. It should not be used on pregnant or nursing women. Carbaryl and malathion, the acetylcholinesterase-inhibiting pedicu locides, have replaced gamma benzene hexachloride following evidence of the emergence of resistance to organochlorines Oral cotrimoxazole Ivermectol 3–12 mg stat Remaining nits may be removed using a fine-tooth comb. Patients should be re-evaluated 1 week or 2 weeks after the last pediculocide application; retreatment may be necessary if lice are found or eggs are observed at the hair-skin junction. Affected family members and contacts should be treated. Combs and brushes should be washed Secondary bacterial infection should be treated with appropriate doses of systemic antibiotics, e.g. erythromycin or cloxacillin, before the application of any pediculocide.

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They are most often on the legs and other uncovered areas such as forearms and face but sometimes they are scattered in small groups all over the body. The lesions are erythematous weals. It is difficult not to scratch the spots, which become crusted and may get infected—they are then purulent and sore. Sometimes one new spot provokes

 

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This is directed essentially toward prevention. All measures possible such as nets, covered clothing and repellants may prove futile. Treatment is then aimed at topical antipruritics (crotamiton), oral antihistamines and antibiotics if needed. Counseling forms a major portion of management with the parents be reassured of the disorder’s self-limiting course.

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mpetigo ontagiosa efinition/ escription D

BAC

Impetigo is a contagious acute pyogenic infection, which is at first vesicular and later crusted. It is a superficial infection of the upper layers of the epidermis and may be caused by Staphylococcus aureus, by Group A beta (β)-hemolytic streptococci or by both.

pidemiology/ tiology E

Papular urticaria is a reaction pattern to insect bites most commonly affecting children. Crops of very itchy red bumps, 0.2–2 cm in diameter, appear every few days. Sometimes each spot develops a fluid-filled blister. It is sometimes called “insect bite allergy”. In infants, it is given the name Strophulus infantum and in the more chronic states, called lichen urticatus. It is thought to be an allergic reaction to insects in the environment. Often after a few years, the child becomes desensitized to these insects and the reaction dies down. The most common identified causes are mosquitoes. It can be nearly impossible to work out, what a patient is reacting to. There have been reports of allergy to bird mites, carpet beetles, caterpillars and insects that live in masonry disturbed by renovation. Quite often, there exists an atopic background.

Treatment

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all the old ones to come up again and itch intensely (Fig. 18.6.3). The spots seem to remain for a few days to a few weeks and can leave persistent marks or scars, especially if they have been scratched deeply. Recurrence is the hallmark and itching is very disturbing. It can be a marker of atopy.

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Figure 18.6.3 Papular urticaria—lesions over legs of the infant

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Impetigo predominantly affects infants, preschool children and young adults during hot humid seasons. Predisposing factors include crowded living conditions, poor hygiene and neglected minor trauma. “Impetiginization” also occurs on lesions of eczema, scabies and pediculosis capitis (itchy conditions). It is important to obtain cultures of household and other close contacts, and those who are positive should be treated.

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Vesicles that rapidly progress to large, thin-roofed, flaccid bullae with little or no surrounding erythema characterize the condition. The contents of the bullae are clear at first; later on, they may be turbid. After rupture, erosions and brownish crusts form. Central healing and peripheral extension may give rise to circinate lesions (Fig. 18.6.5). The lesions are scattered and discrete, and occur on the trunk, face, intertriginous sites and hands.

Figure 18.6.4 Impetigo over the back of right thigh. Note circinate lesions that may be mistaken for ringworm infection

Figure 18.6.5 Bullous impetigo of Staphylococcal origin. Early diagnosis will prevent the development of “Staphylococcal scalded skin syndrome”  

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Erythromycin (30–50 mg/kg/day) in divided doses for 5–7 days Cloxacillin (25–50 mg/kg/day) in divided doses for 5–7 days Systemic treatment is required even when only a few localized lesions are present. This helps in combating colonization of anterior nares or nearby apparently healthy skin by staphylococci. Such colonization may lead to relapses or treatment failure if topical antibiotics are used alone. The use of systemic antibiotics is also

 

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Bullous impetigo occurs mainly in the newborn and in infants and young children, but may occasionally affect adults. It may occur in epidemic form in infant nurseries. Phage Group II staphylococci, which produce an extracellular exotoxin, is the causative agent. Phage Group II staphylococci also produce, besides bullous impetigo, a rare exfoliative disease, the staphylococcal scalded skin syndrome (SSSS). C

Systemic Antibiotics

ullous mpetigo

Bullous impetigo (staphylococcal impetigo, impetigo neonatorum) occurs as scattered thin-walled bullae arising in normal skin and containing clear yellow or slightly turbid fluid without surrounding erythema. E

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Gram’s stain of early vesicle shows Gram-positive intra cellular cocci, in chains or clusters. Use of a moistened culture swab to dissolve crusts may be necessary to isolate the pathogens. Biopsy is usually not necessary, but if done, it will show an acantholytic cleft in the stratum granulosum with leukocytes and cocci (subcorneal pustule).

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emoval of the crusts: This is done using warm olive oil or potassium permanganate 1/8,000 compresses. Removal of the crusts permits delivery of a sufficient concentration of topically applied antibiotics to the site of the lesion. Solutions such as potassium permanganate are not suitable for hairy areas like the scalp. Topically mupirocin 2% ointment/sisomicin 1% cream/fusidic acid 2% cream/ gentamycin 0.1% cream or any other suitable topical antibiotic is useful. A cream is preferred to an ointment. The antibiotic should be applied three to four times daily.

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The early lesions are thin-walled vesicles that rupture quickly leaving red wet erosions, or dry up forming gummy, golden-yellow/reddish-brown crusts. The crusts eventually separate and leave erythema that fades without scarring. The lesions are scattered and discrete, 1–3 cm in diameter, round or oval and show central healing (Fig. 18.6.4). There may be also some large confluent lesions. Satellite lesions may result from autoinoculation. The regional lymph nodes may be enlarged and tender. The face is the common site, but lesions also occur on the scalp, arms, legs and buttocks. I

essential in cases caused by streptococci to prevent possible renal complications.

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nvestigations/ ermatopathology Gram’s stain of early vesicle shows Gram-positive cocci, extracellular and within polymorphonuclear leukocytes Culture reveals S. aureus.

Treatment Sparkling cleanliness with local and general hygiene is the hallmark of management. Mupirocin 2% ointment is effective treatment for some cases of bullous impetigo, and should be applied to the lesions and nostrils. Fusidic acid 2% cream can also be used. Standard treatment, however, is the administration of systemic antibiotic: – Cloxacillin (25–50 mg/kg/day in 4 divided doses for 10 days) or alternatively, and if S. aureus is sensitive, erythromycin (30–50 mg/kg/day in 4 divided doses for 10 days). –

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The incubation period is few days. A prodrome occurs less often than commonly thought. Patients may have malaise and anorexia; fever and chills can develop rapidly, before cellulitis is apparent clinically. Higher fever (38.5°C) and chills are usually associated with streptococci; lower fever (37.5°C) is usually associated with staphylococci. Ask for history of previous treatment of prior episode(s) of cellulitis in an area of lymphedema. The patient may be an IV drug user, and the organism may have entered through drug injection. Immunocompromised patients are susceptible to infection with bacteria of low pathogenicity.

Skin Findings

Entry sites: Breaks in skin, ulcers and chronic dermatosis. The typical lesion is a plaque: red, hot, edematous and very tender area of skin of varying sizes; borders are usually poorly defined, irregular and slightly elevated; bluish-purple color is seen with H. influenzae (Fig. 18.6.6). Vesicles, bullae,



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Cellulitis affects children less than 3 years old and also older individuals. The most common organisms are Group A β-hemolytic Streptococcus pyogenes and S. aureus. In children, the common organisms include Haemophilus influenzae, Group A streptococci and S. aureus. Risk factors include diabetes mellitus, hematologic malignancies, IV drug use, chronic lymphedema, immuno compromise and pre-existing dermatosis (e.g. tinea pedis).

erosions, abscesses, hemorrhage, and necrosis may form in the plaque. Lymphangitis may occur. Cellulitis may also occur on the trunk at operative wound sites. In children, the cheek, periorbital area, head and neck are the most common sites, and H. influenzae is usually the causative organism. On the extremities, cellulitis is usually caused by S. aureus and Group A streptococci. The regional lymph nodes can be enlarged and tender.

aboratory examination of blood: White blood cell count and ESR may be elevated • ultures: Material for culture is obtained from: primary lesion, aspirate or biopsy of leading edge of inflammation, blood. Cultures are positive in only onequarter of cases. Fungal and mycobacterial cultures are indicated in atypical cases. L

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Cellulitis is an acute, spreading infection of dermal and subcutaneous tissues, characterized by red, hot, tender area of skin, often at the site of bacterial entry, caused most frequently by Group A β-hemolytic streptococci or S. aureus.

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Figure 18.6.6 Cellulitis following furuncles on the forehead. Note illdefined borders

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Supportive measures include rest, immobilization, elevation, moist heat and analgesics Given that most cases are caused by Group A β-hemolytic streptococci and/or S. aureus, initial therapy is best directed at both organisms For mild early cellulitis: If staphylococci are suspected or if agent is not known, use oral cloxacillin 0.5–1 g every 6 hours. The alternative in penicillin-allergic patients is oral erythromycin 0.5 g every 6 hours For more severe infections, use penicillin 1–2 lacs units/kg body weight + cloxacillin 2 g 25–50 mg/kg tid IV. Ampicillin 25 mg/kg IV every 4 hours may be also used. The alternative in penicillin-allergic patients is vancomycin 10–15 mg/kg tid IV. Subsequent antibiotic therapy is modified, according to response and cultured bacteria.

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Mild or limited episodes of erysipelas usually respond to oral penicillin, cephalosporins or erythromycin. More extensive and severe cases require hospitalization and IV antibiotics. Bed rest, limb elevation, cold packs and analgesics add to the child’s comfort and speed resolution of the illness. Longterm administration of oral penicillin may be warranted to prevent recurrences in selected cases. Table 18.6.1 lists down the difference between cellulitis and erysipelas as they are of prognostic significance. C

uruncles and arbuncles D

efinition/ escription

A furuncle, also called acute deep folliculitis and boil, is an acute, deep-seated, red, hot, very tender, inflammatory nodule that evolves from a staphylococcal folliculitis. A carbuncle is a conglomerate of multiple coalescing furuncles.

pidemiology/ tiology E

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The lesion is well demarcated, shiny, red, edematous, indurated and tender; vesicles and bullae sometimes develop (Fig. 18.6.7). The face (often bilaterally), arms and legs are the most common sites, although not in that order. Patches of peripheral redness and regional lymphadenopathy occasionally occur. High fever, chills, and malaise are common. Erysipelas may be recurrent and may result in chronic lymphedema. The characteristic appearance suggests the diagnosis. The causative organism is difficult to culture from the lesion but may occasionally be cultured from blood. Staining bacteria by direct immunofluorescence may also identify the causative organism, but the diagnosis is usually based on the clinical

Treatment

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Furuncles occur in children, adolescents and young adults. They are more common in boys. Carbuncles occur predominantly in men, and usually in middle or old age. Predisposing factors include chronic staphylococcal carrier state in nares or perineum, friction of collars or belts, obesity, excessive sweating, bactericidal defects [e.g. in chronic granulomatosis, defects in chemotaxis, hyperimmunoglobulin E (IgE) syndrome], malnutrition and diabetes mellitus. Furuncles and carbuncles may also complicate scabies, pediculosis or abrasions.

 

Figure 18.6.7 Erysipelas with blistering on the dorsum of left foot. Note the well-defined border

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A superficial cellulitis with marked lymphatic vessel involve ment caused by Group A (or rarely Group C or G) β-hemolytic Streptococci. An interdigital fungal infection of the foot may provide a nidus for infection. The legs are the most frequent anatomic location.

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morphology. Erysipelas of the face must be differentiated from herpes zoster, angioneurotic edema and contact dermatitis.

rysipelas

A furuncle appears as a bright-red, tender, indurated, round, follicular nodule evolving into a fluctuant abscess, with central suppuration and necrotic plug (Fig. 18.6.8). The abscess may rupture discharging purulent, necrotic debris, and forming an ulcer with an erythematous halo. The ulcer then heals leaving a scar. There may be an isolated single lesion, or few, scattered, discrete lesions. The lesions occur

 

Table 18.6.1 Cellulitis versus erysipelas Cellulitis Etiology Group A β-hemolytic streptococci, Staphylococcus aureus, Haemophilus influenzae Fever Low/high Margin Poorly defined Blister In the plaque Lymphatic Usually involved Recurrence Less frequent Treatment May need surgical intervention Long-term penicillin No need

Erysepelas Group A (C or G) β-hemolytic streptococci High Defined Advancing margin Markedly involved More frequent Appropriate medical In selected cases

1037

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(mupirocin) should be applied locally, and the patient should also receive systemic antibiotics. Heat should be applied to the auricle and the side of the face. Nasal furuncles should be treated in the early stages by the application of hot saline solution compresses inside and outside the nostril, until softening occurs. They should not be incised but steamed. Antibiotics should be given internally and applied locally. On the upper lip and nose, great care must be exercised and immediate energetic treatment instituted because of the dangers of sinus thrombosis, meningitis and septicemia developing from boils on these parts. Incision should not be made and trauma must be prevented by the use of an adequate dressing; local and systemic treatment should be prescribed. Adequate doses of systemic antibiotics are essential. Recurrent furunculosis may be difficult to control. This may be related to persistent staphylococci in the nares, perineum and body folds. Effective control can sometimes be obtained with frequent showers (hot baths) with povidone-iodine soap and antibacterial ointments (mupirocin) applied daily to the inside of the nares. The difference between furuncles and carbuncles are described in Table 18.6.2.

 

Figure 18.6.8 Multiple furunculosis

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Warm compresses and systemic antibiotics may arrest early furuncles. Cloxacillin, erythromycin or a cephalosporin should be given orally, according to the severity of the condition. When the furuncle has become localized, showing definite fluctuation, a free incision with drainage should be done without delay and the cavity should be packed with iodoform or vaseline gauze. In furuncles of the external auditory canal, irrigations and 1038 early incisions should not be attempted. An antibiotic ointment

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Herpes simplex virus (HSV) is caused by HSV-1, HSV-2 [genital (sexual)] following exposure of abraded skin or mucosal surfaces to the virus. After inoculation, the virus travels to the sensory ganglion, where it replicates and establishes latency. Recurrence occurs when the virus subsequently migrates along the peripheral sensory nerve. Lifelong latency and periodic recurrences are hallmarks of the disease. Incubation period: 3–7 days. F

linical eatures

Grouped vesicles on erythematous base followed by erosions and healing. Lymphadenopathy and systemic complaints are common during primary infection. Abrupt onset of illness, fever, listlessness or irritability, inability to eat and/or drink, gingivitis (with markedly swollen, erythematous and occasionally bleeding gums), increased drooling in infants due to pain on swallowing, vesicular Table 18.6.2 Furuncles versus carbuncles Furuncles Carbuncles Single deep follicle Multiple coalescing furuncles Children, adolescents Middle old age Bright-red, tender, indurated, round, Conglomerate of multiple follicular nodule coalescing furuncles, with separate “heads” Diabetes less common Diabetes more common  

•

Blood culture should be done in the cases with fever and/or constitutional symptoms before beginning treatment. If blood culture is positive, then IV antibiotics are necessary Incision and drainage of abscess for Gram’s stain, culture, and antibiotic sensitivity studies may be needed If the condition is recurrent, diabetes mellitus must be ruled out.

tiology



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Herpes implex

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only where there are hair follicles and in areas subject to friction and sweating, e.g. nose, neck, face, axillae and buttocks. A carbuncle is a conglomerate of multiple coalescing furuncles with separate “heads”. In the initial stage of the infection, it appears as a red, tender, hard, dome-shaped nodule, rapidly increasing in size to reach a diameter of 3–10 cm or more. Suppuration begins after 5–7 days and pus is discharged from the multiple follicular orifices. Necrosis of the intervening skin leaves a yellow slough surmounting a crateriform nodule. In some cases, the necrosis develops more acutely without a preliminary follicular discharge, and the entire central core of the lesion is shed, to leave a deep ulcer with a purulent floor.

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lesions on the tongue, buccal mucosa and palate with extension, at times, to the lips and face. (These may rupture and coalesce to form large, ulcerated areas.) Tender submandibular or cervical adenopathy are features of primary infection. Herpes labialis, gingivostomatitis, whitlow, keratoconjunctivitis are caused by HSV-1. Whereas Herpes progenitalis, Herpetic vulvovaginitis, severe form of Herpes encephalitis are caused by HSV–2. Genital herpes infections should arouse suspicion of child abuse. Lifelong latency and periodic recurrences are hallmarks of HSV infection. Ultraviolet light, stress, hormonal changes, immunosuppression, and infections precipitate reactivation. Disseminated infection with multiorgan involvement occurs when host immunity can no longer contain the viral replication, which is seen in neonates and immunocompromized children. Kaposi varicelliform eruption is a form of disseminated Herpes virus infection occurring in diseases like seborrheic dermatitis, atopic eczema. • nvestigations: Tzanck smear prepared from a fresh uninfected vesicle will show multinucleate giant cells. Serology and other tests are required in disseminated lesions • ifferential diagnosis: Neonatal sepsis, aphthosis • Treatment: Acyclovir oral or parenteral according to severity. Kaposi varicelliform eruption is managed as a dermatological emergency. D

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Figure 18.6.9 Erythematous rash over the back consisting of scaly papules—pityriasis rosea

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Pityriasis osea

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ymptomatic: Avoid irritant woolen cloths, hot baths and soap. A mild corticosteroid cream and an oral antihistamine may help. Pruritus may be controlled by ultraviolet-B (UV-B) treatment if this is begun in the 1st week of the eruption. The protocol is five consecutive exposures starting with 80% of the minimum erythema dose and increasing 20% each exposure. C

Molluscum ontagiosum efinition/ escription D

Molluscum contagiosum is due to infection with a poxvirus. The incubation period ranges from 14 days to 6 months.

pidemiology/ tiology E

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• Herald patch: (80% of patients) 2–5 cm, bright red with fine scaling. It usually occurs on the lower trunk or thighs, but may appear anywhere. In abortive pityriasis rosea, the condition is limited to the herald patch and does not proceed beyond (Figs 18.6.9 and 18.6.10) • xanthem: Fine, dull-pink or tawny, scaling, macules and papules with typical marginal collarette of thin scales. The lesions are oval, scattered, discrete and predominantly macular. They are usually confined to trunk and proximal aspects of the limbs (vest and pants distribution), but an inverted type of pityriasis rosea (on face and extremities) is also known. The long axes of the lesions follow the lines of cleavage in a “Christmas tree” distribution.

Figure 18.6.10 Extensive lesions of pityriasis rosea—front of trunk showing scaly patches

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Pityriasis rosea affects 2% of dermatological outpatients. Most patients are 10–35 years old. The condition occurs more commonly in spring and autumn, and one attack usually gives long-lasting immunity. For these reasons, an infectious (viral) etiology is strongly suspected though not yet proven.

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Pityriasis rosea is a benign, self-limited, exanthematous, maculopapular, red, scaling (Greek pityron, “bran”) eruption that occurs largely on the trunk.

Molluscum contagiosum occurs in both children and 1039 adults, and is highly contagious. It is more common in

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1040 Viral warts are common, contagious, epithelial tumors caused by at least 60 types of human papillomavirus (HPV).

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Tinea apitis efinition/ escription

Tinea capitis is a dermatophytosis of the scalp, the acute infection being characterized by follicular inflammation with painful, boggy nodules, which drain pus and result in scarring alopecia (kerion), and the subacute to chronic infection by scaling patches. E

Viral Warts

NG C

Cryotherapy using liquid nitrogen (10–15 seconds) Simple mechanical methods like expression of the contents of the papule by squeezing it with forceps held parallel to the skin surface, superficial curettage, or shaving off the lesions with a sharpened wooden spatula, followed by application of a silver nitrate stick, phenol or strong iodine solution Light electrocautery.

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Treatment

Treatment depends on lesion location, type, extent and duration and the patient’s age, immune status and desire to have the lesions treated. Most common warts disappear spontaneously within 2 years or with simple nonscarring treatment (e.g. a flexible collodion solution containing 17% salicylic acid and 17% lactic acid applied daily, after gentle peeling, by the patient or parent), or the physician may freeze the wart (avoiding the surrounding skin) for 15–30 seconds with liquid nitrogen. This procedure is often curative but may need to be repeated in 2–3 weeks. Electrodesiccation with curettage is satisfactory for one or a few lesions, but it may cause scarring. Laser surgery may be useful but may cause scarring. Recurrent or new warts occur in about 35% of patients within 1 year of treatment, so methods that scar should be avoided as much as possible.

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Direct microscopic examination of Giemsa-stained central semisolid core (obtained by pointed scalpel without local anesthesia) reveals “molluscum bodies” (inclusion bodies).

Treatment

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There is a variable number of small (usually 2–4 mm in size, but may rarely grow slowly reaching a diameter of 10 mm), discrete, waxy and pearly-white to skin-colored, hemispherical papules with smooth surface and umbilicated center. The papules are sessile and never pedunculated (Fig. 18.6.11). On squeezing of fully developed lesions, a white curd-like substance can be expressed. In occasional instances, a papule of molluscum contagiosum appears markedly inflamed. Ultimately, the lesions involute spontaneously. During involution, there may be mild infla mmation and tenderness. The sites of predilection include the face and eyelids, neck, forearms, trunk (particularly around the axillae), anogenital area, and thighs.

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males than in females. Infection may be acquired through direct contact, or indirectly through fomites and towels.

Common warts (verrucae vulgaris) are sharply demarcated, rough-surfaced, round or irregular, firm and light-gray, yellow, brown or gray-black nodules, 2–10 mm in diameter. They appear most often on sites subject to trauma (e.g. fingers, elbows, knees, face) but may spread elsewhere. Periungual warts (around the nail plate) are common, as are plantar warts (on the sole of foot, which are flattened by pressure and surrounded by cornified epithelium. They may be exquisitely tender, and can be distinguished from corns and calluses by their tendency to pinpoint bleeding when the surface is pared away. Mosaic warts are plaques formed by the coalescence of myriad smaller, closely set plantar warts.

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Figure 18.6.11 Molluscum contagiosum. Note the pearly dome-shaped papules with central umbilication

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Warts may appear at any age but are most frequent in older children and uncommon in the elderly. It may be single or multiple and may develop by autoinoculation. Appearance and size depend on the location and on the degree of irritation and trauma. The course may be variable. Complete regression after many months is usual, but it may persist for years and may recur at the same or different sites.

Tinea capitis affects children mainly; adults are rarely affected. Favus (inflammatory form) may affect any age. All the three major agents, namely (1) Epidermophyton,

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Where possible, infected hair should be clipped away to reduce the infectivity of the child • Oral griseofulvin (ultramicrosize): – Dose: 10–12.5 mg/kg body weight/day (maximum: 750–1,000 mg/day). Griseofulvin should be taken after meals for better absorption • “Gray patch” scaly ringworm: 125 mg bid for 1 month or 2 months • “ lack dot” ringworm: Longer treatment and higher doses are required and should be continued 2 weeks after Wood’s lamp, KOH examination, and cultures are negative • erion: 250 mg bid for 1 month or 2 months; antibiotics may be needed if there is accompanying bacterial infection. Careful removal of crusts using wet compresses should not be neglected. Kerion should never be incised! • avus: Griseofulvin should be given for 10 weeks. Itraconazole may be used instead of griseofulvin for treating certain infections, e.g. those due to Trichophyton tonsurans, although it appears to be less effective in infections caused by Microsporum canis. Topical antifungal preparations may be used as an adjunct to oral therapy, e.g. clotrimazole cream, econazole cream, miconazole cream, etc. Ketoconazole shampoo can be used to prevent spread in the early phases of therapy.



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• “Gray patch” scaly ringworm: Well-defined, round or oval patch covered with small grayish-white scales. The scales tend to be more densely arranged around the openings of the hair follicles. The hairs in the affected area are broken-off into small stumps. Some hairs are not involved due to the fact that the causative dermatophyte affects only anagen hair (85%) and spares telogen hair (15%). In most cases, the lesions are single or few in number, but multiple patches may be present rarely. Resolution is not followed by scar formation. Caused by Microsporum audouini and Microsporum canis • “ lack dot” ringworm: Round or oval patch studded with black dots. The black dots represent the upper ends of infected hairs broken-off just at the point of their emergence from the scalp. More than one patch may be present. Caused by Trichophyton tonsurans and Trichophyton violaceum • erion (Greek, “honeycomb”): Boggy, elevated, purulent, inflamed nodules and plaques that are painful and drain seropus (Fig. 18.6.12). Hairs do not break off but fall out, and can be pulled easily without pain (i.e. loose). Kerion heals with scarring alopecia. Caused mainly by dermatophytes of animal origin • avus: The lesion shows the so-called sulfur cups or scutula. These are dry, yellowish, saucer-shaped, adherent crusts surrounding the openings of hair follicles. A patch of favus is formed of many sulfur cups, some of which may coalesce forming larger areas of crusting with no specific appearance. The hairs in the

Examination of scalp under Wood’s lamp: – Examination of scalp with filtered ultraviolet (Wood’s lamp) reveals bright-green hair shafts in scalp infections caused by Microsporum audouini and Microsporum canis (ectothrix). Trichophyton schoenleinii (favus) fluorescence is grayish-green Trichophyton tonsurans (endothrix), however, does not exhibit any fluorescence Direct microscopic examination with 10% potassium hydroxide (KOH): – Spores can be seen invading the hair shaft (Trichophyton tonsurans and Trichophyton violaceum). –

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Duration of lesions: Weeks to months. Symptoms include loss of hair and pain, and tenderness in inflammatory type (kerion).

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Pityriasis Versicolor

 

Pityriasis versicolor is a chronic, asymptomatic, superficial fungus infection of the trunk, characterized by white or brown scaly macules. 1041 Synonym: Tinea versicolor

Figure 18.6.12 Inflammatory type of tinea capitis—kerion

efinition/ escription D

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involved area are not broken-off and some of them are coarse, lusterless and erect (coconut hairs). Favus runs a slowly progressive course, and may involve the whole scalp in neglected cases, with formation of scars that eventually end in permanent cicatricial alopecia • ystemic findings: Regional lymphadenopathy may be present, especially in chronic and superinfected cases.

Pedia ric ubs eciali ies

(2) Trichophyton and (3) Microsporum cause tinea capitis; although, the last two are more common.

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Pityriasis versicolor is caused by Malassezia furfur, the pathogenic mycelial phase of the normal flora yeast Pityrosporum orbiculare. It is considered noncontagious by many authorities. It is more common in adolescents and young adults. Predisposing factors: Climatic factors appear to be important, as the disease is far more common in the tropics and in the summer in temperate climates. High levels of cortisol appear to increase susceptibility—both in Cushing’s syndrome and with prolonged administration of corticosteroids (topical or systemic).

linical valuation E

 

Treatment • Topical agents: – Short applications of selenium sulfide (2.5%, to be washed off in 30 minutes) for 12 nights. Repeat every 2 weeks – Sodium thiosulfate (25%) solution in water applied once or twice daily – Miconazole cream – Topical ketoconazole (2%) either as shampoo or cream • ystemic therapy: – Ketoconazole 200 mg orally daily with breakfast for 10 days. It can cause on rare occasions liver cell damage. Relapses are very common, whatever the primary treatment, and it is better to retreat each episode rather than resort to long-term suppressive therapy. Patients should be warned that repigmentation may take several months, as otherwise they will often report treatment failure even when the organisms have been destroyed, simply because the hypopigmentation persists. –

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topic ermatitis efinition/ escription D

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Direct microscopic examination of scales prepared with KOH or Parker Quink ink/KOH technique reveals spherical, thick-walled yeasts and coarse mycelium often fragmented to short filaments. These short hyphae and round cells are commonly referred to as “spaghetti and meatballs”. Wood’s lamp examination shows faint-yellow fluorescence of scales.



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ites of predilection: Upper trunk, upper arms, neck, abdomen, axillae, groins, thighs and genitalia. The face is rarely affected.

Figure 18.6.14 Confetti-like patches of pityriasis versicolor over the back

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Skin lesions consist of sharply marginated, scattered, discrete, round or oval macules, with fine branny scaling (pityriasis = bran-like). The scales can be easily scraped off with the edge of a glass microscope slide. The macules vary in color from brown of varying intensities and hues to white, hence the term versicolor. They range in size from 1 cm to very large confluent areas more than 30 cm (Figs 18.6.13 and 18.6.14).

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Figure 18.6.13 Scaly hypopigmented patches of pityriasis versicolor over the sides of the neck

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Atopic dermatitis is an acute, subacute, but usually chronic pruritic inflammation of the epidermis and dermis, often occurring in association with a personal or family history of hay fever, asthma, allergic rhinitis or atopic dermatitis.

The onset of atopic dermatitis is usually in the first 2 months of life and by 1st year in 60% of patients. It is slightly more

1042

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• General: – The most important aspect of the management of a child with atopic eczema is sympathetic explanation of the nature of condition to the parents – Education of the patient to avoid rubbing and scratching is most important – Topical preparations are valuable but are useless, if the patient continues to scratch and rub the plaques. Topical antipruritic (menthol/camphor) lotions are helpful in controlling the pruritus – Warn parents of the special problems with herpes simplex and frequency of superimposed staphylococcal infection, for which oral erythromycin or cloxacillin is indicated. Acyclovir is indicated if HSV is suspected. • pecific: – H1 antihistamines are probably useful in reducing itching – Hydration (oiled baths) followed by application of unscented emollients (e.g. hydrated petrolatum) is a basic daily treatment needed to prevent xerosis. Soap showers are permissible in order to wash the body folds, but soap should not be used on the other parts of the skin surface – Topical anti-inflammatory agents such as corticosteroids, hydroxyquinoline preparations and tar are the mainstays of treatment. Of these, corticosteroids are the most readily accepted by the patient – Systemic corticosteroids should be avoided, except in rare instances for only short courses.

Figure 18.6.15 Eczematous reaction on the face of an infant—atopic dermatitis

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eborrheic ermatitis efinition/ escription D

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Changes are seen in the epidermis and dermis. There are varying degrees of acanthosis with rare intraepidermal intercellular edema (spongiosis). The dermal infiltrate is comprised of lymphocytes, monocytes and mast cells with few or no eosinophils.

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Atopic dermatitis patients have a tendency to develop generalized infections, especially herpes simplex. Superimposed staphylococcal infection is also frequent White dermographism on stroking involved skin and/or delayed blanch to cholinergic agents

 

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pecial eatures F

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kin lesions include: Erythema, papules, scaling, excoriations and crusting. Xerosis or dry skin is the hallmark of atopic dermatitis. Lichenification occurs with time. Lesions are usually confluent and ill defined. Atopic dermatitis passes in three different phases: 1. nfantile eczema: Infantile eczema (age: 2 months to 2 years) affects the cheeks and may extend to the forehead. The lesion is an erythematous, edematous patch covered with vesicles. Eventually, it becomes exudative and crusted. Itching may interfere with sleep. There is no lichenification (Fig. 18.6.15). 2. Childhood phase (Besnier’s prurigo—age: 5–12 years). The flexural surfaces of the limbs and neck are affected. The lesions consist of itchy papules and lichenified plaques. 3. Adulthood phase (disseminated neurodermatitis in adults). The flexures are the most commonly involved sites; the front and sides of the neck, and the eyelids may also be affected. Pruritus is severe. The lesions consist of chronic lichenified papules becoming confluent to form poorly defined reddish-brown plaques. There is no oozing (chronic).

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Bilateral cataracts occur in up to 10% in the more severe cases; the peak incidence is between 15 years and 25 years of age Ichthyosis vulgaris and keratosis pilaris are present in 10% of children Periorbital pigmentation, infraorbital fold in eyelids (Dennie-Morgan sign) and loss of lateral portions of eyebrows (Hertoghi’s sign) may be present in some.

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common in boys than girls. Over two-thirds have personal or family history of allergic rhinitis, hay fever or asthma. An allergic work-up is rarely helpful in uncovering an allergen. It is also considered by many to be related, at least in part, to emotional stress.

Seborrheic dermatitis is a very common chronic dermatosis characterized by dull or yellowish-red, sharply marginated lesions covered with greasy looking scales. It occurs in skin areas with a rich supply of sebaceous glands such as the face and scalp, and in the body folds, and presternal and 1043 interscapular regions. Dandruff (visible desquamation from

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The histopathology is not diagnostic, but generally shows features of both psoriasis and chronic dermatitis. Changes are seen mainly in the epidermis and include – Focal parakeratosis, with few pyknotic neutrophils, moderate acanthosis, and spongiosis (intercellular edema) are noted There is also nonspecific inflammation of the dermis The most characteristic feature is neutrophils at the tips of the dilated follicular openings, which appear as crusts/scales. –

•

Cradle cap (scalp) Lesions on the trunk (including flexures and napkin area) Leiner’s disease (nonfamilial and familial C5 dysfunction): Erythroderma appearing during the 1st few weeks of life, failure to thrive and diarrhea. Dandruff is usually the earliest manifestation of seborrheic dermatitis. At a later stage, perifollicular redness and scaling gradually extend to form sharply marginated patches that may remain discrete, or coalesce to involve the greater part of the scalp, and

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Infantile Variants (Fig. 18.6.16)

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Seborrheic dermatitis causes considerable itchiness. It also gives rise to soreness and much discomfort, when it is exudative and affects the major flexures. The severity and course of seborrheic eruptions are very variable, but all show a tendency to chronicity and recurrence. There are several morphological variants, which in the adult form occur in various combinations and degrees of severity.



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ffected age groups include: Infancy (confined to the 1st months of life)—the sebaceous glands are active at birth, but when stimulation by maternal androgen ceases, they become inactive for 9–12 years • Puberty: The majority of patients are between 18 years and 40 years of age; occasionally, cases are seen in old age. At all ages, the condition is more common in males than in females. –

extend beyond the frontal hairline as the “corona seborrheica”. In chronic cases, there may be some degree of hair loss. Behind the ears, there may be redness and greasy scaling, and a crusted fissure often develops in the fold. Adherent masses of sticky scale and crusts may extend into the adjacent scalp. Both sides of the pinna, the periauricular region and sides of the neck may be involved. Otitis externa, irritable and intractable, may accompany seborrheic dermatitis on other sites, or may occur alone. On the face, seborrheic dermatitis characteristically involves the medial side of the eyebrows, glabella and nasolabial folds. Areas of erythema and scaling occur, usually associated with scalp involvement. Blepharitis is common. The margins of lids are red and covered by small white scales. Yellow crusts may form and separate to leave small ulcers, healing to form scars, with destruction of lash follicles. Episodic variation in intensity is common, often being precipitated by tiredness, stress or sunlight exposure. A superficial form of seborrheic dermatitis of the chin is common in young boys in the early stages of growing a beard, but is cured when the beard is shaved off. In the flexures, notably in the axillae, the groins and the anogenital and submammary regions, and the umbilicus, seborrheic dermatitis presents as an intertrigo with diffuse, sharply marginated erythema and greasy scaling. A crusted fissure develops in the folds, and with sweating, secondary infection and inappropriate treatment, a weeping derm atitis may extend far beyond them. In both sexes, the genitalia may be involved and the lesions show the usual range from minimal erythema and scaling to severe crusted dermatitis; chronic, thickened, dull red, scaly patches of the psoriasiform variety may develop later. I

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the scalp surface) appears to be the precursor of seborrheic dermatitis, as it may progress through redness, irritation and increased scaling of the scalp to frank seborrheic dermatitis.

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Treatment

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Figure 18.6.16 Diffuse scaling over the scalp, forehead and face of an infant—seborrheic dermatitis  

1044

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• Topical therapy: – Scalp: - Removal of crusts with 2–3% salicylic acid in olive oil is very helpful, especially in infants and children - Shampoos containing selenium sulfide or zinc pyrithione or tar, and more recently, keto conazole-containing shampoos - Topical vioform-hydrocortisone lotion or betame thasone lotion following one of these medicated

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Figure 18.6.17 Erythema over the convexities and classically sparing the depth of the intertriginous areas—a case of Napkin’s dermatitis

are the convexities such as the prominences of the pubis, thighs and buttocks. The classical “tide mark dermatitis” refers to the erythematous border sparing the depths of the flexures (Fig. 18.6.17). Rarely violaceous nodules may be a presentation—the infantile gluteal granuloma— suggesting candidal reaction.

Treatment

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shampoos, for more severe cases. In very severe involvement, for short periods only, clobetasol propionate 0.05% scalp application is excellent – Face: This is a difficult therapeutic problem Topical nonsteroidal creams such as ketoconazole have been largely disappointing. Using the “foam” from a ketoconazole shampoo on the paranasal areas is very effective Hydrocortisone acetate cream, 1% or 2.5% bid with or without vioform is helpful in some. Avoid prolonged fluorinated corticosteroids because of side effects (telangiectasia, erythema and perioral dermatitis) that can occur, even with hydrocortisone acetate Ketoconazole creams and 3% sulfur and 2% salicylic acid in oil-in-water emulsion-type base are alternatives to topical corticosteroids or can be used in combination for chronic resistant lesions, especially on the face and chest Controlled, randomized, double blind studies have established oral ketoconazole as an effective treatment for seborrheic dermatitis. It must be noted that seborrheic dermatitis is not an approved indication for oral ketoconazole, and it is rarely used in this disease for prolonged periods, largely because of the potential side effects, especially hepatotoxicity. Oral ketoconazole in high doses (400 mg) has been shown to lower serum testosterone levels.

The disease is characterized by the development of erythema in its early stages. This may be followed by the formation of vesicles that rupture to ooze out serous discharge. The lesions resolve with scaling. Areas affected

cne Vulgaris efinition/ escription

Acne is a common chronic inflammation of the piloseba ceous units that affects many adolescents during puberty. The skin eruptions primarily appear on the face, upper back and/or chest and manifest as comedones, papules, nodules, cysts or papulopustules, often but not always, followed by pitted or hypertrophic scars. 1045 ­

linical valuation E

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Napkin dermatitis, also known as diaper rash or nappy rash, is very common. Some babies seem to get sore bottoms very easily, others very rarely, but they all grow out of it when they stop wearing nappies. Factors associated with the etiology include: • rritant contact dermatitis: Urine and feces will cause a rash on any skin left in contact for long enough. Sometimes ammonia is formed and burns the skin • Infection with bacteria and Candida yeasts • ther skin disorders: Psoriasis and atopic dermatitis can affect the napkin area. The nappies themselves are not responsible. Washing powder or nappy cleanser is not either, as long as the nappies have been thoroughly rinsed to remove them.

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Napkin dermatitis is an inflammatory disorder characterized by the development of erythema, papules and sometimes vesiculation with scaling affecting the napkin or diaper area of usually infants.

Topical antibiotics, antifungals and mild steroids, alone or in combination are found useful. Helpful tips to parents include: • Use disposable nappies if possible • If you use cloth nappies, use nappy liners to keep the skin dry and make sure the nappies are rinsed and dried well after washing • Change the nappies frequently—do not leave your baby in a wet or dirty nappy • Wash the baby’s bottom at every change. Use warm water to remove all urine and bowel motions. Soap might sting if a rash is present; use aqueous cream or bath oil instead. Pat dry carefully • Moisturize dry skin at every nappy change. Dimethicone (silicone) barrier creams can also help • Apply prescription creams according to directions. Strong steroid creams should not be applied to a baby’s bottom.

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noninflamed comedones. For most patients, start with tretinoin 0.01% gel and increase after 1 month to 0.025%, applied nightly after washing with a mild soap. Topical antibiotics are applied during the day. • or severe forms: – Oral tetracyclines added to the above—minocycline, 50–100 mg bid, i.e. could be tapered to 50 mg/day – In females only, severe acne can be controlled with high doses of oral estrogens combined with progesterone. However, cerebrovascular disorders are a serious risk – Oral 13-cis-retinoic acid is highly effective for cystic acne. This treatment requires experience. As retino ids are teratogenic in pregnant females, it is necessary that female patients have a pretreatment pregnancy test and they must be on oral contraceptives at least 1 month prior to beginning treatment, throughout treatment and for 2 months after treatment is discontinued. Furthermore, a patient must have a negative serum pregnancy test within the 2 weeks prior to beginning treatment. Dosage: 0.5–1 mg/ kg/day with meals for a 15–20 week course, which is usually adequate. About 30% of patients require two 4-month courses with a 2-month rest period in between. Careful monitoring is necessary during therapy, especially in patients with elevated serum triglycerides before therapy is begun.



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or mild acne: – Topical antibiotics (clindamycin, erythromycin) – Benzoyl peroxide gels (2–5%) – Topical retinoids (vitamin A acid) are effective but require detailed instructions and gradual increases in concentration. Improvement occurs over a period of 2–5 months, and may take even longer for

efinition/ escription

Urticaria and angioedema are composed of transient weals (at times spelt as wheals—edematous papules and plaques, usually pruritic) and of larger edematous areas that involve the dermis and subcutaneous tissue (angioedema). Urticaria and/or angioedema may be acute recurrent or chronic recurrent. There are some syndromes with angioedema in which urticarial weals are rarely present (e.g. hereditary angioedema). E

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omedones: Open (blackheads) or closed (whiteheads) (Fig. 18.6.18) • Papules: With (red) or without inflammation • Nodules: Noduloulcerative lesions, or cysts 2–5 cm in diameter • cars: Atrophic depressed (often pitted) or hypertrophic (keloid) scars. Seborrhea of the face and scalp is often present. Acne lesions are round; nodules may coalesce forming linear mounds. The lesions may be isolated and single (e.g. nodule) or scattered and discrete (e.g. papules, cysts, nodules). The sites of predilection include the face, neck, upper arms and trunk. S

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Skin lesions include:

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Acne starts at the age of 10–17 years in females and 14–19 in males, but it may appear first at 25 years of age. It is usually more severe in males than females, but may persist in women till the age of 35 years. Multiple factors—genetic, exposure to acnegenic mineral oils and dioxin, some drugs like lithium, hydantoin and systemic corticosteroids, endocrine factors (androgens), emotional stress (school, social problems), pressure on skin by leaning face on hands, are known to exacerbate acne. Acne is not caused by chocolate or fatty foods, or in fact, by any kind of food apart from iodine-containing products. C

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Figure 18.6.18 Early acne vulgaris with comedones and papules  

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Angioedema and urticaria can be classified as IgE-mediated, hypocomplementemic, or related to physical stimuli (water, cold, sunlight and pressure) or idiosyncratic. The syndrome, angioedema-urticaria-eosinophilia syndrome, is related to action of the eosinophil major basic protein. General types include acute urticaria (< 6 weeks), often IgE-dependent with atopic background and chronic urticaria: (> 6 weeks), rarely IgE-dependent; the etiology is unknown in 80–90%; often emotional stress seems to be an exacerbating factor. Intolerance to salicylates may be present.

The duration of lesions is hours. Skin symptoms include pruritus, pain on walking (in foot involvement), flushing, burning and wheezing (in cholinergic urticaria). Constitutional

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rythema Multiforme efinition/ escription

Erythema multiforme is a reaction of the skin to different causes as viral infections (commonly herpes simplex), bacterial, mycotic or parasitic infections, drugs or systemic diseases (rheumatic fever, systemic lupus erythematosus, etc.). This reaction pattern of blood vessels in the dermis with secondary epidermal changes is exhibited clinically as characteristic erythematous iris-shaped papules and vesiculobullous lesions typically involving the extremities (especially the palms and soles) and the mucous membranes. The characteristic lesions are also known as target lesions. The eruption begins rapidly with varying degrees of constitutional symptoms. It is distributed bilaterally and symmetrically in a centrifugal pattern. Stevens-Johnson syndrome is a severe bullous form of erythema multiforme; the mucous membranes are severely involved, and there are severe general constitutional symptoms.

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mergency cases: Emergency treatment should start with injection of adrenaline subcutaneously. Hydrocortisone IV should follow but not before adrenaline.

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Try to prevent attacks by elimination of etiologic chemicals or drugs: aspirin and food additives, especially in chronic recurrent urticaria. Detection of the cause and its elimination is the most important step in the treatment, but is rarely successful. The cause can be known from careful history taking rather than from laboratory investigations or skin testing. Antihistamines are effective in controlling symptoms if given in the proper dose. H1 blockers, e.g. hydroxyzine, ceterizine, levocetirizine; and if they fail, H1 and H2 blockers (e.g. doxepin). Prednisolone is indicated for angioedema-urticariaeosinophilia syndrome. Danazol is indicated as long-term therapy for hereditary angioedema; whole plasma or C1 esterase inhibitor may be used in the acute attack.

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Changes are observed in the dermis, and include edema of the dermis or subcutaneous tissue, dilatation of venules and mast cell degranulation. In necrotizing vasculitis, biopsy is diagnostic. In angioedema-urticaria-eosinophilia syndrome, major basic protein is present outside the eosinophils around blood vessels and collagen bundles. There is dermal edema, a perivascular lymphocytic infiltration and diffuse eosinophilic in infiltration. General laboratory tests: • erologic tests: – Search for hepatitis-associated antigen – Assessment of the complement system – Assessment of specific IgE antibodies by radioaller gosorbent test (RAST) • Hematologic tests: – Erythrocyte sedimentation rate is often elevated in persistent urticaria (necrotizing vasculitis), and there may be hypocomplementemia – Transient eosinophilia is observed in urticaria from reactions to foods and drugs

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High levels of eosinophilia are present in the angioedema-urticaria-eosinophilia syndrome • pecial examinations: – Screening for functional C1 esterase inhibitor – Ultrasonography for early diagnosis of bowel involvement; if abdominal pain is present; this may indicate edema of the bowel.

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symptoms may be present in the form of fever in serum sickness and in the angioedema-urticaria-eosinophilia syndrome. In angioedema, hoarseness, stridor and dyspnea also occur. Patients may have arthralgia (serum sickness, necrotizing vasculitis, hepatitis). Skin lesions consist of: • Transient pruritic papular weals: Many small (a size of 1–2 mm is typical in cholinergic urticaria) • Weals: Small (1 cm) to large (8 cm), edematous plaques • ngioedema: Skin-colored enlargement of portion of the face (eyelids, lips, tongue) or extremity (Fig. 18.6.19).

Age and Sex

 

Figure 18.6.19 A case of angioedema

Patients are usually 20–30 under the age of 20 years. Erythema multiforme is more frequent in males than in females.

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The duration of lesions is several days; lesions develop over 10 days or more. Patients may have a history of prior episode of erythema multiforme. Skin lesions may be pruritic or painful. Mouth lesions are painful and tender. Constitutional symptoms may be present in the form of fever, weakness and malaise. Skin lesions consist of: • Macules (48 hours) evolving to papules, 1–2 cm; lesions may appear for 2 weeks • Vesicles and bullae (in the center of papule forming the so-called iris or target lesions) • Lesions are dull red. Iris or target lesions are typical (see above). Lesions may be localized to the hands or generalized (Fig. 18.6.20). They are usually bilateral and often symmetrical. The sites of predilection include the dorsa of hands, palms, soles, forearms, feet, elbows and knees; the penis (50%) and vulva may be also involved • Mucous membranes: Lesions may occur in the mouth and on the lips (99%) (Fig. 18.6.21) • Other organs: Pulmonary manifestations may be present; the eyes may be affected with corneal ulcers and anterior uveitis.

Figure 18.6.21 Involvement of oral and conjunctival mucosae in erythema multiforme  

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rugs: Sulfonamides, phenytoin, barbiturates, phenylbutazone and penicillin • nfection: Especially following herpes simplex, myco plasma • diopathic: In more than 50% of cases, no cause can be detected. I

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ymptomatic: In severely ill patients, systemic corticos teroids are usually given (prednisolone 50–80 mg daily in divided doses, quickly tapered), but their effectiveness has not been established by controlled studies. Control of herpes simplex using oral acyclovir may prevent development of recurrent erythema multiforme.

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Toxic pidermal Necrolysis Toxic epidermal necrolysis (TEN) is a cutaneous druginduced or idiopathic reaction pattern characterized by tenderness and erythema of skin and mucosa, followed by extensive cutaneous and mucosal exfoliation. It is potentially life threatening due to multisystem involvement. Patients become severely dehydrated and protein-depleted. They require intensive care and are best managed in a manner similar to burns patients. ynonym: Lyell’s syndrome.

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Changes are observed in the epidermis and dermis. An inflammatory process is seen characterized by perivascular mononuclear infiltrate, and edema of the upper dermis; in lesions with bulla formation, there is eosinophilic necrosis of keratinocytes with subepidermal bulla formation. All attempts must be made to rule out occult viral, fungal and bacterial infections.

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Causes

Age and Sex

Figure 18.6.20 Acutely ill child with erythema multiforme  

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Patients are usually adults more than 40 years old; the disease affects both sexes equally (some studies have reported a higher incidence in middle-aged and elderly women).

Ask about history of drug intake. Toxic epidermal necrolysis occurs within days of ingestion of the offending drug (when a drug is the cause); a newly added drug is most suspected. A prodrome occurs in the majority of patients and consists of mild-to-moderate skin tenderness, fever, malaise, headache, conjunctival burning or itching, myalgias, arthralgias, nausea and vomiting, and/or diarrhea. Skin symptoms are present in the form of marked tenderness of rash, pain, pruritus and paresthesia. Patients are usually

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A biopsy will confirm the clinical diagnosis. Early findings include vacuolization/necrosis of basal keratinocytes and individual cell necrosis throughout the epidermis. Late lesions show necrosis of the entire epidermis with formation of subepidermal split above the basement membrane. Little or no inflammatory infiltrate is seen in the dermis.

Treat as a thermal burn patient in a burn unit of a hospital. Silver sulphadiazine is extremely effective, but must be used with caution over large areas for fear of absorption and resultant neutropenia. The role of corticosteroids is controversial. There is general agreement that corticosteroids should not be used in TEN that has progressed to involve 20% or more of body surface. But it is still unproven whether they may arrest the progression of TEN if given in the first 24–48 hours ntravenous fluid replacement: Water, electrolytes, albumin and plasma ebridement: Remove only frankly necrotic tissue Watch for signs of sepsis (fever, hypotension and change in mental status) onjunctival care: Erythromycin ointment Frequent suctioning is needed in oropharyngeal involvement to prevent aspiration pneumonitis Avoid reexposure to offending drug.

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Figure 18.6.22 Toxic epidermal necrolysis—note positive Nikolsky’s sign

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The prodromal rash is described as morbilliform or erythema multiforme-like. A tender erythema is initially observed. Small blisters then form, becoming irregularly confluent. The entire thickness of the epidermis becomes necrotic and shears off in large sheets, but large blisters only rarely form. Epidermal sloughing may be generalized, resulting in large denuded areas resembling a second-degree thermal burn. The idiopathic form is usually not preceded by rash but starts with erythema, which is rapidly followed by sloughing and denudation. The initial erythema affects the face and extremities, becoming confluent over a few hours or days. Denudation is most pronounced over pressure points. Scalp, palms and soles may be less severely involved or spared, but nails may be shed. Nikolsky’s sign is usually positive (Figs 18.6.22 and 18.6.23).

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Skin Findings

Mucous membranes are also severely affected; look for erythema and sloughing of lips, buccal mucosa, conjunctiva, genital and anal skin. The diagnosis is based on clinical findings and confirmed by biopsy.

Pedia ric ubs eciali ies

mentally alert, but are in distress due to severe pain. Acute renal failure and erosions in lower respiratory tract and gut may complicate the condition.

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Acrodermatitis enteropathica is a genetic disorder of zinc absorption, presenting in infancy, characterized by a triad of acral dermatitis (face, hands, feet, anogenital), alopecia and diarrhea; nearly identical clinical findings occur in older individuals with acquired zinc deficiency due either to dietary deficiency or failure of intestinal absorption.

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crodermatitis enteropathica: In infants bottle-fed with bovine milk, days to few weeks. In breast-fed infants, soon after weaning • cquired zinc deficiency: Older children. A

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crodermatitis enteropathica: Autosomal recessive 1049 trait resulting in failure to absorb zinc A

Figure 18.6.23 The child seen in Figure 18.6.22 with peeling of skin over face and neck

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pidermolysis ullosa efinition/ escription

Epidermolysis bullosa (EB) are a group of dermatoses characterized by easy bullae formation on mild mechanical pressure, and hence, the name mechanobullous disorders. The dreaded complications are bleeding, infection and scarring.

pidemiology/ tiology E

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Patients are irritable with depressed mood. Infants and children have growth failure (Figs 18.6.24 and 18.6.25).

Dietary or IV supplementation with zinc salts with two to three times, the recommended daily allowances restores normal zinc status in days to weeks. Oral zinc in a dosage of 10 mg/kg of elemental zinc is as effective as parenteral administration and needs to be continued for at least 6 months.

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Treatment

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Skin, mucous membrane and hair are involved. The skin lesions often become secondarily infected with Candida albicans and S. aureus. The lesions are initially pink, and later, brightly erythematous. They are initially confined to the face (particularly perioral), scalp and anogenital area. Later, the hands and feet, flexural regions and trunk become involved. There is impaired wound healing.

omplete blood count: Reveals anemia hemistry: Serum/plasma zinc levels are low rine: Urinary zinc excretion is reduced ermatopathology: Intraepidermal clefts and blisters are observed with acantholysis. U

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cquired zinc deficiency: Secondary to reduced dietary intake of zinc Malabsorption (regional enteritis, following intestinal bypass surgery for obesity) – Increased urinary loss (nephrotic syndrome) – Prolonged parenteral nutrition without supplemental zinc – Predisposition for acquired zinc deficiency: Pregnancy, growing child or adolescent. – –

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All forms of EB are genetic and most present at birth. There is no gender predilection. Most babies have impaired quality of life due to the psychological effects of easy blistering and scarring.

Several clinical types and subtypes have been described. Five of them need to be known (Fig. 18.6.26).  

Figure 18.6.24 Acrodermatitis enteropathica—note acral lesions and scanty hair

Figure 18.6.26 Epidermolysis bullosa in an infant. Note the blistering and scarring over the lower limbs  

Figure 18.6.25 Posterior aspect of child seen in the figure  

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Treatment of EB is essentially supportive. Sterile dressings and topical antibiotics (2% mupirocin) form the mainstay of therapy. Cutaneous infections unresponsive to topical antibiotics will need systemic antibiotics (cloxacillin). Nutritional support is essential in the form of soft flexible intragastric feeding in selected children. Attempts of intermittent esophageal dilatation may be fruitful. Apparently, the management of severe forms of EB demands optimal care from the combined efforts of parents, pediatricians, and dermatologists. Genetic counseling plays an important role. S

Figure 18.6.27 Staphylococcal scalded skin syndrome—exfoliation and erythema over face and neck

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Treatment For a newborn, hospitalization and treatment with IV cloxacillin, 200 mg/kg body weight/day in divided every 4 hours, are preferable. Hospitalize infants with extensive sloughing of skin or if parental compliance to treatment is questioned. With reliable home care and mild involvement, cloxacillin, 30–50 mg/kg body weight/ day, can be given orally. Topical care includes baths or compresses, and mupirocin or bacitracin, or silver sulfadiazine/ointment.

cknowledgment ­

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The author wishes to thank Dr Parimalam Kumar, Associate Professor of Dermatology, hanjavur edical ollege, han javur, for her input and assistance in preparing the manuscript.

ibliography 1. Bhave SY. Adolescent Health: Case Scenarios, 1st edition. New Delhi: Byword Books Private Limited; 2011.



 

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• A low-grade fever may be present. The child is irritable • kin findings: – Bullous impetigo: Lesions are often clustered in an intertriginous area and consist of intact flaccid, purulent bullae. Rupture of the bullae results in moist red and/or crusted erosive lesions • Generalized taphylococcal scalded skin syndrome: It is a very tender, ill-defined erythema occurs initially. With epidermolysis, the epidermis appears wrinkled. The unroofed epidermis forms erosions with red, moist base. Initially, lesions are present on the face (periorificially), neck, axillae and groins, becoming more widespread in 24–48 hours. The initial erythema and later sloughing of the epidermis are most pronounced periorificially on the face, and in the flexural areas and pressure points: on the neck, axillae, groins, antecubital area and back • carlatiniform syndrome: Presentation is like scarlet fever but without pharyngitis, tonsillitis and strawberry tongue Nikolsky’s sign (gentle lateral pressure causes shearing off of superficial epidermis) is positive (Fig. 18.6.27) • Mucous membranes: Usually uninvolved.

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Age: Staphylococcal scalded skin syndrome occurs mainly in infants and young children. Adults with immunosuppression or renal insufficiency are subject to SSSS Etiology: S. aureus of phase Group II, mostly Type 71.

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ynonyms: Pemphigus neonatorum, Ritter’s disease.

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• Gram’s stain: – ullous impetigo: Findings include pus in bullae and clumps of Gram-positive cocci within polymorphonuclear leukocytes (PMNL) – Generalized taphylococcal scalded skin syn­ drome: Gram-positive cocci are only observed at colonized site, not in the areas of epidermolysis • acterial culture: – Bullous impetigo: S. aureus is isolated – Generalized staphylococcal scalded skin syndrome: S. aureus is only present in colonized site of infection, i.e. umbilical stump, conjunctiva or external ear canal; culture of sloughing skin or bullae usually yields no pathogens.

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Staphylococcal scalded skin syndrome is a toxin-mediated epidermolytic disease characterized by erythema and widespread detachment of the superficial layers of the epidermis, resembling the effects of scalding. It occurs mainly in newborns and infants under 2 years of age. Severity ranges from a localized form, bullous impetigo, to a generalized form with extensive epidermolysis and desquamation.

 

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6. Paller AS, Mancini AJ. Hurwitz Clinical Pediatric Dermatology: A Textbook of Skin Disorders of Childhood and Adolescence, 4th edition. Toronto: Elsevier Saunders; 2010. 7. Parthasarthy A. Partha’s Fundamentals of Pediatrics, 1st edition. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2007. 8. Thappa DM. Clinical Pediatric Dermatology, 1st edition. India: Elsevier Publishers; 2008. 9. Thomas J. Atopic dermatitis. In: Thomas J (Ed). Pediatric Dermatology Ward Rounds, 1st edition. New Delhi: Jaypee Brothers; 2007. pp. 17-19.

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2. Bhave SY. Bhave’s Textbook of Adolescent Medicine, 1st edition. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2006. 3. Gowrishankar NC, Lakshmi S, Ravikumar T, et al. Management Update for Common Pediatric Problems, 1st edition. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2004. 4. Irvine AD, Hoeger PH, Yan AC. Harper’s Textbook of Pediatric Dermatology, 3rd edition. London: Blackwell Publishing Ltd.; 2011. 5. Jones SL. Paediatric Dermatology, London: Oxford University Press; 2010.

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ruption Hematoma

Very rarely a bluish, purple elevated area of gingival tissue, commonly caned “eruption hematoma” develops a few weeks before the eruption of a primary or a permanent tooth. The blood-filled “cyst” is most frequently seen in











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evelopment of eeth

The teeth are derived from highly specialized cells of ectodermal and mesodermal origin. Ectodermal cells perform special functions such as enamel formation, odontoblastic stimulation and determination of the shape of the crown and root. These cells disappear after performing

Table 18.7.1 Primary dentition Eruption sequence Central incisors 6–7 months Lateral incisors 8–9 months Canine 16–18 months First molar 12–14 months Second molar 20–24 months Completion of enamel formation Central incisors 11/2 months Lateral incisors 21/2 months Canine 9 months First molar 6 months Second molar 11 months Central incisor (6–7 months) Lateral incisor (8–9 months) Canine (16–19 months) First molar (12–14 months) Upper jaw second molar (20–24 months)  







































































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The primary dentition needs special care, and should be preserved till its anticipated exfoliation. The main functions are: • Mastication • Appearance • Speech • Psychology of having teeth • Stimulation of growth of the jaw through mastication • Prevention of malocclusion through maintaining arch length. Premature loss of primary molar leads to more severe malocclusion • Guides occlusion.



The primary dentition comprises of 20 teeth: four incisors, two canines and four molars in each jaw. The permanent dentition comprises of 32 teeth: four incisors, two canines, four premolars and six molars in each jaw. They are represented as follows with two digits for easy reference. Primary dentition 55 54 53 52 51 61 62 63 64 65 85 84 83 82 81 71 72 73 74 75 Permanent dentition 18 17 16 15 14 13 12 11 21 22 23 24 25 26 27 28 48 47 46 45 44 43 42 41 31 32 33 34 35 36 37 38 The primary (Table 18.7.1 and Fig. 18.7.1) and permanent (Table 18.7.2 and Fig. 18.7.2) dentitions have distinct morphological characteristics, which identify them as incisors, canines, premolars and molars.

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Dental diseases affecting the child may or may not be symptomatic. Further certain physiological changes like eruption of a tooth, may be associated with inflammation, etc. Pediatricians should equip themselves to differentiate the physiological changes from pathological lesions. Involving the parents in the prevention, treatment and recurrence is particularly important in pediatric practice. Prevention of dental disease should start from educating the pregnant mother. Dental diseases affecting the child are not the same that affect the adult. The target organs are the same like teeth, gingiva, etc. but the etiopathogenesis are different because: • The primary dentition is morphologically different • Food habits are different from that of the adult • Poorer control over maintenance of oral hygiene. The pediatrician should be aware that teeth and jaws are in the formative stages. They should guide the parents, not only in the prevention of dental diseases, but also in ensuring ideal and optimal growth of the dentition, both primary and permanent.

their functions. Mesodermal cells persist throughout their life and form dentine, pulpal tissue, cementum, periodontal membrane and alveolar bone. Each tooth, in achieving morphologic and functional maturity, through a well-defined and characteristic lifecycle is composed of many stages. These stages of development are: • Growth • Calcification • Eruption • Attrition • Resorption and exfoliation.

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primary second molar to first permanent molar regions. This condition develops as a result of trauma, which usually subsides within a few days when tooth erupts through the tissue and the hematoma subsides.

Dental caries continues to affect a large number of children, and hence, they should receive significant attention in



every day practice. Due to the high incidence, the treatment and prevention of this disease continues to occupy a major portion of dental practice in children. Dental caries is preceded by the formation of microbial plaque. It is generally, accepted that acid resulting from the action of microorganisms on carbohydrates causes dental caries. It is characterized by a decalcification of the inorganic portion, and is accompanied or followed by disintegration of the organic substances of the tooth. It has been seen to affect the primary and permanent dentition. C

tiopathogenesis of ental aries D

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Bacteria, appropriate substrates (sucrose) and individual susceptibility are the three major factors in the etiopatho genesis of dental caries. Dental caries is classified as: • Smooth surface caries • Pit and fissure caries. ­

 

Table 18.7.2 Permanent dentition Eruption sequence permanent dentition Central incisors 7–8 years Lateral incisors 8–9 years Canine 11–12 years First premolar 10–11 years Second premolar 10–12 years First molar 6–7 years Second molar 12–13 years Completion of enamel formation Central incisors 4–5 years Lateral incisors 4–5 years Canine 6–7 years First premolar 5–6 years Second premolar 6–7 years First molar 21/2–31/2 years Second molar 7–8 years Lateral incisor (8–9 years) Canine (9–12 years) First premolar (10–11 years) Second premolar (10–12 years) First molar (6–7 years) Second molar (12–13 years)

 

Figure 18.7.2 Eruption sequence—permanent dentition

 

Figure 18.7.1 Eruption sequence—primary dentition

Smooth surface caries: Smooth surface caries develops on the proximal surfaces of the teeth on the gingival third of the buccal and lingual surfaces. It is generally, preceded by the formation of a microbial or dental plaque. The earliest manifestation of incipient caries of the enamel is the appearance beneath the dental plaque of an area of decalcification, which resembles a smooth chalky white area. First change is usually a loss of interprismatic or interrod substance of the enamel, with increased prominence of rods. There is an appearance of transverse striations of the enamel rods, dark lines or bands occurring in right angles, to the enamel prisms. Another change is the accentuation of the incremental striae of retzius due to loss of minerals, which causes the organic structure to appear more prominent. Pit and fissure caries: Pit and fissure caries develops in the occlusal surface of the premolars, molars and in the lingual

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Nursing bottle syndrome Milk bottle syndrome Nursing caries. Various theories have been put forward for the etiopathogenesis of dental caries of enamel and dentin (Figs 18.7.3A and B).

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Advanced Lesions Decalcification of the walls of the individual tubules leads to their confluence. A thickening before complete disintegration of the enamel can be distinguished, beginning on the dentinal side of the lesion (Fig. 18.7.3D). C

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iagnosis of ental aries



A sharp probe can be used to examine the tooth under good illumination, to detect the presence of dental caries. Occlusal caries can be detected best by mouth mirror and explorer even at the early stages where radiograph cannot detect. The radiograph is sometimes useful for a complete oral examination by the dentist. The interproximal lesion appears as a small radiolucent area of the enamel. Opaque discoloration in the enamel is usually, the earliest evidence of dental caries. There may not be any pain even when dental caries has involved enamel. The enamel caries can be there for several months but when the caries extents into the dentine, it spreads very fast and reaches the pulp, which becomes very painful. Hence, periodical dental check-up with proper illumination, with a sharp explorer and mouth mirror will help to detect dental caries, which can be filled with metal or any other restorative resins. It must also be understood that the enamel is incapable of regeneration. Hence, there is a need for a foreign material to repair the decayed enamel. However, remineralization in the enamel has been found to be possible with topical fluorides and suitable diet, rich in calcium and phosphorus.

Management of ental aries C

According to Massler (1945), “Rampant caries is defined as suddenly appearing, widespread, rapidly burrowing type of caries, resulting in early involvement of pulp and affecting those teeth usually regarded as immune to ordinary decay.”

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The initial penetration of the dentin by caries may result in alterations in the dentin described as dentinal sclerosis. It is a reaction of vital dentinal tubules and a vital pulp, which results in decalcification of the dentinal tubules that tends to seal them off against further penetration by microorganisms.

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Dental caries, left untreated extends to the dentinoenamel junction where greater number of dentinal tubules act as a tract leading to the dental pulp, along with the microorganisms (Fig. 18.7.3C).





Microorganisms acting on carbohydrates produce enough acid to decalcify tooth structure, particularly acidogenic streptococci, lactobacilli, diphtheroids, yeast, staphylococci and certain strains of Sarcinas, including S. mutans, S. sanguinis and S. saliva.

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Though there are several etiological factors for early childhood caries, which was earlier referred to as rampant caries, one of the important factors that deserves special mention is sugar-containing liquid oral medicines. Some of these pharmaceutical preparations have been reported to have mean sugar content of 55% to make them more palatable and mask the unpleasant taste of drugs, especially for children. Sucrose also acts as a preservative, solvent and a bulking agent. It is also cheap, nonhygroscopic and easy to process. Sugars, metabolized by bacteria to acid end products, lower pH within the bacterial plaque and cause ionic dissolution, leading to enamel and dentin demineralization. Further diminution of salivation and mastication during night, increases the cariogenic potential of medicines. Some sedatives, anticonvulsants and antihistamines also lower the salivary flow, which further enhances the cariogenic process. Today, the most widely used caloric sweeteners are xylitol and sorbitol, replacing sucrose in tablets, chewing gums, pharmaceutical preparations. Xylitol has gained special attention, because it cannot be metabolized by oral microflora and practically no acid is formed. In addition to poor dietary habits such as frequent consumption of sugar-containing products like snacks, biscuits, ice cream, etc. lack of oral hygiene, bottle-feeding during the night, is also associated with early dental caries. High frequency of sucrose intake increases the cariogenicity of plaque with resultant dental caries formation.

Acidogenic Theory

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surface of the maxillary incisors. It may appear brown or black and feel soft. A fine explorer when passed over the tooth surface will “suffer a catch”. The enamel directly bordering the pit or fissure may appear opaque or bluish white, which denotes the undermined lesion.

• Reduction in the intake of freely fermentable 1055 carbohydrates: Frequency of eating and eating between meals has a direct bearing on the incidence of

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Figures 18.7.3A to D (A) Dental caries of enamel; (B) Dental caries of dentin; (C) Pulpitis; (D) Root abscess

 

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dental caries, particularly in children. The incidence is more when there is more sugar intake • Topical application of fluorides is very useful • Discouraging sweets help • Plaque control can be achieved by tooth brushing, flushing, scaling and antiseptic mouthwashes • Water fluoridation: It is important to understand that fluoride incorporation is beneficial only at the time of calcification of the tooth. There is evidence pointing to considerable tooth decay inhibition when the community water supply having fluoride in the drinking water is approximately 1 ppm, marked inhibition of dental caries without producing significant mottling of the enamel is seen • iet: Feeding during sleep should be discouraged. During sleep, salivary flow is diminished and swallowing reflex is absent. Hence, stagnation of milk is possible. The clearance of milk can be encouraged by intake of water. It has been observed that incidence of dental caries is high whenever bottle-feeding is preferred to breastfeeding. Further breast-feeding also help in proper development of orofacial structures. Drinking more soft 1056 drinks causes increased susceptibility to dental caries. High-protein diets, fats, phosphates and detergent diets have been found to be cariostatic. Sucrose,

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sweets, chocolates, jams and ice cream are found to be cariogenic etergents diet: Any food that sticks to the teeth favors caries activity. Hence, such foods should be avoided. Detergent diets play a useful role in the prevention of dental caries. It serves two functions: (1) the fibrous content helps in better blood circulation in the gingival and (2) it removes all the food debris and plaque between teeth and gums and leaves the mouth clean. It has been observed that cheese and peanuts inhibit caries activity. Almonds and groundnuts are rich source of calcium and phosphorus. Amongst dried fruits, apricots, figs and dates also provide rich source of calcium and phosphorus Pit and fissure sealants: This is a very important treatment procedure, which protects susceptible surfaces. With improved utilization of this underutilized preventive measure, significant economic and health benefit can be realized estoration of the decayed tooth: The first step is to prevent further progression of the lesion. Gross superficial excavation of the caries and filling the cavity with zinc oxide—eugenol will temporarily arrest the caries process and prevent its rapid progression to the deeper tissues. Further, it helps in the sterilization of the cavity walls. These cavities can be later filled by permanent filling material. Dental amalgam have been studied extensively for safety and it has with stood the test of time, there is still a place for dental amalgam. A new method of treating dental caries that involves neither drill, water, nor electricity called atraumatic restorative treatment (ART) consists of manually cleaning dental cavities with hand instrument and filling them with an adhesive fluoride releasing material traumatic restorative technique: The ART is a procedure based on removing carious tooth structure using hand instrument alone and restoring the cavity with an adhesive restorative material. At present, the restorative material of choice is glass ionomer cement.

cute Herpetic Gingivostomatitis

Acute herpetic gingivostomatitis is an infection of the oral cavity caused by a specific virus. Secondary bacterial infection complicates the clinical picture. This is caused by the HSV. The condition usually occurs during and immediately after an episode of febrile disease such as pneumonia, influenza or typhoid. It also tends to occur during periods of anxiety, strain or exhaustion and during menstruation.

Clinical Features This condition appears as a diffuse, erythematous, shiny involvement of the gingiva and the adjacent oral mucosa with edema and gingival bleeding. In the initial stage, it is characterized by the presence of discrete spherical gray vesicles, which may occur on gingiva, the labial and

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Management The treatment consists of: • Local treatment for alleviation of the acute inflammation should be started immediately • Systemic—appropriate supportive treatment to correct malnutrition and suitable antibiotics.

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While dental caries has been regarded as the major dental disease throughout the world affecting the child, malocclusion is only next. Malocclusion may involve four tissue systems: 1. Teeth 2. Bones 3. Muscle 4. Nerves. The teeth are irregular, jaw relationship may be good and muscle and nerve function normal. Teeth may be regular in their alignment but an abnormal jaw relationship may exist so that the teeth do not meet properly during function.

Habits

Treatment Specific antifungal agents such as nystatin has been beneficial in the treatment, suspensions of nystatin, held in contact with the oral lesion, have been successfully used in even chronic or severe cases of the disease. Painting the lesion with gentian violet is an older, but effective treatment.

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mpact of pediatric oral habits: Oral habits can manifest in variety of activities, which may or may not be a concern to the child or parents. They include digit sucking, mentalis habits, lip wetting, lip sucking, abnormal swallowing, tongue thrusting, posture habits and self-mutilation. Assessment of such habits should be identified immediately to avoid longterm effect on the craniofacial complex and dentition. R







The two types of candidiasis are: 1. Mucocutaneous candidiasis 2. Systemic candidiasis. The mucocutaneous form includes oral or oropharyngeal forms. The systemic form involves chiefly the eyes, kidneys and skin through hematogenous spread.

A well-defined punched-out, crater-like depressions at the crest of the interdental papillae is always seen. The surface of this gingival crater is covered by grayish, pseudomembranous slough, demarcated from the remainder of the gingival mucosa by a pronounced linear erythema. The other salient features are constant radiating, gnawing pain that is intensified by eating spicy or hot foods, metallic taste, pasty saliva and hypersalivation. Halitosis is always present much to the annoyance of the child and others which is often very penchant. Local lymphadenopathy and a slight elevation in temperature are common. However, in severe cases, high fever, increased pulse rate, leukocytosis, loss of appetite and general lassitude are also seen.



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Candidiasis is a disease caused by infection with a yeast-like fungus, Candida albicans; although, other species may also be involved. This microorganism is relatively a common inhabitant of the oral cavity, gastrointestinal tract and vagina of clinically unaffected persons. This disease is said to be the most opportunistic infection in the world. Acute pseudomembranous candidiasis is one of the more common form of the disease. It may occur at any age, but is especially prone to occur in the debilitated or the chronically ill, or in infants. The oral lesions are characterized by the appearance of soft, white slightly elevated plaques most frequently occurring on the buccal mucosa and tongue, but also seen on the palate, gingival and floor of the mouth. The plaques resemble milk, curds consist chiefly of tangled masses of fungal hyphae with intermingled desquamated epithelium, keratin, fibrin, necrotic debris, leukocytes and bacteria. The white plaque can be wiped away with a gauze leaving a normal appearing mucosa or an erythematous area. Chronic hyperplastic candidiasis is often spoken of as the leukoplakia type of candidiasis. The oral lesions consist of firm, white persistent plaques, usually on the lips, tongue and cheeks. These lesions persist for many years.

Acute necrotizing ulcerative gingivitis (ANUG) is an inflammatory destructive disease of the gingiva, commonly known as Vincent infection. Spirochetal organism and fusiform bacilli termed Borrelia are always found in the disease.

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buccal mucosa, soft palate, pharynx, sublingual mucosa and tongue. After 24 hours, the vesicles rupture and form painful small ulcers with a red, elevated halo like margin and a depressed yellowish grayish white central portion. Course of the disease is limited to 7–10 days, the diffuse erythema and edema persist for several days. Scarring does not occur, localized form consists of numerous pinpoint vesicles. The vesicles rupture and form painful ulcerations. The disease is accompanied by generalized soreness of the oral cavity, which interferes with eating and drinking. The ruptured vesicles are the focal sites of pain and sensitivity to touch, thermal changes, foods such as condiments and fruit juices. In infants, the disease is marked by irritability and refuse to take food. Herpetic involvements of lips or face with vesicles and surface scab formation may be present. Cervical adenitis, fever as high as 101°F and generalized malaise are common. Treatment is only supportive and symptomatic. Antibiotic therapy is of considerable aid in the prevention of secondary infection.

ole of Pacifiers

Pacifiers can cause malocclusion of the anterior teeth and also posterior cross bites, depending on the frequency,

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Treatment planning is based on: • Case history • Clinical examination • Plaster study casts • Radiographs—periapical, bitewing and panoramic • Facial photographs. Treatment should also include: • Correction of abnormal pressure habits, if any • Extraction of retained primary teeth • Extraction of supernumerary teeth, depending on the merits of each patient. The cause of malocclusion should be identified, and wherever possible, should be eradicated before starting the treatment. Otherwise, the treatment can be incomplete, and moreover, there can be relapse of the malocclusion. This is 1058 particularly more relevant when there is a pernicious habit existing. The treatment for malocclusion is usually simple



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• Spacing: Loss of contact between the teeth occurs when arch length is more compared to total width of the teeth or when the teeth moves out of arch alignment • rowding: When arch length is less compared to total width of the teeth, crowding occurs • verjet: This is the horizontal distance between the palatal surface of upper incisors and the labial surface of lower incisors when teeth are in occlusion • verbite: This is the vertical distance covered by the upper incisors over the lower incisors when teeth are in occlusion • rossbite: Normally, lower teeth are slightly overlapped by the upper teeth but if the lower teeth are positioned outside the upper arch when teeth are in contact, then it is crossbite, which can be anterior or posterior • pen bite: It can be anterior or posterior with space present between the incisal/cuspal edges of the upper and lower teeth during occlusion • ip incompetence: Lips do not contact each other during the rest position • otation: Teeth are rotated.

1. Ahiropoulos V. Fluoride content of bottled waters available in Northern Greece. Int J Paediatr Dent. 2006;16(2):111-6. 2. Balappanavar AY, Nagesh L, Ankola AV, et al. Antimicrobial efficacy of various disinfection solutions in reducing the contamination of toothbrush—a comparative study. Oral Health Prev Dent. 2009;7(2):137-45. 3. Bond SW, Fields CD. Formulating sugar-free oral liquid medicines. In: Rugg-Gunn AJ (Ed). Sugarless: The Way Forward: Proceedings of an International Symposium Held at the University of Newcastle at Tyne, UK, September, 1990. London: Elsevier Applied Science; 1991. 4. Bottled Water Industry in India. [online] Available from: www. gits4u.com/water/water16.htm [Accessed October 2012]. 5. Brown D. Amalgam use in pregnant women. Br Dent J. 1998;184(11):524-5. 6. Carlisle D. Feeding babies with cleft lip and palate. Nurse Times. 1998;94(4):59-60. 7. Curzon MEJ, Roberts JF, Kennedy DB. Kennedy’s Pediatric Operative Dentistry, 4th edition. Bristol, UK: John Wright and Sons; 1996. 8. Feigel RJ. The use of pit and fissure sealants. Pediatr Dent. 2002;24(5):415-22. 9. Gardner DE, Norwood JR, Eisenson JE. At-will breast feeding and dental caries: four case reports. ASDC J Dent Child. 1977;44(3):186-91. 10. Gower WA. Self-assessment picture tests in dentistry: Pediatric dentistry. Baltimore: Mosby-Wolfe; 1994. 11. Gupta H, Gupta P. Fruit drinks how healthy and safe? Indian Pediatr. 2008:45(3);215-7. 12. Hobson P, Fuller S. Sugar-based medicines and dental disease – progress report. Community Dent Health. 1987;4(2):169-76. 13. Larsson E. The prevalence and aetiology of prolonged dummy and finger-sucking habits. Eur J Orthod. 1985;7(3):172-6. 14. Nacht ES. Ten Steps for effective staff delegation in pediatric dentistry. J Clin Pediatr Dent. 1994;18(2):76-6. 15. Newburn E. The potential role of alternative sweeteners in caries prevention. Isr J Dent Sci. 1991;2(4):200-13. 16. Osborne JW, Summitt JB, Robert HW. The use of dental amalgam in pediatric dentistry: review of the literature. Pediatr Dent. 2002;24(5):439-47. 17. Phantumvanit P, Songpaisan Y, Pilot T, et al. Atraumatic restorative treatment (ART): a three-year community field trial Thailand – Survival of one-surface restorations in the permanent dentition. J Public Health Dent. 1996;56(3 Spec No):141-5; discussion 161-3. 18. Qin M, Liu H. Clinical evaluation of a flowable resins composite and flowable components for preventive resin restorations. Oper Dent. 2005;30(5):580-7. 19. Rcisine S, Douglass JM. Psychosocial and behavioural issues in early childhood caries. Community Dent Oral Epidemiol. 1998;26(Suppl). 20. Rock WP, Grudy MC, Show L. Diagnostic Picture tests in Pediatric Dentistry. London: Wolf Medical Publications; 1988. 21. Roos EH, Donly KJ. In vivo dental plaque pH variation with regular and diet soft drinks. Pediatr Dent. 2002;24(4): 350-3.

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The most prevalent type of malocclusion in the primary dentition is anterior open bite, secondary to pernicious habits. In the mixed dentitions, crowding is the most common type of malocclusion. There is no difference in the incidence of malocclusions, according to sex. It is interesting to note that the primary dentition usually has good occlusal relationship, particularly in breastfed children. Malocclusion may develop later when the primary teeth are shed and permanent teeth erupt.



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when treatment is given in time. Most malocclusion responds well to removable appliances. However, fixed app liance gives more effective result for severe malocclusion.



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strength and duration of the pacifier use. Anterior open bite and maxillary construction are often seen with pacifier use.

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Conventional radiographs are still the most frequently carried out procedure. Proper immobilization is essential. Radiograph is taken in supine anteroposterior (AP) for children less than 3 years of age and in erect posteroanterior (PA) for older children. Computed tomography, nowadays spiral CT, is the next best cost-effective imaging technique for complete chest evaluation. Magnetic resonance imaging and MR angiography are now increasingly used for assessing relationship of mediastinal vessels to mediastinal masses or for primary vascular diseases like aortoarteritis, coarctation, etc. Sonography has limited role in chest diseases due to reflection of ultrasound beam by air. However, for pleural diseases, mediastinal or pulmonary lesions abutting the chest wall and for cardiac and major vessel evaluation, sonography is a quick and easy technique, which can be carried out even at bedside.

Normal Chest X-ray Usually, only a frontal chest radiograph (AP or PA) is taken. If any abnormality is detected or in patients with high index of suspicion, appropriate lateral radiograph is also taken.

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Conventional radiology, i.e. plain radiography and contrast studies (e.g. barium studies, excretory urography and contrast studies for the lower genitourinary tract) still remain the mainstay of pediatric radiology. However, with the introduction of ultrasound, CT and MRI, the diagnostic algorithm in a number of diseases has changed dramatically. Role of important imaging modalities is discussed under each organ system.



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Patient rotation and quality of exposure are first checked because improper patient position or exposure can be disastrous. Next, the film is read either from out-to-in or vice versa. Carefully examine, in a sequence, always comparing with the opposite side for soft tissues, bones under review (ribs, clavicles, scapulae, humeri, etc.); aeration of each lung in the upper, mid and lower-thirds as well as medial-mid and outer-thirds; vascularity in each of these zones; tracheal position, diaphragm position and shape; costophrenic angles; mediastinal silhouette on each side; cardiac size and shape; retrocardiac space; position, size and density of each hilum; and last but not the least, look under the diaphragms for free air and dilated loops. Lateral radiograph is usually, taken to localize a lesion already detected on the frontal films, for evaluation of the hilar nodes and for assessing the position of diaphragm. In a case with suspected free pleural effusion, a lateral decubitus view film is required with the affected side lower and closer to the film cassette.

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Over the last several decades, pediatric radiology has not only emerged in the forefront, but has established itself as a definite subspecialty. A pediatric radiologist should not only have knowledge of general radiology, embryology and basic pediatrics, but should also be acutely aware of the indications, technicalities of various procedures and should be radiation conscious. Although problem-oriented approach is ideal; in this chapter, an organ approach is used to present the essentials.

Interpretation

Normal thymus: An anterior mediastinal soft tissue “mass” is a common finding on conventional chest radiograph (Figs 18.8.1A and B) in normal children up to the age of 3 years, and is due to normal thymus. A number of radiographic signs are helpful to identify it as normal thymus, e.g. “wave sign”; “sail sign”; change in shape during respiration and shrinking under the stress of steroid therapy (which reverts to the original size on stoppage of steroid).

Pathological Conditions Discussions on important neonatal chest conditions like hyaline membrane disease, transient tachypnea of the newborn and meconium aspiration, are beyond the scope of this chapter. • evelopmental anomalies: Agenesis of a lung is an extremely uncommon clinical entity. Completely opaque hemithorax on a frontal chest radiograph and absent pulmonary artery or main bronchus on the pulmonary angiogram or bronchogram, respectively, confirms the diagnosis. Persistence of pleuroperitoneal canal results in herniation of intestinal loops into the chest cavity (Fig. 18.8.2). Clinically, the baby presents with respiratory distress • Foreign body inhalation: One of the most important, noninfective cause of acute respiratory distress in D

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Figure 18.8.2 Congenital diaphragmatic hernia on the right side. Note the bubbly bowel loops in the right hemithorax, mediastinal shift to the left and paucity of bowel loops in the abdomen. Important differential diagnosis (D/D) of bubbly chest includes congenital cystic adenomatoid malformation, pneumatoceles and multiple lung cysts

 

Figures 18.8.1A and B Normal (A) frontal and (B) lateral chest radiograph: Note a large right anterior “mediastinal mass” due to normal thymus (sail sign). Correlation with clinical information is mandatory before assigning a pathological label

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children is inhalation of foreign body, which could be either radiolucent (in about 90%) or radiopaque (in 10%) (Figs 18.8.3A and B). Radiographic findings depend upon a number of factors. Collapse (Fig. 18.8.3C), hyperlucent enlarged lobe (or lung) due to ball valve type of block or consolidation may be seen. In a suspected case of radiolucent foreign body inhalation and with equivocal chest radiographic findings, deep expiratory film may be very useful for the correct diagnosis • acterial pneumonia: It is most commonly caused by Haemophilus influenzae (between 6 months and 12 months of age), Streptococcus pneumoniae (1–3 years of age) and Staphylococcus aureus up to 1 year of age. About 50% of Staphylococcal pneumonia cases are com-

Pulmonary tuberculosis is one of the most commonly seen chest conditions in India. A wide spectrum of radiologic findings is observed in these children. Primary complex (Figs 18.8.7A and B) consists of the pulmonary parenchymal focus, draining lymphatics (rarely seen on chest radiograph) and mediastinal nodal enlargement. As the infection becomes progressive, then radiological changes of postprimary tuberculosis are seen. Findings may include only nodal enlargement, pleural effusion (Fig. 18.8.8), lobar or segmental consolidation; pneumonic consolidation with air bronchogram (Figs 18.8.9A to C) and pulmonary cavitations. Lymphatic or venous seeding in lungs produces

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plicated by pneumatoceles (Fig. 18.8.4). Staphylococcal or Pneumococcal pneumonia may produce a roundshaped pneumonia termed as round pneumonia, which may mimic hydatid cyst or metastatic lesion. Abscess (Figs 18.8.5A to C) is not an uncommon complication. Empyema is another important complication necessitating imaging and many a times surgical intervention • Viral infection: Unlike bacterial infections, which result in air space disease, viral infections tend to affect predominantly the airways. The resultant radiologic picture is bilateral hyperinflation with perihilar striations (Fig. 18.8.6), the latter due to peribronchial thickening (cuffing). Radiograph may even appear normal. Pathologic-cum-clinical term used to describe this condition is bronchiolitis or “bronchitis”. Thus, in a child presenting with acute respiratory distress but with very subtle radiologic changes, one should suspect this clinical entity.

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Figure 18.8.4 Staphylococcal pneumonia with pneumatocele



miliary tuberculosis. Following healing, by chemotherapy or by development of body immunity chest radiograph may become either completely normal or residual changes like calcified nodes, pulmonary scar, pleural thickening or loss of volume may be seen. Bronchiectasis is another common clinical problem, which usually follows infection by tuberculosis and viral or bacterial pneumonias. After the chest radiographs, thin section, high-resolution CT is the imaging modality of choice to detect subtle bronchiectasis. Bronchograms are rarely, if ever, used nowadays. On a chest radiograph; round, soft tissue density, either single or multiple is most commonly due to hydatid cyst in our country. Computed tomography would readily show its content to be fluid. If the lesion is abutting the chest wall or diaphragm, then ultrasound can also be used for characterizing the soft tissue mass. Primary lung tumors are rare in children. Metastatic lung disease is much more common, and is usually from a Wilms tumor. Mediastinum is divided into three compartments, viz. (1) anterior, (2) middle and (3) posterior. It is important to remember that the radiological division of the mediastinum is different from the anatomical division. Masses can arise from any one of the structures normally present in these compartments. Germ cell tumor is an anterior mediastinal malignant tumor. Lymph nodes, bronchogenic cyst, pericardial tumors and hiatus hernia are important masses of middle mediastinum, while neurogenic tumors predominate in the posterior mediastinum.





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Figures 18.8.3A to C Foreign body inhalation: (A) Radiograph showing collapse right lower lobe; (B) Computed tomography mediastinal window is showing intraluminal foreign body in right lower lobe bronchus (C) and collapse right lower lobe

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Figures 18.8.5A to C Lung abscess in evolution: (A and B) Initially (A) consolidation which progressed to a huge lung abscess with a large air-fluid level; (C) The finding is confirmed on computed tomography

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Figure 18.8.6 Viral pneumonia, bronchiolitis; Bilateral, generalized hyperinflation with minimal flattening of both domes. Note minimal perihilar striations, better appreciated on the left side due to peribronchial soft tissue thickening

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maging echniques Conventional radiographs still remain the mainstay for the evaluation of musculoskeletal diseases. Computed tomography and MRI provide detailed soft tissue, articular and bony imaging, and are thus helpful, especially for examination of masses regarding their content, extent and degree of vascular and marrow involvement. Magnetic resonance imaging is superior to CT due to its better soft tissue resolution and multiplanar capability. Sonography has a role in the evaluation of congenital dislocation of hip, hip effusion and soft tissue masses. Scintigraphy is the primary modality in the detection of metastatic disease and osteomyelitis.

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Figure 18.8.8 Free pleural effusion on the right side, running along the lateral chest wall

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Figures 18.8.9A to C Primary progressive type of pulmonary tuberculosis—an uncommon presentation



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Before interpreting abnormality, one must have knowledge about the normal development of bone, parts of different areas of skeletal system and a number of normal variants, which may mimic abnormalities. Rickets is still a relatively common clinical problem in India. Vitamin D deficiency results in failure of normal mineralization of the growing cartilage into bone. Classic radiographic findings are found in the most rapidly growing ends of bone, and include generalized osteopenia, disappearance of zone of provisional calcification, cupping with fraying and irregularity of the metaphyseal ends and perpendicular striations extending from the metaphyseal end toward epiphysis (Figs 18.8.10A and B). Enlargement of the anterior ends of ribs (rachitic rosary) and lower ends of radius and ulna may also be noted. Thalassemia major (homozygous form): Radiographic changes are at times dramatic (Figs 18.8.11A to C), and are the result of marrow hyperplasia.

Congenital syphilis is caused by transplacental spread. Bone lesions may appear even up to 2 months later. Hallmark of this condition is metaphysitis (Figs 18.8.12A to C), i.e. a metaphyseal lucent band located directly beneath a dense band in the subphyseal region. Focal destructive bony lesions in diaphysis, periostitis and pathological fracture may also occur. Skeletal tuberculosis is still prevalent in India. Tuber culosis may affect any part of the skeletal system. In the spine, it typically affects the vertebral body. Partial collapse produces para (and/or pre) vertebral abscess and short angle gibbus. Long bone tuberculosis may be isolated or affect an adjacent joint. A high index of suspicion, chest radiograph, biochemical and hematological findings, family history and positive tuberculin test —all help in establishing the diagnosis in an equivocal case. Developmental dysplasia of hip (congenital dislocation of hip) is a common clinical problem. Following a thorough clinical examination, ultrasound is usually the first screening modality to confirm the diagnosis. On plain radiographs, a 1063

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Osteogenic sarcoma is the most common primary malignant bone tumor between 10 years and 25 years of age, and is usually located in the metaphysis of a long bone, especially around the knee. Typically, the tumor matrix is ossified and its metastases to lungs may also be ossified. Metastatic disease affecting the skeletal system is common in the pediatric age group. Commonly, it is due to a round cell tumor—acute lymphoblastic leukemia, neuro blastoma, lymphoma, rhabdomyosarcoma or Ewing’s sarcoma. Skeletal survey shows generalized demineralization, “moth-eaten” osteolytic lesions diffusely involving all the bones, metaphyseal lucent bands, periosteal new bone formation with loss of focal areas of cortical line due to tumor invasion. Radiology of skeletal system would be incomplete without a few words on the methodology for skeletal

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Figures 18.8.10A and B Rickets: Primarily a metaphyseal disease. Note cupping of metaphyseal ends of both radius and ulna, widened physis, perpendicular striations extending from metaphysis into physis toward the epiphysis. (A) Generalized osteopenia is seen in the background; (B) Posttreatment radiographs show healing

Figures 18.8.12A to C Congenital syphilis, both lower limbs antero posterior view: (A) Characteristic metaphyseal changes (metaphysitis) and periostitis seen in all the long bones. Epiphysis is normal; (B and C) Important differential diagnosis (D/D) is scurvy, which is characterized by osteopenia with subperiosteal hemorrhage lifting up the periosteum and metaphyseal changes

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Figures 18.8.11A to C Thalassemia major: Chest X-ray (CXR) showing marked expansion of the ribs: (A) Striking “hair-on-end” appearance in the skull; (B) and osteoporosis, widening of medullary spaces of all the bones of hands with coarse trabecular pattern, loss of lateral concavity of small bones of hand and moulding abnormality of distal ends of long bones; (C) Radiographic changes reflect marked degree of marrow proliferation

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maturity assessment or bone age assessment. Earlier method of observing the appearance and fusion of ossifi cation centers is an obsolete technique; even though in India, it is still the only method used in most hospitals. More accurate methods are by using an atlas either by GreulichPyle or Tanner-Whitehouse 3 (TW3) method. The latter is, at present, the most accurate method for assessment of skeletal maturity in a child.

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Figure 18.8.14 Perforation of gastrointestinal tract with free peritoneal air seen between the right diaphragm and liver. Both sides of the intestinal walls are visible, another sign of presence of free peritoneal air  

Once again, plain radiograph coupled with contrast examination (barium studies) play a major role in a large number of gastrointestinal tract (GIT) disorders. Sonography, CT and MRI provide valuable information, especially in cases of masses, mesenteric vascular and nodal status, retroperitoneal anatomy, trauma, and abscess or other fluid collections.

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Erect plain abdominal radiographs are usually, adequate in intestinal obstruction (Figs 18.8.13A and B), perforation with free air (Fig. 18.8.14) or necrotizing enterocolitis (NEC) with classical intramural air (Fig. 18.8.15), calcified mesenteric or retroperitoneal nodes, diseases of the spine (e.g. tuberculosis) and a host of other conditions are also readily diagnosed on plain radiographs. However, contrast examination with barium is required for the diagnosis of mucosal diseases, e.g. polyps or ulcer; intestinal muscular wall diseases, e.g. congenital hypertrophic pyloric stenosis (Fig. 18.8.16) and stricture,

 

Figure 18.8.15 Necrotizing enterocolitis in a newborn: Classical linear gas shadows due to intramural gas (pneumatosis intestinalis) and bubbly appearance

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Figures 18.8.13A and B Abdomen, anteroposterior erect view in a newborn with vomiting and abdominal distention: (A) Multiple, small, air-fluid levels predominantly in the central abdomen. Absent gas in the colon and rectum; A case of ileal atresia. Number, type and distribution of bowel loops and air-fluid levels help in localizing the level of obstruction; (B) Barium enema revealed microcolon

obstruction, Hirschsprung’s disease, etc. Gastrointestinal tract related masses require a cross-sectional imaging modality, i.e. sonography, CT or MRI, with or without intravenous contrast. Esophageal atresia is diagnosed on day 1 of life, usually with negative contrast, i.e. air only, but positive contrast (i.e. barium or nonionic isotonic contrast) may also be used (Fig. 18.8.17). Thus, for GITrelated conditions, a radiologist can choose a specific imaging modality in a particular case to derive maximum information with minimum cost and harm (radiation, invasive technique) to the patient.

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regarding involvement of adjacent structures. Angiography is rarely required either for preoperative arterial road map in cases of tumor or for diagnosing primary vascular diseases, e.g. aneurysm, arteritis, etc. Plain radiographs have very limited role, if any.

Most common clinical problem is to differentiate medical from surgical type of jaundice. This differentiation is made by observing presence or absence of dilatation of biliary channels. Sonography can readily identify dilatation of intra and/or extrahepatic biliary channels, level of obstruction and many a times, even the cause, e.g. calculus, pancreatic head tumor or choledochal cyst. Choledochal cysts are congenital ectatic dilatation of biliary channels either totally extra, intrahepatic or a combination of the two. Sonography is usually, adequate for its diagnosis (Fig. 18.8.18A) but endoscopic retrograde cholangiopancreatography (ERCP) (Fig. 18.8.18B) or magnetic resonance cholangiopancreatography (MRCP) may also be done to demonstrate it preoperatively (Fig. 18.8.18C). Biliary atresia, an important differential diagnosis (D/D) of neonatal jaundice requires ultrasonography (US) coupled with nuclear scan for diagnosis. Nowadays, MRCP is the first and usually the only imaging modality required to differentiate it from neonatal hepatitis. However, intraoperative cholangiogram is the most definitive investigation for its diagnosis. Liver tumors are common and of these malignant neoplasms (hepatoblastoma or hepatocellular carcinoma) are the most common. Any of the cross-sectional imaging modality can diagnose and stage it. A cystic liver spaceoccupying lesion (SOL) is usually, due to hydatid cyst or liver abscess in India. Splenic enlargement is another common clinical pro blem. Malaria and kala-azar are two important medical causes while portal hypertension, usually secondary to extrahepatic block in the splenoportal axis, is the most important surgical cause. Initial evaluation of portal hypertension and portal biliopathy is with ultrasound, which can be confirmed by splenoportovenography, arterial portography and nowadays with 3D-CT arterial portography (Fig. 18.8.18D).

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Hepatobiliary System Nowadays, ultrasound is usually the first imaging modality for evaluating diseases of the hepatobiliary system. In the presence of a tumor, contrast-enhanced CT (CECT) tailored for the suspected pathology is usually adequate. However, MRI with its multiplanar capability may add new information

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Figure 18.8.17 H-(or N) type of tracheoesophageal fistula: Tube esophagogram showing communication between esophagus and trachea

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Figure 18.8.16 Congenital hypertrophic pyloric stenosis, upper gastrointestinal barium study. Pyloric canal is markedly narrowed, elongated with indentation at the base of duodenal cap. Currently, sonography is the first and many a times the only investigation of choice since it can diagnose the condition in a large number of patients





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For evaluation of the upper renal tracts, sonography, especially color duplex sonography coupled with plain abdominal radiographs is usually adequate for anatomical assessment. However, it needs to be supplemented by a functional study. Nowadays, renal scintigraphy is preferred due to its low radiation dose, higher sensitivity and more

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Figures 18.8.18A to D Huge, extrahepatic, cystic choledochal cyst on ultrasound (A); and on endoscopic retrograde cholangiopancreatography (ERCP) (B); Note the slightly dilated right main bile duct entering the cyst on ultrasound. Gallbladder should be documented separate from the cyst. Magnetic resonance cholangiopancreatography (MRCP) image (C) elegantly documenting the choledochal cyst (D) Portal biliopathy: magnetic resonance imaging (MRI) axial (D1) and coronal (D2), computed tomography (CT) axial (D3) and coronal (D4) images showing portal cavernoma causing biliary dilatation. Threedimensional CT (3D-CT) (D5) showing exquisite detail of the portosplenic axis and the collaters developed (Note: LR COLL, SMV, SV)

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Pathological Conditions

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Figures 18.8.20A and B (A) Micturating cystourethrography. Vesicoureteric reflux (VUR) on both sides. Urinary bladder shows trabeculation and sacculations due to neurogenic dysfunction (neurogenic bladder); (B) Same information could be seen on magnetic resonance (MR) urography

Figure 18.8.21 Micturating cystourethrography shows marked dilatation of posterior urethra, thin urinary stream and narrowing at the junction of posterior and anterior urethra due to posterior urethral valves. Also note gross vesicoureteric reflux on the right side  





Hydronephrosis is one of the most important and common problems encountered in pediatric practice. Sonography and contrast study not only diagnose it reliably, but also provide a clue to its possible cause, e.g. pelviureteric junction (PUJ) obstruction (Fig. 18.8.19), calculus, etc. and it can also delineate an associated hydroureter, if present. A number of congenital anomalies can be seen, e.g. horseshoe kidney, crossed ectopia, low lying kidney, etc. Of the solid renal masses, Wilms tumor is the most common. On cross-sectional imaging, it is seen as a solid tumor with variegated enhancement due to areas of necrosis. In 10%, it may be bilateral. For staging purposes, CT or MRI may be done in addition to sonography. Bladder tumors are relatively rare in children, and of these, a malignant tumor, rhabdomyosarcoma, is the most common. On the cystogram phase of a contrast study, characteristic lobulated filling defects are seen from the bladder base. This appearance gives it the name of “sarcoma botryoides”. Vesicoureteric reflex (VUR) is one of the most important causes for urinary tract infection. Voiding cystourethrography (VCUG), either using contrast or an isotope, is required

to diagnose it (Figs 18.8.20A and B). The latter is reported to be more accurate. Nowadays, even sonocystography is used in certain clinical situations to diagnose VUR with the added advantage of lack of ionizing radiation. The most common cause for urinary outflow obstruction in a male child is posterior urethral valve (PUV). Micturating cystourethrography (MCU) is mandatory for its diagnosis (Fig. 18.8.21). Back-pressure changes in the bladder and associated VUR is common. Magnetic resonance urography

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objective assessment of renal function. Excretory urography is required when complex anatomical details need to be clarified or in patients with ureteric disease. Computed tomography or MRI is added in the work-up of a case of tumor or trauma. For examination of the lower urinary tract, sonography for bladder and contrast examination for urethral evaluation, are usually adequate.

 

Figure 18.8.19 Nephrostogram of left kidney shows dilated, rounded renal pelvis with caliectasis, a case of pelviureteric junction obstruction. Ureter is not opacified even on delayed images

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Pathological Conditions The term “craniosynostosis” denotes premature fusion of cranial sutures. Depending upon the pattern of sutural closure, the shape of the head varies and different names are used to describe them, e.g. brachycephaly (fused coronal sutures) and scaphocephaly (sagittal sutures fusion). Besides the plain radiographs, CT and nowadays 3D-CT, is the investigation of choice to assess the sutural status. Growing fracture at times may mimic a widened suture (Figs 18.8.23A and B). Intracranial calcification (Figs 18.8.24A to C) could be seen in postinfectious states, e.g. cytomegalovirus (CMV), toxoplasma infection, tuberculous meningitis; in brain tumors, hypoparathyroidism and/or in dysplastic brain tissue. Cytomegalovirus produces periventricular calcifications (a “calcified mould of the ventricles”) whereas, toxoplasmosis produces diffuse cerebral calcification. Bilateral basal ganglia calcifications have been reported in acquired immunodeficiency syndrome (AIDS) encepha lopathy also. Computed tomography is essential for anatomical localization. Skull vault may be affected in a number of diseases, e.g. histiocytosis (Fig. 18.8.24); neuroblastoma metastases

 

Figure 18.8.22 Growing fracture: Frontal radiograph of face and skull showing a linear oriented lytic lesion with beveled margins in left frontal bone

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Conventional radiographs of the skull should include at least frontal and lateral view. Depending upon the suspected clinical disease, more views can be taken, e.g. for sinuses, atlantoaxial junction, pituitary fossa, etc. Plain X-rays of the spine are routinely done in all cases of spinal dysraphism, scoliosis, back pain, etc.



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Transfontanel cranial US has a role to play, only if the anterior fontanel is open. Diagnosis of hydrocephalus, intracranial bleed, congenital malformations and tumors of the brain can be made. However, US has its own limitations. Computed tomography is the most cost-effective technique for cranial imaging. For posterior fossa, brainstem and white matter diseases, however, MRI is far superior to CT. For the evaluation of spine and its contents, MRI is the modality of choice. But if it is not available, then myelogram with nonionic media followed by postmyelo-CT should be routinely done.

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has been tried to be useful for demonstrating VUR. Moreover, it is free of radiation.

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Figures 18.8.23A to C Intracranial calcification: Noncontrast computed tomography (NCCT) axial sections showing periventricular calcification in congenital cytomegalovirus (CMV) infection (A). Axial NCCT images (B and C) showing intracranial calcifications in the bilateral basal ganglia’s and cerebellar hemispheres—typical presentation of calcification in hypoparathyroidism

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Figures 18.8.24A and B Skull X-rays: Multiple, large “geographic” type bone destruction, characteristic of histiocytosis. These type of bone lesions indicate relatively slow growing pathology







(Fig. 18.8.25), hematological and metabolic diseases and various skeletal dysplasia’s. Infectious conditions, like brain abscess (Fig. 18.8.26), tuberculomas (Fig. 18.8.27) and neurocysticercosis (NCC) (Figs 18.8.29A and B) are readily diagnosed with CT and MRI. Hydrocephalus, one of the most common causes of a large head in children, is readily diagnosed on any one of the cross-sectional imaging modalities (Fig. 18.8.29). Similarly, other intracranial pathologic lesions can be imaged. Spinal dysraphism (Figs 18.8.30A to C) is the most common congenital abnormality affecting the spine. It is a complex disorder. Information required by the surgeon regarding level of spinal involvement, contents of the sac, presence or absence of diastematomyelia (transfixion of the spinal cord by a bony spur congenitally) demyelinating changes in the cord and associated hydrocephalus and Arnold-Chiari malformations—can all be, nowadays, 1070 reliably, noninvasively delineated by MRI. If MRI is not available, then myelogram with nonionic contrast followed by CT is mandatory.

Figure 18.8.26 Brain abscess: Axial computed tomography (CT) showing multiple ring enhancing lesions in bilateral frontal and right occipital lobes with perilesional edema  

 

Figure 18.8.25 Skull lateral view: Multiple lytic lesions with sunray type of periosteal reaction in a case of neuroblastoma with skull metastases

 

Figure 18.8.27 Tuberculomas; contrast-enhanced CT (CECT) axial sections showing multiple ring enhancing lesions with hypodense centers and perilesional edema in bilateral high parietal lobes

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Figures 18.8.28A and B Neurocysticercosis (NCC): Multiple hyperdense lesions in brain suggestive of NCCS; note the eccentric scolex

 

Figure 18.8.29 Hydrocephalus with ventriculitis: Axial CT showing dilated ventricles with enhancing ventricular margin and periventricular ooze

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Figures 18.8.30A to C Diastematomyelia: Radiograph showing bony septum in the spinal canal at L2 level with spina bifida from L3 onward (A) T2 weighted (T2W) axial magnetic resonance imaging (MRI) images (B) showing splitting of the cord into two (C) Chiari III malformation—sagittal T2W MRI showing herniation of tonsil and brainstem (Chiari II) with occipital meningoencephalocele

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5. Hoffman AD, Hilton SW, Edwards DK (Eds). Practical Pediatric Radiology, 2nd edition. Philadelphia: WB Saunders and Company; 1994. p. 260. 6. Kirks DR. Practical Pediatric Imaging, 2nd edition. Boston, MA: Little, Brown and Co.; 1984. pp. 561-62. 7. Kuhn JP, Slovis TL, Haller JO (Eds). Caffey’s Pediatric Diagnostic Imaging, 10th edition. St Louis: Mosby; 2004. 8. Mukhopadhyay S, Gupta AK. Imaging in childhood tuberculosis. In: Seth V (Ed). Essentials of Tuberculosis in Children. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 1997. pp. 240-263. 9. Shaw D. The chest. In: Carty H, Shaw D, Brunelle F (Eds). Imaging Children. Edinburgh: Churchill Livingstone; 1994. pp. 19-36. 10. Swischuk LE. Skeletal system and soft tissues. In: Swischuk LE (Ed). Imaging of the Newborn, Infant and Young Child, 4th edition. Philadelphia: Williams and Wilkins; 1997. pp. 678-892.









1. Barkovich AJ, Raybaud C (Ed). Pediatric Neuroimaging, 5th edition. Philadelphia, PA: Lippincott Williams and Wilkins; 2011. pp. 367-568. 2. Berry M, Mukhopadhyay S, Chowdhury V, Puri S, Gupta AK (Eds). Paediatric Imaging (AIIMS-MAMC-PGI Imaging Diagnostic Series), 2nd edition. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2004. 3. Blickman JG (Ed). Pediatric Radiology: The Requisites, 2nd edition. St Louis, MO: Mosby; 1997. 4. Castillo M, Mukherji SK. Malignant and benign tumors. In: Castillo M, Mukherji SK (Eds). Imaging of the Pediatric Head, Neck and Spine. Philadelphia: Lippincott-Raven; 1996. pp. 191-255.





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The main sources of outdoor air pollution are: • Emissions from automobile exhausts • Power plant emissions • Industrial emissions • Open burning of solid wastes • Construction related activities • Loose soil accumulate on the road side • Pollens, which are seasonal, or fungi in the atmosphere. Urban air pollution is largely and increasingly caused by the combustion of fossil fuels for transport and automobile exhausts that can be categorized into three categories: 1. Substances that mainly affect the airways: Oxides of nitrogen, sulfur dioxide, ozone, suspended particulate matter and photochemical oxidants. 2. Substances that produce a toxic effect: Carbon mon­ oxide and lead. 3. Substances with carcinogenic effect: Polycyclic aromatic hydrocarbons and aldehydes.

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erobiologicals: These include dust mites, fungi, cock­ roaches, pollens, and pets. Dust mites are microscopic organisms found in the dust that measures 0.1–0.5 mm in size. They are predominantly seen in the places with high humidity, in carpets, upholstered furniture, stuffed toys, woolen blankets and mattresses. It takes about 100 dust mites/gram of dust to develop sensitivity and 500 dust mites/gram of dust to develop wheezing. Dust mites concentration varies inversely with altitude. Fifty percent of persistent asthma is caused by dust mite allergy. Pollens and fungi produce allergy in 7.5% of children. About 25% of persistent asthmatics are sensitive to cockroaches. Pollen concentration will increase in the atmosphere when the temperature is high and humidity is low, and the wind speed is 1 km/hour. The tree pollens are 1073

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The environmental issues vary from developed country to developing country. The key environmental pollution problems that affect our children’s health are from: • Air pollution – Outdoor air pollution – Indoor air pollution • Water pollution – Surface water pollution – Ground water pollution • Chemical pollution – Persistent organic pollutants (POPs) • Noise pollution • Exposure to radiation. The windows and timing of exposure to pollutants have different impact as shown in Table 18.9.1.

responsible for producing respiratory infections, pneu­ monia, respiratory allergy and chronic pulmonary disease.



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Children are the future citizens of this world and decision makers and keepers of our planet. However, we are burden­ ing them with pollution in their environment like (a) physical environment, (b) biological environment by the physiologic interaction with innumerable chemicals, pesticides, fertilizers and toxins, and (c) the social environment in which the day to day circumstances of living as well as regulation that may affect the day to day living. The vulnerability of children to environment pollution begins with exposure in the mother’s womb, e.g. drugs, tobacco smoke and lead, and they are affected and suffer because they breathe more air, consume more water, more food and absorb more toxic chemicals per unit of bodyweight in comparison to adults. Nearly 352 million children between the ages of 5 years and 12 years engage in economic activities; 50% of these children work in hazardous occupations with poor hygienic conditions, which adversely affect their growth and development, safety and future health. Nearly 30% of global burden of disease can be attributed to environmental factors. Thirty six percent of the overall disease burden is due to modifiable environmental risk factors in the age group of 0–4 years and 34% among children of 0–14 years.

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Table 18.9.1 Timing and impact of pollutants Timing Impact of pollutants Less than 2 weeks of gestation Prenatal death, less prone for teratogenic effect 3–8 weeks of gestation Major morphological abnormalities After 8 weeks of gestation fetal period Minor morphological abnormalities

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Air pollutants produce ill effects on all systems of human body including behavioral changes. The lung, being an organ with the largest surface area, will receive the brunt of air pollution. Both outdoor and indoor air pollutions are

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espiratory allergies: Allergic rhinitis increased from 22.5% in 1994 to 27.5% in 1999 and asthma in children less than 18 years of age increased in prevalence from 9% to 29.5% in 2 decades. This steady rise has been correlated with the change in the demography of the city (Fig. 18.9.1).

ccupational lung diseases: Children who are exposed to various minerals and chemicals such as silica, asbestos, coal dust, cement, chalk, mica and iron oxide for long periods of time because of their parent’s occupation may suffer from pneumoconiosis, interstitial fibrosis, etc.

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Respiratory infection: These infections constitute 45% of outpatients, 30% of inpatients and 50% of intensive care unit admission; of these, 10% of inpatients admissions are due to pneumonia. About 28% of all deaths in India are caused by indoor air pollution. In a study in rural areas, the prevalence of acute respiratory infection was found to be 10.5 times more in children living in single room hut in comparison to double room hut dwelling.

School survey studies have also shown an increase in the prevalence of asthma and abnormal lung functions in children who go to schools located near heavy traffic areas that experience traffic congestion (Fig. 18.9.2). It was also found that urban children suffered more asthma attacks than rural children (Fig. 18.9.3). Children coming from urban ill ventilated homes, exposed to tobacco smoke and dirty fuel usage for cooking have more prevalence of asthma (Figs 18.9.4 to 18.9.6). Asthma was less in summer time but it has increased in the prevalence for the past few years due to production of ozone from emission of slow moving traffic in bright sunlight with oxygen. Ozone is extremely irritant to respiratory tract. The data is shown in Figure 18.9.7. Asthma episodes increase during Diwali festival by 100% due to increase of sulfur dioxide (SO2) in the atmosphere due to burning of crackers.

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found in April to June, grass pollens in July to November, weed pollens in November to January. Only 5% of urban and 7.5% of rural children own pets; of these, 80% are dogs and they are not a major cause of allergy in India. Cat’s urine and saliva are more allergic. rritants: The source and effects of various irritants are described in Table 18.9.2.

 

Table 18.9.2 Source and effect of irritants Irritant Source Effect on newborns and children Tobacco smoke (major indoor Prenatal maternal exposure (active or passive smoking) Effects on newborn and infants: pollutant) Low birthweight Increased infant mortality Decreased lung function Increased wheeze Decreased resistance to respiratory infections Postnatal parental smoking Improper lung development Decreased forced expiratory volume at 1 second (FEV1) Increased lung hyperreactivity Persistent wheeze Asthma exacerbation Otitis media Formaldehyde (colorless gas) Plywood, furniture, tobacco smoke, poorly vented wood Headache and gas stoves Respiratory tract irritation Pneumonia Pulmonary edema Combustion of gases, wood burning stoves, tobacco Blurred vision Combustion by products (particles, smoke, poorly ventilated fire places, heaters and carbon monoxide, carbon dioxide, automobile exhausts nitric oxide, nitrogen dioxide and partially oxidized organic substances) Drowsiness Emphysema Respiratory infection Asthma Decreased lung capacity Death from carbon monoxide poisoning Cleaning agents and aerosol Hair sprays, fabric softener, paints, perfumes, deodorants Irritation of mucous membranes of respiratory tract and eyes Headache Mental confusion Abdominal pain Triggering of asthma

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Figure 18.9.3 Asthma urban/rural children and semirural children (age 6–15 years); Urban children suffer more from asthma than rural children

Figure 18.9.4 Ventilation of house/asthma

Figure 18.9.5 Cigarette smoking parents versus asthma prevalence in children

Figure 18.9.6 Cooking fuel versus prevalence of asthma in children

 

 

 

 

 

Figure 18.9.2 Children of heavy traffic school areas suffer more from asthma, which further increases in low socioeconomic children

 

Figure 18.9.1 Trends in asthma prevalence in Bangaluru/the change in the demography of the city

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Several constituents of ground water contamination due to industrial clusters are reported to be caused by electroplating units, tanneries, dyeing, printing units, distilleries and paper mills. The heavy metal and toxic compounds present in the effluent may pose considerable health risks to the population using such contaminated water.

 

Figure 18.9.7 Seasonal pattern of asthma episodes



The problem of air pollution is likely to become worse in the future.

Preventive Measures for Air Pollution

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Public Health Education to Prevent Water Pollution •

Water Pollution Sources of Surface Water Pollution

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Waterborne diseases spread more rapidly in urban communities where the density of population is more with no or poor access to water. The World Health Organization (WHO) guidelines for good potable water is the Escherichia coli count should be less than 10 microbes/100 mL and a higher count always indicates fecal contamination.

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Control of automobile emissions by using more public transport and newer fuel Control of outdoor and indoor pollution Avoiding overcrowded places Use of clean fuel for cooking Construction of houses to needs with good cross ventilation and decorate to our needs Avoiding tobacco smoke—most dangerous pollutant Drying of mattresses, pillows, blankets in the sunshine once in a week Use of indoor plants and exposing them to sunlight once a week and remove water from tray Control of cockroaches, better garbage disposal Control of automobile exhaust fumes Long term urban transport planning Certification of in use vehicles Carpooling, traffic management Monitoring of hot spots in the city Coordination of various municipal and utility services Use of better technology to reduce emissions Alternatives for fossil fuels Education of children, society and policy makers on the adverse effects of air pollution.

• Waterborne diseases: Water contaminated by fecal matter and urine may produce gastroenteritis, dysentery, amoebiasis, cholera, typhoid, paratyphoid and viral hepatitis. Gastroenteritis is the second biggest killer of the children under the age of 5 years. It has been noted that about 69% of people equate visual cleanliness with safe water. However, even today, around 80% of the rural population and 60% of the urban slum population practice open defecation • Water-related vectorborne disease: Examples of diseases transmitted by the bite of mosquitoes are malaria, dengue fever, Japanese encephalitis and filarial disease • Water-based disease: Example of diseases transmitted by aquatic invertebrate animals and stagnant water contaminated by rat urine are leptospirosis, guinea worm and schistosomiasis. The incidence of leptospirosis is increasing in urban slum areas, especially during the rainy season • Water-based chemical diseases: The major chemicals that enter and contaminate the water are fluoride, arsenic, nitrites, mercury and lead. Their effects are described in Table 18.9.3.

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Industrial waste pits, discharge of effluents on land Septic tanks Oil well Chemicals in ground water.

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Education of public about use of safe drinking water, toilet hygiene Use of water filters Prevention of waste production and pollution Prevention of waste from various sources entering water protecting the source of water Water storage at home should be covered Avoid using dirty hands or implements to fetch water Drinking water can be purified by chlorination, boiling, slow sand filters and solar disinfection.

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Table 18.9.3 Chemicals contaminating water and their effects Chemical Mechanism Fluoride Affects 6 million children less than 14 years Drinking water with more than 1 mg fluoride/liter

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pentachlorophenol. They helped a great deal in agriculture, which helped the world economy. Once adverse effects due to their persistence and accumulation in the environment became known, most uses were discontinued.

Noise Pollution Noise is known to affect 800 million people globally. The major chronic effect of noise induced hearing loss is the result of cumulative effect of the magnitude of sound and the duration of exposure. India is known to have the largest deaf population in the world and noise pollution is known to be one of the significant causes. -

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Table 18.9.4 Hormonal effect of persistent organic pollutants Persistent organic pollutants Hormonal ill effect DDT, dieldrin, endosalfan, methoxychlor Estrogenic PCBs—alkylphenols, phthalates, mycotoxins, phytoestrogens Dioxins, PCBs, phytoestrogens Antiestrogenic DPT, vinclozolin Antiandrogenic PCBs, Dioxins Antithyroid PCBs, DDT Antiprogestin’s Abbreviations: DDT, Dichlorodiphenyltrichloroethane; PCBs, Polychlorinated biphenyls; DPT, Diphtheria, pertussis and tetanus  

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They are man made organic pollutants, and are the most dangerous and hazardous compounds synthesized. They include pesticides, industrial chemicals, chemicals used in consumer products and byproducts of certain manufacturing and combustion process. They have long half lives and hence persist in the environment for years or decades. They bioaccumulate and penetrate the food chain thus, polluting and exposing all living things. They disperse universally and travel in air, water currents and in living organisms. Most POPs are lipophilic— and remain in fat tissue, not well metabolized or excreted, even small doses ingested daily accumulate to measurable amounts over time. They are endocrine disruptors, mimic, modify or block the actions of naturally occurring hormones as listed in Table 18.9.4. Prenatal exposure of pesticides negatively affects fetal growth like smaller head circumference and shorter birth length. The major sources of human exposure are food, soil, indoor environment, toys and other objects, air and leaching from medical products. The important organic chlorine pesticides developed after dichlorodiphenyltrichloroethane (DDT) and widely used after World War II include— aldrin, dielrin, endrin, chlordane, heptachlor, indane and

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Ill effects Dental fluorosis Skeletal fluorosis Nonskeletal fluorosis Arsenic (As) Ingesting water with As content more than 0.01 mg/liter over a Skin rashes, hyperkeratosis period of 5–15 years Cancer of lung, bladder, kidneys Mercury All mercury in India imported, used in equipments, batteries and Major health effects: Psychological, GIT cramps, colitis thermometers Poisoning occurs by ingestion and inhalation Persistent cough, emphysema, asthma, sinusitis Excessive perspiration Alzheimer’s disease, Parkinson’s disease, autism also reported Nitrites Seepage from septic tank, pit latrines and organic manures into Ingestion of water with more than 45 mg/L of nitrites—“blue baby ground water syndrome”, meth hemoglobinemia Chronic ingestion and in cancer Lead Ingestion of water from lead pipes, food containers, paint and Lead level more than 10 µg/dL in blood: Progressive GIT, hematologic, insecticides peripheral and central nervous system involvement Inhalation of polluted air from leaded petrol, battery storage, crystal Anorexia, abdominal pain, vomiting glass, ceramic glazes, enamel jewelry, plastic and rubber stabilizers, surma, vermillion Anemia, blue line in gums Headache, seizures, altered sensorium Peripheral neuropathy Behavioral disturbances Lower IQ, poor school performance Abbreviations: GIT, Gastrointestinal tract; IQ, ntelligence quotient

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Table 18.9.5 Ill effects of ionizing radiation Dose exposure Adverse effects on health (REM) 0–10 None to premature ageing Mild malnutrition of offspring Genetic and teratogenic effects 10–50 Premature ageing Genetic and teratogenic effects Radiation sickness Transient effects in lymphocytes and neutrophils 50–150 Acute radiation sickness Burns Abortion, stillbirths Decreased leukocytes Tumors 150–250 Gastrointestinal (GI) symptoms Fetal or embryonic death Serious infections, death 250–600 Gastrointestinal symptoms Loss of hair Bleeding from gastrointestinal, renal and nasal sites Marked destruction of bone marrow leading to death 600–1,000 Destruction of GI Respiratory, hemopoietic, endocrine spleen and genital problems Bleeding diathesis and death Abbreviation: REM, Radiation equivalent of mean

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Radiation is the emission of energy (as electromagnetic waves) or particle matter from unstable atoms. Some types of radiation are harmful to life while others, such as heat energy and light radiating from the skin, are beneficial. Source of radioactive substances: Natural sources of ionizing radiation are the most common, and include cosmic rays from space and radioactive minerals. In source areas, the gas radon found in soil, rocks, building materials and granite stone are highly radioactive.



adiation Hazards

1. AAP SmartBrief. Study: Prenatal exposure to pesticides negatively affects fetal growth. June 15, 2011. 2. Childhood Lead Poisoning. Geneva, Switzerland: World Health Organization Press; 2010. p. 13. 3. Etzel RA, Balk SJ (Eds). Pediatric Environmental Health, 2nd edition. Elk Grove Village, Illinois, USA: American Academy of Pediatrics; 2003. p. 721. 4. Mendis S, Alwan A (Eds). Prioritized research agenda for prevention and control of noncommunicable diseases. Geneva, Switzerland: World Health Organization Press; 2011. 5. Indrayan A, Bachani D, Pandey A, et al. Burden of Disease in India. New Delhi: National Commission on Macroeconomics and Health; 2005. 6. Paramesh H, Cherian E. Prevalence of asthma and its relation to cooking fuel and ventilation of the house. 5th International Conference on Environment and Health Proceedings, Bengaluru; 2010. pp. 17 9. 7. Paramesh H, Cherian E. Tobacco smoke as an indoor pollutant on children health. 5th International Conference

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Effective noise control programs in industries and use of protective aids Plantation of trees near schools, hospitals, public offices and libraries to reduce noise by 6–10 db Residential zones planned away from main roads, factories, airport and railways Perforated plywood and other porous material to be used for office floors or ceilings Implementation of noise control regulation by auto­ mobiles, social and religious functions and prayer halls.

Artificial sources of ionizing radiation include X ray machines, radioactive isotopes used in diagnosis, and treatment and nuclear reactors. Radiation hazards to health depend on the dose, duration of exposure and organs exposed. The ill effects of ionizing radiation are listed in Table 18.9.5.

















Remedial Measures •

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City area 45–55 db Rural area 25–30 db Urban residential 35–40 db Suburban areas 30–40 db Urban business 40–45 db Industrial area 50–60 db Music theater 30–35 db Hospitals 30–35 db Restaurants 50–55 db Public offices 50–60 db The background noise level has increased over the last few decades. The noise level appears to double every decade.









Painful Discomfort Hearing impairment on prolonged exposure Annoying Intrusive





135 db 110 db 88 db 80 db 65 db



Psychological and physical effects of different decibel levels

s

extbook of Pediatric T

Noise may be broadly classified as: • ndustrial noise: This includes noise from machines in factories, industries and mills. Significant among them are noise from mechanical saws and pneumatic drills • ransport noise: This includes road, railway and air traffic noise • ommunity noise: This includes noise from musical instruments, indiscriminate use of amplifiers and other gadgets in commercial establishments.

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-





8.

on Environment and Health Proceedings, Bengaluru; 2010. pp. 59 62. Paramesh H. Epidemiology of asthma in India. Indian J Pediatr. 2002;69(4):309 12. Paramesh H. Indoor air pollution and child health. In: Sachdeva A (Ed). Pediatric and Adolescent Environmental Health. IAP Presidential Action Plan. 2004. pp. 76 8. Persistent Organic Pollutants: Impact on Child Health. Geneva, Switzerland: World Health Organization Press; 2010. State of Environment Report and Action Plan. Government of Karnataka and World Bank; 2003. pp. 217 26.

Pediatric Sub

on Environment and Health Proceedings, Bengaluru; 2010. pp. 43 4. Paramesh H. Asthma and the environment. Indian J Pediatr. 2006;73:S51 S55. Paramesh H. Asthma in children: seasonal variation. Int J Environment and Health; 2008;2(3/4):410 6. Paramesh H. Cherian E. Environmental pollution and children respiratory health. In: Paramesh H (Ed). Textbook of Practical Pediatric Pulmonology. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2009. pp. 192 7. Paramesh H. Emergency room visits for acute wheezing in children during Diwali festival. 5th International Conference

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Section

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19.1 19.2 19.3 19.4 19.5 19.6 19.7 19.8 19.9 19.10 19.11 19.12



























Community Pediatrics

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Section Editor : Piyush Gupta

Vital Statistics: Joseph L Mathew Indicators of Child Health: Piyush Gupta Primary Health Care and Child Health: Piyush Gupta Integrated Management of Neonatal and Childhood Illness: Shashi N Vani National Rural Health Mission: RK Agarwal National Health Programs Related to Child Health: Pukhraj Bafna Rights of the Child: Swati Y Bhave Art of Parenting: S Yamuna Child Abuse and Neglect: Meenakshi Mehta Child Labor: S R Banerjee Adoption and Care of Orphans: RD Potdar Prevention and Control of Injuries: K Nedunchelian

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Baseline survey of sample units

To assess the resident population of the sample areas

Continuous (longitudinal) enum­ eration of vital events by an enumerator

To collect the primary data for the sample

Independent retrospective half yearly surveys for recording births and deaths by a supervisor

To update house lists, household schedule and list of women in the reproductive age group (and pregnancy status)

Matching of events recorded during prospective continuous enumeration and retrospective half yearly survey

Quality control measures to check reliability of data

Field verification of unmatched and partially matched events

To ensure completeness of data

Filling of verbal autopsy forms for finalized deaths

To assign causes of death

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Purpose

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Sample registration system step

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able 19.1.1 Steps of the SRS data collection and compilation process











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Figure 19.1.1 Sample sets used for SRS data collection since its inception  

Vital statistics are systemically collected and compiled data about vital events of life viz birth and death; they sometimes additionally include events such as marriage, divorce and adoption. These socio-demographic data directly and indirectly reflect the health profile of a community. They can also reflect the adequacy of health services such as family planning, maternal and reproductive health, immunization programs; in a community. The data are also the basis for projections on population growth and time trends. They are also used for the construction of life tables. A vital statistics system is formally defined as the process of (1) collection of information on the frequency of occurrence of specified and defined vital events, characteristics of the events and the person(s) concerned and (2) the compilation, processing, analysis, and evaluation of the data in conventional statistical formats. Vital statistics are usually collected and compiled by government agencies which record the births and deaths within the jurisdiction. In India, the main sources for vital statistics data are from (1) the population census, (2) civil registration system records of vital events, (3) sample registration system (SRS), (4) demographic surveys conducted by the National Sample Surveys Organization (NSSO) and (5) health surveys such as the National Family Health Survey (NFHS) and District Level Household Surveys (DLHS). The Registration of Births and Deaths Act (1969) made the registration of births/deaths compulsory instead of voluntary. This improved data collection significantly. In order to make it even more robust, the Office of the Registrar General, India, initiated the nation-wide SRS. The SRS involves a dual-component data collection system in randomly selected sample units across the country. One component is the “field investigation” which is the continuous enumeration of births and deaths in the sample area by an enumerator. This is complemented by an independent six-monthly retrospective survey by a supervisor. The data obtained independently through the two sources are then matched. Unmatched or partially matched events are re-verified and confirmed. This qualitycontrol step ensures reliability of the data collected. The SRS sampling frame is revised every 10 years. Figure 19.1.1 presents the sampling units at different time periods. Since 1999, the SRS also includes the “Survey of Causes of Deaths (Rural)”. This uses the “Post Death Verbal Autopsy” technique to estimate the most probable cause of death. Specially trained professionals then verify and assign the final cause of death. Table 19.1.1 summarizes the main components of SRS in India. The vital statistics data collected are represented as indicators that convert the absolute numbers to rates.

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Joseph L Mathew

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Vital Statistics





19.1



These are useful for comparing data from different areas and time frames. Table 19.1.2 summarizes the key vital statistics indicators and the calculation for these. Table 19.1.3 shows selected current vital statistics data for India; with a focus on data relevant to the pediatric age- 1081 group. It should be recognized that national data is the

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Calculation

Crude birth rate (CBR)

(Number of live births during the year/mid year population) × 1,000

Crude death rate (CDR)

(Number of deaths during the year/mid year population) × 1,000

Age specific mortality rate (ASMR)

(Number of deaths in a particular age group/mid year population of the same age group) × 1,000

Infant mortality rate (IMR)

(Number of infant deaths during the year/number of live births during the year) × 1,000

Neonatal mortality rate (NMR)

(Number of infant deaths of less than 29 days during the year/number of live births during the year) × 1,000

Early neonatal mortality rate

(Number of infant deaths of less than 7 days during the year/number of live births during the year) × 1,000

Late neonatal mortality rate

(Number of infant deaths of 7 days to less than 29 days during the year/number of live births during the year) × 1,000

Post neonatal mortality rate (PNMR)

(Number of infant deaths of 29 days to less than 1 year during the year/number of live births during the year) × 1,000

Perinatal mortality rate (PMR)

(Number of stillbirths and infant deaths of less than 7 days during the year/number of live births and stillbirths during the year) × 1,000

Stillbirth rate

(Number of stillbirths during the year/number of live births and stillbirths during the year) × 1,000

General fertility rate (GFR)

(Number of live births in a year/mid year female population in the age group 15–49 years) × 1,000

Age specific fertility rate

(Number of live births in a particular age group/mid year female population of the same age group) × 1,000

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Vital statistics indicator

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Table 19.1.2 Key vital statistics indicators

 

Table 19.1.3 Selected current vital statistics data for India (SRS, January 2011) Crude birth rate (2009)

22.5 per 1,000 population

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Crude death rate (2009)

7.3 per 1,000 population

General fertility rate (2000)

102.8

Total fertility rate (TFR) (2009) Natural growth rate (2007)

3.2

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Infant mortality rate (2009)

Infant mortality rate (2009) – boys Infant mortality rate (2009) – girls -

Under five mortality rate (2009)

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Under five mortality rate (2009) – boys

50 per 1,000 live births 50 per 1,000 live births 51 per 1,000 live births 66 per 1,000 live births 62 per 1,000 live births 70 per 1,000 live births

Stillbirth rate (2009)

22 per 1,000 total births

-

Under five mortality rate (2009) – girls

34 per 1,000 live births

Maternal mortality ratio (2008)

230 per 100,000 live births

Life expectancy at birth (2009)

65 years

Life expectancy at birth (2009) – males

63 years

Life expectancy at birth (2009) – females

66 years





1. Census of India 2011. Government of India. Ministry of Home Affairs. Office of the Registrar General and Census Commissioner, India. Available from censusindia.gov. in/2011-common/VitalStatistics.html [Accessed July 15, 2011]. 2. Health information of India. Government of India. Central Bureau of Health Intelligence. Available from www.

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ibliography

cbhidghs.nic.in/hia2005/chap2.asp [Accessed July 15, 2011]. 3. Sources of vital statistics in India. Available from mospi.nic. in/Mospi_New/upload/vital_stat_2010/topic.pdf [Accessed July 15, 2011]. 4. Vital Statistics/Sample registration. Government of India. Ministry of Home Affairs. Office of the Registrar General and Census Commissioner, India. Available from censusindia.gov. in/Vital_Statistics/SRS/Sample_Registration_System.aspx [Accessed July 15, 2011]. 5. World Health Statistics 2011. World Health Organization. Available from www.who.int/whosis/whostat/2011/en/ index.html [Accessed July 15, 2011].



Neonatal mortality rate (2009)

average of a wide range of data; the variations between rural and urban areas and data from different states are not reflected in the national average. B

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Box 19.2.1 Mortality indicators of child health









• Infant mortality rate – Probability of dying between birth and exactly 1 year of age expressed per 1,000 live births – Neonatal mortality rate – The number of deaths among live births during the first 28 days of life per 1,000 live births • Early neonatal mortality rate – The number of child deaths less than 7 days of life expressed as per 1,000 live births in that reference year • Late neonatal mortality rate – The number of child deaths between 7 and 28 completed days of life expressed as per 1,000 live births in that reference year • Post neonatal mortality rate – The number of child deaths of 29 days to less than 1 year of age expressed as per 1,000 live births in the reference year • Perinatal mortality rate – The number of death of fetus after 28 completed weeks of gestation plus the number of early neonatal deaths per 1,000 total births • Stillbirth rate – The number of stillbirths per 1,000 births (live and stillbirths) during the reference year.

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under-5 (2004) are shown in Figure 19.2.2. Under nutrition is the leading risk factor, causing 21% of deaths, besides micronutrient deficiency, and suboptimal breast-feeding. Under-5 mortality per 1,000 in selected countries is listed in Table 19.2.1.

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Figure 19.2.1 Distribution of deaths occurring before attaining age of 5 years Source: World Health Report, 2005 (Reproduced with permission)

I

It is an indicator of the well-being of all children below the age of 5 years. It also reflects income and education of parents, the prevalence of malnutrition and disease, availability of clean water, efficacy of health services, and health and status of women. Under-5 mortality rate (U5MR) is also useful to evaluate effectiveness of various public health interventions. Under-5 mortality fell worldwide from 146/1,000 in 1970 to 79/1,000 in 2003. More than 50% of all child deaths are concentrated in just six countries: China, Democratic Congo, Ethiopia, India, Nigeria and Pakistan. A total of 10.4 million children are still dying every year globally before they are 5 years of age; in addition to 3 million stillbirths. A distribution of all deaths prior attaining the age of 5 years is shown in Figure 19.2.1. Causes of deaths of children

ortality Rate

United Nations (UN) estimates show that the global IMR has decreased from 87 per 1,000 live births during 1975–1980 to less than 50 per 1,000 today. A comparison of infant mortality in a few parts of the world is given in the Table 19.2.1. India at the beginning of the last century had an IMR of more than 200 per 1,000 live births (219 in 1916–1920). Figures 19.2.3A and B depict the decline of infant mortality during the last century. The current IMR in India is 50 per 1,000 live births (SRS, 2011). State-wise IMR according to SRS, 2009 is depicted pictorially in Figure 19.2.4.

auses



Main causes of infant mortality during the neonatal and postneonatal periods are different. Majority of neonatal deaths are accounted for by low-birth weight, infections, birth asphyxia and congenital anomalies, whereas post neonatal mortality occurs primarily due to infections (diarrhea, respiratory infections, malaria, measles and other 1083 vaccine preventable diseases) and malnutrition. ­







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ortality Rate

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nder-5

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Indicators are markers of health status, service performance or resource availability defined to enable the monitoring of objectives, targets and service performance. Definitions of most important mortality indicators of child health are given in Box 19.2.1. Perinatal mortality and neonatal mortality reflect the health and care of women during pregnancy and perinatal period, whereas infant mortality has been described as one of the most sensitive indices of health and quality of living of a population.

community PED A R S

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Figure 19.2.2 The causes of deaths of children under-5, 2004 Source: Global Burden of Disease, World Health Organization (WHO), 2008

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Table 19.2.1 Under-5 mortality rate per 1,000 in selected countries (2007) Country

Under-5 mortality rate

2 160 58 45 107 107 77 27 173 173 173 49 86 173 140 6 62 11 43 189 110 189 160 151 13

257 6 84 22 22 36 119 4 4 4 66 31 4 11 196 55 176 90 3 21 3 6 8 170

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Neonatal (0–27 days) mortality rate

Infant (0–1 years) mortality rate

Child (1–5 years) mortality rate

60 3 36 30 13 18 17 41 2 2 3 34 17 1 5 54 32 41 53 1 8 2 3 4 40

165 5 47 56 20 19 30 75 3 4 4 50 25 3 10 117 43 83 73 2 17 3 5 7 103

92 1 14 28 2 3 6 44 1 0 0 16 6 1 1 79 12 93 17 1 4 0 1 1 67

Source: State of the World Children, 2009; Figures for Indian 1 for year 2009  

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Afghanistan Australia Bangladesh Bhutan Brazil China Egypt Ethiopia Finland France Germany India Indonesia Japan Malaysia Mali Nepal Niger Pakistan Singapore Sri Lanka Sweden UK USA Zambia

Under-5 mortality rank (maximum 1)

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Figures 19.2.3A and B Infant mortality rate in India. (A) 1901–1993 (Source: Health Information of India, 2004); (B) 1994–2007 (Source: National Health Profile, 2008)



Low-birth weight (<2,500 g) as a result of maternal malnutrition, decreased spacing between births, large family size, and a high fertility rate are the principal factors resulting in high infant mortality. Non-practicing of exclusive breastfeeding, non-compliance with immunization on account of illiteracy, ignorance, cultural and social beliefs pose the greatest risk of deaths to the infant. Finally, poverty, poor standards of living, inaccessibility to safe water and proper sanitation contribute in a compounded fashion.

Prevention Preventive measures have to be aimed at improving the nutritional status of the mother, providing good and

eonatal

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eonatal and Perinatal

ortality Rate

ortality

Of approximately 8 million global infant deaths occurring annually, 4 million can be ascribed to the neonatal period; 98% of them in developing countries. Almost 75% of the estimated 4 million neonatal deaths occur in the early neonatal period, i.e. first 7 days following birth. Neonatal deaths contribute to 40% of all childhood deaths and more than 50% of infant mortality. Hence, priority should be given to perinatal and neonatal mortality in order to decrease infant mortality. Neonatal mortality rate in selected states is tabulated in (Table 19.2.2). India accounts for 20% (25 million) of global births and 25% (0.9 million) of global newborn deaths. India has seen a substantial reduction in IMR and NMR in recent decades. Since the early 1970s, the IMR declined from 140 per 1,000 live births to 50 (2010). The NMR has declined from 1085 72 per 1,000 live births in 1972 to 34 in 2010—a reduction of

 

Figure 19.2.4 State wise distribution of IMRs, 2009 (per 1,000 live births) Source: SRS Bulletin October, 2009



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essential antenatal care, safe delivery, essential newborn care, promotion of breast-feeding, immunization, early detection of illness (achievable by growth monitoring) and their management, family planning, efficient services for reproductive and child health (RCH), provision of safe water, sanitation, improving the social and economic condition of the people and providing health education to the receptive audience. On a national level, National Plan of Action for Children, 1992, needs to be followed politically, emotionally and with national commitment to the rights of children. The Government has to strive hard to implement policies for achieving use of oral rehydration salts (ORS), exclusive breast-feeding, universal immunization coverage, and 100% female literacy. Simultaneously, various health programs need constant re-enforcement with involvement of Non-Government Organizations (NGOs) and non-health sector.

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Table 19.2.2 Comparative rural/urban mortality indicators, 2005–2006, India

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Indicator

Combined

Rural

Urban

Maximum

Minimum

Crude death rate (2009)

7.4

8.0

5.9

9.0 (Orissa)

4.8 (Delhi)

Infant mortality rate (2009)

50.0

58.0

36.0

70.0 (MP)

12.0 (Kerala)

Percentage of infant/total deaths

18.5

20.1

12.6

27.8 (Rajasthan)

3.4 (Kerala)

Infant deaths

47.6

49.0

39.6

60.5 (Kerala)

34.7 (Himachal)

Neonatal mortality rate

37.0

41.0

23.0

53.0 (Orissa)

11.0 (Kerala)

Early NMR

28.0

31.0

16.0

41.0 (Orissa)

9.0 (Kerala)

Late NMR

9.0

9.0

7.0

—

—

Post neonatal mortality rate

20.0

22.0

16.0

—

—

Perinatal mortality rate

37.0

40.0

24.0

54.0 (Orissa)

17.0 (Kerala)

Still-birth rate

9.0

9.0

8.0

19.0 (Himachal)

2.0 (Bihar)

Source: Mortality Statistics in India 2006. Central Bureau of Health Intelligence (CBHI)



1. Census of India. www.censusindia.gov.in. From: http:// cbhidghs.nic.in/index2.asp?slid=1000&sublinkid=706 [Accessed August, 2011]. 2. Indicators of Child Health. Available from:www.searo.who. int/LinkFiles/Child_Health_&_Development_Indicators.pdf [Accessed August, 2010]. 3. Maternal, Newborn and Child Health Situation in India. Available from w3.whosea.org/linkfiles/whd_05_fact_file_ india_fact_file_india.pdf [Accessed August, 2011]. 4. The State of the World’s Children 2009. Available from www. unicef.org/sowc09/ [Accessed August, 2011].

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It refers to death of the fetus/newborn after 22 weeks of pregnancy, during birth, or within 7 days after delivery per 1,000 total births (WHO, 1997). However, Government of India is using a cut-off of 28 weeks for calculation of PMR in India. More than 6 million perinatal deaths occur each year worldwide; 3 million of these happen during late pregnancy and birth (stillbirths), while 3 million newborns die in the first week (early neonatal mortality). Perinatal deaths are more likely in the developing than in the developed world, where only 2% of the estimated perinatal deaths occur. Africa has the highest PMR of 75 per 1,000 total births. Almost 40% of the estimated total perinatal deaths take place in south-central Asia, where 30% of world’s births occur. Perinatal mortality in these areas results from poor nutritional status of women, insufficient 1086 prevention of pregnancy-related complications, and even under-supervised deliveries. Some of these causes are



ortality Rate

To achieve desired reduction in infant and neonatal mortality the quality and reach of antenatal care needs to be enhanced and home-based newborn care using integrated management of neonatal and childhood illness (IMNCI) protocols should be implemented. Facility based care of neonates should be improved through strengthening of infrastructure, provision of extra nurses, and skills upgradation of physicians and nurses. The special care newborn units (SCNUs) need to be created for managing sick newborns. Apart from strengthening the health care, the country has to make rapid strides in social sector as well because women education, empowerment, early careseeking, and a balanced growth in economy also contribute in reducing the neonatal and IMRs. We should either push for universalization of institutional delivery for all women, or use an at-risk approach to ensure institutional deliveries for high-risk women and provide a skilled birth attendant in the community for the remaining women. It should be possible to enhance the capacity of the existing health delivery system to handle this load of deliveries. This may also include a public-private partnership.



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Perinatal

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rooted in the social, cultural and economic structure of the society.



almost 50%. The reduction to in NMR is probably due three possible reasons: (1) a major decline in neonatal tetanus (NNT) due to a successful maternal tetanus toxoid (TT) immunization program, (2) a gradual increase in institutional deliveries and skilled attendance and (3) birth spacing leading to indirect benefits for neonatal survival. However, the process of NMR decline has slowed down in recent years. Infections, asphyxia and prematurity are the leading causes of neonatal deaths all over the world. A similar pattern is seen in India where they contribute to 33%, 21% and 15% of the total neonatal deaths respectively. It is noteworthy that most of these deaths can be prevented by better community level maternal newborn care and care at the health facilities [Indian Council of Medical Research (ICMR), 2008]. The NMR varies widely from as low as low as 11 in state of Kerala to as high as 53 in state of Orissa. Other states accounting for high burden of neonatal deaths include Uttar Pradesh, Chhattisgarh and Madhya Pradesh.

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Percentage of early neonatal to

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Primary health care is essential health care based on practical, scientifically sound and socially acceptable methods and technology made universally accessible to individuals and families in the community through their full participation and at a cost that the community and country can afford to maintain at every stage of their development in the spirit of self-reliance and self-determination. Health care system in India consists of many components and levels. So far, the interaction between these components of the system has been very poor. Despite the three tiers of health care facilities, there are no well-organized referral linkages between the primary, secondary and tertiary care institutions in the same locality. The major effort should be on strengthening the first link between the people and health system, i.e. the PHC services.

 

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Primary Health are in the 11th Plan



s

chc

The rural health infrastructure consists of sub-centers, and community health centers ( s) (Fig. 19.3.2).

phc

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Rural Health are Services

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Sub- enter For 5,000 population (or 3,000 in the case of hilly, tribal, sparsely populated or desert areas), it is the most peripheral contact point between the PHC system and rural community. One sub-center has one auxiliary nurse midwife (ANM)/female health worker, one male health worker, and one part-time attendant. One lady health visitor (LHV) supervises six sub-centers. Sub-centers are assigned tasks relating to interpersonal communication to bring about behavioral change in the community and provide services maternal and child health (MCH), family welfare, nutrition, immunization, and control



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The Eleventh-Five Year Plan aimed to focus on National Rural Health Mission (NRHM) strategies; these are described elsewhere in detail in this chapter. Population-centric norms will be replaced with flexible norms comprising habitationbased needs, community-based needs, and disease patternbased needs. Steps will also be taken to reorganize Urban Primary Health Care Institutions (UPHCIs) and make them responsible for the health care of people living in a defined geographic area, particularly slum dwellers. The Eleventh-Five Year Plan will ensure accessibility as a major issue, especially in rural areas; availability of essential drugs and supplies, vaccines, medical equipment, along with the basic infrastructure like electricity, water supply, toilets, telecommunications, and computers for maintaining records. Home-based neonatal care will be provided, including emergency life saving measures (Fig. 19.3.1).

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Historical Perspectives In India, primary health centers (PHCs) in each community development (CD) block having a population of 60,000– 80,000 was launched as an integral part of the CD program on October 2, 1952. Over the past 55 years the health services organization and infrastructure have undergone extensive changes and extension in stage following review by the Mudaliar Committee (1962), Chadha Committee (1963), Mukherjee Committee (1966), Jungalwala Committee (1967), Kartar Singh Committee (1973) and Srivastava Committee (1975). Progressive changes have been introduced into the program over the Sixth and Seventh-Five Year Plan Period when the national norms for population coverage were adopted. During the Eighth and Ninth Plans, the emphasis was mainly on consolidation of the existing health infrastructure rather than expansion. The focus during the 10th Plan was on reorganization and restructuring the existing Government Health Care system at the primary, secondary and tertiary care levels with appropriate referral linkages; development of appropriate two-way referral systems utilizing information technology (IT) tools; building up an efficient and effective logistics system for the supply of drugs; horizontal integration of all aspects of the current vertical programs; evolving treatment protocols; improvement in the quality of care; exploring alternative systems of health care; improving medical education and research; and building up a fully functional, accurate Health Management Information System (HMIS). However, none of these goals could be fully achieved.

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Figure 19.3.1 Five fingers of PHC Source: Gupta P. Textbook of Preventive and Social Medicine, 3rd edition. New Delhi: CBS; 2010.

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FRUs because they either do not have any specialist or the posted specialists are not from the four specified specialties.

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National Rural Health Mission (2005–2012) aims for as overhaul of the existing PHC system, by promoting policies that strengthen public health care management and service delivery. The key components include the following:

 

Figure 19.3.2 Rural health infrastructure Source: Gupta P. Textbook of Preventive and Social Medicine, 3rd edition. New Delhi: CBS; 2010.

of communicable diseases. Basic drugs for minor ailments are also available.



For each block/1 lakh population, a community health center is the first referral unit (FRU) for four PHCs offering 30 beds, one operation theater, X-ray machine, labor room and laboratory facilities and should be staffed at least by four specialists, i.e. a surgeon, a physician, a gynecologist and a pediatrician supported by 21 paramedical and other staff. More than 4,000 CHCs are functioning at present. The facility survey carried out by the Department of Family Welfare showed that although more than 9% of the CHCs have out-patient and in-patient facilities and 1088 an operation theater, only about one-third had adequate equipment. A majority of the CHCs do not function as the

hild Health Services



Availability of child health services is a must at all levels of health care. Essential newborn care is the first step toward establishing an effective chain to reduce infant mortality and increase the national output. Promotion of breastfeeding in the community essentially protects the children from their two biggest enemies-infection and malnutrition. Organization, planning, and execution of immunization services are the cardinal preventive measure for control of many life-threatening or disabling communicable illnesses. Growth monitoring is considered to be the fundamental tool for early detection of childhood morbidities. Management of common neonatal and childhood illnesses in an integrated manner is the final solution to reduce morbidity and mortality in this age-group. Adolescents have their special needs, which should be recognized and tackled. Parents should be enlisted as partners in their children’s health. They should understand ways of promoting good health, recognizing illness, and taking appropriate action, wherever essential. Appropriate counseling and guidance should be provided to them regarding the problem, care, possible complications and prognosis in acute life-threatening illnesses, chronic ailments, genetic and metabolic afflictions, infectious diseases and nutritionrelated disorders. Child health clinics should form a part of the PHC. Earlier, they have been present in a scattered manner, named as well-baby clinics, high-risk clinics, under-5 clinics, etc. Over the years, their scope has broadened to cover all aspects of pediatric and adolescent health. Child health services should be provided in a cordial, compassionate, and caring manner.

ommunity Health enter C

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For 30,000 population (or 15,000–20,000 in the case of hilly, tribal, sparsely populated or desert areas), primary health center is the first contact point between village community and the medical officer. It is manned by a medical officer, supported by fourteen paramedical and other staff. It acts as a referral unit for six sub-centers. It has four to six beds for patients. A primary health center is supposed to be equipped to render preventive, promotive and curative services. Primary health centers are maintained and funded by the State Government. At the national level there are more than an adequate number of PHCs and doctors posted at PHCs but their distribution across states is uneven; there are no functional PHCs in many remote areas in dire need of health care. Essential drugs for the treatment of common ailments are not available in a majority of the PHCs. It is obvious that PHCs are functioning sub-optimally and not providing the expected health and family welfare (HFW) services.

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• Accredited Social Health Activists (ASHA): A female health activist in each village • Village Health Plan (VHP): Prepared through a local team headed by Panchayat • Strengthening of rural hospitals: By upgrading the FRUs as per norms setup by the Indian Public Health Standards (IPHS) • District Health Plan (DHP): Strengthening delivery of PHC and integrate it with sanitation, hygiene, safe water and nutrition programs • Decentralization: Integration of vertical HFW program, and optimal utilization of funds and infrastructure through DHP and VHP.

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1. Bulletin on Rural Health Statistics in India. New Delhi: DGHS, Ministry of Health and Family Welfare, Government of India, 2009. 2. From Alma-Ata to the Year 2000. Reflections at the Midpoint, Geneva: WHO, 1988. 3. Gupta P. Textbook of Preventive and Social Medicine, 3rd edition. New Delhi: CBS Publishers, 2010. 4. Primary Health Care. A Framework for Future Strategic Directions. Geneva: WHO, 2003. 5. The Primary Health Worker. Working Guide for Training and Adaptation, Geneva: WHO, 1980. 6. WHO. The World Health Report 2008. Primary Health Care: Now More than Ever. Geneva: WHO, 2008. 7. World Bank. Global Monitoring Report. New York: United Nations, 2008.



ibliography



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In 1974, India reaffirmed its constitutional obligations to children in the “National Policy for Children”. The policy states that “it shall be the policy of the state to provide adequate services to children, both before and after birth and through the period of growth, to ensure their full physical, mental and social development. The state shall progressively increase the scope of such services so that, within a reasonable time, all children in the country enjoy optimum conditions for their balanced growth”. In 1990, the Government of India endorsed all the 27 survival and development goals for the year 2000, agreed on at the World Summit for Children. The summit also drew attention to four sets of rights of children: (1) Right to survival, (2) Right to protection, (3) Right to development and (4) Right to participation. In 1992, India ratified the convention on the rights of the child and adopted the “National Plan of Action: A Commitment to the Child”. This plan has now been translated into state programs of action for children and further into district plans. The plan

is guided by the principle of “First call for children,” i.e. the essential needs of children should be given highest priority in the allocation of resources at all times.

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Integrated management of neonatal and childhood illness clinical guidelines are targeted for two groups: 1. Young infants from birth to 2 months of age Many deaths occur beyond neonatal age of first 4 weeks. Hence, this group includes infants up to 2 months of age



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Nearly 70% of deaths in under 5 years children are caused due to a very few common illnesses like acute respiratory infections (ARI) (mostly bacterial pneumonia), diarrhea, measles, malaria and malnutrition or a combination of these conditions. Malnutrition and anemia may not be the direct cause of death, but these are compounding factors with other common childhood illnesses and worsen the condition. Every day, millions of parents seek health care for their children, majority of whom suffer because of these few common childhood illness. They visit various hospitals, health centers, dispensaries, private practitioners and traditional healers adding to the burden of the health care providers who are not trained to assess, classify and decide the further approach of management rationally and start early treatment appropriately. They do not have adequate diagnostic and therapeutic facilities, adequate supply of basic essential drugs, or the training for offering quality care. Very often, lack of time and awareness regarding parent counseling and preventive and promotive health care services like nutrition advice and immunizations are lacking. Many sick children never reach a health care facility due to lack of awareness of the parents or non availability of services nearer their homes or sheer poverty. There are many inequities in the health care of these children from deprived families. During past three decades or so many successful 1090 interventions like ORS for diarrheal diseases, rational use of antibiotics for pneumonias and other ARIs, early use of

Integrated management of neonatal and childhood illnesses strategy has been introduced in more than 100 developing countries all over the world. In the beginning, IMNCI did not include the care of newborns in first week after birth as it was linked with the care of mothers. In India, the neonatal mortality constitutes almost 50% of U5MR or 70–80% of infant mortality. Majority of neonatal deaths occur in the first week of life. Hence, neonatal care has been included and the modified strategy of Integrated Management of Newborn and Childhood Illness has been adopted. Now, many other countries have included neonatal care in their IMNCI. Some African countries have included human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) control program in their IMNCI. Many such adaptations have been made depending on the local needs. C

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Despite introducing several effective health care interven­ tions for past three decades and more, every year nearly 11 million children die globally before reaching the age of 5 years. Majority of them die due to a few common illnesses for which we have the knowledge and the capability to prevent or treat. But these children mostly from poor and deprived families are denied these benefits and unnecessarily succumb to death. In response to this challenge WHO and United Nations Children’s Fund (UNICEF) designed a fresh strategy named Integrated Management of Neonatal Childhood Illness (IMNCI) in the early 1990s for the developing countries of the world to provide effective and affordable interventions to reduce childhood morbidity and mortality and also to improve child health and development. Both preventive and curative health care interventions have been included in IMNCI.

antimalarials, immunizations under expanded program on immunization/universal immunization program (EPI/ UIP), anemia control program, vitamin A supplement program etc. have been incorporated in National Health Programs as vertical programs and have helped in bringing down the childhood mortality to some extent. But, for the further reduction of infant and under 5 mortality, a different strategy was needed and in this background, WHO and UNICEF conceived IMNCI approach. It is not a new program. It is an effective strategy or a different approach integrating all the vertical health care programs aiming for the holistic care of the young children up to 5 years of age, a care not dependent on sophisticated technology or costly equipment or drugs.



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This is yet another adaptation of IMNCI approach in India started since November 2009. Following were a few important considerations for initiating facility based IMNCI (F IMNCI) in India for the first time. Facility based care for severely ill children are complementary to primary care for providing continuum of care for the severely ill children. Good quality in patient care is required to enhance the impact of primary care and better outcome. There is acute shortage of specialists (pediatricians) at facilities. Thus, it becomes important to build the skills of medical officers and staff nurses at these facilities to manage referred sick infants and children and bridge the gap of specialists to some extent. Facility based IMNCI is an integration of existing IMNCI package and the facility based package with certain added components like asphyxia management and care of newborns. Critical element of F IMNCI is again evidence based integrated approach with a focus on severely ill newborns and children. Salient features of training modules of F IMNCI are stated in Box 19.4.1.

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2. The second group includes young children of 2 months up to 5 years of age. The clinical guidelines have been developed and they represent an evidence based syndromic approach to case management. That includes rational, effective and affordable use of drugs and simple diagnostic tools. The clinical decisions based on intuitions, empirical considerations and without the support of solid evidence are discouraged. The standardized clinical guidelines may not lead to specific diagnosis of a disease, but helps the health worker to classify the condition requiring: (1) emergency management and immediate referral, (2) treatment at the out patient health facility with available resources or (3) advice for home management. Color coded standard management charts are provided to help in assessment, classification and planning further line of management. • Pink classification: Child needs referral and in patient care • Yellow classification: Child needs specific treatment, provide it at home [e.g. antibiotics, antimalarials, oral rehydration therapy (ORT)] • Green classification: Child needs no medication. ome care adviced. Integrated management of neonatal and childhood illness provides adjustments of interventions to the capacity of the health system and active involvement of family and the community in the health care process.

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are of Newborn and oung nfants ( nfants nder 2 Months of ge)

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Management of diarrhea, ARIs (pneumonia), malaria, measles, acute ear infection, malnutrition and anemia Recognition of illness and at risk conditions and management Prevention and management of iron and Vitamin A deficiency Counseling on feeding of all children below 2 years of age Counseling of feeding for malnourished child between 2 months to 5 years of age. -

•

Module 1 Emergency triage assessment and treatment (ETAT): Maintain temper­ ature; Check and treat hypoglycemia; Airway and breathing; Give oxygen; Circulation; Coma and Convulsions; Dehydration.

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are of nfants and hildren (2 Months up to 5 ears of ge)

Box 19.4.1 Salient features of training modules of F-IMNCI

Module 2 Facility based care of sick young infant: Care at birth including neonatal resuscitation; Care of newborn in postnatal wards; Management of sick newborn; Management of low birth weight babies; Neonatal transport. Module 3 Facility based care of sick children: Case management of children presenting with cough or difficult breathing, case management of children presenting with fever, case management of children presenting with diarrhea, case management of children with severe anemia, case management of children with severe malnutrition, effective implementation with proper supplies and supervision are required for good results from F IMNCI. -

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Keep the infant warm Initiate breast feeding immediately after birth and continue exclusive breast feeding Counseling for early and exclusive breast feeding Cord, skin and eye care Recognition of illness in newborn and management and/or referral Immunization Home visits in the postnatal period.

The entire 0–5 year period is covered including first week of life Almost 50% of training time is allotted for management of young infant up to 2 months The order of training is reversed; now begins with management of young infants Reduced duration of training (8 days) Separate training material for physicians and other health workers

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ibliography 1. IMNCI, State Institute of Health and Family Welfare, Jaipur, 6 Jan 2010. Accessed on 30 July, 2011. 2. Integrated Management of Neonatal and Childhood Illnesses [IMNCI] – A guidebook for private practitioners, WHO publication, Department of Child and Adolescent Health, 2002. 3. Patwari A, Raina N. Integrated Management of Childhood Illnesses: a robust strategy. Indian Pediatr. 2002;69(1):41 8. 4. Students Handbook IMNCI (Integrated Management of Childhood Illness), Prepared by World Health Organization, Department of Child and Adolescent Health and Development and The Ministry of Health and Family Welfare, Government of India, 2003.

Depending on the scope of practice, private practitioners can adapt IMNCI approach in their clinical work. It will definitely



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Antenatal care/birth preparedness Skilled birth attendance Management of important problems like asthma, tuberculosis (TB), etc.



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All newborns: Three visits (1st within first 24 hours of birth, 2nd on 3rd or 4th day of birth and 3rd on 7–10 days after birth) For low birth weight (LBW) infants: Three more visits (14th, 21st and 28th day of birth).

-

•

chedule of Home Visits for the Newborns



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Promote and support early and exclusive breast feeding Teach the mothers to recognize the signs of illness for which to seek care Identify illness at visit and facilitate referral Advise on cord care and hand washing.



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Home Visits for oung nfants

improve their quality of care and rationalize the use of drugs and investigations. In many areas, the community members prefer to take treatment from family physicians/private practitioners than from public health facilities for several reasons. The community health workers also refer their cases to local private doctors. If the private doctor adopts the same IMNCI approach there will be definitely a better continuum of care benefiting the patients and community at large. Unlike many other health care interventions where training is given to doctors in public service alone, IMNCI training is available for family physicians also. If properly implemented and supported by strengthening the health system assuring quality training to all the functionaries, ensuring regular adequate supplies, good supervision and monitoring and community based services like good counseling and behavior change communication IMNCI in India has a great potential to achieve its main goal of reducing newborn and under 5 mortality in children within a short time and come closer to Millennium Development Goals.



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Management now consistent with the policies of Ministry of Health and Family Welfare (MoHFW), Department of Women and Child Development (DWCD) and National Anti Malaria Program (NAMP) Home based care by health workers has been added. -

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Box 19.5.1 Statistical data of NRHM for IMR UCTION

Infant mortality rate reduced to 30/1,000 live births by 2012

O

Maternal mortality reduced to 100/100,000 live births by 2012 Total fertility rate reduced to 2.1 by 2012 Malaria mortality reduction rate: 50% up to 2010, additional 10% by 2012 Tuberculosis directly observed treatments (DOTS) series: Maintain 85% cure rate through entire Mission Period and also sustain planned case detection rate Upgrading all CHCs to IPHS Increase utilization of FRUs from bed occupancy by referred cases of less than 20% to over 75% Engaging 400,000 female ASHAs

related programs from village level upward, innovations and flexible financing. The mission seeks to establish functional health facilities through revitalization of existing infrastructure and fresh construction or renovation wherever required. Simultaneous correction in manpower planning is envisaged. Mission also seeks to ensure availability of requisite drugs and equipment at all levels of public health facilities. Outreach activities in underserved specially inhabited by vulnerable populations are to be improved through provision of Medical Mobile Units in every district. Improving availability of critical manpower includes introduction of a trained voluntary community health worker (ASHA) in every village of 18 high focus states, additional ANM at sub-center, staff nurses at the PHCs to make them operational round the clock and additional specialists and paramedical staff at the CHCs. In order to institutionalize community led action for health Panchayati Raj institutions, right from the village to district level, have been given ownership of the public health delivery system in their respective jurisdiction. Village health and sanitation committee (VHSC) are formed in each village. To facilitate local action, the NRHM provides untied grants at all levels [village, gram panchayat, block, district, VHSC, student health center (SHC), PHC and CHC]. To bring in quality accountability in the health services, Indian Public Health Standards (IPHS) have been setup for various levels of health facilities. Indian Public Health Standards provide benchmarks of infrastructure including building, manpower, equipment, drugs and quality assurance through introduction of treatment protocols. National Rural Health Mission recognized that delegation of financial and administrative powers at various levels would be necessary for successful implementation of 1093 decentralized plans. States are encouraged to prepare their

• •

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Expected utcomes from the

ission

Key Features of the

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In terms of statistical data, the following outcomes are expected (Box 19.5.1).

ission

Some of the key features of NRHM are to make the public health delivery system fully functional and accountable to the community, human resources management, community involvement, decentralization, rigorous monitoring and evaluation against standards, convergence of health and



• •

Reduction in child and maternal mortality Universal access to public services for food and nutrition, sanitation and hygiene and universal access to public health care services with emphasis on services addressing women’s and children’s health and universal immunization Prevention and control of communicable and noncommunicable diseases, including locally endemic diseases Access to integrated comprehensive PHC Population stabilization, gender and demographic balance Revitalize local health traditions and mainstream AYUSH Promotion of healthy life styles.



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The goal of the mission is to improve the availability of and access to quality health care by people, especially for those residing in rural areas, the poor, women and children.





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National Rural Health Mission (NRHM) was launched on 12th April, 2005 throughout the country with special focus on 18 states with weak public health indicators and/or weak health infrastructure. These are Arunachal Pradesh, Assam, Bihar, Chhattisgarh, Himachal Pradesh, Jharkhand, Jammu and Kashmir, Manipur, Mizoram, Meghalaya, Madhya Pradesh, Nagaland, Orissa, Rajasthan, Sikkim, Tripura, Uttarakhand and Uttar Pradesh. National Rural Health Mission currently provides support to states for strengthening system of health care in rural areas through provision of physical infrastructure, human resources, equipment, emergency transport, drugs, diagnostics and other support. It covers all programs in health sector except HIV/AIDS.

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Based on a careful consideration of the evidence brought out by the independent studies, some of following recommendations have been made to increase the impact of the mission. There is a need to ensure that all facilities across the country have the basic protocols in place. There is a need to design training and skill development programs in such a manner that medical officers, nurses, paramedics and community health workers are able to operationalize basic protocols after training. The expansion of nursing and paramedic institutions in deficient States needs top most attention to enable an increase in the density of skilled health workers in the rural areas. Malaria, TB and disease surveillance require a community approach that NRHM has initiated through its decentralized institutions. All programs not only in the health sector but also in water, sanitation, education and nutrition ought to become accountable to the village level Health and Sanitation Committees in order to ensure full convergence at the ground level (Table 19.5.1). While resources have reached institutions across the length and breadth of the country under NRHM, a time has come for every facility to develop its detailed institutional plan for making use of untied resources being made available to it. Timely utilization of such resources, their effectiveness and their efficiency ought to be assessed from time to time. Governance reforms and greater supervision in this regard will help. The challenge of NRHM is to craft credible public systems and this would also call for new systems of public recruitments which are institution specific and based on service guarantees with complete local level accountability. National Rural Health Mission has promoted this culture of local recruitments and local accountability through contractual appointments. There is a need to develop a new paradigm of public recruitment based on the learning of the last 5 years.





In its journey of last 5 years, NRHM has tried to push health reforms in partnership with the State and Union Territories (UTs). Based on a careful evidence based assessment of progress as recorded by independent studies and review missions, it is clear that NRHM has led to increase in out patient and in patient cases, institutional deliveries, availability of ambulances, presence of community health worker in every village, better availability of drugs and diagnostics and most importantly a sincere effort to craft a credible public system. National Rural Health Mission provided an opportunity at each level from the village to the sub-center, the PHC, the CHC, the sub-divisional hospital, and the district hospital to create a community institution under the umbrella of Panchayati Raj local Government system, with provision of untied funds to meet institution and village specific needs for health care. The studies on Janani Suraksha Yojana (JSY) have brought out the fact that institutional deliveries have increased tremendously across more so in states like Madhya Pradesh (MP), Orissa, Rajasthan, Assam, Bihar and over the last 2 years in Uttar Pradesh as well. While resources are available with government facilities for improving the quality of care, pace of refurbishment and improvement of quality in health facilities has not kept pace with the demand for institutional delivery services in many states. The SRS data has indicated that IMR is down to 50 in 2009. Similarly, reduction in maternal mortality as expected in SRS 2007–2009 is 212. It is expected that there would be a significant decline on maternal mortality on account of the large scale interventions for strengthening health system under NRHM and demand side financing under JSY. The thrust on institutional deliveries and assured referral transport, together with efforts to improve the quality

ission—



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Journey ver Last 5 ears (2005–2010)

ational Rural ealth oving Forward

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Reproductive and Child Health Program, Phase II (RCH II), is an integral component of the NRHM. Important steps have been taken within the mandate of this program to ensure universal and equitable access to quality MCH services based on the principle of continuum of care. Reproductive and Child Health Program, Phase II has focused on reducing social and geographical disparities in access to and utilization of RCH services in order to accelerate the achievement of its goals. The major components of the RCH program are Maternal Health, Child Health, Nutrition, Family Planning and Adolescent Reproductive and Sexual Health (ARSH).

of care in facilities is likely to further increase the pace of reduction of MMR. Eight states are below 200 in 2004–2006 and Kerala was already at 95. The country’s TFR is about 2.6 according to SRS 2009. But, much of that decline has been in the Southern India. Total fertility rate remains high in most populous states of Northern India. Empowered action group (EAG) states accounted for 46% of India’s 2011 population and 53% of its population growth. There is no doubt that quality needs to improve manifold and that even after addition of 7.49 lakh ASHAs as community health workers, over 73,000 nurses and ANMs, over 18,000 doctors, AYUSH practitioners and over 14,000 paramedics, lab technicians, etc. under NRHM, there is still a long way to go on human resources.

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National Mental Health Program (NMHP)

National Program for Prevention and Control of Deafness

ibliography





1. National Rural Health Mission, Meeting People’s Health Needs in Partnership with States: the Journey So Far, 2005-2010, Ministry of Health and Family Welfare, Government of India. Available from www.mohfw.nic.in/NRHM/Documents/5_ Years_NRHM_Final.pdf [Accessed July, 2011]. 2. NRHM 2005-2010, Mission Document. Available from fpload. nic.in/NRHM/Documents/Mission_Document.pdf [Accessed July, 2011].





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National Iodine Deficiency Disorders Control Program

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National Program for Control of Blindness launched in 1976 provides relief to the needy by camp approach and by establishing permanent eye care facilities coupled with health education measures. Under this program, the concept of District Blindness Control Societies has been implemented to decentralize management of eye care service in the district and evolve a partnership among Government, Non-Government and Private Sector. Mental health program was launched to ensure availability of minimum mental healthcare and to encourage application of mental health knowledge in general healthcare. National Mental Health Programs present focus is to provide mental health treatment at district level, strengthen infrastructure of psychiatry at state level and development of mental health professionals. Program was launched with an objective of preventing avoidable hearing loss, early identification, diagnosis and treatment of ear problems; medically rehabilitate persons with deafness, and to develop institutional capacity for ear care services by providing support for equipment and material and training personnel. The primary thrust of this program is iodization of edible salt in a phased manner.

3. National Rural Health Mission, Meeting People’s Health Needs in Rural Areas, Framework for Implementation 2005-2012, Ministry of Health and Family Welfare Government of India, Nirman Bhawan, New Delhi. Available from 202.71.128.172/nihfw/ nchrc/index.php?q=content/government guidelines-nationalrural-health-mission-framework-implementation-2005-2012 [Accessed July, 2011]. 4. NRHM. The progress so far. Available from164.100.52.110/ NRHM/Documents/NRHM_The_Progress_so_far.pdf [Accessed July, 2011].

National Program for Control of Blindness



National Program for Prevention and Control of Cancer, Diabetes, Cardiovascular Diseases (CVDs) and Stroke (NPCDCS)



National Integrated Disease Surveillance Program (NIDSP)

Six such diseases, namely malaria, filariasis, dengue/dengue hemorrhagic fever, chikungunya, japanese encephalitis ( E) and Kala-azar, are of public health importance in India. The National Vector Borne Disease Control Program is an umbrella program responsible for planning and guidance for prevention and control of vector borne diseases. National Integrated Disease Surveillance Project was launched in November, 2004. It is a decentralized, State based Surveillance Program intended to detect early warning signals of impending outbreaks and help initiate an effective response in a timely manner. Considering the rising burden of chronic non-communicable diseases (NCD) this new program was initiated. Focus of the program is on health promotion and prevention, strengthening of infrastructure including human resources, early diagnosis and management and integration with PHC system through NCD cells at different levels. J

National Vector Borne Disease Control Program (NVBDCP)

X

 

Table 19.5.1 Schemes under the NRHM from the I plan onward Reproductive and Child Health Second phase of RCH program, i.e. RCH – II commenced from 1st April, 2005. The main objective of the program is Program to bring about a change in mainly three critical health indicators, i.e. reducing TFR, IMR and maternal mortality rate with a view to realizing the outcomes envisioned in the Millennium Development Goals. Various components include maternal health, child health (including school health program), immunization family planning, adolescent health and nutrition. Revised National Tuberculosis Tuberculosis continues to be a major public health problem. Revised National Tuberculosis Control Program is being Control Program (RNTCP) implemented in the entire country. Under the program, diagnosis and treatment facilities including the supply of anti-TB drugs are provided free of cost to all TB patients. National Leprosy Eradication Leprosy case load in the country has come down significantly. Multidisciplinary team (MDT) services have been Program sanctioned for all the districts in the country and implemented through District Leprosy Societies.

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These services are mainly handled by multipurpose health workers. Their job is to: • Record occurrence of pregnancy in their work area on the basis of history of missed periods • Screen women identified as pregnant for any of the under mentioned “risk” factors. – Age less than 17 years or over 35 years – Height less than 145 cm – Weight less than 40 kg or more than 70 kg – History of bleeding in previous pregnancy – History of stillbirths – History of cesarean section as indicated by scar in lower mid abdomen Identify women with moderate “and” severe anemia -

Several measures have been undertaken by the Govern­ ment of India to improve the health of the people after independence, under the constitution of India. The subject of health facilities, their planning, establishment and administration falls under the purview of respective Governments of States of the Union. Government of India has introduced National Health Programs from time to time, which are either centrally, partially sponsored or completely funded by the center. To improve the health of the people prominent measures are National Health Programs launched by the central government for the control/ eradication of the communicable diseases, improvement of environmental sanitation, raising the standard of nutrition, control of population and improving rural health. According to changing health scenario, new programs are being added and existing ones are modified. The important National Health Programs are listed in Box 19.6.1.

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The Government of India launched “NRHM” on 5th April, 2005 for a period of 7 years (2005–2012), recognizing the importance of health in the process of economic and social development and to improve the quality of life of its citizens. This mission seeks to improve rural health care delivery system. The main aim of NRHM is to provide accessible, affordable, accountable, effective and reliable PHC and bridging the gap in rural health care through creation of a cadre of ASHA. This has been discussed in the previous section of this chapter. C

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Maternal and child health refers to the promotive, preventive, curative and rehabilitative health care for mothers and children, which include maternal health, child health, family planning, school health, handicapped children adolescence and health aspects of care of children in special settings like day care. The ultimate objective of MCH services is life long health.

Reductions of maternal, perinatal, infant and childhood mortality and morbidity Promotion of reproductive health Promotion of physical and psychological development of the child and adolescent within the family.

 

Box 19.6.1 National Health Programs National Programs Related to Mother and Child Care: • Maternal and child health program • Integrated child development services (ICDS) scheme • Child survival and safe motherhood (CSSM) program • Reproductive and child health program • Integrated management of neonatal and childhood illnesses National Programs Related to Control of Communicable Diseases: • National program of immunization • Acute respiratory infection control program • Diarrheal disease control program • Tuberculosis control program • Leprosy eradication program • Malaria and other arthropod-borne disease control program • National Filaria control program (NFCP) • National guinea worm control program • Acquired immune deficiency syndrome and sexual transmitted disease (STD) control program National Programs Related to Control of Nutritional Deficiencies and Disorders: • Nutritional programs • Mid-day meal program • Anemia prophylaxis program • Vitamin A deficiency control program • National iodine deficiency disorder control program (NIDDCP). National Programs Related to Control of Non-communicable Diseases: • National school health program • Cancer control program (CCP) • National mental health program • Drug de-addiction program • National diabetes control program • National program for control of blindness.

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The MCH services are essentially delivered through the staff members of the PHCs and sub centers comprising of medical officers, health assistants (female and male) and multipurpose female health workers, also called as ANM and multipurpose male health workers. Traditional birth attendants (TBAs) and village health guides support to the services. In ICDS blocks, Anganwadi workers (AWWs) also help in various MCH programs tasks. Maternal and Child Health Programs clinics/immuniz­ ation clinics are conducted on one or more fixed days in a month in a sub center which is for every 5,000 populations in rural area and 3,000 populations in urban area. Home visits are also done by health workers. Medical officer of PHC is the leader of the team where curative services, MCH and other preventive and promotive services are conducted. The CHCs are upgraded PHCs where some additional health care services like anesthesia, dentistry and pathology are available. In selected district under CSSM program approximately with 5 lakhs population, one FRU is created with provision of a surgeon, an obstetrician, a pediatrician and an anesthetist along with facilities of blood transfusion and operations. Other complicated cases are either sent to district hospitals or nearest teaching hospital attached to medical college. -

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ntenatal are

risk” babies contribute so largely to perinatal, neonatal and infant motility. The basic criteria for identifying these “at risk” babies are listed in Box 19.6.2.

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Administrator two doses of TT Provide iron and folic acid tablets to pregnant women for a period of 180 days. The “at risk” pregnancies identified by above mentioned criteria make the basis of 80% of total morbidity and mortality.

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Integrated child development service scheme was launched in 1975 in pursuance of the national policy for children in 33 CD blocks. The network consists of 5,659 projects in rural and urban slum pockets. Integrated child development service scheme represents one of the world’s largest and most unique programs for early childhood development, breaking the vicious cycle of malnutrition, morbidity, reduced learning capacity and mortality.  

Box 19.6.2 Children “at-risk” • • • • •

Birth weight less than 2.5 kg Twins Birth order 5 and more Artificial feeding Weight below 70% of the expected weight (i.e. II and III degrees of malnutrition) • Failure to gain weight during three successive months • Children with protein energy malnutrition (PEM), diarrhea • Working mothers/single parent

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The following activities are conducted by female multi­ purpose health worker under the supervision of the medical officer at primary health center. • Monitoring of growth of children to detect weight gain or malnutrition • Immunization against vaccine preventable diseases • Treatment of common illness as per the IMNCI guidelines • Referral of cases to health institutions • Implement National Health Programs • Impart health and nutrition education to community It is necessary to identify and register “at risk” children and give them special intensive care because these “at

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The aims of good intranatal care are: • Thorough asepsis • Delivery with minimum injury to the infant and mother • Readiness to deal with complications like prolonged labor, antepartum hemorrhage, convulsions, malpre­ sentations, prolapse of the cord, etc. • Care of the newborn at delivery – resuscitation, care of the cord, care of the eyes, etc. The mothers are advised regarding breast feeding, immunizations, family planning and general hygiene. The health care of the delivered woman continues to be supervised by the health worker at the sub center or at her home under the supervision of health visitor or female multipurpose worker. Initial health care of the newborn baby is also undertaken by these health workers.

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The primary aim of antenatal care is to achieve at the end of a pregnancy, a healthy mother and healthy baby. Ideally this care should begin soon after conception and continue throughout pregnancy. For all pregnant women the package of antenatal care comprises of (1) anemia screening, (2) eclampsia and pre eclampsia detection, (3) multiple pregnancy screening, (4) hemoglobin estimation, (5) blood pressure recording and (6) fundal height measurement. The pregnant mothers are given advice on diet generally consumed by them. Breast examination is done to exclude retracted nipples. The expectant mothers are advised about the personal hygiene, other necessary warnings and articles needed at the time of labor and after labor on arrival of newborn. They are also advised regarding spacing.

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upplementary nutrition: The target group for supple­ mentary nutrition is children below 6 years and nursing and expectant mothers from low income group • mmunization: Children are immunized against six preventable diseases and pregnant mothers are given immunization against tetanus • Health check-up: Here, ICDS provides (1) antenatal care of expectant mothers (2) postnatal care of nursing mothers and care of newborns and (3) care of children under 6 years of age which consists of: – Record of weight and height from time to time – Watch over developmental milestones – Immunization – General check up every 3–6 months – Treatment of prevalent diseases – Deworming – Prophylaxis against Vitamin A deficiency and anemia – Referral of serious cases to hospital – Maintenance of health records. • Nutrition and health education: To all women in the age group of 15–45 with priority to pregnant and nursing mothers, nutrition and health education is imparted by AWWs • Referral services • Non formal preschool education. A

eproductive and hild Health Program

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In 1997, the National Family Welfare Program has been renamed as reproductive child and health (RCH) program. RCH has been defined as “People have the ability to reproduce and regulate their fertility, women are able to go through pregnancy and child birth safely, the outcome of pregnancy is successful in terms of maternal and infant survival and well being, and couples are able to have sexual relations free of fear of unwanted pregnancy and of contracting sexually transmitted diseases”.

omponents

Components of RCH program are listed in Box 19.6.3. • Reproductive and child health program integrates all interventions of fertility regulation, MCH with reproductive health for both men and women • Services provided in RCH are client oriented, demand driven, high quality and based on need of community through decentralized participatory planning and target free approach • Reproductive and child health envisages upgradation of level of care. Comprehensive emergency obstetric and newborn care is provided at sub district level which are FRUs. Reproductive and child health facilities at PHCs are also upgraded • Services of obstetric care, medical termination of pregnancy (MTP) and intrauterine device (IUD) insertion in PHCs level are improved • Specialist facilities for STD and RTI are available in all district hospitals and a good number of sub district level hospitals -

dministration

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The administrative unit of an ICDS project is a CD block in rural areas, the tribal development block in tribal areas and a group of slums in urban areas. The focal point for the delivery of ICDS is the trained local women known as AWW. An Anganwadi is established for a population of 1,000 in rural and urban areas and 700 in tribal areas. For a population of 100,000 in a CD block 100 AWWs are employed on a part

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To improve the nutritional and health status of pre school children in the age group of 0–6 years To lay the foundation of proper psychological development of the child To reduce the incidence of mortality, morbidity, malnutrition and school dropout To achieve effective coordination of policy and implementation amongst the various departments to promote child development To enhance the capability of the mother to look after the normal health and nutritional needs of the child through proper nutrition and health education. -

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time basis, supervised by four to five female supervisors (Mukhya Sevika). A child development project officer (CDPO) is the overall in charge of ICDS work in CD block. At present, there are two schemes for adolescent girls, i.e. “Kishori Shakti Yojana” and “Nutrition Program for Adolescent Girls.” These programs are implemented through the administrative setup of ICDS scheme at the state, district, block and Anganwadi center level. Two more schemes are being implemented at the ICDS level: (1) Rajiv Gandhi Scheme for empowerment of adolescent girls – “SABLA” for 11–18 years of age and (2) Indira Gandhi Matritva Sahyog Yojana (IGMSY). During the year 2009–2010, about 6,705 ICDS projects and 11.5 lakh Anganwadi centers/mini Anganwadi center are functional in the country. About 718.45 lakh children and 156.86 lakh pregnant and lactating mothers (Total 875.31 lakh) are getting the benefit of ICDS scheme. The impact of program on the lives of children is evident in several important areas like increased birth rate, reduced incidence of malnutrition, increased immunization coverage and a reduced infant and child mortality rate in areas covered by the ICDS. R

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The beneficiaries are children below 6 years, pregnant and lactating women, women in the age group of 15–45 years and adolescent girls in selected blocks.

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• Population stabilization • Maternal health (essential obstetric care) • Reproductive tract and sexually transmitted infection control program (HIV/AIDS and Cancer of Reproductive System) • Newborn and child health through IMNCI (including Diarrheal disease control program, Respiratory infection control program, Breastfeeding, Baby Friendly Hospitals Initiatives, Immunization, etc.) • Prevention and control of anemia • Prevention and control of Vitamin A deficiency • Universal immunization program • Polio eradication: pulse polio program • Adolescent health (sexuality development, Adolescence education and vocational component) • Tribal health • Urban health • Effective family planning (ensuring informed choice, counseling, gender equality and greater male participation) • Prevention, detection and management of genetic and environmental disorders • Prevention and management of infertility and other reproductive disorders • Reproductive health care of elderly persons.

iarrhea disease control: India is the first country in the world to introduce low osmolarity (i.e. ORS). Zinc is being added as an adjunct to ORS for the management of diarrhea. The incidence of diarrhea reduced by provision of safe drinking water cute respiratory disease control: Management of ARI and prevention of deaths due to pneumonia is now an integral part of RCH program. Peripheral health workers are trained to recognize and treat pneumonia Prevention and control of vitamin deficiency in children: Under this program doses of vitamin A are given to all children under 5 years of age. The first dose (1 lakh units) at 9 months of age, second dose (2 lakh units after 9 months and subsequent doses (2 lakh units each) given at 6 months intervals up to 5 years of age. It covers subclinical deficiency of vitamin A Prevention and control of anemia in children: To manage anemia, infants from the age of 6 months to 5 years are to receive iron supplements in liquid formulation in doses of 20 mg elemental iron and 100 mcg of folic acid for 100 days in a year. Children 6–10 years of age will receive 30 mg of elemental iron and 250 mg folic acid for 100 days in a year. Children above this age group would receive iron supplement in the adult dose.

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Box 19.6.3 Components of RCH program

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Special program is taken up for urban slums, tribal population and adolescence, the vulnerable group of population.

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• Nutrition rehabilitation centers: Nutrition rehabilitation centers (NRCs) are being set up in the health facilities for impatient management of severely malnourished children, with counseling of mothers on proper feeding • ntegrated management of neonatal and childhood illnesses: This strategy is one of the main interventions under the RCH II/NRHM • Pre-service MN : It is included in the curriculum of medical colleges of the country • acility based MN : This is to empower the health personnel with the skill to manage newborn and childhood illnesses at the country level • ick newborn care units: As of January, 2010 about 267 sick newborn care units (SNCUs); 1,772 FRUs providing newborn care services and 5,892 PHCs with newborn care corners are operational in India • Home based newborn care: It has been developed for 1099 the use of ASHA in some of the states. F

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This program which started in 1992 had the following components: • Early registration of pregnancy • To provide minimum three antenatal check ups • Universal coverage of all pregnant women with TT immunization • Advice on food, nutrition and rest • Detection of high risk pregnancy and prompt referral • Clean and safe deliveries by trained personnel • Birth spacing • Promotion of all institutional deliveries. These services have been integrated in RCH program and the major interventions are: • Essential obstetric care • Emergency obstetric care • 24 hour delivery services at PHCs/CHCs • Medical termination of pregnancy • Control of reproductive tract infections (RTI ) and STD • mmunization: In 1992, the universal immunization program (UIP) became a part of CSSM program and RCH program in 1997. It will continue to provide vaccines for polio, tetanus, diphtheria (DPT), measles and TB • ssential newborn care: The main components of es­ sential newborn care are resuscitation of newborn with asphyxia, prevention of hypothermia, prevention of infec­ tion, exclusive breastfeeding and referral of sick newborn

Reproductive and child health program phase II began from 1st April, 2005. Under RCH II more flexibility has been given to the states for planning their own interventions for achieving the goals. The major strategies under the second phase of RCH are: • Essential obstetric care • Emergency obstetric care • Strengthening referral system

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This program was launched in India in 1970–1971. Special nutrition program provided supplementary feeding of about 300 calories and 10 gm of proteins to children below 6 years of age per day. About 500 calories and 25 gm of proteins to expectant and nursing mothers and 600 calories

Ministry of Health and Family Welfare

2. Prophylaxis against nutritional anemia

Ministry of Health and Family Welfare

3. Iodine deficiency disorders control program

Ministry of Health and Family Welfare





6. Integrated child development services program

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Ministry of Social Welfare Ministry of Social Welfare







4. Special nutrition program (SNP) 5. Balwadi nutrition program

Ministry of Education Ministry of Human



7. Mid-day meal program 8. Mid-day meal scheme

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Ministry

1. Vitamin A prophylaxis program

Program



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Table 19.6.1 Nutrition programs in India

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pecial Nutrition Program

The mid day meal program (MDMP) is also known as “School Lunch Program” or “Noon Meal Program”. It was started in 1961 throughout the country. This national program of nutritional support to primary education was formally launched in 1995 and revised in 2004 was aimed at improving: (1) school attendance, (2) reduce dropouts and (3) a beneficial impact on children’s nutrition. Priority is given to children belonging to backward classes, scheduled castes and scheduled tribe families coming from under privileged backgrounds. The mid day meal scheme runs through central assistance provided by Government of India to states by way of free supply of food grain at the rate of 100 gm per student per day to provide a cooked mid day hot meal with minimum 300 calories and 8–12 gm of protein content to all children in class I–V for 200 school days or equivalent pre cooked food or through the supply of 5 kg of wheat/rice per month per children in a family for 10 months. To be eligible the beneficiary has to attend school for 20 days in a month. Some broad principles should be kept in mind while formulating mid day meals for school children, like • The meal should be a supplement and not a substitute to the home diet • The meal should supply at least one third of the total energy requirement and half of the protein need • The cost of the meal should be reasonably low • No complicated cooking process should be involved. t should be easily prepared in the schools • To reduce the cost of the meal locally available foods should be used as far as possible • To avoid monotony the menu should be changed frequently. The major hurdles in the implementation of mid day meal scheme are frequent interruptions in the supply of raw materials, low budget allocation per beneficiary, lack of effective monitoring and supervision and wrong identification of beneficiaries. Studies have shown that, in the long run we can hope to improve the nutritional status of our children only through improvement in the economic conditions of the community to a level at which families can afford balanced diets; sponsored feeding programs cannot be the permanent answer to the problem. -

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There is definite correlation between nutrition, immunity and infection and the vicious cycle goes on. Malnutrition alters immunocompetence and increases the risk of infection. The nutrition plays a crucial role in the reproduction of poverty from one generation to the next. The cost of under nutrition in terms of development and productivity are enormous. Government of India has initiated several large scale supplementary feeding programs aimed at overcoming specific deficiency diseases through various ministries to combat malnutrition as follows in Table 19.6.1. A number of programs were implemented in the past from time to time with some success. Some of these are mentioned below:

Mid- ay Meal Program





Nutrition affects growth and development of a child. Malnutrition is by far the most important single cause of illness and death globally. Malnutrition is a multifaceted problem. Under privileged section of the society like rural, tribal and urban slums are worst affected by malnutrition particularly pregnant and lactating women and children are at higher risk. In the community, the undernutrition leads to various diseases commonly as: • Protein energy malnutrition • Nutritional anemia • Nutritional blindness • Iodine deficiency disorders • Deficiency of vitamins and trace element.

and 20 gm of proteins in severely malnourished children for 6 days a week. Vitamin A, iron and folic acid tablets were also supplied in the last trimester of pregnancy. Now a days, majority of beneficiaries and funds of SNP have been shared by ICDS program. Some of the other major nutritional programs are: • Tamil Nadu Integrated Nutrition Project (TINP) • Wheat Based Supplementary Nutrition Program • World Food Program • Applied Nutrition Program (ANP).



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Resources Development

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Pediatric Tuberculosis To address the concern expressed by pediatric experts about the diagnosis and treatment practices for pediatric patients under RNTCP, in 2003 a consultation of national experts and international experts on pediatrics and TB culminated in national workshop on the “Management of pediatric TB under RNTCP”. This workshop resulted in modification of the existing RNTCP guidelines for the diagnosis and treatment of pediatric patients. A major recommendation was that the drugs for pediatric TB cases under RNTCP should be supplied in patient wise boxes (PWBs). Now, treatment will be based on children body weight with two generic pediatric PWBs: (1) for the 6–10 kg weight band and (2) for the 11–17 kg weight band. Children weighing less than 6 kg will be treated with loose anti TB drugs. This is to be a global “first” for the RNTCP, as no other DOTS program in the world has such PWBs for the treatment of children with TB. Children have also been identified as a high risk group. The administration of bacillus Calmette-Guérin (BCG) as an essential component of the universal program of immunization to all newborns and infants up to 9 months of age is important. -

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National Leprosy radication Program The National Leprosy Control Program (NLCP) has been in operation since 1955 as a centrally added scheme to achieve control of leprosy through early detection of cases. During 2007–2008, Special activities in the form of block and urban Leprosy Awareness Campaigns, providing treatment to newly detected leprosy cases was carried out along with screening of preschool children and youth. All the anti 1101 -

Objectives • Promotion of positive health • Prevention of diseases • Early diagnosis, treatment and follow-up • Awakening health consciousness in children • Provision of healthful environment. Components The different aspects of school health service vary according to local priorities and are manifold, as follows: • Health appraisal of school children and school personnel: Regular periodic medical examination; daily morning inspection; health card of students • Remedial measured and follow-up • Prevention of communicable diseases including immunization program • Healthful school environment: The location, site, structure, classrooms, furniture, doors and windows, color, lighting, water supply, eating facilities and lavatory arrangements of the school are the parts of environment in which the school child grows and develops. A healthful school environment is necessary for the best emotional, social and personal health of the student • Nutritional services • First aid in emergency care: A fully equipped First Aid Post should be provided in every school according to regulations of St John Ambulance Association of India • Mental health: It is increasingly realized that there is need for counselors and psychologists in schools for guidance of students • Dental care • Eye care • Health education: This can cover personal hygiene, environmental health and family life education • Maintenance of school health records: This will have cumulative information on health aspects of school children and will be useful in evaluating school health programs providing a useful link between home school and community.

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National Tuberculosis Program (NTP) has been in operation since 1962 but Government of India, WHO and World Bank together reviewed the NTP in 1992 and a revised strategy for NTP was evolved in a phased manner as Pilot Phase I, Pilot Phase II (approved for a period of 5 years from October 2006 to September 2011) and Pilot Phase III with the salient features of: • Achievement of at least 85% cure rate of infectious cases through supervised short course chemotherapy involving peripheral health functionaries • Augmentation of case finding activities through quality sputum microscopy to detect at least 70% estimated cases • Involvement of NGOs: Information, education and communication and improved operational research.

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Box 19.6.4

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School health services are comprehensive care of the health and well being of children throughout the school years. It is an economical and powerful means of raising community health. It started in India in 1909 at Baroda in an under developed state because of shortage of resources and insufficient facilities. The school health committee setup by the Government of India in 1960 recommended that school health service should be an integral part of the general health services which are, largely administered through PHCs in rural areas. Health problems of school children vary from one place to another which mostly includes malnutrition; infectious diseases; intestinal parasites; disease of skin, eye and ear dental caries. Objectives and components of school health services are listed in Box 19.6.4. School health programs have beneficial impact on students, family, nation and all people at large. It is the most efficient and cost effective way to improve students’ health and their academic performance. Carefully designed and implemented comprehensive health education program

can prevent many adverse behaviors like tobacco use, drug abuse, unhealthy dietary practices, unsafe sexual behavior and physical inactivity. It is also an efficient means of improving students, health, life skills, self esteem in behavior.

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To prevent further transmission of HIV To decrease morbidity and mortality associated with HIV infection To minimize the socio economic impact resulting from HIV infection.



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The Government of India has initiated programs of prevention and raising awareness under NACP I (1992– 1999) and NACP II (1999–2000) and now the third National Program Implementation Plan (NACP III, 2007–2012). The primary goal of NACP III is to halt and reverse the epidemic in India over the next 5 years for prevention, care, support and treatment to be achieved through these four stages: 1. Prevention of new infection in high risk groups and general population 2. Providing greater care, support and treatment to a large number of people living with HIV/AIDS 3. Strengthening the infrastructure system and human resources at the district, state and national levels 4. Strengthening a nation wide Strategic Information Management System.

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National pediatric AIDS initiative: NACO launched National Pediatric AIDS Initiative on 30th November, 2006. A guideline for pediatric ART including diagnosis of HIV in children has been developed. School AIDS education program: This is one of the important activities of NACP focusing toward student youth to raise awareness level and develop a safe and responsible life style. A training module called “Learning for Life” has been prepared and distributed to all the states.

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National AIDS Control Program (NACP) was launched in India in 1987. The Ministry of Health and Family Welfare has setup National AIDS Control Organization (NACO) as a separate wing to implement and closely monitor the various components of the program. The aim of the program is:

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Voluntary Counseling and Testing (VCT) is a key entry point for a range of intervention in HIV prevention and care like preventing HIV transmission from mother to child during child birth, referrals for STD treatment, condom promotion, care and support for treatment for opportunistic infections, management of HIV TB coinfection and more recently for referrals to designated medical center for anti retroviral therapy (ART). Voluntary Counseling and Testing is a non coercive, confidential, and cost effective approach that provides information, education and communication to motivate behavior change in HIV positive individuals. In 2006–2007, voluntary counseling, testing and Prevention of Parent to Child Transmission (PPTCT) services were merged to form Integrated Counseling and Testing Centers (ICTCs) to expand the coverage.

National ilaria ontrol Program National Filaria Control Program has been in operation since 1955. The activities were mainly confined to urban areas but now have been extended to rural areas since 1994, managed by the district malaria team and the PHC staff. The current strategy of filariasis control is based on chemotherapy and vector control. In India the National Health Policy (2002) goal is to “Eliminate Lymphatic Filariasis (ELF) by 2015”.

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National Malaria Control Program (NMCP) has been launched in 1958. Since then the program has undergone many changes. A Strategic Action plan for malaria control in India 2007–2012 has been developed by Directorate of National Vector Borne Disease Control Program. According to the revised drug policy, there is no scope of presumptive treatment in malaria control. India is predominantly characterized by unstable malaria transmission which is seasonal. The childhood deaths result mainly from cerebral malaria and anemia which are higher is rural and remote areas. Malaria still continues to pose a major public health threat in India particularly due to Plasmodium falciparum. Primary health center is the focal point of all antimalarial activities which includes epidemiological surveillance, laboratory examination of blood smear of fever cases, administration of chloroquine to all fever patients, spraying and anti larval operations, radical treatment of malaria positive cases and improvement of the environment. Malaria control is now incorporated into the health service delivery programs under the umbrella of NRHM which has been elaborated elsewhere in this book.

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leprosy drugs are supplied free of cost to the patients from central government funds. District leprosy societies have been formed in every district. Rehabilitation of leprosy patients included physical, social and vocational rehabilitation, where voluntary organizations are playing a major role. The stigma of leprosy as a punishment for past sins is deeply rooted in the Indian psyche. The prejudices and misconceptions of the public as well as sufferers are corrected through health education. Recently, WHO has announced Enhanced Global Strategy for further reducing the disease burden due to leprosy (2011–2015).

Early diagnosis and treatment of STD is now recognized as one of the major strategies to control spread of HIV infections. Most of the recently recognized STDs are now referred to as second generation STDs. The diagnosis and treatment of STD based on syndromic approach (simplified

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To reduce the backlog of blindness through identifi­ cation and treatment of blind To develop eye care facilities in every district To develop human resources for eye care services To improve quality of service delivery To secure participation of voluntary organizations is eye care To enhance community awareness on eye care.

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The strategy evolved in this program includes: (1) developing institutional capacity, (2) developing human resource for eye care, (3) strengthening service delivery and (4) promoting outreach activities and public awareness. Targets for 11th 5 year plan include development of pediatric ophthalmology units, besides other activities. “Vision 2020: The Right to Sight” is a global initiative to reduce avoidable (preventable and curable) blindness by the year 2020. India is also committed to this initiative.

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Globally, “drug culture” is fast making inroads into the lives of young people from all walks of life. The Government of India is signatory to several conventions aimed against spread of narcotic drugs. A Narcotics Co ordination Committee of secretaries was setup in March, 1994 which took important decisions regarding establishment of deaddiction centers. Subsequently and expert committee was setup by Government of India which recommended

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The CCP was launched in 1975–1976 as a central sector project. It was renamed as National Cancer Control Program (NCCP) in 1985 and revised in 2004. The objectives of NCCP are: • Primary prevention of cancers by health education • Secondary prevention by early detection and diagnosis of common cancers such as cancer of cervix, mouth, breast and tobacco related cancers by screening/self examination methods • Tertiary prevention by strengthening of existing cancer treatment facilities including palliative care in terminal stage.

India was the first country in the world to launch national level blindness control program. The National Program for ontrol of Visual Impairment and Blindness was launched in 1976 as cent percent centrally sponsored which incorporated the earlier Trachoma Control Program (1963). The program was decentralized in 1994–1995 with formation of District Blindness Control Society (DBCS) in each district of the country. The objectives of the program are:

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National Program for ontrol of lindness

ibliography 1. Chauhan LS, Arora VK, Central TB. Division, Indian Academy of Pediatrics. Management of pediatric tuberculosis under the revised national tuberculosis program. Indian J Pediatr. 2004;71(4):341-3.

The Government of India has launched the NMHP in 1982, keeping in view the heavy burden of mental illness in the community and the absolute inadequacy of mental health care infrastructure in the country. The objectives of NMHP are: • Provision of mental health services at district level • Improvement of facilities in mental hospitals • Training of trainers of PHC personnel in mental health • Program for substance use disorders.

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1. Health promotion for the general population 2. Disease prevention for high risk group 3. Assessment of prevalence of risk factors.

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Realizing the magnitude of the problem, the Government of India launched a fully centrally assisted National Goiter Control Program (NGCP) in 1962 which was renamed as NIDDCP with a view to cover a wide spectrum of Iodine deficiency disorders like mental and physical retardation, deaf mutism, cretinism, still births, abortion etc. The NIDDCP has three components: 1. Initial survey to identify endemic areas 2. Supply of iodized salt to the identified areas 3. Resurvey after 5 years of continuous supply of iodized salt to assess impact of the measures.

Diabetes has emerged as a major public health problem in India. Diabetes is the second most common chronic disease in childhood occurring in 1 in every 1,500 by age of 5 and 1 in 350 in age 8. The premature morbidity and mortality in most productive phase of life is posing a serious challenge to Indian society and economy. The pilot program interventions, launched on 4th January in 2008 in seven states have been grouped in three components:



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the establishment of a National Drug Abuse Monitoring and Information System. The deaddiction centers provide treatment to patients and carry out other functions as envisaged by the expert committee.

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STD treatment) is being introduced at PHC level. The control of STD may be considered under the following heads: (1) initial planning (2) intervention strategies (3) support components and (4) monitoring and evaluation.

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14. Government of India. TB India 2010. RNTCP Status Report, Central TB Division, New Delhi: Ministry of Health and Family Welfare, 2010. 15. Government of India. Annual Report 2009 2010, NACO, New Delhi: Ministry of Health and Family Welfare, 2010. 16. Government of India. National Health Profile 2009. DGHS, New Delhi: Ministry of Health and Family Welfare, 2010. 17. KishorJ. National Programs of India, 9th edition. New Delhi, 2011. 18. Lal S. Health and development of school children. Indian J Community Medicine. 1998;23:3 6. 19. Nutritional Foundation of India. A report of the workshop on “mid day meal programs in schools in India the way forward” July 31 August 01, 2003, New Delhi, 2003. 20. Pachauri S. Defining a Reproductive Health package for India. New Delhi: South East Asia Regional Working Papers No. 4, 1995. 21. Park K. Text book of Preventive and Social Medicine, 21st edition. Jabalpur: Banarsidas Bhanot, 2011. 22. Schemes of the Department of Women and Child Development. A Synopsis. New Delhi: Department of Women and Child Development, Ministry of Human Resource Development, Government of India, 1991. 23. UNICEF. State of World’s Children. Geneva: UNICEF, 2009. 24. WHO. The World Health Report 2006.Working Together for Health. Geneva: WHO, 2006. 25. WHO. Promoting Health Through Schools. Expert committee on comprehensive school health education and promotion, WHO TRS No.870. Geneva: WHO, 1997. 26. Walia BNS, Vani SN. National Health Programs. IAP Textbook of Pediatrics, 3rd edition. 2006.pp.155 81.







































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2. Dua AS. Programs for the control of Leprosy, TB and malaria in national commission on macroeconomic and health burden of disease in India. New Delhi: Ministry of Health and Family Welfare, Government of India, 2005. 3. Government of India. Annual Report 2009 2010. New Delhi: DGHS, Ministry of Health and Family Welfare, 2011. 4. Government of India. National Health Profile 2009. New Delhi: DGHS, Ministry of Health and Family Welfare, 2011. 5. Government of India. Reproductive and Child Health Program, Schemes for Implementation. New Delhi: Department of Family Welfare, Ministry of Health and Family Welfare, 1997. 6. Government of India. Integrated Disease Surveillance Project, Training manual for state and district surveillance officers. New Delhi: Ministry of Health and Family Welfare, 2005. 7. Government of India. Statement on National Health Policy. New Delhi: Ministry of Health and Family Welfare, 1983. 8. Government of India. Health Information of India 2006. New Delhi: Ministry of Health and Family Welfare, 2006. 9. Government of India. Family Welfare Statistics in India 2009. New Delhi: Ministry of Health and Family Welfare, 2010. 10. Government of India. Annual Report 2007 2008. New Delhi: Ministry of Health and Family Welfare, 2008. 11. Government of India. Indian Public Health Standards for Community Health Centers, Revised, New Delhi: Ministry of Health and Family Welfare, 2007. 12. Government of India. Revised Nutritional and Feeding Norms for Supplementary Nutrition in ICDS Scheme, New Delhi: Ministry of Women and Child Development, 2009. 13. Government of India. Annual Report 2009 2010. DGHS, New Delhi: Ministry of Health and Family Welfare, 2010.

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riminal law ( ndian penal code, 1860): Nothing is an offence which is done by a child under 7 years of age (Section 82). Nothing is an offence which is done by a child above 7 years of age under 12, who has not attained sufficient maturity of understanding to judge the nature and consequence of his conduct on that occasion (Section 83). • Law ( hild arriage Restraint Act, 1929): “Child” means a person who, if a male, has not completed 21 years of age, and if a female, has not completed 18 years of age.

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The UN Convention on the Rights of the Child, 1989 (Article I) defined the child as below 18 years of age. There are various definitions of child in various laws in India: • For obtaining medical care in a Government health facility, a child is defined as one who is less than 12 years of age • During the initial census of India, persons below the age of 14 years were defined as children and most of the Government programs on children are still targeted for the age-group below 14 years. The legal definition of child varies from 7 years to 18 years of age as evident from the various laws in India, but after the introduction of the Juvenile Justice Care and Protection of Children Act, for all practical purposes, a child is considered as a person below 18 years.

This is a comprehensive legislation to provide justice and opportunities to children of India for their growth and development. “Juvenile” or “Child” means a person who has not completed 18 years of age, The Act is based upon the provisions of the Indian Constitution and four broad rights of the UN Convention on the Rights of the Child including right to Survival, Protection, Development and Participation. The Act came into force with effect from 1st April, 2001. Certain amendments have been effected in the Act recently. One of the important amendments includes the definition of adoption and that no juvenile in conflict with law can be placed under imprisonment for any term, which may extend to imprisonment for life. The Act has, therefore, been made more child-friendly to protect children from exploitation and violence as provided in the World Fit for Children (WFFC) targets. C

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Who is a hild?

he Juvenile Justice ( are and Protection of hildren) Act, 2000 C

The UN Convention on the Rights of the Child (UNHRC) is a guiding instrument for implementing all rights for all children up to the age of 18 years. There are other important documents related to child rights. The National Policy for Children states that children are supreme assets of India and we have to provide them with the four basic rights: (1) right to survival, (2) right to development, (3) right to good health, education and (4) protection from abuse and exploitation and most importantly, to participate in the decisions that have an impact on their own lives. Every child has a right to a formal identity, including birth registration, the right to nationality and the right to be cared for by their parents. Health workers, teachers, police personnel, social workers and others who work with children should be well equipped with the skills and ability to identify and authority to respond to child abuse in any form. Media has a unique role to play in ensuring that the rights of children are respected and that violators are brought to justice.

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• Labor aws (Apprentice Act, 1951), Factories Act, 1948: It states that a person shall not be qualified to be engaged as a worker unless he/she is not less than 14 years of age. • he hild Labor (Prohibition and Regulation) Act, 1986: Prohibit employment of children below 14 years in hazardous occupations and processes and also regulating the working conditions of children in other employment. In the last 5 years, the number of hazardous “Occupations” listed in the schedule of the Act has increased from 7 to 13 and “Processes” from 18 to 57. The notice for prohibiting employment of children as domestic servants and in tea shops and dhabas, etc. is with effect from 10th October, 2006. l

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This covers the following: (1) to secure for every child its inherent right to be a child and enjoy a healthy and happy childhood; (2) survival, life and liberty; (3) protection from economic exploitation and all forms of abuse; (4) protection of the girl child; (5) care, protection, welfare of children of marginalized and disadvantaged communities and (6) ensuring child-friendly procedures. Other important aspects addressed are (1) promoting high standards of health and nutrition; (2) assuring basic minimum needs and security: play and leisure, early childhood care for survival, growth and development, free and compulsory primary education, protection from economic exploitation and all forms of abuse, protection of the girl child, empowering 1105 adolescents, equality, freedom of expression, freedom to

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India has a National Commission for Protection of Child Rights and Child Courts. There are also commissions at state level. This ensures speedy trial of offences against children or of violation of child rights and matters connected thereto. The aims of this commission are to:spread awareness of child rights; review all the laws and other documents for children; setup a mechanism to hear complaints about violation of child rights; undertake and promote research in the field of child rights; and examine the situation of children. The powers of the commission are similar to a civil court under Civil Procedure Code (CPC) and they can forward a matter to a Magistrate to be tried under Criminal Procedure Code (CrPC).

These have been established for speedy trial of offences against children or of violation of child’s rights. In each district the Court of Sessions appoints a special public prosecutor.

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ntegrated hild Protection Scheme, 2006

The aim of Integrated Child Protection Scheme (ICPS) is based on the Cardinal principles of “protection of child rights” and “best interests of the child”. It covers (1) punitive measure against perpetrators of abuse and crimes and (2) rehabilitation for all children in need of care and protection. The target groups are children in need of care and protection; children in conflict with the law; children in contact with law; and any other vulnerable child. The Ministry of Women and Child Development views Child Protection as an essential component of the country’s strategy to place “Development of the child at the center of the 11th Plan”. Violations of the child’s right to protection, in addition to being human rights violations, are massive, under-recognized and under-reported obstacles to child survival and development. The ICPS also promises to provide a powerful platform to promote government partnerships with civil society actors and international organizations.



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This covers all rights to all children up to the age of 18 years. The action plan includes the following (1) system of identi fication, investigation, reporting, follow-up and referral of children at-risk; (2) care, protection and developmental programs for all children; (3) child beggars; (4) facilitate convergence with related Ministries; (5) rehabilitate all children in need of care and protection; (6) professional counseling services; (7) children affected by disasters; (8) developmental and protective services to children of sex workers and prisoners; (9) children are not used in armed conflict and (10) prevent the use of children, including adolescents. The guiding principles of the National Plan of Action for Children, 2005 are: • To regard the child as an asset and a person with human rights • To address issues of discrimination emanating from biases of gender, class, caste, race, religion and legal status in order to ensure equality • To accord utmost priority to the most disadvantaged, poorest of the poor and least served child in all policy and programmatic interventions • To recognize the diverse stages and settings of childhood, and address the needs of each, providing to all children the entitlements that fulfill their rights and meet their needs in each situation.

new Article 51(a) to provide opportunities for education to children between the ages of 6–14 years.

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seek and receive information, freedom of association and peaceful assembly and (3) strengthening family ensuring child-friendly procedures. All matters and procedures relating to children, viz. judicial, administrative, educational or social, should be child friendly. All procedures laid down under the juvenile justice system for children in conflict with law and for children in need of special care and protection shall also be child-friendly.

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Right to Free and ompulsory Education The law came into effect in the whole of India except the state of Jammu and Kashmir from 1st April, 2010. This also includes children with disabilities. Subsequently, the 86th Constitutional Amendment Act 2002 has inserted a new Article 21(8) which provides for free and compulsory education to children of the age-group of 6–14 years being a Right to Education. The same Amendment Act provides for amendment of the Article 45 as Directive Principle of the State Policy to provide provision for early childhood care and protection Bill up to the age of 6 years. It is also made a fundamental duty of parents and guardians under

Acknowledgments Dr Chhaya Prasad and Dr Samir Dalwai for their help in writing this chapter.

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s Parenting an Art or Science?

Parenting practices and styles influence the inculcation of habits, behavior and personality of the children. All along we have had no formal training on parenting as parenting has been considered an art that is learnt from the previous generation by observation. With rapid economic progress, India has quick urbanization, migration with increase in nuclear families, liberalization and globalization with the associated confusion about traditionality versus futuristic approach to upbringing of children. In view of this, the science behind parenting is tapped based on evidence to help the knowledge thirsty educated parents of India to see their children grow with appropriate inputs. C

Parent- hild Bond Parent-child bond is determined by: • Temperament of the child • Attachment pattern established during early childhood • Parenting style • Communication style of parents.

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Temperament or innate nature of a child is the trait with which a baby is born in this world. When the parental expectation and the temperamental trait of the child match, the bonding is better because the positive cues given by the parent to the child and the cheerful responses received by the parent from the child are pleasurable and promote attachment. ctivity level, rhythmicity, approach and withdrawal, adaptability, threshold of responsiveness, intensity of reaction, quality of mood, distractibility, attention span and persistence are nine temperamental traits. Thus a child who is active, rhythmic, quick to warm up, with immediate response to cues, easily accommodative, with cheerfulness, with sustained attention and perseverance would be able to win the hearts of the parents and parental figures more easily than a child who is lethargic, chaotic, slow to warm-up, who withdraws at approach, and stays grumpy, whining, with decreased attention span and increased distractibility.

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Attachment Pattern Established during Early hildhood Continuous and consistent reception of warmth, love, care, attention, compassion and encouragement from parents makes a child feel secure with parents even before they turn two. This security is expressed at reunion with parents after a span of separation. Securely attached child is confident of a happy reunion with parents while a child who has received inconsistent responsiveness and attention from parents may either develop an insecure avoidant attachment pattern or insecure ambivalent attachment pattern with expression of avoidance and clinginess respectively. Some children might have received resentment or neglect from parents, who are either preoccupied or ignorant about their role as parent, where the child develops a disorganized attachment pattern. The kind of attachment established during early childhood not only enhances the parent-child bonding but also determines the relationships the child would enjoy with friends and marital relationships in future.

Parenting Styles Depending on the parental demand and responsiveness to their children, Diana Baumrind classified parenting styles into four types: 1. Authoritarian: Highly demanding and less responsive 2. Permissive/indulgent: Highly responsive and not demanding, but over indulging 1107 3. Authoritative: Highly demanding and highly responsive with role modeling

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India is not only a country of physical, political, linguistic, cultural, religious multiplicity but also a country with diversity in health needs and distribution. On the one hand, we have been losing many children less than 5 years in large numbers to infectious diseases and other fatal illnesses of childhood; on the other hand, we are also seeing a large number of children and adolescents with high-risk behaviors that are detrimental not only to their personal growth but also a deterrent to the generation of a healthy human capital for India. India would continue to be young till 2050; pediatricians have a window of opportunity and a duty to invest on the holistic health of the children and adolescents to build a wholesome nation. Studies from many parts of the world have documented that family connectedness, school connectedness, presence of trustworthy adult and spiritual beliefs as the protective factors associated with healthy adolescence free from highrisk health behaviors like violence, substance use including smoking, drunken driving, suicide and high-risk sexual behaviors. Establishment of family connectedness is dependent on the two way communicative relationship between parents and the children. Temperament of the child, attachment pattern established during early childhood, parenting styles and practices, emotional regulation in the family context are some of the determinants of creation of strong family connectedness during adolescence.

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Feature/parenting style

Authoritarian

Permissive/Indulgent

Authoritative

Neglectful

Demandingness

High

Nil

High

Nil

Responsiveness

Less

High

High

Nil

Style of communication

Aggressive

Passive/submissive

Assertive

Poor/limited to few words

Expression of love

Care is considered as love

Well-expressed

Well-expressed

Rarely expressed

Demonstrative love

Not expressed

Well-expressed

Well-expressed

Nil

Time spent with children

Less

High

High

Minimal

Value inculcation

Through instruction, “do as i say, and not do as i do”

Left to child as, “whatever you do is right for you!”

“We are value loaded and follow what we practice” explanations are provided for each expectation

No attempt at value inculcation is made

nsistence on discipline

High with psychological control like black mailing, name calling and sometimes physical abuse

Nil

Firm and high with explanation and negotiation and differential reinforcement like encouragement for positive behaviors and ignoring negative behaviors

Nil

Role modeling

Minimal

Nil, entire household is child centered

Very high

Nil

Compassion

Nil

High

Very high

Nil

Freedom of speech and expression

Nil

Total freedom, child will not know how to make use of the freedom, gets confused and anxious

Freedom of expression is given, with lot of inputs from parents on the right and the wrong. Guidance on modification is offered with compassion

As there is not much of contact, expression is determined by the children who feel not guided

Moralistic

Highly moralistic

Willing to relax all moral values to see happiness in children

High, but not judgmental. Guidance is offered always

Not applicable

Opinionated

Yes

Nil

Not opinionated but explains possible opinions that can be formed by certain behaviors

Not applicable

Care of children

Care is complete, all acts of service done in a methodical but in an impersonal manner. Attempt to self-care is not encouraged. Dependency is seen as obedience and subordination.

Very good with personal attention to begin with, later with scare that the child might scold the parents for lapses

Very good with personal attention, involving children in inculcation of habits of self-care very early in life, generation of independence and preparation of the children to survive without the support of parents is practiced

Care is not adequate and children usually fend for themselves with breach in self-care and hygiene

Appreciation and encouragement

Rarely offered

Offered more than necessary as the parents are scared at consequences if not offered

Offered in right doses at right occasions

Not offered as the parents are rarely aware of accomplishments

Criticism

Liberal and frequent

Nil

Yes but with explanations and ways to rectify

Rarely take-note of deviance in behaviors or actions

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Table 19.8.1 Characteristic feature of the four parenting styles

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Permissive/Indulgent

Authoritative

Neglectful

Outcome in children

Submissive or rebellious, lack of self-control and selfesteem and self-confidence as they have been controlled always. Performance anxiety is high and accomplishments are less

Self-driven, anxious at outcomes as they have not been exposed to challenges appropriately with guidance from parents; selfesteem low with reduced confidence at new activities

Self-motivated, selfdisciplined, self-confident, children with high self-esteem and frequent success in many tasks

Feel that they lack direction or may latch on to people to receive direction which may be right or wrong

Children’s perception about the parents

Strict, controlling parents who gave no space for growth

neffective parents who offered no guidance and direction

Excellent parents who were available always but at the same time encouraged independence

Non-available parents who were totally away in mind, body and actions

ommunication Style of Parents

Parents may use any of the four styles of communication between themselves, with children and with others: • Aggressive style communicates authority with minimal empathy and is used by authoritarian parents • Passive style of communication is practiced by permissive parents who are meek, submissive and are usually not capable of taking decisions • Passive aggressive style is not an enjoyable style where there is no direct manipulation or aggression, but nonconformation or non-cooperation are expressed by maintaining either silence, humor, withdrawal or sulking for prolonged periods of time. This style is annoying as it is difficult to understand the persons’ thoughts • Assertive style of communication is by far the best style used by authoritative parents who express their intent with firmness. This style entertains mutual respect and helps in effective parenting. C

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he Role of the amily ontext in the Development of Emotion Regulation



Emotion regulation consists of internal and external processes involved in initiating, maintaining, and modulating the occurrence, intensity and expression of emotions. Emotional regulation helps in the socialization process that happens from infancy to adulthood by modulating ones expression of emotions by understanding the actual emotions, with respect to tone, intensity and dynamics like duration of the emotional experience (Flow chart 19.8.1). Internal processes would be child-specific factors like temperament of the child, child’s responsiveness or reactivity to external cues, stage of development, individual thoughts about emotions, and the associated physiological responses to each of the emotion.



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External processes would depend on the emotional climate of the family and on the specific characteristics of the parents and the parent figures. Emotional climate of the family is further determined by the status of the marital relationship, parenting styles practiced, attachment patterns established, emotional coaching by parents like “When you are angry take a deep breath etc.”, emotional expressivity of parents, social referencing like adapting the responses of significant others at similar situation, parental role modeling, the predominant emotional state in the family, etc. Parent-specific factors are related to the mental health of the parents and the kind of emotional regulation they have imbibed from their parents. With increasing age the dependency on parents for emotional regulation comes down but the influence of peer group intensifies. • Influence of parenting styles and parenting practices on certain aspects of growth and development in children and adolescents are being studied extensively. The previous endorsement of authoritarian parenting to inculcate certain qualities and habits in children is being replaced by new understanding that are encouraging parents to practice authoritative parenting styles • Eating practices: In a study on the influence of parenting styles and the consumption of fruits and vegetables by preschoolers, authoritative parenting style emerged as a better style in ensuring cooperation. This has been attributed to the utilization of teachable moments by parents to give information on the benefits of consumption of fruits and vegetables, practical methods like role modeling by both parents, firmness in maintaining discipline with respect to eating schedules, restriction of availability of junk foods within the household and limiting accessibility to the same outside the home and enhancement in the availability of fruits and vegetables at all times of the day. Similarly, children with overweight and obesity are less common in families with authoritative parents • Physical activity: Although studies on the influence of parenting style on physical activity are not many, the 1109 knowledge gained has been quite different. Children’s



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eglectful: Not demanding and not responsive and not available. The following Table 19.8.1 will highlight the additional characteristics of each of the parenting style. 4.

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Flow chart 19.8.1 Factors determining the emotional regulation of the children in the family context

Parenting Programs Inculcation of authoritative parenting skills in parents is gradually being adapted in the developing world based on the evidence generated by the developed world. Indian Academy of Pediatrics has also created the Happy Parenting Program in 2010 where a self-training module titled, “Stepping Stones – Pediatricians, recipe for Happy Parenting” along with a CD containing slides for introspective learning have been posted to all its members 1110 who are now equipped to train the parents.

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Recommended Research ptions in the ndian ontext As of now the parenting styles practiced in India are diverse and in multiple combinations as the parenting responsibility is not limited to biological parents only. The recent generations of parents who are evolving from a collectivistic society to individualistic practices are usually not consistent with the parenting style. Hence, knowledge about the parenting received and the styles being practiced can be accessed from various groups of urban, semi-urban, rural parents by using qualitative research methods and then arrive at new hypotheses for further research. C

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participation in sports, acquisition of skills in a game and excelling in the tournaments has been more commonly associated with permissive style of parenting. Logistic support to continue sports activities is higher in households with permissive parents Externalizing behaviors: Externalizing behaviors like usage of aggression and violence is more common in families with authoritarian style as the children learn by observing parents. It is also widely seen in children brought up by permissive parents because the parents might have failed to establish their role in disciplining between 2 years and 6 years when the externalizing behaviors begin and reduce respectively. Authoritative parents are quiet clear about establishing their role and achieving cooperation from children as they practice methods of differential reinforcement which reduces the negative behaviors.

onclusion

Parenting is a science that is based on human development, temperament and interpersonal relationships. Use of warm, responsive, firm, authoritative parenting style helps in bringing up children as healthy, self-confident, self-reliant and independent adults. Pediatricians can start introducing parenting principles during well-baby visits when parents are usually receptive. Parenting programs can be included as a primary prevention activity to prevent behavior disorders in children.

Acknowledgment Dr Deepak Ugra, President IAP 2010, for approving the manuscript after critical evaluation.

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8.

parenting during the first year of life predict future child conduct problems. J Abnorm Child Psychol. 2008;36(8):1139-58. Morris AS, Silk JS, Steinberg L, et al. The role of the family context in the development of emotion regulation. Soc Dev. 2007;16(2):361-88. O’Connor TM, Hughes SO, Watson KB, et al. Parenting practices are associated with fruit and vegetable consumption in preschool children. Public Health Nutr. 2010;13(1):91-101. Spijkers W, Jansen DE, de Meer G, et al. Effectiveness of a parenting program in a public health setting: a randomised controlled trial of the positive parenting program (Triple P) level 3 versus care as usual provided by the preventive child healthcare (PCH). BMC Public Health. 2010;10:131. Ugra D, Yamuna S. Stepping stones – pediatricians’ recipe for happy parenting. Mumbai: Indian Academy of Pediatrics, 2010.

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and family meals: cross-sectional and 5-year longitudinal associations. J Am Diet Assoc. 2010;110(7):1036-42. 2. Buschgens CJ, van Aken MA, Swinkels SH, et al. Externalizing behaviors in preadolescents: familial risk to externalizing behaviors and perceived parenting styles. Eur Child Adolesc Psychiatry. 2010;19(7):567-75. 3. Chang L, Schwartz D, Dodge KA, et al. Harsh parenting in relation to child emotion regulation and aggression. J Fam Psychol. 2003;17(4):598-606. 4. Darling N. Parenting Style and its Correlates. Available from www.kidneeds.com/diagnostic_categories/articles/ parentcorrelates.pdf. [Accessed 20 July 2011].



1. Berge JM, Wall M, Neumark-Sztainer D, et al. Parenting style

5. Lahey BB, van Hulle CA, Keenan K, et al. Temperament and

community PED A R S

Bibliography

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Since the first term “Battered Baby Syndrome” given for chronic repetitive injuries due to abuse by Henry Kempe, the definition of child abuse and neglect (CAN) has been broadened to include any problem resulting from lack of reasonable care and protection of child and adolescents by their parents, guardians or caretakers. “Child Abuse”, “Child Neglect”, “Child Maltreatment”, “Physical Abuse”, “Child Battering”, “Silverman’s Syndrome”, “Illegitimate Child Syndrome”, “Parental Dysfunction” and most recently “Non-Accidental Injury” (NAI) are terms often used interchangeably. The distinction in child abuse and child neglect is probably the element of deliberateness in the former. Although the exact etiology of child abuse is not known, it is thought to be due to interaction of three primary factors as shown in Tables 19.9.1 and 19.9.2.

• Physical: Cuts, bruises, hematoma, fracture, head injury, visceral injury, burns, ophthalmic injury, blunt trauma,



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India may be feeling proud with her booming economy, IT, new medical interventions, decreasing IMR, birth rate and increasing life expectancy, yet due to increased morbidity, the quality of life has deteriorated particularly those of infants. our children are underprivileged, deprived of food, shelter, health, education, security, even right to live, social status, often abandoned, and most important love and feeling of being wanted. A sizable numbers of these are forced to work in a variety of sectors organized/unorganized, support their families despite suffering from deprivation, exploitation and abuse. Quite a few unknowingly resort to antisocial activities. Furthermore, children in all societies in the process of their normal upbringing are often neglected, maltreated, abused intentionally or unknowingly by their parents, caretakers. Child abuse—physical, sexual or emotional is a significant community problem of enormous gravity and unconscionable crime. The norms of child rearing differ culturally with wide differences between conservative and advanced societies. Child abuse, although an old phenomenon, it has been the subject of serious societal concern in recent years. Although earlier known in economically advantaged nations, now it has spread globally, more so in disadvantaged and endangered communities engulfing thousands of children, resulting as street children, refugees, children in armed conflicts, orphans of AIDS, prostitutes, disabled children and those trapped in trafficking, sale and kidnapping.

injury due to slapping, pushing, squeezing, kicking, shaking,—“shaken baby syndrome” (Fig. 19.9.1) Nutritional: Failure to thrive, marasmus, stunting, deprivation of varying severity exual: Rape, incest, fondling, pornography, prostitution, involvement in sex-related activities, exhibitionism, coercion and female feticide and infanticide, neglect of girl child and female discrimination–deprivation from food, education, clothing, entertainment, love and social status and early girl child marriage ehavioral: Wariness of adult contact, aggressiveness/ withdrawal, apprehension when other children or adults cry shout, prefers to stay away from home as much as possible, excessive compliance, attaching readily to strangers, frequent absenteeism and unwillingness to go to school, not reporting injury to parents or giving inappropriate explanation of an injury motional: Humiliation, depression, extremely low selfesteem, passive, withdrawn, tearful, apathetic, aggressive or demanding behavior, constant high anxiety, poor social and interpersonal skills, persistent habit disorders such as sucking, biting, or rocking, self-destructive behavior, and unexplained academic delays, comparison with siblings/ other children, girl child neglect/discrimination Non-accidental poisoning, e.g. pium Abandonment/desertion ubstance abuse: Drugs which alleviate mood or create illusions, happiness, e.g. Cocaine, marijuana, etc. and alcohol and allied substances Medical neglect: By the professionals and health care personnel dealing with the medical management of the child and if neglected could be potentially fatal xploitation: – Sexual: Children used for prostitution/sex related trade, pornography and allied abuses-trafficked children, devdasis, etc. – Entertainment: Use of children as jockeys for camel race in the Gulf countries, street dancing and street shows/games—with non-domesticated animals— monkeys, bears, elephants, camels, snakes, etc, rope walking, pole climbing, making pyramids for religious celebrations, fire jumping, or fire swallowing in circus or marine activities (Fig. 19.9.2 and Fig. 19.9.3) – Social benefits: Use of children by schools, orphanages, NG s, etc. for formal welcome programs, in rallies in parades, making children wait in extreme hot or cold weather for longhours without provision of drinking water, toilet facilities – Political: For wars, for party propaganda during elections, etc. S

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Table 19.9.1 Factors affecting CAN Values and norms of discipline and physical punishment

Family structure

Number of members in the family, joint/nuclear family, socio-economic status

Family and situational stresses

Poverty, illiteracy, unemployment, alcohol abuse, isolation, poor housing, caste system and landlessness

Parent-child relationship

Punitive child rearing style, excess/ unwanted children, role reversal

Economic

Lack of economic opportunities, rural urban migration

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Family norms

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Sociocultural factors

Child producing stresses Mentally retarded, physically handicapped, disabled, deformed, chronically ill

Behavior

Hyperactive and behaviorally different, strong willed

Difficult

Temperamental

Types

Too many children, girls, premature infants, foster child, boys twice more common than girls to be victims of physical abuse

RICS

T

Disabled

Parent producing stresses Low self-esteem , depression, character disorder, psychiatric illness

Past experiences

Unhappy childhood experiences, neglected/abused as a child, emotionally deprived

Addictions

Parental substance abuse

Sex of the child

Disappointment over the sex of the child

Child rearing

Ignorance of child rearing, unrealistic expectations

Familial violence

Violence among adult family members

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Psychological

 

Table 19.9.2 Predictions – known to correlate and precipitate child abuse The parents Age

Young mother, age < 18 years

Own experiences

Abused/experienced family disruption in their childhood

Anxiety

Lack of family support, unreasonably fearful of caring for their child

Expectations

Have unreasonable expectations of their child and treat him/her as much older child

Temperament

Poor impulse control

Rigid discipline

May be generally rigid/authoritarian, e.g. incidence of abuses more than in some strict religious groups and families of military personnel

Aggressive parent

Usually the father may be aggressively psychopathic and assault others within/without his family, psychiatrically ill

The child Unwanted, denial of pregnancy, request for abortion, adoption

Afterbirth attachment

Separated from mother at birth, because of prematurity, maternal illness, preventing/interrupting initial attachment with mother

Emotional

Disappointing because of defect/disability, child of opposite sex other than wanted

Temperament

Hyperactive by day, troublesome/cries at night

Demanding

Difficult because of illness

Different

Different from rest of the family

Gender

Girls three times more likely than boys to be victims

­

Unwanted

Social Basic

Crisis in housing, disconnection of services, lack of safe water, hygiene, sanitation, unhealthy environment

Unemployment

Loss of work, unemployment increases abuse by fathers

Economic

Poverty and economic crisis

Loneliness

Loneliness/isolation of mothers when partners have left/working away from home

Marital crisis

Marital crisis, new liaisons, step children, unwanted pregnancy

Traditional practices

Harmful practice—child marriages, caste system, child forced to work/earn to support family, girl child discrimination, Devdasi tradition

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Matka dens, garages, roadside peddlers selling all sorts of articles, newspaper vendors, in railways, on the vending machines, selling cinema/lottery tickets, cards (Fig. 19.9.4) – Kidnapping: Use of kidnapped children for begging, as hooligans, for thefts, stealing, house breaking, gambling and similar antisocial activities – Trafficking of children: For various antisocial activities—namely slavery, prostitution, and sex related trades, domestic and industrial labor, war, smuggling, entertainment, etc. • Neglect: For food, protection, housing, education, health, and medical problems, entertainment, family bonding most being loved, being wanted and girl child neglect • Miscellaneous: “Munchausen’s Syndrome by Proxy” is a manifestation of fabricated illness usually created by an adult-a parent/guardian, in a child who may mimic a real illness, with an objective of drawing attention of medical personnel and in turn getting self-importance. This condition has to be diagnosed by eliminating real illnesses and having a strong suspicion of such an entity. Although rare, timely vigilance is worthwhile, as it may turn fatal before it is diagnosed and due care is given in time. D

 



Figure 19.9.1 Found by police with multiple injuries of left upper limb, neck and scalp

When to suspect child abuse: Child abuse is not an obvious diagnosis at initial consultation. ne should suspect child abuse, in all cases of injuries at uncommon distribution sites, or having unusual pattern: suspected if the child victims and the parents’ history is at variance or if the features do not match with known conditions/ disease/disorder Clinical manifestations are bizarre and often symmetrical. Child is drowsy, unconscious or emotionally scared. He/ she is too shocked to reveal anything. Importantly, the injuries are more serious/grievous than expected from the given history. O

•

iagnosis

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ffects of hild buse and Neglect C

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Figure 19.9.2 Boy with heavy stone

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Child abuse can have severe and deleterious short and longterm effects on cognitive, socio-economic and behavioral development. • Short-term/immediate: ften noticeable, withdrawn, quiet, depressed, excessive crying, frightful, non-comm unication with family members/friends/schoolmates • Long-term/delayed: Unless correlated with past abuse, these are difficult to prove. These include low IQ, motor problems, hyperactivity, physical defects, increased intensity to reactions, less social responsibility, poor impulse control, aggressiveness, marked anxiety, feeling of rebellion, more prone to later crime, drug abuse, poor social and marital adjustment and sexual difficulties • Neglect: Compared to abused children, more cognitive and academic deficits, may feel worthless, social withdrawal, limited peer interactions and internalizing as opposed to externalizing problem.

 

Figure 19.9.3 Boy with monkey street show

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Labor: Both in organized/unorganized sectors— for industries like carpet, lock, glass, fireworks, tin, cigarette watch, gunpowder, chemical dye, bullet and explosives manufacturing and storage, as street children for unorganized sundry jobs on the teastalls, eateries, food joints, liquor bars, small clubs/

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1. Foreman DM. Detecting fabricated or induced illness in

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ibliography

9. 10. 11.





12.



13.

14. 15.











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8.





7.





6.





5.



It depends on diagnosis and type of abuse. Physical abuse needs appropriate treatment of the injuries. Appropriate information should be relayed to police/physician/ caretaker. Victims of sexual abuse often go undetected because of social stigma and hence repeated offences are common. Prevention requires strong need and advocacy for sex education in schools. Child laborers require food, shelter, health care, education, social stability and entertainment, which need to be provided by employers, government, or NG s. Economic help, rehabilitation with own family is always preferable. Personal care is advisable wherever possible. Abandoned babies need urgent and long-term medical and health care, besides placement in promotive institutions or orphanages. Process should be initiated to facilitate adoption. Children in endangered situations (kidnapped, trafficked, wars, refuges, HIV/AID affected, orphans, prostitutes, children in dangerous trades, fireworks, circus, etc.) require immediate comprehensive help and longterm rehabilitation.

4.



 

Management

3.

Women and Child Development, Government of India. New Delhi: CANCL News; 2008. pp.30-2. Kanth AK. Legal and judicial implications of child abuse in India-Global to national perspective. Pediatrics Today. 2008;12(3):101-13. Mehta MN, Lokeshwar MR, Bhatt S, et al. Rape in children. Child Abuse and Negl. 1979;3:673-7. Mehta MN, Munshi NN, Krishnan P. Adoptions: follow-up from an orphanage in Bombay. Child Abuse and Negl. 1983;7(1):78-82. Mehta MN, Prabhu SV, Mistry HN. Child labor in Bombay. Child Abuse and Negl. 1985;9(1):107-11. Mehta MN, Prabhu SV, Mistry HN. Types of physical health problems in working children. In: Naidu US, Kapadia K (Eds). Child Labor and Health. Naidu US and Kapadia K (Eds). Bombay: Tata Institute of Social Sciences; 1982.pp.138-49. Mehta MN. Abuse of abandoned children in India. ICCW News Bull. 1990;37:3-7. Mehta MN. Child abuse and neglect. In: Gupta S (Ed). Recent Advances in Pediatrics 4. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd. 1994.pp.58-87. Mehta MN. Child abuse and neglect. In: Banerjee SR (Ed). Community and Social Pediatrics. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd. 1995.pp.157-74. Mehta MN. Physical abuse of abandoned children in India. Child Abuse and Negl. 1982;6(2):171-5. Mehta MN. Sexual abuse in children. Pediatrics Today. 2008;12(3):121-6. Mehta MN. Sociomedical aspects of child abuse. J Appl Med. 1992.pp.257-62. National Study on Child Abuse (NSCA) Report released in March 2007. Ministry of Women and Child Development. New Delhi: Report in Hindustan Time; March 9,10,2007. UNICEF-State of World’s Children 2008. Report from Hindustan Times. New Delhi. March 25,2008.

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Figure 19.9.4 Children working at tea stall

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children. BMJ. 2005;331(2):978-9.

2. Kacker L. Child Protection Scenario in India. Ministry of

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hild Labor







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Major orms of hild Labor and eterminants of its Pattern C

It is not a simple task to define the notion of “child”, “child work” and “child labor”. The problem is compounded by differences in social and cultural perceptions. It is also not easy to draw a distinction between work and labor. The dictionary meaning of “workers” is an employee especially in manual or industrial work, while a laborer is one, who, for wages does work that requires strength or patience rather than skill or training. In many situations, these two words are synonymous. According to Child Labor (Prohibition and Regulation) Act, 1986, a “child” is a person who has not completed 14 years of age. As per the 1983 report of the Director General of International Labor Organization (ILO), child labor includes children prematurely leading adult lives, working long hours for low wages, under conditions damaging to their health and to physical and mental development. The UNICEF has given a comprehensive formulation in its attempt to define child labor: (1) Starting full-time work at too early an age, (2) Working too long within or outside the family so that the children are unable to attend the school, (3) Work resulting in excessive physical, social and psychological strain upon the child, (4) Work and life on the street is dangerous and unhealthy, (5) Inadequate remuneration for working outside the family, (6) Too much responsibility at too early an age, (7) Work that does not facilitate the psychological and social developments and (8) 1116 Work that inhibits the child’s self-esteem as in bonded labor and prostitution.

Absence of compulsory education at the primary level, parental ignorance regarding the ill effects of child labor, the ineffective implementation of child labor laws, nonavailability and non-accessibility of schools, boring and impractical school curriculum and cheap child labor are some other factors which encourage child labor. For the immature minds and bodies, it is difficult to understand the exploitation of child labor in the absence of adult guidance. The figure translates into 13.2% of all children between ages 10 years and 14 years being subjected to child labor. Of 12.6 million children in hazardous occupations, India has the highest number of laborers in the world less than 14 years of age. Although the Constitution of India guarantees free and compulsory education to children between the ages of 6 and 14 years and prohibits employment of children younger than 14 years in hazardous environments. Child labor is present in almost all sectors of the economy. F

D

efinition

auses of hild Labor

D

The problem of child labor continues to pose a challenge before the nation. The Indian Government has been taking various proactive measures to tackle this problem. However, considering the magnitude and extent of this problem and that it is essentially a socio-economic problem inextricably linked to poverty and illiteracy, it requires concerted efforts from all sections of the society to make a dent in the problem. Child labor in India is a human rights issue for the whole world. t is a serious and extensive problem, with many children under the age of 14 year working in the carpet making factories, glass blowing units and making fireworks with bare little hands. According to the statistics given by the Indian Government, there are 20 million child laborers in the country, while other agencies claimed that it is 50 million. Any working child who is under the age specified by law is designated as a child laborer. The word “work” means full-time commercial work to sustain self or add to the family income. Any child who is employed in activities to feed self and family is being subjected to “child labor”.

In conclusion, a simple workable definition of child labor is any work within or outside the family that threatens health and mental development of the child by denying him or her fundamental as well as non-fundamental rights.

Two types of workers are classified, namely, main and marginal. Main workers are those who are engaged in a fulltime economic activity and marginal workers are those who are part-time workers. Many children work in their families as helpers in different household chores, caring for younger siblings. It has been observed that this sort of work discourages school attendance. Rural children are often involved in non-domestic work which is agricultural in nature and quite a good proportion of them are involved in work which is generally seasonal. In cities, on the other hand, children are found to work in market places and almost in every street corner. They are engaged in a variety of working situations such as vendors, waiters in restaurants, helpers in all kinds of shops, private houses, in industries such as carpet weaving, sari-embroidery, brassware, precious stone polishing, leather tannery, Bidi (handmade cigarettes) making, bangle manufacturing, glass industry, brick field, match and fire industries, construction sites, garages, gas station, fishing, mines, handloom industries, lock industry and rag-picking. Girls at a fairly early age are recruited to the profession of prostitution. Children involved in gainful employment sometimes are bonded laborers in the backward areas of

ntroduction



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xploitation of hild Labor C

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ccupational Health Hazards

Any occupation which allows the working children to come in contact with harmful substances like chemicals, as in the balloon and lock industry or fire in glass industry, match and fireworks, or cotton puff and dust as in power loom industry is termed intrinsically hazardous, which may have an adverse effect on physical and psychological development of children. Various occupational health hazards are depicted in Table 19.10.1.



Child labor is economically unsound, psychologically disastrous, physically as well as morally harmful and precludes the full enfoldment of a child’s potentialities. It

 

Table 19.10.1 Occupational health hazards in children

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abuse. Most of the poor child workers go to work without adequate food, clothing and proper shelter. They ultimately become victims of a wide range of diseases like diarrhea, general weakness and various viral and bacterial infections. Other potential common psychological problems include habit disorders; personality disorders like timidity, irritability, sensitiveness, temper tantrums, obstinacy, daydreaming, negativeness, fear, jealousy, inferiority complex; psychoneurotic disorders such as nervousness, tremors, headache, pain, hyperventilation syndrome, masturbation, etc.; antisocial behavior like stealing, sexual offences, premarital sex; depressive psychosis and anxiety neurosis; drug abuse, and psychosexual problems.

co

some developing countries. Progenies of single parent households are more likely to join the labor force at an early age. Another factor is the birth order of child, the first child having the highest probability of being gainfully employed. Moreover, during the last few decades, in developing societies, the mortality rates have declined markedly, which has resulted in the survival of a larger number of children. The proportion of children under 14 years of age as compared to 15–19 years of age-groups is higher among the poor. Thus, poor families are left with only young children as potential workers. To summarize, children are engaged in various activities such as visible, invisible, formal, informal, paid or unpaid. Boys are usually engaged in relatively larger number of occupations than girls. Types of work for urban children are classified below: 1. Within the family – Domestic house tasks: Cooking, child care, fetching water, cleaning utensils, washing clothes, etc. – Handicrafts and cottage industries, weaving, leather work, wood work, etc. – Within the family but outside home: Domestic service, construction work, mining, i.e. quarry mines; informal economy, i.e. laundry, recycling rubbish 2. Outside the family – Bonded labor – Apprentices – Skilled traders: Carpets, embroidery, brassware works, gem polishing, etc. – Industries/unskilled occupations, mines, etc. - Commercial: Shops, restaurants and hotels - Begging.

Disease/disability

Balloon factories

Pneumonia, bronchopneumonia, breathlessness and even heart failure

Match and firework

Breathing problems, severe burns, muscle fatigue from lifting heavy loads, deformities due to long hours of work in one position

Lock industry

Tuberculosis and respiratory tract diseases, asthma, acute breathlessness, acid burns, acute headache

Glass industry

Heat strokes, conjunctivitis, TB and burns, life span reduced by a third due to heat and dust

Slate industry

Silicosis, TB, pneumoconiosis

Power loom industry

Byssinosis, fibrosis of lung tissue and TB

Bidi industry

Nicotine poisoning: nausea, headache blackouts and muscle fatigue, loss of eye sight

Brass industry

Additional burns and TB.

Zari industry

Eye diseases, postural deformities and spinal problems

Domestic workers Shop bays, etc.

Overwork physical and sexual abuse, drug addiction, isolation from society

Carpet industry

Poisoning from coloring agents, lung diseases from fiber dust

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Health Hazards for Working hildren

Occupation

Chronic starvation and unhealthy environment does contribute to ill health in all children, whether working or otherwise. Also many children start working at a very early age and do hazardous work for 12–15 hours a day without any holiday. Several occupations may not be hazardous by themselves but the environment makes them such. These environmental factors include ventilation, dust, gases, fumes, odors, lighting, noise, humidity, crowding, vibrations and ionizing radiations. All the children are in the process of growing and attaining their full physical stature and therefore, their growth is likely to be affected, resulting in stunting. This has been proved in several studies. Children who started working early in life suffered from deterioration in their nutritional status but such impact was not seen for those children who started work after the age of 11 years. Health effects of labor on children also vary according to the type of work situation. Children who are engaged in their own household jobs or family-based industries may have no direct adverse health effects. On the other hand, bonded and wage child workers may have greater effects on health because of the exploitative and unregulated nature of work, in which children are more exposed to health hazards, heavier workload and physical and mental

Source: Health for the Millions, New Delhi, Voluntary Health Association of India, 1989.

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The National Child Labor Policy (NCLP) was formulated in 1987 and ten industries were selected for remedial action.

1. Banerjee SR. Agricultural child labor in West Bengal. Indian 2. Banerjee SR. Child Labor in India. London: Antislavery Society,



Pediatr. 1993;30(12):1425-8.











7. 8.





6.

9.





5.

10.





4.

11.





3. Banerjee SR. Child labor. Gupta S (Ed). Recent Advances

12.





1979.



ational hild Labor Policy

ibliography

B

The NCLP aims to revitalize and coordinate employment generating the asset-building anti-poverty programs in the designated areas, to strengthen the labor law enforcement machinery and to provide the children with better facilities for education, nutrition and health. However, the NCLP can only cover, at best, 30,000 children, a minute fraction of the total 44 million working children in India.

C

A

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nitiative gainst hild Labor

Abolition of child labor is not possible from developing countries in the near future. However, the improvement in condition of work and work environment should be seriously considered. Child Labor (Prohibition and Regulation) Act, 1986 was enacted to replace the Employment of Children Act, 1938. This Act is the culmination of the process of consideration that the Government has been giving to this pervasive problem figuring in the economic and social landscape in the country. This law is aimed to identify processes and industries which are hazardous, with a view to ban child labor in these sectors and to regulate the condition of work in non-hazardous industries. The implementation of this Act depends largely on labor inspectors. However, it has been found that there are not enough inspectors and most are easily threatened and bribed. Thus, in this view, the future action program is set out under the following three heads: (1) The legislative action plan, (2) Focusing of general development program for benefiting child labor, wherever possible and (3) Project based plan of action in areas of high concentration of child labor engaged in wage/ quasi wage employment. N

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also deprives them of education, training and skills which are essential pre-requisites of earning power and economic development. Sexual abuse is a common problem faced by girl children who work as a contract labor. The working girls in sleazy “B” and “C” grade hotels, lodging house, restaurants and also in domestic houses are exposed to physical assaults and sexual abuses by their employers and customers.

in Pediatrics. Vol. II. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 1992.pp.134-6. Banerjee SR. Child labor. In: Banerjee SR (Ed). Community and Social Pediatrics. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 1995.pp.364-83. Banerjee SR. Child labor in suburban areas of Calcutta, West Bengal. Indian Pediatr. 1991;28(9):1039-44. Banerjee SR. Female working children. Indian Pediatr. 1990;27(11):1153-8. Banerjee SR. Occupational health hazards of working children. J Indian Me Assoc. 1995;93(1):22-4. Mendelievich E. Children at Work. Geneva: International Labor Office; 1980. Pinto GJ. Child Labor. New Delhi: United Nations Children’s Fund; 1987. Rodgers G. Standing G. Economic Roles of Children in Lowincome Countries. Geneva: International Labor Organization; 1980. Shah PM. Advances in International Maternal and Child Health. London: Oxford University Press; 1987. Singh S, Verma RBS. Child Labor in Agriculture. Lucknow: Print House. 1987.pp. 238-40.

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Adoption and are of rphans C





community PED A R S

19.11

RD Potdar Every doctor should be conversant with the process of adoption, be able to and should advise any prospective adoptive parents on all aspects of adoption. The doctor can help in all the following standard steps of adoption process always using sympathy and empathy at all stages.

I T IC

Preparation for adoption, mentally, physically, procedure and document-wise: The ideal age difference between at least one parent and the baby to be adoptive should be not more than 40 years so that they have enough time and physical strength on their side to look after the baby till it becomes a young adult and legally a major. Parents should be equipped with the following documents viz. marriage certificate, proof of age, income certificate and bank balance and property certificates (if any), Doctor’s certificate regarding their health and also their infertility status, references and photographs when they go to apply for a baby for adoption. C

Pre-Adoption ounseling and Home Study Preparation This is done by the social worker of the agency and consists of social and family background of both parents, current marital and family relationships, attitudes and motivation toward infertility, childlessness and adoption, anxieties regarding child’s illegitimacy, social and genetic background, sharing the fact of adoption with family and the child, parenting experience, aspirations and financial capabilities, recommendations of their friends and referees. M

hoosing a hild, edical Screening and ertifying the “Fit for Adoption” Report C

In India, two laws govern the process of adoption. First, “The Hindu Adoption and Maintenance Act 1956” governs all Hindus adopting children and the second, “The Guardians and Wards Act of 1890” governing adoptions by parents who are not Hindus by religion. In inter-country adoptions children are given for adoption under the “The Guardians and Wards Act of 1890” in foster care till they are finally adopted according to the law of the country of adoptive parents.

Preparation for Adoption

C

Laws

aking up a Decision to Adopt

“Childless couples who are involuntarily childless have a desire for parenthood combined with complex set of emotions ranging from guilt of infertility to apprehensions to fears related to the social status, family acceptance and reactions of decision to adopt, unforeseen elements of taking home a child borne by parents not known and their own capabilities regarding coping up with a new challenge in life.

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Adoption is essentially a social process by which the reciprocal need of childless parents and an orphan (or parent-deprived) child is satisfied. Legally it may be defined as “Transfer of rights and responsibilities concerning the child from biological or birth parents to the adoptive parents irrevocably”. Adoption is also an instrument through which one can ensure the following important children’s rights accepted by the UN Convention of Rights of Children and the world community at large. These are: • Inherent right to life survival and development • Right to name and nationality • Child’s interest being always a primary consideration • Special protection from physical harm and neglect • No discrimination through universal brotherhood • Social security through education, employment and earning • Special attention to disabled children. Considering the above definition and objectives, adoptions could be divided into various types like intrafamily adoptions, single parent adoptions, adoption of older children, adoption of disabled or “special needs” children and inter-country adoptions. Whatever the type it is always prudent not to do it secretly (by feigning pregnancy) but do it properly within the law of the country. Since the emotional, psychological, social and legal consequences of adoption are far reaching in nature it must be conducted in a very open and supportive environment. Parents should be strongly advised not to arrange private or secret adoptions through hospitals and medical practitioners directly. Adoption must always be done through an institute which has been recognized as a “Fit Person Institute” by the Central Government. In all states of India, there are many orphanages and adoption agencies recognized in this manner.

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Definition

While it is true that “choosing” can imply a bias of an arbitrary and discriminatory selection or rejection, in the Indian context it should be left to the social worker to place a child who is near compatible to adoptive parents in looks,

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Every doctor must be aware of these problems and be able to either counsel the family himself or convince and refer them to the appropriate agencies.

­

Follow-up after adoption is necessary for advice and care in the following crisis situations which are likely to arise in some of the babies: • Sudden change crises, where the baby may (and parents) may take long time to cope up with the suddenness of change in environment, climate, living conditions, language, noise level, food styles and surrounding strange faces resulting into different types of reactions like anxiety, rejection or aggression or any combinations of these • Behavior crisis is likely manifest after first few years and may be as a result of pampering and overprotection (or even a covert rejection) by one or both parents and other family members. There may be a considerable delay in detection and management of likely behavior problems due to the unwillingness of the parents to seek interventions by adopting an attitude of “keeping all in the family”. Such problems may become worse in adolescence if not tackled earlier • Communication and identity crisis may come-up at any age if the child’s sense of security is not well ensured by the parents and immediate family members. This problem is more likely to comeup in intercountry adoptions because of the obvious difference in skin color • Crisis of assimilation is likely to occur in intercountry adoptions in a small number of cases where the young adults may face discrimination in getting jobs, married, etc.

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Encouraging, nsisting and Helping the Parents Encouraging, insisting and helping the parents to tell the child about his or her adoption is most vital postadoptive follow-up actions. Every child who is adopted must be told that he or she is adopted by the parents themselves howsoever it may appear difficult for them. When a child comes to know the fact from sources other than his parents, it can cause such a severe trauma (of betrayal or breach of trust) that it might even ruin relations between the parents and the child forever totally defeating the very objective for which the adoption was undertaken in the first place. Later the age of the child when the trauma happens, worse are the consequences for the parents. It is therefore necessary and appropriate to encourage all adoptive parents to tell the child as early in life as possible when the child can comprehend the concept of biological and adoptive parenthood. If done between the ages of 6 years and 10 years most children take into their stride and future problems can be averted. Golden rules of child adoption are summarized in Box 19.11.1.

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M

Vast majority of orphans who go for adoption after 1 month of their age and those who were not abandoned immediately after a hospital delivery are highly vulnerable to sepsis, malnutrition, frequent attacks of acute respiratory and gastrointestinal and skin infections. They may be frankly marasmic and lack immunity increasing the incidence of morbidity and mortality amongst them. In the management of sick orphans three actions are of utmost importance. First is immunization against hepatitis B in addition to standard schedule, second is the urgency of action when even slightly sick and the third is early use of higher antibiotics even if prima facie it may appear an irrational and expensive proposition. By introducing simple inputs such as IV fluids, oxygen therapy and higher antibiotic therapy in the orphanage itself prior to transferring to a big hospital a large number of such babies can be saved. Apart from this the care of orphans and adopted babies should be like any other normal baby. In post-adoption care, in addition to problems of general health and standard immunization schedule, an extra eye should be kept on feeding and sleep patterns, motor develop ment pattern, speech and language development which may appear delayed for some time initially. Advice of patience and perseverance is usually very rewarding in most cases.

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edical are of the rphans and Adopted abies



Follow-up and Post-adoption ounseling



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color of the eyes and complexion. This is likely to ensure better adjustment and integration of the baby in the new family and society. While doing the medical screening for fitness the doctor should remember that this baby should be examined and certified fit, normal or otherwise in the context of the situational background that the baby may have suffered physical, nutritional and emotional deprivation in the recent past. Clinical examination consists of identification data, anthropometry, systemic examination, detection of any gross deficiency disorders and overt or covert anomalies and their correctability potential, clinical clues to metabolic disorders if observed and physical and mental milestones evaluation. Standard investigations which are expected to be done are hemogram, urinalysis, tuberculin test, X-ray chest, stool examination for parasites, tests for Venereal Disease Research Laboratory (VDRL), HIV, hepatitis B, TORCH (toxoplasmosis, other infections rubella, cytomegalovirus and herpes) titers and any other indicated tests with special reference to hypothyroidism, hemolytic anemia, chromosomal anomalies, and metabolic screening tests for mental retardation like phenylketonuria, galactosemia, aminoaciduria, etc. The entire exercise should be a balanced one to ensure welfare and maintain interest of both the baby and the adoptive parents with a little more tilt toward child’s interest since the child is a totally dependent being.

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Box 19.11.1 Golden rules of adoption

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Golden rules of adoption • The primary responsibility for providing care and protection to children shall be that of his/her family • Adoption shall be resorted to for the rehabilitation of the children, who are orphan, abandoned or surrendered through such mechanism as may be prescribed • In keeping with the provisions of the various guidelines for adoption issued from time to time, by the state government, or the central adoption resource agency and notified by the central government, children may be given in adoption by a court after satisfying itself regarding the investigations having been carried out, as are required for giving such children in adoption • The state government shall recognize one or more of its institutions or voluntary organisations in each district as specialised adoption agencies in such manner as may be prescribed for the placement of orphan, abandoned or surrendered children for adoption in accordance with the guidelines notified under sub-section (3) • Provided that the children’s homes and the institutions run by the state government or a voluntary organization for children in need of care and protection, who are orphan, abandoned or surrendered, shall ensure that these children are declared fit for adoption by the committee and all such cases shall be referred to the adoption agency in that district for placement of such children in adoption in accordance with the guidelines notified under sub-section (3) till the 2 months period for reconsideration by the parent is over in the case of surrendered children, and without his consent in the case of a child who can understand and express his consent • The court may allow a child to be given in adoption: (1) to a person irrespective of marital status, (2) to parents to adopt a child of same sex irrespective of the number of living biological sons or daughters or (3) to childless couples.

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Prevention and ontrol of njuries

ge

Injuries occur at a particular age when a child or an adolescent encounters a new task or hazard against which they may not have the skills to handle. In view of exploratory nature of toddlers they are at highrisk for injuries especially burns, drowning, and fall as well as they do not know that medications can be poisonous or some houseplants are not to be consumed. Many parents expect young school-aged children to walk home from school, the playground, or the local store, tasks for which most children are not developmentally ready. Young school-aged children are at-risk for pedestrian injuries, bicycle-related injuries, motor vehicle occupant injuries, 1122 burns and drowning. The lack of skills and experience lead to

S

Risk for injury is primarily related to poverty, educational status and presence of hazardous environments, rather than to race alone. E

S

ocio- conomic tatus and nvironment

Mortality from fire, motor vehicle crashes and drowning are higher among poor children. Other factors are singleparent families, teenage mothers, multiple care providers, family stress and multiple siblings; which are primarily due to poverty rather than independent risk factors. Poor children are exposed to more hazards in their living environments, in the form of poor housing, which is less likely to be protected by smoke detectors, etc. The roads are more likely to be major thoroughfares. Neighborhoods experience higher levels of violence and they are more likely to be victims of assault.

ural vs Urban tatus

Injury rates are higher in rural and homicide in urban areas. Case fatality from injury are generally twice as high in rural areas than in urban areas, due to increased severity of some injuries (such as motor vehicle crashes occurring at higher speeds) and poor access to emergency medical and definitive trauma care services. Agricultural injuries are confined to rural areas.

trategies to Prevent and ontrol njuries I

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isk actors

thnicity

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A

R

A total of 357,021 accidental deaths were reported in India during 2009. There was an overall increase by 4.3% when compared to the year 2008. Males accounted for 77.4% and children for 6.4% of total accidental deaths. Attributable to unnatural causes (falls, poisoning, traffic accidents) were 93.8% and natural causes (heat stroke, flood, cyclone, landslide, etc.) were 6.2%.

Males have higher rates of injury than females. Variation in exposure to risk, greater risk-taking behavior, combined with greater frequency of alcohol use, may lead to the disproportionately high rate of motor vehicle crashes among teenage males and not due to developmental difference between the sexes. Children with psychiatric problems, especially attention deficit-hyperactivity disorder (ADHD) are at more risk for injuries.

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pidemiology

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Term “accident” represents an incident occurring by chance that cannot be predicted and prevented, whereas “injury” represents an event occurring at predictable circumstance among individuals who are at highrisk. The term “injury” is preferable in the sense that it promotes awareness program as well as leads to proper planning of prevention and possibility of injury control. Injury control comprises “primary prevention” attempting prevention of injuries, as well as “secondary” and “tertiary” prevention, representing trauma care and rehabilitation respectively. Consider physical and social environment of children at which injury occurred, instead of trying to attribute it to accident proneness of children. Those who are prone for injury are more likely to be unsupervised, having families in disharmony and hazardous environments conducive for injuries. Injuries can be “unintentional” or “intentional” (assaults and self-inflicted).

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Injuries are important cause of preventable morbidity and mortality among children and adolescents of developed as well as developing countries.

particularly motor vehicle injuries, drowning burns and risk of intentional trauma among teenagers. Alcohol and other drugs often add to these limitations. Work-related injuries are associated with child labor. Age also determines the severity of injury and long-term disability. For example, outcome of head injuries among young children is poor when compared to adolescents or adults.

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• Promotion of awareness: “Passive intervention” is for entire population, irrespective of individual’s involvement;

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Head trauma is the leading cause for mortality. Education programs to be organized by physicians and service organizations in promoting the use of bicycle helmets to children. Separate bicycle path is an ideal option. I

Pedestrian njuries Mostly injuries occur during the day, with a peak in the after school period. Risk is more with factors like high traffic, high speed, absence of play space near home, household crowding and low socio-economic status. Young children are more prone since poor ability to judge distance and speed of vehicle and easily distracted by playmates or other environmental factors. Other factors are poor socio-economic status, low educational status, living in mobile homes, etc. Prevention is by multifaceted approach. Younger children should never cross streets alone until 10 years of age. Select streets with little traffic. Following legislation and police enforcement will be useful (1) measures to slow the speed of traffic, (2) to route traffic away from schools and residential areas, (3) networks of “one way streets”, (4) proper placement of transit or school bus stops, sidewalks in urban and sub-urban areas, (5) edge stripping in rural areas to delineate the edge of the road and (6) strictly implementing parking rules.

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Injuries to passenger vehicle occupants are the predominant cause of motor vehicle death among children and adolescents, with the exception of the 5–9 year old group, in whom pedestrian injuries are common. Infants or children weighing less than 10 kg should be placed in the rear seat facing backward. Toddlers and children can be placed in the rear seat in a forward-facing toddler seat. Children in the back of uncovered vehicles, face the possibility of being thrown out leading to head injury

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Traffic accidents are the major contributors of accidental deaths of unnatural cause. The leading cause of serious and fatal injuries among all age-groups. Injury can be to the occupant, driver or both. O

Bicycle Injuries

urns

Flame burns resulting from ignition of clothing is common followed by household fire injuries, especially among small children. Using non-flammable fabrics will minimize this. Scalds from hot liquids and foods are most common in children less than 5 years. Avoid taking hot drinks while holding an infant, keeping children away from pots, cooking stove. Fireworks are seasonal injuries, supervision by adults while children use fireworks is mandatory. Smoking constitutes half of the household fires. The combination of smoking and alcohol use will increase risk for injury and 1123 mortality. Smoke detectors are inexpensive, at the same time

otor Vehicle njuries I

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Falls form the majority of the injuries among children. Mostly falls are from vehicles, walkers, staircase and while on play etc. Prevention is by raising the level of railing of staircase and play ground to be provided with energy absorbent materials like sand, rubberized surface or coir mats.



Twice more among teenagers when compared to elder drivers, five to ten folds more likely to encounter fatal crash while driving at night compared with driving during the day. The difficulty of driving at night combined with the inexperience of teenagers appears to be a deadly combination. The inexperience in driving and driving in a drunken state is more dangerous.



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Driver Related Issue

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and those in covered trucks carbon monoxide poisoning if exhaust system is not proper. The safest place for children is in the rear seat, properly restrained for their age and size. Educational and legislative interventions for children traveling in the rear seat are found to be successful. Audio visual aids can be shown to parents in waiting rooms.

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whereas “active intervention” requires behavior change of parents and children. Community education is an active intervention, whereas product and environment modification are passive interventions • ducation to parents: Behavior modification is the most important step toward injury control. Focus should be specific, for example: use of car seat restraints, helmets, use of smoke detectors, etc. This will be successful than very vague general instructions • odification of product design: More useful than repeated attempts on behavior change among the parents or children. Lowering the water heater temperature, installing smoke detectors, and using child-resistant caps for containers with medicines and household products are examples of effective product modifications. Many interventions require both active and passive measures. Seat belts provide passive protection when used, but behavior change is required to use it regularly • odification of the social and physical environment: Greater effort is required when compared to individual product modification, but very effective in controlling injuries. Safe roadway traffic and speed limits are examples of such interventions. Changes in the social environment through legislation is needed sometimes, such as laws mandating child seat restraint and use of seat belt, bicycle helmet and stream lining motor vehicle licensing laws, etc. • Prevention campaigns combining two or more of these approaches have been particularly effective in controlling injuries.

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Homicide may be in “infantile” and “adolescent” groups. The earlier group may be subjected to “child abuse” by care takers and the later due to firearm injuries from peers or otherwise.

With common household substances is a subject by itself and as it is out of scope for this article not been dealt in detail. The prevention can be by keeping the poisonous substances out of reach of children, stored in proper containers with child-resistant caps.

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ibliography 1. Rivara FP, Grossman D. Injury Control. In: Kliegman RM,

Poisoning



More common in infants and toddlers, which may be due to food, nuts, parts of toys, etc. being aspirated into the airway or smothering accidentally by pillow, bed sheet and strangulation while play with swings.

Berhman RE, Jenson HB, Stanton BF (Eds). Nelson’s textbook of pediatrics, 18th edition. Philadelphia: Saunders. 2008. pp.366-74. 2. The National Crime Records Bureau (NCRB). Accidental deaths and suicides in India. New Delhi: Ministry of Home Affairs, Government of India, 2009.

uffocation

anagement

Management consists of preventing further injury, transport, maintenance of vitals, and advanced management of the injury. Emergency treatment may need to be instituted immediately in case of respiratory or cardiovascular com promise. Following transfer to a trauma care center, accurate evaluation of the injuries and appropriate management are essential. “Post Treatment Stress Disorder” among parents and children who survived near fatal injuries is yet another important issue, which should be addressed to.



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Homicide

rowning

Common among older children and adolescents during swimming or boating, children less than 5 years of age, as they do not know the consequence of getting into the water and do not call for help, they are more prone to submersion injury. Fencing of pools and avoiding allowing toddlers unattended at swimming pool/bath tub will prevent drowning. When intoxicated with alcohol risk is many folds. S

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effective method of preventing majority of these deaths. Sometimes burns result from fire setting (exploratory play) by children or adolescents. Burns following exposure to corrosives, especially acids and electric shock to be kept in mind.

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Section

20 Pediatric Procedures Section Editor : A Parthasarathy









20.1. Common Procedures in Pediatric Practice: Baldev S Prajapati 20.2. Physiotherapy and Rehabilitation: Somu Sivabalan

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Counseling



Explain the parents in detail regarding the procedure including its indications, technique of the procedure, possible complications, etc. If the child is older and able to understand, talk to him also, in simple language. By this, cooperation is available from parents as well as the child. It decreases the anxiety of all and the procedure can be performed smoothly. An informed consent is must for all the procedures. In certain procedures like lumbar puncture, pleural and pericardial tapping, liver biopsy, renal biopsy, exchange transfusion, bone marrow aspiration and biopsy, it is the prudent to get signed consent.

Procedure Room and Lighting Separate procedure room is desirable. It should have good daylight and should be well illuminated and well equipped. All the equipments and drugs to perform the procedure as well as to manage any emergency if it arises should be made available.

Containers

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It is very important to confirm that proper containers are available for collection and transferring the specimens.

dentification of the Patient

edation

nesthesia

Local anesthesia may be achieved by infiltrating tissues around the site with 0.5–2% lignocaine. The maximum dosage of 1% lignocaine that can be infiltrated is 0.3 mL/ kg. An alternative is to apply lignocaine cream to small area of the skin 60 minutes prior to performing the procedure, protected by adhesive dressing. Sedation or general anesthesia may be needed in certain cases.

sepsis

The physician should scrub hands and forearm using an effective cleaning agent like 4% chlorhexidine or hexachlorophane before undertaking any procedure. Wearing of sterile gloves by the doctor is very important both for his and the patient’s safety. The site of the patient’s skin is then cleaned with 70% isopropyl alcohol and the surface is allowed to dry, the surface is then again washed three times with 10% povidone-iodine or 0.5% chlorhexidine gluconate in 70% isopropyl alcohol. It should be cleaned in a circular fashion from the center outwards.

ntramuscular njection

Common Sites Muscles commonly used for intramuscular injection (IM) are vastus lateralis, deltoid and gluteus medius. Children do not have well-developed gluteus medius and therefore it is not the site of preference for IM injections. It has been documented that some vaccines like hepatitis B and antirabies vaccines administered at gluteal region produce very poor antibody response. The vastus lateralis (anterolateral aspect of thigh) is the preferred site in infants. The site in vastus lateralis is the middle-third of the area between the greater trochanter and lateral femoral condyle (Fig. 20.1.1). In case of deltoid, the site for injection is midway between acromion process and deltoid insertion; it comes to 3–5 cm below the acromion process. This site may be

Children are afraid of procedures and their reactions in form of crying and struggling, and frightened appearance increases the parental anxiety. It affects the performance of the person who is performing the procedure. It results 1126 in increased rate of failure and complications related to procedure. In this situation sedation to the child may help.





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It should be a routine to identify the child before performing the procedure. It should be confirmed with hospital staff as well as the parents that you are dealing with the correct child.

Physical restraint of the frightened child may be essential for the successful outcome of any practical procedure. The child may be wrapped with a blanket taking care to prevent aspiration or airway obstruction. The help of the person who is assisting is very crucial in deciding the outcome of the procedure.

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General Considerations

Restraint

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It is very essential for every medical student and practicing pediatrician to learn performing common pediatric procedures. The procedures are best learnt by observation, performing the procedure under supervision and repetitive performances. It should be practical, methodological and safe for both patient as well as for the individual who perform the procedure.

Promethazine 1 mg/kg/dose or Triclofos sodium 20 mg/kg/ dose by oral route will suffice in most of the cases. Diazepam, ketamine and general anesthesia are other options as per indications.

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Technique (WHO Technique)

Technique

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The site of injection should be exposed well For anterolateral aspect of thigh, the child may be laid supine or be held in mother’s lap. For deltoid, child may be held in mother’s lap or may sit The muscle selected for injection should be relaxed The skin over injection site should be cleaned with spirit. A circular motion of swab is used proceeding from puncture site and extending outward for 5 cms. Let the spirit evaporate and skin become dry, otherwise spirit entering into tissues is painful The syringe is filled with the medicine In children, usually 23 G needle with 25 mm length is used for IM injections Stretch the skin flat and push the needle down at 90° (Fig. 20.1.2) Aspiration before injecting the vaccine is not required Inject the vaccine at the rate of 1 mL per 10 seconds The needle is withdrawn and injection site is pressed for few seconds. Do not rub the injection site Needle should be withdrawn smoothly with steady movement Discard the needle and syringe as per standard guidelines.

•

Alternative to WHO technique, ACIP technique may be used. It is also called bunching technique. In this technique, bunch the muscle and direct needle inferiorly along long axis of leg at an angle of 45°. It stabilizes leg and increases the muscle mass.

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ubcutaneous njection

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ntradermal njection

Indications for intradermal (ID) injection are bacille Calmette-Guérin vaccination, Mantoux test, skin tests for allergy, test for sensitization of certain drugs like penicillin. Antirabies vaccine also can be given by ID route.

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Common sites are arm, anterior abdominal wall and thighs. Atrophic and infected areas are avoided The skin is cleaned and disinfected with spirit 26 G needle with 13 mm length is commonly used for SC injection The skin is raised into a fold with thumb and index finger of the left hand The midpoint of the fold is pierced with the needle held at 45° with its surface. The tip of the needle is advanced into the subcutaneous tissue (Fig. 20.1.2) Aspiration is not required Drugs or vaccine is injected, needle is withdrawn and site is pressed for few minutes. I

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fear of development of intramuscular hematoma. Insulin and heparin like drugs as well as measles, mumps, rubella (MMR), varicella, etc. Vaccines are given by SC route.

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used in children above 5 years and adults. The quantity of drug should be less than 5 mL. Only watery injections with less viscosity should be injected at deltoid region.

Drugs or vaccines are injected subcutaneously when slow absorption and long duration of action are desired. Another indication of subcutaneous (SC) injection route is a coagulopathy, which makes IM injection hazardous, for •

Ventral (volar) aspect of forearm is commonly used for ID injection Skin is cleaned with spirit or clean water A measured amount of antigen (usually 0.1 mL) is drawn into the syringe 26 or 27 G needle with ¼–½ inch (6.35–12.7 mm) length needle is used for ID injection The skin is held taut between thumb and index finger of the left hand. The syringe is held at an angle of 10–15° with the skin. Needle is inserted for about 2 mm, so that entire needle bevel penetrates the skin and the injected solution raises a small bleb of about 5 mm in diameter. The development of perifollicular puckering (Peau dl orange) indicates successful ID injection (Fig. 20.1.2) The needle is withdrawn

Figure 20.1.2 The position of the needle during different ways of administering injections Source: Nursing Care of Children. In: Waechter EH, Philips J, Holaday B (Eds),  

 

Figure 20.1.1 Site for intramuscular injections in an infant Source: Essential Procedures In Pediatrics. In: Prajapati BS (Ed), 1st edition. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2003.

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Peripheral ntravenous ccess

Technique

Peripheral intravenous access is one of the mainstays of modern medicine. It allows blood sampling, administration of medicines, fluids, nutrients, blood and blood products. Intracaths and scalp vein needles are commonly used for this purpose. Various sites for venous access are as follows in order to preference (Fig. 20.1.3): • Veins on dorsum of hand • Superficial radial vein on radial aspect of wrist • Superficial veins over volar aspect of forearm • Basilic vein and median cubital vein over antecubital fossa

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A tourniquet is placed over the limb, 3–4 cm proximal to the site selected for venepuncture, taking care not to pinch the skin of the child. The pressure should be such that it occludes venous flow by continuous arterial blood flow Tapping sharply over the vein causes mechanical reflex dilatation of the vascular walls. It should be light otherwise pain will cause vasoconstriction Active or passive pumping of extremity enhances blood flow and distends veins

Figure 20.1.4 Technique of venepuncture with scalp Source: Prajapati BS (Ed). Essential Procedures in Pediatrics, 1st edition. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2003

 

Figure 20.1.3 Common sites for venepuncture Source: Prajapati BS (Ed). Essential Procedures in Pediatrics, 1st edition. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2003

 

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It is a safe and easy way of administering drugs. The human rectum represents a body cavity in which drugs can be easily introduced and retained. The absorption of the drugs is well through this route. Rectal administration of drugs is indicated in patients who are not able to take orally due to nausea and vomiting, having convulsions, uncooperative children, before surgery, etc. If the child can understand, it should be explained to him. The child should be relaxed. He is kept in lateral position with knees flexed towards abdomen or in supine position with legs taken upwards towards abdomen, and the drug is inserted into the rectum through anal orifice, and buttocks are held firmly to prevent expulsion of the drug. Paracetamol, diazepam, midazolam, paraldehyde, glycerine, bisacodyl, diclofenac sodium, steroids, neomycin, artesunate and many more drugs can be administered through rectal route. When rectal preparations are not available, some liquid preparations like Injection Diazepam may be given per rectum. For this purpose, a lubricated tube is inserted into the rectum to a distance of about 5 cms and then the medication is administered through it using a syringe. The buttocks are held together for a couple of minutes. Local irritation and ulcerations in rectum may develop as complications of this procedure.

Superficial veins over dorsum of foot and long saphenous vein on medial aspect of leg above the ankle • Veins of scalp in newborns and infants • External jugular vein. Straight, large and easily accessible peripheral veins in healthy subcutaneous tissues are ideal for venous access. Veins of the upper extremities are preferred because there are many potential sites and more comfortable to the patient. The distal and superficial veins are preferred as complications are more following extravasation and thrombophlebitis in proximal and deep veins. When the veins are not visible, they can be palpated at common sites and can be accessed. Scalp vein needle is a hollow needle with butterfly plastic handle and a plastic tube, at the other end of which, a syringe or infusion set can be attached. It is useful for venous sampling of blood and short-term use of intravenous route (Fig. 20.1.4). Vein is counter punctured very easily on movement of the limb. Intracaths are plastic catheters over a hollow metallic needle. The metallic needle just projects beyond the tip of plastic catheter. The metallic needle is to provide stiffness during insertion into the vein, after which it is withdrawn. The plastic catheter is then advanced further gently so that vein is not counter punctured. The plastic catheter is well tolerated. Intracaths and scalp vein needles are available in various sizes from 26 G to 16 G. In children commonly, we use 26–21 G depending on age of the child and requirement.

Rectal dministration of rugs

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The site is circled and it is recorded in patient’s chart The reaction is observed in defined time. A

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ntraosseous nfusion

Peripheral percutaneous venous access is the fastest method of obtaining vascular access in children. However, during lifethreatening emergencies, rapid access to venous compartment through peripheral or central venous route is occasionally difficult or an impossible procedure for a pediatrician to perform. Small peripheral vessels in children often collapse during shock and efforts at setting up an IV line in a peripheral vein may fail. When IV access cannot be established within three attempts or 90 seconds time, intraosseous route should be used as per the recommendations.

Common Sites •

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Specially designed needles, Jamshidi type available for intraosseous infusion should be used, if available. Hypodermic needle can also be used. 20 to 16 FG needle can be used for children below 18 months of age, and 16–12 FG for older children. Identify the site of placement. Patient’s leg should be restrained; a small sand bag is placed behind the knee. The use of local anesthesia is optional, but usually recommended as it may be more painful once the child is resuscitated. Aseptic precautions are must. Insert the needle perpendicular to the skin and advance to the periosteum and then with a screwing motion penetrate into the marrow. A distinct “give way” sensation indicates that your needle is in marrow. Confirm that the needle is firmly embedded in the bone. Insertion of needle to a depth of 1 cm is usually adequate as the distance from skin through the cortex is rarely more than 1 cm in infants and children. The needle should maintain erect posture without support. Trocar is removed and correct position is verified by aspiration of marrow and easy flushing with 5–10 mL of normal saline without signs of extravasation. The needle should be secured and apply sterile dressing over the site. It should be watched for local complications like extravasation and infection. As soon as the peripheral IV route is established, intraosseus needle should be removed. Emergency drugs and fluids can be administered intraosseously essentially the same dosage and rates as given by intravenous route.

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Technique (Fig. 20.1.6)

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2–3 cm above the lateral condyle of the femur in the midline Medial surface of the distal tibia proximal to the medial malleolus.

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Anteromedial surface of the proximal tibia, one or two finger breadths distal to tibial tuberosity to avoid damage to epiphyseal growth plate

 

Figure 20.1.5 For inserting the IV canula on the dorsum of the hand. The hand may be held flexed at the wrist to occlude venous return and make the veins prominent

Figure 20.1.6 Intraosseous cannulation technique Source: Chameides L (Ed) Textbook of Pediatrics Advanced Life Support.  

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A warm moist towel may be applied to the site for several minutes. It causes venous dilatation Aseptic precautions are mandatory The methylated spirit is applied over 4–5 cm area at planned site. Let it dry The skin is pulled taut distally to stabilize the vein with a nondominant hand. It is punctured by the needle bevel up at 15–30° angle parallel to the vein (Fig. 20.1.5). After the entry into the subcutaneous tissue, the needle is aligned parallel to the skin surface and along the long axis of the vein. Its tip is depressed a little and is advanced until it penetrates the vein. Then, it is made parallel to the vein again and advanced until it is passed fully into the vein. Blood is collected if indicated and then the IV set is attached to it The tourniquet is removed and the infusion is started by releasing the clamp on the tubbing. A hub of the cannula and IV set are secured to the skin with the adhesive plaster For flushing the cannula, normal saline should be used and not the distilled water. Distilled water causes pain at IV site and it also causes hemolysis If venepuncture is performed only for collection of blood, pull the needle gently after collecting the required sample and apply steady pressure at the site with a piece of spirit swab for few minutes.

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Venous Cutdown (Venesection) Venous cutdown is now rarely resorted to in the present scenario of cannulas and intraosseous access. It is mainly useful when routine intravenous access has failed in conditions such as shock or when large amounts of fluids have to be given for a long time as in total parenteral nutrition.

Sites • •

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Cannula is fixed by tieing proximal ligature on the vein with cannula in vein Ends of proximal and distal ligatures are trimmed Wound is sutured by silk sutures in a way so that cannula or tube does not get kinked or obstructed Dressing is applied and remaining part of the tube is properly fixed with dressing IV drip is connected to the venesection needle.

Complications • • • • •

Wound infections Thrombophlebitis Deep vein thrombosis Air embolism Injury to adjacent nerves and vessels. As alternate route is possible, earliest venesection tube should be removed.

Technique (Fig. 20.1.7) • • • • • • • • • • •

Get all the instruments ready Prepare the part aseptically. Then it is draped with sterile towels 0.5% Xylocaine is infiltrated subcutaneously at the site of incision. In emergency, local anesthesia can be skipped A 1–2 cm long transverse incision is made 1.5 cm above and in front of medial malleolus, over the saphenous vein The vein is exposed by blunt dissection, opening the blades of mosquito forceps parallel to the vein Pass the tip of mosquito artery forceps under beneath the vein and elevate atleast 1 cm above the vein Pass two silk ligatures under the vein Separate the proximal and distal ligatures for full length of exposed vein Tie the distal ligature and hold the ends with mosquito forceps With venesection scissors put “v” shaped cut on anterior wall of the vein at middle of the exposed part Introduce polyethylene tube of suitable size proximally through the cut in the vein till the free flow of blood is obtained

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Lower limb: Most preferred site is saphenous vein near ankle Upper limb: Median cubital or basilic vein in front of elbow Cephalic vein at the wrist at anatomical snuff box External jugular vein in the neck.

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xternal Jugular Vein Puncture

The external jugular vein is formed below the ear and behind the angle of mandible, passes downwards and obliquely backward across the surface of sternocleidomastoid muscle and ends in subclavian vein lateral to anterior scalene muscle.

Technique (Fig. 20.1.8) •

• • • •

Place the patient in supine. Both the shoulders should touch the table and head is rotated fully to one side and extended partly over the end of the table so as to extend the vein. Making the child cry makes the vein prominent. Restraining the child properly is very important. Clean the overlying skin. Use proper size of the cannula. Keep the cannula in the direction of the vein with the point aimed towards the same shoulder. Make the venepuncture midway between the angle of mandible and midclavicular line.

Source: Prajapati BS (Ed). Essential Procedures in Pediatrics, 1st edition. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.; 2003

Source: Silver HK, Kempe CH, Bruyn HB (Eds). Handbook of Pediatrics, 13th edition. Singapore: Lange-Maruzen Asia Publications; 1980.

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Figure 20.1.7 Venous cutdown

Figure 20.1.8 Position for jugular vein (both internal and external) puncture. The arrow shows the direction of insertion of the needle for external jugular vein puncture

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Technique (Fig. 20.1.9) • Restraining the infant in frog leg position • Clean the inguinal area properly. The part is cleaned properly with spirit – iodine–spirit • The femoral artery is located just below the midpoint of inguinal ligament • The femoral vein lies medial to the artery • Skin is pierced about 1–2 cm as below the inguinal ligament directly over the femoral vein and the needle is advanced at an angle of 30–45° with the skin while maintaining the gentle negative suction. As the vein is punctured, the blood is withdrawn in the syringe. If no blood is obtained while needle is inserted, suction should be maintained as the needle is slowly withdrawn. Sometimes needle passes through both the walls of the vein and blood is obtained only when the needle is being withdrawn • On removal of needle, apply firm pressure over the site of puncture for atleast 3–5 minutes to avoid oozing and hematoma formation. Precautions • As far as possible avoid this procedure • Strict asepsis is must as there is potential risk of septic arthritis and osteomyelitis • Be careful regarding piercing the femoral artery, which can be identified by bright red color of blood as jet flow of it. If artery is pierced inadvertently, remove the needle and apply pressure for a long time and check the limb periodically for pulsations, color and warmth.

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In view of the risks of femoral venepuncture, it should be used as a last resort for collection of blood samples in neonates and infants.

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It is used for exchange transfusion. It may be used for rapid replacement of fluids and blood especially in extreme preterm neonates. Now-a-days, exchange transfusion is also preferred by peripheral route. The umbilical vein spirals through the cord and is at 12 o’clock position at the level of the abdominal wall. Here it turns cephalad and runs slightly towards right to enter the porta hepatis. It continues with left portal vein, communicates with left hepatic vein and then with inferior vena cava. The umbilical vein is much wider than umbilical arteries.

emoral Vein Puncture

mbilical Vein Catheterization

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Proceed as described for veins of extremities. After removing the needle, apply constant pressure at puncture site for 5 minutes while the child is sitting.

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Technique • • •

The child should be in supine position with gentle restraining. A padded crucifix splint is used to restrain the baby Sterilize and drape the skin around the umbilical stump The cord is then cut cleanly about 2 cm above the umbilicus and umbilical vein is located at 12 o’clock position. The blood clot in the vein is expressed or pulled out by fine forceps (Figs 20.1.10A and B)

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B Figures 20.1.10A and B Cutting the umbilical cord for vessel catheterization. Insertion of umbilical catheter in umbilical vein  

 

Figure 20.1.9 Internal jugular vein puncture technique Source: Silver HK, Kempe CH, Bruyn HB (Eds). Handbook of Pediatrics, 13th edition. Singapore: Lange-Maruzen Asia Publications; 1980.

Source: Prajapati BS (Ed). Essential Procedures in Pediatrics, 1st edition. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2003.

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• • •

llen Test ( igs 20.1.11 to )

Infection Vessel perforation Thrombosis of portal vein and portal hypertension in the future Liver infarction Liver abscess Necrotizing enterocolitis Cardiac arrhythmias.

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mbilical rtery Catheterization A

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It is very useful and frequently used for repeated sampling of arterial blood and for continuous arterial pressure monitoring. The radial artery is easily accessible at the wrist in the groove between the tendon of the flexor carpi radialis medially and the distal radius laterally. Before puncturing the radial artery, carry out the Allen test to assess the ulnar collateral circulation.

•

Complications • • •

Radial rtery Catheterization

It is used for periodic monitoring of arterial blood gases and for constant monitoring of blood pressure in a neonate. There are two umbilical arteries and the lumen appears patent.

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Technique

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D Figures 20.1.11A to D Allen test  

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Prepare the umbilical stump as for venous cathe terization Identify the artery and insert the catheter gently in the caudal direction, pulling the umbilical stump superiorly Position the tip of the catheter at either high (in the lower thoracic aorta above the diaphragm between T4– T11 vertebrae) or low position (in the abdominal aorta opposite 14 vertebrae) Keep observing the color of the lower limbs during the procedure Fix the catheter in place using purse string sutures at the place Strap the free end of the catheter to the abdominal wall after filling it with heparinized saline and closing the end with a rubber stopper Every time before sampling, remove the heparinized saline in the syringe along with same blood, then collect

Make the patient’s hands warm to make pulsations easily demonstrable Have the patient open and close the hand held out in front and then clinch the fist tightly closed Occlude both radial and ulnar arteries for 30 seconds. Have the patient open the hand. Hand becomes pale due to occlusion of radial and ulnar arteries Release the pressure over the ulnar artery and observe the open hand for return of normal pink color. Return of normal color within 6 seconds indicates patency of the ulnar artery and an intact arch with good collateral circulation Delay of appearance of normal color from 10 seconds to 15 seconds indicates slow filling of the ulnar artery and collaterals Persistent blanching for more than 15 seconds indicates an incomplete arch or poor collaterals.

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If the cord is dried up, it can be excised flush with the umbilicus, which can expose the orifice of the umbilical vein at 12 o’clock position. This can be gently dilated with Hagar’s dilator and then catheterized If both these methods fail, supraumbilical cut down will become necessary Remove the umbilical vein catheter within 24–48 hours The catheter tip should be advanced upto thoracic portion of the inferior vena cava While passing the catheter, the resistance is felt at the ductus venosus. The catheter should be passed 1–2 cm beyond this point.

Vessel perforation Thromboembolism Air embolism Hypertension Necrotizing enterocolitis Infarction of distal extremities Renal infarction.

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Special Points

Complications

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the sample and reinfuse the previously collected blood to the child.



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Mark the catheter for the correct distance to be inserted, which is about 20% of the crown heel length The catheter is passed into the vein slowly and gently, giving caudal traction on the cord stump till free flow of blood is obtained Flush the catheter with heparinized saline The free end of the catheter should be strapped to the abdominal wall.

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Source: Prajapati BS (Ed). Essential Procedures in Pediatrics, 1st edition. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2003.

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Do not perform the procedure if Allen test is delayed. Observe the color of palm periodically after cannulation. Before sampling blood, flush the line with 2% normal saline. Do not infuse medications and blood products through the arterial line except flushing fluid.

one Marrow spiration

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Iliac crest: this is the most preferred site in children. It is performed at 1 cm below the posterior iliac crest • Tibia: at the upper end of tibia, just below tibial tuberosity on its medial aspect • Sternum: it should be used in children beyond 7–8 years of age. Manubrium sterni can be used 1 cm above sternomanubrial angle, slightly to one side of the midline • Rarely, lumbar spinous processes may be used.

Technique • • •

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Common Sites

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Patient’s hand should be supported and dorsiflexed at the wrist approximately 60° with both hands and lower forearm secured to a board. A roll of gauze behind the wrist will maintain dorsiflexion. • Locate the radial artery just proximal to head of radius • Clean the area and observe the absolutely aseptic precautions • Infiltrate the skin with local anesthetic agent • Insert the catheter needle at about 30° angle to the surface of the skin and advance the catheter and needle stylet into the artery until blood appears in hub of the needle • Remove the needle and attach the hub of the catheter to the connecting tubing • Secure the catheter at the place with silk sutures • Fix the wrist in a neutral position to the board. It is essential as flexion at wrist can disturb the arterial line • Cover the insertion site with sterile dressing.

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Technique (Figs 20.1.12A and B)

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fevers. Needle aspiration, trephine biopsy and surgical biopsy are three methods available for bone marrow examination. Needle aspiration is commonly practiced in most of the cases in children. It should be done with caution when a defect in clotting mechanism is suspected.

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Same test can be performed to check patency of radial artery If ulnar collateral circulation is good, radial artery puncture can be performed.

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This is a very common ward procedure indicated in children with blood dyscrasias, malignancies and undiagnosed

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Atropine should be given as premedication Aseptic and antiseptic precautions are must during the whole procedure Local infiltration of 1% lignocaine from skin to periosteum. In some irritable children, general anesthesia is desirable for successful outcome of the procedure The needle for bone marrow aspiration should be stout and made of hard stainless steel. It is about 7–8 cm long with a well fitting stylet and an adjustable guard (Figs 20.1.13A and B). The point of needle and edge of bevel should be sharp. The Sahan and Klima needles are most commonly used needles. Some people prefer to use stout hypodermic needles so that it can be disposed after use and complications of reuse of the needle can be avoided The needle with the guard adjusted 0.5–1 cm from the tip of the needle is introduced into the iliac crest or sternum with screwing or boring movements keeping the needle vertical. The force required varies but needs to be considerable. Sudden giving in of resistance indicates entry of the needle into the bone marrow. Leave the needle and if it remains steady, it indicates that the needle is in the bone marrow The stylet is withdrawn and marrow is aspirated with the syringe. About 0.2 mL of marrow is aspirated. This procedure is performed swiftly to obtain only bone marrow particles as slow sluggish aspiration causes dilution of marrow with blood.

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B Figures 20.1.13A and B Bone marrow aspiration needle  

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Figures 20.1.12A and B Radial artery (A) anatomy and (B) catheterization technique

Source: Prajapati BS (Ed). Essential Procedures in Pediatrics 1st edition. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2003.

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To prevent dilution of marrow with blood, aspirate material only till it appears beyond nozzle of syringe. It is sufficient material for examination. Aspiration beyond it increases the chances of marrow dilution The needle is withdrawn and smear is prepared with marrow. With good material and well prepared smear marrow, particles can be seen by naked eyes Press the site for 5 minutes. Apply tincture of benzoin seal at puncture site Along with smears of bone marrow, smears from peripheral blood should be prepared and sent for examination.

Complications • • • •

Local pain and hematoma Injury to mediastinal structures in case of aspiration at sternum Infection Dry tap.

Lumbar Puncture Figure 20.1.14 Position for lumbar puncture  

This procedure is performed to obtain cerebrospinal fluid (CSF) sample for analysis in diagnosing infections and other disorders of central nervous system. It is also used for monitoring CSF pressure, intrathecal drug administration and removing CSF in some cases of hydrocephalus.

Source: Prajapati BS (Ed), Essential Procedures in Pediatrics. 1st edition. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2003.

Contraindications

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Marked raised intracranial pressure with closed fontanel as shown by papilledema because of the risk of herniation of brain substance through foramen magnum Local infection Cardiovascular and respiratory instability.

Technique • •

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Informed written consent is must The patient is placed on his side at the edge of the table or bed with the knee drawn up towards abdomen and the head flexed to get maximum flexion of the spine (Fig. 20.1.14). If the child is newborn or child has respiratory problem, child should be firmly fixed at shoulders and buttocks only without flexing neck and drawing up knees. In infants, sitting position allows easier identification of the midline. An experienced assistant has a vital role in positioning, restraining and comforting the patient Aseptic and antiseptic precautions are must Routinely, local anesthesia is not used. But in older children those are irritable; local anesthesia may be useful for performing the procedure smoothly Site of puncture is defined by palpating the iliac crest, which corresponds to L3–L4. Hold the needle between index and middle fingers, the thumb acting as guard at open end In children instead of lumbar puncture needle with stylet, simple hypodermic needle is commonly used. 22–18 FG disposable needles are well suited for infants

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Complications • Infection • Conning • Headache • Injury to local structures • Epidermoid tumor. S

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and children. Some people have good experience with the use of disposable scalp vein for lumbar puncture in neonates and children upto age of 2 years. Scalp vein set no. 23 with 2 cm length is suitable for neonates Gently introduce the needle in midline at above mentioned space, needle being directed towards umbilicus. Entry into the subarachnoid space is indicated by giving the way sensation and free flow of CSF Collect the CSF 0.5 cc in EDTA bulb for cell count and 1 cc in plain bulb for biochemistry. It should also be collected in sterile bulb for culture. Cerebrospinal fluid for cell count should be examined at the earliest, usually within 30 minutes Remove the needle and apply firm pressure for few minutes Apply tincture benzoin seal at puncture site In a case of raised intracranial pressure, head should be kept little down to prevent herniation of brain through foramen magnum Monitor the patient for some time after the procedure for pulse and respiration.

ubdural Tap

It is indicated for diagnosis of subdural hematoma, effusion and empyema.

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Before subdural tapping, ultrasonography or CT scan study of cranium is desirable Informed written consent is must Scalp should be shared, atleast 5 cm posterior to the anterior fontanel and 5 cm lateral to midline and anteriorly upto forehead Sedation may be required in irritable infants Child should be in supine position with head at the edge of the table One person should hold the head at the middle position and another person hold the shoulders (Fig. 20.1.15) Strict aseptic and antiseptic precautions should be taken. Sterilize the area Lateral margins of anterior fontanel are palpated along the coronal sutures and the site is chosen either for lateral as possible or at the area of maximum transillumination It should be atleast 2–3 cm from the midline to prevent injury to the underlying sagittal sinus A zig-zag puncture is used to prevent later leakage of subdural fluid A disposable no. 20 gauge needle is used. The skin is first pulled to one side and then needle is passed perpendicular to the scalp through the suture line and into the subdural space to a depth of approximately 0.3– 0.6 cm. A definite pop giving the way is felt on entering the subdural space. The flow of fluid will be there on entering the subdural space. If flow of fluid is not there, slight adjustment or rotation of the needle may be necessary The subdural fluid is allowed to drain spontaneously. The fluid should not be aspirated for fear of drawing pial vessels into the point of needle The subdural fluid is collected in EDTA and plain bulbs for examination. Smear for Gram’s stain should be prepared. It should also be collected for culture The subdural tap must be performed on both the sides. Samples from both the sides should be kept separate and labeled properly indicating right and left side

Maximum 10 mL of fluid should be tapped from each side Subdural fluid will be either blood stained or xanthochromic but not clear. If it is clear, it is most likely CSF through ventricular tapping Remove the needle and sterile benzoin seal is done. Dressing should be done tightly with sterile gauge and adhesive tap.

Complications • •

Trauma to blood vessels and hematoma formation Infection leading to subdural empyema.

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Ventricular Tap This procedure is useful in newborns for diagnosis of ventriculitis and intraventricular hemorrhage. It is also performed to relieve the acute rise of intracranial pressure in non-communicating hydrocephalus. In some conditions, it may be done to administer intraventricular drugs.

Technique • • • • • • • •

•

Before ventricular tapping, ultrasonography or CAT scan study of cranium should be done Informed written consent should be taken Scalp should be shaved Sedation, if necessary Aseptic and antiseptic precautions Child should be in supine position with head at middle edge of the table One person should hold the head at middle position and another person should hold the shoulders The ventricle is entered by passing no. 23 FG needle in neonates and no. 22 FG in infants, 4–5 cm long disposable needle through lateral margin of anterior fontanel and keeping the direction of needle slightly inwards towards inner canthus of opposite eye or nasion (Fig. 20.1.16) Depending on the degree of ventricular dilatation and size of the patient, the ventricle is reached at the depth of about 2.5 cm

Figure 20.1.16 Ventricular tapping. The needle should be directed forwards and inwards towards nasion

Source: Prajapati BS (Ed). Essential Procedures in Pediatrics, 1st edition. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2003.

Source: Prajapati BS (Ed). Essential Procedures in Pediatrics, 1st edition. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2003.

 

 

Figure 20.1.15 Position of head for performing subdural tap

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Entering the ventricle, gives the way No syringe suction should be applied Cerebrospinal fluid should be collected in EDTA and plain bulbs for examination. Smear should be prepared for Gram’s stain After removing the needle, press at puncture site for some time Sterile benzoin seal is done. Dressing should be done with sterile gauze and adhesive tap In a case of hydrocephalus, CSF can be drained in large quantity For administering drugs in ventricles, drug should be taken in the syringe and after ventricular puncture it should be attached with the needle. Let the CSF come in syringe, get the medicine diluted in CSF and then inject back into the ventricle. Drug should not be diluted in any solution.

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Complications • • •

Ventriculitis Injury to brain tissues Intraventricular hemorrhage. I

Nasogastric Tube nsertion Nasogastric tube is passed for either aspiration of gastric contents or administration of feeds or therapeutic substances. Now a days, silastic and polyethylene tubes are being used because they have less tissue reactions.

iagnostic: Gastric aspirate test for diagnosis of neonatal septicemia Shake test for lung maturity in preterm babies Examination of gastric contents for mycobacterium tuberculosis • Assessment of upper GI tract bleeding • Measurement of gastric volume.

Figures 20.1.17A and B Method of inserting a nasogastric tube in a child Source: Management of the Child with a serious Infection or Severe

Therapeutic • Paralytic ileus • Intestinal obstruction • Enteral feeding • Administration of therapeutic substances.

Contraindications • • • •

Esophageal stricture Ingestion of alkali-may cause esophageal perforation Head and neck injury preventing passage of tube Nasal fracture.

Technique • •

The head is raised in semi upright position The distance from nose to ear lobe and from ear lobe to xiphoid process is determined to measure the length of the tube to be passed. The point is marked on the tube (Figs 20.1.17A and B) 1136 • The more patent nostril is selected for passing the

Malnutrition-Guidelines for care at the First-Referral level in Developing Countries Department of Child and Adolescent Health and Development, World Health Organization. Geneva; 2000.

tube The terminal part of the tube is lubricated with a lubricant. It is avoided in newborns to prevent aspiration of an oily substance. In that case, it is wet with water • The tube is passed into the nostril, its curve directs downwards. It is passing along the floor of the nose. In case of difficulty, it is tried in another nostril. Resistance is felt when it reaches the nasopharynx. Getting the patient to sip a little water helps to overcome it • With swallowing of the saliva or water by the patients, the tube is advanced into the esophagus • If the patient gags or the tube coils up in the mouth, the tube is withdrawn partly and again it is passed • The tube is passed up to the mark as measured length of the tube to be passed • Confirmation of proper placement is done by the following tests: – Aspiration of stomach contents on applying suction •

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Complications Pulmonary aspiration Esophageal perforation Gastric perforation Nasal necrosis Esophageal stricture. Instead of nasogastric tubing, nowadays orogastric tubing is preferred to avoid certain complications.

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Gastric Lavage

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It is useful in poisoning to remove the substance from the stomach. In corrosives and hydrocarbons ingestion, gastric lavage is contraindicated. In corrosives, passing the tube may cause perforation. Since passing the gastric tube is likely to induce vomiting, it increases the risk of aspiration of hydrocarbons into the trachea and lungs, which causes pneumonia. After passing the tube in the stomach as described in nasogastric tube insertion, lavage of the stomach using aliquots of normal saline is done in cases of poisoning. It is continued till the color of the lavage is normal.

bdominal Paracentesis

Abdominal paracentesis is performed for diagnostic purpose in case of ascites, peritonitis and hemorrhage. In huge ascites, it is also done to relieve discomfort and respiratory embarrassment. In some situations, drugs may be instilled in peritoneal cavity such as malignancies.

Technique • •

The patient should be placed in supine position. If the patient is not comfortable in supine position, reclining or upright position may be used Site for paracentesis is selected in midline, midway

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Complications • • • • • • •

Intestinal perforation or laceration Peritonitis Post paracentesis shock Electrolyte imbalance Hypoproteinemia Perforation of urinary bladder Pneumoperitoneum.

Liver iopsy B

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between umbilicus and pubic symphysis or in an iliac fossa lateral to the rectus abdominis • The needle should never be advanced through a surgical scar because it can penetrate bowel adherent to the under surface of the scar, or lacerate an omental or mesenteric vessel • Informed written consent should be taken • Aseptic and antiseptic measures must be taken. • Injection atropine as premedication • One percent lignocaine is infiltrated under skin and into the deeper structures at the site selected for paracentesis. Wait for few minutes for full effect of anesthetic agent • The hypodermic needle 20 FG is attached to 20 mL syringe. It is passed into the peritoneal cavity perpendicular to the skin. As the needle enters the peritoneal cavity, it gives the way and ascitic fluid starts to drain through the needle • In a case of tense ascites, needle should be passed obliquely or skin should be retracted caudad before insertion of the needle to produce a Z track effect on withdrawing the needle so that needle tract after paracentesis gets sealed properly and persistent drainage can be prevented after removal of the needle • After removal of fluid, 10–15 mL for diagnostic purpose, the needle is withdrawn and a seal of tincture benzoin is applied locally • If the paracentesis is for therapeutic purpose, the needle should be connected with IV set and regulator of IV set is adjusted in such a way that ascitic fluid is drained slowly. One liter of fluid may be drained over a period of 2–3 hours • The patient should be watched following the proce dure.

Pedia

at the outer end of the tube with a syringe indicates that the tube lies in the stomach – Air is injected into the tube while epigastric area is auscultated. A sound is heard if the tube is in the stomach – Placing a tube in a glass of water and escape of air bubbles in the water indicate that the tube lies in the trachea – Placement of a radiopaque tube can be assessed by radiography The tube is fixed with a tape in a butterfly fashion around the tube or with vertical tapping over the nose and the tube. The tapping is done in such a way that the tube rests in the middle of the nasal lumen and not directly in contact with mucosa. It is not taped over the forehead as it may cause pressure necrosis of the nose The feed or drug should be allowed to go in the tube by gravity method. It should not be pushed by piston. The tube should be flushed with water periodically While removing the tube, pinch the tube end to prevent spilling of the contents into the trachea.

Nowadays, liver biopsy is done under the ultrasound guidance rather than blind biopsy.

Indications • • • • •

Chronic hepatitis Undiagnosed hepatomegaly Neonatal hepatitis Cirrhosis of liver Fever of unknown origin.

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Bleeding tendency Massive and tense ascites Severe portal hypertension.

Prerequisites • • •

Bleeding time, clotting time, platelets count and prothrombin time USG study of liver Premedication: Atropine 0.01 mg/kg IM 30 minutes before the procedure.

Technique

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Vim-Silverman needle, Menghini’s needle and Trucut needles are used for liver biopsy. Tru-cut needle is disposable, easy to operate and has more success rate, so it is common in use Informed written consent is must Patient is kept in supine position, near the edge of the bed or table with the right arm under the head and left arm by the side Preparation of the local area Aseptic and antiseptic precautions are must One percent Lignocaine is infiltrated in the skin, intercostal muscles and Glisson’s capsule. Wait for some time for good effect of the anesthetic agent. Some children may require sedation or general anesthesia The tru-cut needle is introduced under ultrasound guidance into the liver substance with the inner needle retracted. The latter is then advanced, holding the outer cutting sheath steady. The outer sheath is then advanced to cut the liver in the biopsy notch. The whole apparatus is then withdrawn together quickly. The entire sequence should take only few seconds The Vim-Silverman needle has trocar and bifid needle to cut the liver tissue. In Menghini’s needle, the cut piece of liver is sucked into the syringe applied with negative pressure On removal of the needle, the puncture site is sealed with tincture of benzoin.

Figure 20.1.18 Another position for doing thoracocentesis Source: The Harriet Lane Handbook – A manual for Pediatric House Officers. In:  

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Johnson KB (Ed), 13th edition. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd, 1993.

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Thoracocentesis refers to temporary insertion of a needle or a catheter into the pleural space for removal of fluid or air from the pleural cavity. The fluid is collected for diagnostic purpose and in some situations it is done for therapeutic purpose to remove fluid or air, which is in large quantity and causes respiratory embarrassment. Drugs can also be instilled in the pleural cavity by this procedure, if it is indicated, such as in a case of malignancy.

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Written consent is must Injection Atropine as premedication Site of insertion of needle can be decided by chest X-ray, dull note on percussion and ultrasound study of thorax. Best way to perform the procedure is under ultrasound guidance.

• •

It should be performed in sitting position of the patient. Patient can lean forward on the teapoy of suitable height with head resting on his forearms (Fig. 20.1.18) Strict aseptic and antiseptic measures should be taken One percent Lignocaine is infiltrated at the upper border of the rib below the space chosen. Anesthetizing wide area and generous infiltration of local anesthetic agent for good anesthesia help to get good cooperation of the patient, performing the whole procedure comfortably leading to successful performance with minimal chances of complications. Wait for some time for good effect of anesthetic agent A wide bore needle is connected on one side of the three way stop cock and opposite to it a syringe is attached. Three way stop cock is arranged in such a way that there is a single track between the needle, stop cock and syringe The needle is inserted into the chest in the same manner as for the anesthetic needle, finding the intercostal space and stepping over the lower rib with care, thereby preventing damage to underlying structures (Fig. 20.1.19). Slight suction is applied to the syringe so that the fluid is aspirated in the syringe immediately as the needle enters the pleural space Fluid should be withdrawn slowly and steadily A forceps should be attached to the needle at the skin level, which helps to prevent excessively deep insertion of the needle into the thorax The fluid is aspirated in the syringe and then three-way stop cock is turned to connect the syringe with the outlet, which is attached to IV set Collect the fluid in EDTA and plain bulbs. It is also collected for culture. Smear should be prepared for Gram’s stain and Ziehl-neelsen stain.

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The three-way tap is now turned again to connect the syringe with the needle and the pleural space, a further aspiration is carried out. It is expelled into the drainage bag by turning the three way tap. The drainage bag or bottle should be placed well below the level of the patient’s chest As fluid is removed, the lung expands and this often makes the patient to cough The needle is withdrawn and puncture site is covered with a benzoin seal. A sterile gauze is put over it and adhesive tap is applied.

Complications Pneumothorax Hemothorax Infection Unilateral pulmonary edema Hypoproteinemia.

ndotracheal ntubation

Endotracheal intubation is a procedure, which every pediatrician and one working in intensive care units must be well conversant with. The critically ill patient often requires endotracheal intubation. It secures patent airway. It is a prerequisite for mechanical ventilation. Endotracheal suction can most efficiently be done through an endotracheal tube. It is indicated when bag and mask resuscitation fails in a case of an asphyxiated newborn.

Indications

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In neonatal asphyxia – Bag and mask resuscitation fails – Apparently still born baby after adequate suctioning of upper airways – Infants with diaphragmatic hernia – Meconium aspiration –

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Weight/age T size ( in mm) < 1,000 g 2.5 1,000–2,000 g 3.0 2,000–3,000 g 3.5 > 3,000 g 4.0 1–5 years 4–5 5–12 years 5–6.5 Approximately size of ET, ID in mm = Age (years) + 16/4.

Technique

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Laryngoscope - with straight blade for neonates Endotracheal tubes for various sizes with stylet



Source: Prajapati BS (Ed). Essential Procedures in Pediatrics, 1st edition. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2003.



 

Figure 20.1.19 Site of needle for pleural fluid aspiration













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Cardiorespiratory arrest due to any cause Central nervous system depression in a case of head injury or comatose child Diseases of peripheral nervous system, poliomyelitis, Guillain-Barré syndrome, tetanus, organophosphorous poisoning, etc. Administration of general anesthesia.

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The patient is placed in a supine position. The operator stands beyond the patient’s head. Patient’s neck is slightly extended with the head in midline Clear the oropharynx with gentle suctioning Empty the stomach Hold the handle of laryngoscope in left hand with thumb and first three fingers, stabilize the hand with fifth finger resting on patient’s cheek. The blade should be pointing away from oneself Open the baby’s mouth and push the tongue left with the back of right fore finger and steady the head with the rest of right hand While visualizing insert the blade midline until the tip is between base of tongue and epiglottis within the vallecula (Figs 20.1.20A and B) If the infant is making respiratory effort, free flow of oxygen with an oxygen tubing held close to the infant’s mouth and nose is to be provided during intubation Open the mouth further by pulling on laryngoscope handle, simultaneously tilt the blade tip upward slightly to elevate epiglottis and visualize the glottis. Use base of the tongue as pivot rather than maxilla Suction is needed Have the assistant to palpate suprasternal notch with index finger, applying gentle pressure if desired Hold the tube with concave curve anterior and pass it down to right side of the mouth, outside the blade, along with maintaining visualization As the patient inspires, pass the tube through cords 2 cm into trachea or until immediately after tip passes under assistant’s finger in suprasternal notch The tube is then held firmly at the lips with the right hand, and the laryngoscope and stylet are carefully removed Initially confirmation of the tube placement is 1139 accomplished by attaching a resuscitation bag with

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Intubation is not a matter of prestige. If you are unable to do so, please ask for help. Endotracheal route is also used for administration of some drugs like epinephrine, atropine, naloxone, etc.

Complications Hypoxia Bradycardia Apnea Pneumothorax Injury and lacerations to tongue, gums, pharynx, epiglottis, trachea, vocal cords, etc. • Infections • Post-extubation stridor can be managed by nebulized epinephrine or steroids. Some physicians prefer nasotracheal intubation when long-term ventilation is required.

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uprapubic ladder spiration B

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This procedure is performed to collect non-contaminated urine sample in neonates and infants. It is a safe and reliable way of collecting urine samples. It is easy, especially in neonates, as bladder is an intra-abdominal organ in these patients unlike a pelvic organ in older children and adults.

Technique • • • • B

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Figures 20.1.20A and B Position of laryngoscope blade when using (A) curved blade, it is in the vallecula and (B) straight blade, it is over the epiglottis

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Source: Prajapati BS (Ed). Essential Procedures in Pediatrics, 1st edition. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2003.

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Peritoneal ialysis D

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the connector and ventilating the infant. With correctly placed tube, the air entry is heard on both sides of the chest, breath sounds are of equal intensity and air is not heard entering the stomach. While listening the breath sounds, the stethoscope is to be placed at approximately the nipple line Note the centimeter marks on the tube at the level of upper lips and then secure the tube to the infant’s face Final confirmation of placement of the tube can be obtained by chest film, if it is needed Attempts to intubate should not exceed 30 seconds. If you are unable to intubate within 30 seconds, abort and continue with bag and mask and then try again after a few minutes. Repeated attempts may cause serious glottic edema and bleeding

The infant is placed on a flat surface in supine position. The assistant stands opposite the operator and immobilizes the infant by grasping the thorax with one hand and thighs and hips with the other. Make sure that the bladder is full. Local part is cleaned. Aseptic and antiseptic measures are must. A 10 cc disposable syringe with 22 FG, 4–5 cm long needle is taken. The symphysis is located with one finger and the needle is inserted 2 cm above the symphysis in the midline with syringe held at 10–20° angles from perpendicular (Fig. 20.1.21). With a single steady motion the needle is inserted until a perceptive change in resistance is felt as the needle enters the bladder. Light aspiration is applied to aspirate the urine specimen. After removal of needle, a seal of tincture benzoin is applied at puncture site.

Dialysis involves the use of semipermeable membranes that permit the simultaneous passage of smaller molecular weight solutes and water while retarding or inhibiting the movement of large sized particles. The basic principle controlling the transmembrane movement of solute and water are similar whether the membrane is artificial (hemodialysis) or natural (peritoneal dialysis).

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Figure 20.1.21 Suprapubic bladder puncture technique Source: Prajapati BS (Ed). Essential Procedures in Pediatrics, 1st edition. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2003.

Indications

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Blood urea more than 300 mg/dL Serum hyper Kalemia—K+ more than 6.5 q/L not responding to medical line of treatment Severe acidosis Pulmonary edema Acute left ventricular failure Drug intoxications like barbiturates, salicylates, etc. Life threatening electrolyte imbalance.

Contraindications • • • •

Figure 20.1.22 Peritoneal dialysis

Peritonitis Abdominal adhesions Laparotomy done Pleuroperitoneal communication.

 

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Source: Prajapati BS (Ed). Essential Procedures in Pediatrics, 1st edition. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2003.

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Technique (Fig. 20.1.22) • • • • • • •



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Informed written consent Aseptic and antiseptic measures are must Injection atropine 0.01 mg/kg IM 30 minutes before the procedure as the premedication Sedation, if required Proper restraining Bladder is emptied by its own or catheterization, if it is necessary Abdominal wall is prepared, painting spirit – Betadine – spirit. Towel draping The catheter is usually placed in the midline few centimeters below the umbilicus If midline insertion is not possible, the catheter can be inserted in the flank area, outside the line of inferior epigastric artery The site is anesthetized by injecting 1% lignocaine upto peritoneum If there is no ascites, distend the abdomen with 10 mL/kg dialysate solution using 17–20 FG angiocath or needle Needle is withdrawn and a knife blade is used to enlarge the puncture wound in the skin If ascites is present, a very small penetrating incision is made in the skin and the trocar with catheter is stabilized

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• • • •

• • • •

with the fingers of one hand on the skin while the other hand introduces the trocar through the abdominal wall with an alternating drilling motion Penetration upto peritoneum is detected by a definite sensation of giving the way and also by the appearance of fluid in the catheter when trocar is removed On reaching the peritoneal cavity and before removing the trocar, the catheter is gradually advanced in the peritoneal cavity in right or left paracolic gutter and trocar is gradually withdrawn When the catheter is sufficiently introduced in the peritoneal cavity, trocar is removed totally. All the fenestrations on the catheter must be within the peritoneal cavity to avoid subcutaneous fluid infiltration in the abdominal wall. In neonates and infants, IV catheters or simple feeding tube can be used The catheter should be stabilized with adhesive plaster The catheter is connected with the administration tubing through small connector, and dialysis fluid is flown Because hyperkalemia is often present, potassium free fluid is used for the first three–six cycles Time of input of dialysis fluid will be about 10–15 minutes. The fluid is kept in the peritoneal cavity for about 30 minutes. Time for output of dialysis fluid will be about 15–20 minutes. Each cycle will take about an hour. First few cycles should be of half an hour (rapid cycles) Record the weight of the patient prior to the procedure and every 12 hours Total duration of dialysis is about 40 hours depending on the clinical and biochemical parameters Warm the dialysate to body temperature 1141 Infuse it by gravity flow.

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Each cycle should be of 30–50 mL/kg Blood sugar, blood urea, serum creatinine, serum electrolytes and serum proteins should be checked 12 hourly In the presence of fluid overload, use hypertonic dialysate Tip of the catheter should be sent for culture Close the site of dialysis by sterile bandage Peritoneal dialysis related problems like, pain in abdomen, diarrhea, dyspnea, bleeding and fluid delivery should be sorted out appropriately.

Complications • • • • • • • •

Pain may be due to over distention, peritonitis, etc. Bleeding Dialysate leak Outflow obstruction Peritonitis Metabolic complications Thrombosis Pulmonary complications. B

Renal iopsy

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• •

•

• •

Indications • • • •

Steroid resistant nephrotic syndrome Asymptomatic proteinuria Glomerulonephritis associated with conditions like systemic lupus erythematosus, Henoch-Schönlein purpura, etc. Rapidly progressive glomerulonephritis.

•

• •

Contraindications Bleeding diathesis Solitary functioning kidney Ectopic/horseshoe shape kidney Severe uncontrolled hypertension.

Prerequisites • • • •

Bleeding time, clotting time, partial thromboplastin time or activated partial thromboplastin time and platelets count Blood grouping and cross matching Hypertension and uremia should be controlled Informed written consent is must.

Technique • •

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Atropine 0.01 mg/kg IM before 30 minutes of the procedure The patient is placed in the prone position on a firm bed. A pillow is placed under patient’s abdomen. This compresses and fixes the kidneys to the posterior abdominal wall, bringing the kidneys closer to the skin and limiting possible ballottement of the kidney by the biopsy needle.

• • • •

Postprocedure anagement M

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Ultrasonography is commonly used to mark the location of kidneys and point of entry of the needle into the kidney perpendicular to the skin surface and to obtain depth of tissue from skin surface. Usually, lower pole of left kidney is selected for biopsy. The area is prepared and local anesthesia is given. Irritable children may need general anesthesia. A 23 gauge exploring lumbar puncture needle is passed downwards and obliquely toward the lower pole of the kidney. A needle can be felt going through different structures and renal capsule. Experience person feels give in feeling up on penetration of capsule of kidney. The patient is asked to take slow deep breathings. If the needle is in the kidney, a characteristic pendular movement is seen with respiration, the hub of needle swings through a wide arch, moving towards head during inspiration and towards buttock during expiration. If the needle is not in the kidney tissue, it is slightly advanced until it penetrates kidneys and moves characteristically on breathing. The depth of the kidney below the skin is measured on the stem of the needle. A small nick is made over anesthetized area with a scalpel. Franklin modified Vim-Silverman needle and Tru cut needle are commonly used in the practice. Tru cut needle is easy to use and having less failure rate. Therefore, Tru cut needle is preferred nowadays. Tru cut needle is one piece apparatus with a length of 11.4 or 15 cms. The needle with canula covering the obturator is advanced in the kidney to desired length in a direction perpendicular to skin surface. The patient is asked to hold the breath in deep inspiration. The obturator is advanced by firm tap on the handle. The specimen is cut by downward movement of canula over obturator. Entire assembly is removed. The patient is asked to breathe normally. Firm pressure is applied over biopsy site for few minutes and the site is sealed with tincture benzoin. Two good cores of tissue (8–10 mm long) are needed for adequate histological examination. One is immediately fixed in buffered formalin and other in saline (for immune fluorescence study).

• • • • • •

The patient is asked to remain in prone position for 2 hours and in bed for 24 hours. Monitoring temperature, pulse, RR and BP one hourly for 6 hours and then 4 hourly for 24 hours. Urine should be collected in separate bottles during each voiding and should be checked for hematuria. Patient is asked to take ample liquid orally. Diuretics may be given in case of oliguria to flush any clot in the passage. If no frank hematuria and vitals are normal, patient can be discharged after 24 hours with instructions not to do exertion for a week.

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Echocardiographic diagnosis Coagulation profile Resuscitation kit including defibrillator Cardiac monitor IV line Premedication with injection atropine 0.01 mg/kg IM 30 minutes before the procedure.

Technique

• • • •

•

• •

Informed written consent should be taken. Sedation may be required in some patients. If possible, it should be avoided. Child should be seated leaning backward at approxi mately 60° and carefully restrained. The best site is xiphocostal angle. The other sites are fourth, fifth or sixth intercostal spaces 1–2 cm medial to the border of cardiac dullness on percussion. Aseptic and antiseptic precautions are must. One percent xylocaine is infiltrated in the skin at left xiphocostal angle, 3–4 cm below left costal margin. The needle is advanced initially perpendicular to the skin surface and after traversing the soft tissue under the rib cage, its tip is pointed to the left shoulder. While advancing the needle in the deeper structures if it reaches to pericardial cavity, the pericardial fluid is withdrawn in the syringe. Local anesthetic agent should not be injected in the pericardial cavity. The pericardiocentesis needle is passed along the same path until the fluid is obtained. The distance from skin to the pericardium is less than 5 cm in a child. A distinct “give” or “pop” is felt when the pericardium is punctured. Pericardial fluid can then be aspirated. Getting the fluid confirms the position of needle into the pericardial cavity. Normal saline can be injected under 2D echo monitoring, which shows bubbles of saline. If the blood or bloody fluid is withdrawn, it is vital to determine if cardiac chamber or coronary artery has been punctured. Still uremia and malignant diseases can give ­

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Hemopericardium Arrhythmias Vasovagal reactions Infection Pneumothorax Air embolism Perforation of an abdominal viscus, commonly stomach Cardiac arrest and death.

ine Needle spiration iopsy B

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Prerequisites

Complications

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Pericardiocentesis is a procedure for removal of fluid from pericardial cavity for diagnostic purpose or to relieve cardiac tamponade. It is occasionally a life saving procedure. It is a risky procedure. It should be performed only by skilled person under continuous cardiac monitoring. Echocardiographic diagnosis is must before performing the procedure. It gives idea regarding amount of fluid and also helps to determine the anatomical approach.

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Pericardiocentesis

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rise to hemorrhagic pericardial effusion. Blood obtained from heart or coronary vessel clots immediately. Fluid is sent for appropriate examinations. The needle is withdrawn and benzoin seal is done at puncture site. Postprocedure monitoring of heart rate, RR and BP should be done. 2D echo may be performed to study post tapping condition.

Pedia

Complications • Hematuria • Perinephric hematoma • A-V fistula.

Fine needle aspiration biopsy (FNAB) is very useful for cytological and bacteriological evaluation of a mass or a lymph node. It is minimally invasive and requires no sedation. It aids in tissue diagnosis and in determining the course of management.

Requirements • • • • •

1” to 1.5” 20–25 FG needles. 22 FG 1” long is the most commonly used size of needle 10–20 mL plastic disposable syringes Clean glass slides 70–90% ethanol for routine wet fixation Containers for culture media whenever needed.

Technique • • • • • • • • • •

Sterilize the area Anesthesia is usually not required; local anesthetic agent may be used in uncooperative and irritable children Immobilize the lump to be biopsied between your thumb and finger with one hand Hold the syringe in the other hand and insert needle into the assigned area, perpendicular to the skin surface and position the needle within the target tissue Pull the syringe plunger to apply negative pressure While maintaining suction, make several passes through the mass or node Release the negative pressure while needle remains in the target tissue Withdraw the needle Detach the needle, draw 2–3 mL air into the syringe, reattach the needle and blow the aspirates onto the slide Apply the pressure over the puncture site with cotton swab for 5 minutes

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5.







8.





7.

9.





10.

11.





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1. Boon ME, Lykies C. Imaginative approach to fine needle aspiration cytology. Lancet. 1980;2:1031-2. 2. Chameides L. Vascular access. In: Textbook of Pediatric Advanced Life Support. American Heart AssociationAmerican Academy of Pediatrics. 1988. pp. 37-46. 3. Koebke J, McFarland E, Mein M, et al. Venipuncture Proced ures. In: Slockbower JM, Blumenfeld TA (Eds). Collection and Handling of Laboratory Specimens – A Practical Guide. Philadelphia: JB Lippincott Co. 1983. pp. 3-45. 4. Laing IA, Doyle E. Practical procedures. In: Campbell AGM, Mcintosh N (Eds). Forfar and Arneil’s Textbook of Pediatrics,

6.





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Deep biopsies can be done with assistance of radiological imaging techniques like ultrasound. The following situations can give unsatisfactory yield during FNAB: • When needle misses the lesion tangentially • When central area is cystic, necrotic or hemorrhagic and devoid of diagnostic material • When there is a small malignant lesion close to a dominant benign mass • When the target tissue is fibrosclerotic and poor in cells.



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5th edition. New York: Churchill Livingstone. 1998. pp. 182947. Prabha S. Renal biopsy in children. In: Nammalwar BR, Vijayakumar M (Eds). Pediatric Nephrology, 2nd edition. Madras, @ Authors. 1991. pp. 85-9. Prajapati BS (Ed). Essential Procedures In: Pediatrics, 1st edition. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2003. Silver HK, Kempe CH, Bruyn HB. Pediatric procedures. In: Handbook of Pediatrics, 13th edition. Singapore: LangeMaruzen Asia. 1980.pp.629-44. Singh M. Procedures. In: Singh M (Ed). Care of the Newborn, 4th edition. New Delhi: Sagar Publications. 1991. pp. 340-67. Singhi S. Procedures in pediatric intensive care. In: Sachdev HPS, Puri RK, Bagga A, Choudhury P (Eds). Principles of Pediatric and Neonatal Emergencies, 1st edition. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd. 1999. pp. 364-72. Subramanyam L, Thangavelu S, Somu N. Pathophysiology of pleural fluid collection and management of empyema. In: Somu N, Subramanyam L (Eds). Essentials of Pediatric Pulmonology, 2nd edition. Siva and Co: Madras. 1996. pp. 142-9. Waechter EH, Philips J, Holaday B (Eds). Procedures. In: Nursing Care of Children, 10th edition. JB Lippincott Co: Philadelphia. 1985. pp. 1408-13.

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Physiotherapy and ehabilitation Somu Sivabalan •

Physiotherapy or physical therapy aims at physical treatment and management of disease or condition, which enables people to reach their maximum potential. Physiotherapist or physical therapist are healthcare professionals who diagnose and treat individuals of all ages, with medical problems or other health-related conditions, illnesses or injuries that limit their abilities to move and perform functional activities unlike their normal peers. Physical therapy aims at using treatment techniques to promote the ability to move, reduce pain, restore function and prevent disability. In addition, they also device strategies for individuals to prevent the loss of mobility before it occurs by developing fitness and wellness-oriented programs for healthier and more active lifestyles and to develop, maintain and restore maximum movement and functional ability throughout the lifespan in circumstances like aging and sports medicine.

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Improving gross and fine motor skills Balance and coordination Strength and endurance Cognitive and sensory processing and integration Mobility Pain management.

ehabilitation: Goals, utcome and ntervention I

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ehabilitation: Management Focus

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Primary prevention of disability through education and treatment

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valuation

It is the most important component to assess the extent and severity of involvement and also to device management strategies for that particular patient. The evaluation includes: • Observation • Measurement of limb length • Muscle power using manual muscle power grading • Active and passive range of motion using goniometer • Spasticity measured by modified Ashworth scale • Persistent abnormal reflexes • Posture and gait observation.

ehabilitation: ndications I

Rehabilitation means to restore good condition, operation or capacity (useful life) through therapy and education. Pediatric rehabilitation assists in early detection of health problem as well as the diagnosis, treatment and management of infants, children and adolescents with a variety of injuries, disorders and diseases that affect the muscles, bones and joints. Optimization of function through the combined use of medications by the pediatrician and usage of physical modalities, physical training with therapeutic exercise, movement and activity modification, adaptive equipments and assistive devices, orthotics (braces) and prosthetics will help the child to regain the independence and in leading a near normal life. The rehabilitation team comprises of physiotherapists, occupational therapist, speech and language pathologists, psychologists, social workers, special educator, prosthetists and orthotists headed by a doctor. Physiotherapy is an integral part of rehabilitation.

•

Prevention and/or improvement of secondary disabilities such as contractures/deformities Attainment of maximum functional goals of child and family Improve lung function and aid in the clearance of secretions To habilitate the child to lead a near normal life with their disability limitation and to integrate them with the society Appropriate wheelchairs, orthotics, prosthetics and modification of architectural barriers.

Rehabilitation medicine plays an important role in the following conditions: • Neurological conditions like cerebral palsy, autism, developmental delays, spina bifida, muscular dystrophies, poliomyelitis, infantile hemiplegia and peripheral nerve lesions • Orthopedic conditions like congenital talipo equino varus, congenital dislocation of hip, torticollis and posttraumatic stiffness • Genetic and chromosomal abnormalities resulting in motor involvement • Cardiovascular disorders especially postoperative management • Pulmonary disorders like bronchiectasis and chest deformities • Postoperative abdominal surgery and in urological procedures to train the bladder and bowel muscles • Sports injuries - prevention and rehabilitation.

Methods of ntervention I

ehabilitation

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Physiotherapy or Physical herapy

Pediatric Procedures

20.2

To optimize function through the combined use of: • Medications • Physical modalities, e.g. heating or cooling the tissues • Physical training with therapeutic exercise, movement 1145 and activities modification

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The sources of heat may be: • Paraffin wax • Heat pad • Hot moist packs • Interferential therapy • Transcutaneous electrical nerve stimulation (TENS) • Ultrasound therapy.

Several factors determine the choice of modality. These include the objectives of the treatment, the part to be treated, depth of the lesion, state of the skin-nerve supply and the underlying pathology. In pediatric age group, paraffin wax and heating pad are safer. Ultrasound given at the epiphysis end may damage the growth plates. In peripheral nerve lesions like Erb’s palsy and facial palsy, electrical stimulation is indicated and also followed by tendon transfer surgery.

Ice Therapy or Cooling the Tissues

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ehabilitation trategies in Various ommon onditions S

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It is the local or general application of cold for therapeutics and preventive uses. It results in alternate period of vasoconstriction and vasodilatation thus reducing nerve conductivity, muscle spasm and spasticity. It helps in relieving pain, muscle spasm, reducing swelling, spasticity and hematoma formation. Ice can be applied in towels, as a pack or by immersion in a bath depending upon the comfort of the patient. Exercises may be in the form of: • Active/passive exercises • Stretching • Strengthening exercises • Endurance exercise • Coordination exercises • Posture correction • Walking training

Neuromuscular Conditions Poliomyelitis • Acute phase: Rest and positioning with splint • Recovery phase: Passive exercise, active assisted and strengthening exercises • Residual phase: Continue exercise and application of orthotics. C

erebral palsy: Multidisciplinary rehabilitative approach should be initiated at the earliest to get the maximum outcome. There are different techniques available, which 1146 includes neurodevelopment therapy, Rood’s approach and motor relearning theory. The treatment is tailor-made to the

Muscular dystrophy: This is a genetic disorder characterized by progressive muscle weakness, though many types of dystrophies are reported, the Duchenne dystrophy seems quite common. The management includes passive exercise, proper muscular positioning of the weak joints with splints, stretching, chest physiotherapy and appropriate tailormade wheel chair to prevent the worsening of the spinal deformity. rb’s palsy: This is a peripheral nerve lesion of the C5C6 or the whole of brachial plexus due to traction injury. The upper extremity will be in the position of adduction, internal rotation of the shoulder, and extension of elbow and pronated forearm. Some babies recover on their own; early physiotherapy is often required to prevent contractures and regain motor power. However, if the child has not achieved improvement between sixth month and ninth month, surgery is indicated. E

Heating the Tissues

child’s need and presentation (spastic, hypotonic, athetoid or mixed type). The main aim includes: • Reduction of spasticity • Inhibition of abnormal reflexes • Sensory integration • Prevention of deformity/contractures • Treatment of associated problems like hearing, visual and feeding problems These are achieved by: • Proper positioning • Active/passive movements • Facilitating the delaying/missing milestones • Standing training • Walking training with or without supports like ankle foot orthoses, knee ankle foot orthoses, walkers, crutch, etc. Stretching and resting splint helps post botulinum toxin injection for spastic muscles.

orticollis: It is a twisted neck and head is typically tilted in lateral bending toward the affected muscle and rotated toward the opposite side. Birth trauma or intrauterine malposition is also considered to cause damage to the sternocleidomastoid muscle in the neck. This results in a shortening or excessive contraction of the sternocleidomastoid muscle, often with limited range of motion in both rotation and lateral bending. The general stretching of the sternocleidomastoid muscle and positioning will help. T



Adaptive equipment and assistive device, orthotics (braces) and prosthesis. There are various methods of heating or cooling the tissues.

pina bifida: A neural tube defect resulting in vertebral and/or spinal cord malformation. Management includes: • Teaching parents proper positioning and handling of the child • Educating about the anesthetic skin and potential of getting anesthetic ulcers • Passive stretching exercise to prevent contractures • Appropriate splints S

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Increasingly common in pediatrics due to faulty training, musculotendinous imbalance, anatomical misalignment includes flat feet, immature structures, improper footwear and playing surface. T

ypes of injuries: Stress fractures Tendinitis and bursitis Joint disorders – Subluxation – Dislocation – Ligament injuries. Management in general includes rest, ice compression, strapping/taping and anti-inflammatory drugs. This has to be followed by muscle strengthening exercise, proper train ing and education to the child as well as the parents. Surgical correction may be required if conservative treatment fails. –

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Pulmonology hest physiotherapy: It is an airway clearance technique that combines manual percussion of the chest wall by the care-giver, strategic positioning of the patient for mucus drainage with cough and breathing techniques. It is useful for individuals with copious mucus or thick secretions, those with weak respiratory mechanics or those with ineffective cough. Chest physiotherapy consists of various manipulative procedures like the following: • Positioning (postural drainage): Placing the patient in varying positions for optimal gravity drainage of secretions to increase the expansion and prevent occlusion of that individual segment • Percussion (chest percussion, vibration, thoracic squeezing): In conjunction with postural drainage; to hasten clearing of secretion clear from the tracheobronchial tree • Airway clearing technique to facilitate clearance of lower airway secretion through the upper airways by; cough stimulation, huffing, flutter, cough assist devices and/or tracheal stimulation C

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Sports Injuries

Pediatric Procedures

Post-traumatic muscle stiffness: The physiotherapy plan is divided into two phases, i.e. during immobilization and during mobilization. • During immobilization – Reduce edema and prevent the formation of adhesions - limb elevation and isometric exercises – Avoid undue stress-proper positioning is recom mended – Maintain circulation-active movement of extremities – Maintain joint range-range of movement (ROM) exercises – Maintain function-exercises to unaffected limb and parts – Training to use frames, crutches, etc. • During mobilization – To reduce swelling-limb elevation and active movement – Maintain joint range-ROM exercises – Strengthen muscles-strengthening exercises and isometric contractions are given.





1. Immobilization phase • Active movement of all joints of lower limb including hip • Splinting • Isometric exercises 2. Mobilization phase • Mobilization exercises • Passive adduction • Muscle strengthening exercises • Gait training • Weight bearing and weight transfers D

ysplasia: This disorder originates from the abnormal organization of cells into tissues leading to abnormal tissue differentiation, e.g. osteogenesis imperfecta. The management includes: • Instruction to parents about positioning and handling • Supported sitting in stroller and wheel chairs • Encourage developmental activities • Stretching exercises • Ambulation with assistive orthotics devices.

reathing exercise: It is an integral part of chest physio therapy. It plays a significant role in airway clearance and parenchymal expansion by improving the efficiency of respiratory muscles. Diaphragmatic, costal and apical brea thing techniques are for the different segments of the lungs. ­

C

ongenital dislocation of hip: In congenital dislocation of hip, there is dysplasia of acetabulum and femoral head and dislocation of femoral head. Management is divided into two phases:

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ongenital talipes equinovarus: It is also known as club foot. This deformity is characterized by plantar flexion at ankle joint, inversion at subtalar joint and fore foot adduction. Management includes passive stretching, holding in corrected position by adhesive strapping, night splints, gait training and corrective shoes.

B

Orthopedic Conditions

Burns In burns, there is coagulative necrosis of tissue and skin loss. It may be caused due to heat, flame, chemical, electricity or radiations. The main aim and treatment line of rehabilitation are to: • Prevent respiratory complications - chest physiotherapy • Prevent contractures and deformities - splinting and positioning

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Maintain range of motion and muscle strength exercises Reduce scar contracture - soft tissue release techniques by passive stretching or surgical correction.

Cardiovascular In older children who are to undergo cardiothoracic surgery a preoperative preparation for the postoperative care requirements, which require the patient’s cooperation and understanding, could be done. Preoperatively, activities which are to be carried out postoperatively are being taught: • Breathing exercises are taught with emphasis on deep breathing • Incentive spirometry is taught to aid lung expansion • Effective cough instructions and splinting techniques • Postural drainage to remove accumulated secretions • Lower extremity exercises to maintain circulation and prevent deep vein thrombosis (DVT). On postoperative days, the emphasis is on the following activities: • Promote relaxation and relieve pain-positioning in bed • Maintain ventilation-deep breathing exercises, incentive spirometry • Assist in secretion removal-begin with deep effective coughing • Prevent DVT-lower limb exercises • Maintain range of motion-ROM exercises • Correct postural defects-positioning and postural training • Improve exercise tolerance-graded exercise program.

Figure 20.2.1 Hip knee ankle foot orthosis



 

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Augmented Bladder Figure 20.2.2 Knee ankle foot orthosis  

Bladder augmentation, also called augmentation cystoplasty, is a surgical procedure used in children who lack adequate bladder capacity or detrusor compliance. Physiotherapy by means of TENS and exercise to improve the bladder and bowel muscles will help.

Assistive Devices



When there is imbalance in the muscle tissues, assistive devices shall be advised for the ambulation and for support when there is injury or inflammation. The following are the different assistive devices: • Hip knee ankle foot orthosis (Fig. 20.2.1) • Knee ankle foot orthosis (Fig. 20.2.2) • Ankle foot orthosis (Fig. 20.2.3) • Taylors brace (Fig. 20.2.4) • Elbow crutches (Fig. 20.2.5) • Axillary crutches (Fig. 20.2.6). In conclusion, physical therapy is concerned with identifying and maximizing quality of life and movement potential. Whereas rehabilitation aims to enhance and 1148 restore functional ability and quality of life to those with

 

Figure 20.2.3 Ankle foot orthosis

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Pediatric Procedures

 

Figure 20.2.6 Axillary crutches



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My sincere thanks to Mr S Suresh Kumar, Chief Physiotherapist, Sundaram Medical Foundation, Chennai, for his technical input and significant contribution in drafting this text.



cknowledgment

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physical impairments, disabilities or with injuries to the muscles, bones, tissues and nervous system.

1. American Physical Therapy Association. Guide to Physical Therapist Practice, 2nd edition. Alexandria VA: APTA; 2001. 2. Bandy W, Sanders BW, Sanders B. Therapeutic Exercise Techniques for Intervention. Philadelphia: Lippincott William and Wilkins; 2001. 3. Behrens B, Michlovitz S. Physical Agents: Theory and Practice, 2nd edition. Philadelphia: FA Davis; 2005. 4. Cameron M. Physical Agents in Rehabilitation, 2nd edition. Philadelphia: WB Saunders Co; 2003. 5. Campbell S. Physical Therapy for Children, 2nd edition. Philadelphia, WB Saunders Co; 2000. 6. De Turk W, Cahalin L. Cardiovascular and Pulmonary Physical Therapy. New York: McGraw-Hill; 2004. 7. Hertling D, Kessler R. Management of Common Musculoskeletal Disorders: Physical Therapy Principles and Methods, 4th edition. Philadelphia: Lippincott Williams & Wilkins; 2005. 8. Huber F. wells C. Therapeutic Exercise - Treatment Planning for Progression. St Louis: Saunders Elsevier; 2006. 9. Kahn J. Principles and Practice of Electrotherapy, 4th edition. New York: Churchill Livingstone; 2000. 10. Kisner C, Colby L. Therapeutic Exercise Foundation and Techniques, 4th edition. Philadelphia: FA Davis Co; 2002. 11. O’ Sullivan S, Schmitz T. Physical Rehabilitation Laboratory Manual- Focus on Functional Training. Philadelphia: FA Davis Co; 1999. 12. Patricia A Downie (Ed). Cash’s Textbook of Neurology for Physiotherapists. 4th edition. Londen: Faber and Faber; 1989 13. Rose Sgarlat Myers. Saunders Manual of Physical Therapy Practice. WB Saunders Co; 1995. 14. Starkey C, Ryan J. Evaluation of Orthopedic and Athletic Injuries, 2nd edition. Philadelphia: FA Davis Co; 2002.

 

Figure 20.2.5 Elbow crutches

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Figure 20.2.4 Taylors brace

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Section

21 Pediatric Therapeutics





21.1 21.2 21.3 21.4 21.5



Section Editor : SS Kamath Basics of Pediatric Therapeutics: Sandeep B Bavdekar Adverse Drug Reactions, Drug Interactions, Therapeutic Drug Monitoring: Archana Kher Rational Drug Therapy in Children: Arun Phatak Essential Drugs in Pediatrics: Jeeson C Unni Safe Injection Practices: SS Kamath Annexure: Drugs and Dosages: Jeeson C Unni

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Reach an Initial Working Diagnosis ­

This is an important aspect of initiating therapy. A pro visional clinical diagnosis can be reached with the help of detailed history and examination. Appropriate treatment can be started depending on the clinical status of the child. A child in critically ill stage would require immediate therapy aimed at stabilization of vital signs. One should not wait for specific confirmation of the etiological agent as in cases like bronchopneumonia, meningitis, etc. In such serious and life-threatening conditions, therapy can be initiated taking into consideration the patient’s age, likely etiological agent and the pattern of resistance likely to be encountered. The treatment can be changed subsequently on the basis of results of investigations and response to therapy.

Define Therapeutic Objectives The next step is to define therapeutic objectives. In this step, the treating doctor should specify what intends to be achieved through therapy and in what time interval. It might include symptomatic treatment, therapy directed towards cause of illness and even steps to prevent or ameliorate complications. For example, when a patient presents with fever and burning micturition and is diagnosed to have urinary tract infection, therapeutic objectives would include symptomatic relief (relief of pain during micturition), eradication of infectious agent (with the help of appropriate anti-microbial therapy), steps to prevent further attacks of urinary tract infection and preserve renal function. Defining therapeutic objectives helps the doctor prescribe minimum number of drugs and also serves/provides a benchmark for the assessment of success of therapy.

Assess Effectiveness of Therapies There is hardly any therapeutic regimen that is completely effective in all cases. Efficacy is dependent on several factors,

u

Steps in Initiation of Therapy

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which include patient’s own defenses, drug’s pharma cokinetic properties and stage of illness. The treating doctor should be aware of the comparative efficacy of various therapeutic interventions. If the initial response is good, the treatment can be continued irrespective of microbiological studies. At the same time, drug resistance to conventional drugs is not uncommon. This has been encountered, for example, in certain illnesses like typhoid fever, urinary tract infection and malaria.

Th

It is usually believed that every illness should be treated. This principle of therapeutic enthusiasm is clearly appropriate in severe and life-threatening illnesses. It, however, does not apply to all clinical situations. Infants, children and adolescents have intrinsic recuperative capacities. Therefore, therapeutic intervention may not be required in many conditions. It should be borne in mind that drug therapy is not synonymous with good health care. Drug therapy in children differs from that in adults for several reasons: their abilities to metabolize drugs mature overtime and their capacity to excrete drugs reach adult levels by late infancy. Before initiating drug therapy, the treating doctor should undertake the following steps.

ediatric

Sandeep B Bavdekar

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Basics of Pediatric Therapeutics

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21.1

Assess Risk to the Patient Every drug has adverse effects. No drug is completely innocuous. The risk to patient increases when multiple pharmacological agents are used. The physician should be aware of drug interactions and should anticipate them. Every new drug will have its potential adverse effects not known at the time of introduction.

Plan Strategies to Ensure Compliance A patient will not derive benefits from therapy if the drug is not properly administered. The physician must explain to the parents the importance of administering drug, the symptoms it would help control or the manifestations that it might ameliorate and when this is expected to happen and the importance of completing the course. The main focus is on the active drug substance while determining doses, clinical effects and adverse effects. However, issues such as non-palatability or presence of unpleasant smells may influence compliance. It should also be remembered that the sense of smell and taste are well-developed right from the neonatal period. Hence, the doctor should be familiar with the available preparations, their flavors and unpleasant characteristics. Frequency of administration either as a single dose, twice daily or thrice daily will depend on the drugs prescribed, based on the half-life of these drugs.

Consider Costs Involved For many families, expenses involved including travel expenses, cost of drugs, expenses for diagnostic tests and professional fees, if any, are some of the important factors determining compliance. Where oral medications are sufficient to treat an illness; parenteral drugs must be avoided. Generic drugs are generally less expensive. When time-honored cheaper but effective medications are available, one should not push the parents to buy more expensive drugs.

Enquire about Previous Experience Another consideration in choosing a drug is to know what has failed with this patient in the past. This includes questions 1151 about hypersensitivity, adverse reaction, noncompliance

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Special Aspects of Pediatric Pharmacology Children develop and grow, and their response to drug therapy is conditioned by age, size and stage of development. Physiological processes that influence phar macokinetic variables in children change significantly during the first few months. Pharmacodynamic differences between pediatric and other patients are probably small. ­

is important in determining the concentration of drugs at receptor sites.

Protein-Binding Albumin, alpha-glycoprotein and lipoprotein are the most important circulating proteins responsible for drug binding in plasma. The concentration of most of these proteins is low in infancy. These factors will influence the resultant balance between free and bound drug concentrations and hence have an effect on drug distribution.

Membrane Permeability

Gastrointestinal Absorption

Drug Metabolism

Drug absorption in infants and children follows the same principles as in adults. The patient and drug characteristics that affect absorption of a drug from the gastrointestinal tract are, in turn, influenced by several factors. These include age of the child, lower secretion of gastric acid, lower concentration of gastrointestinal enzymes, prolonged gastric emptying and slower peristalsis in the first few days of life, which may affect absorption of drugs from the gastrointestinal tract. For example, plasma concentrations after oral administration of paracetamol and phenytoin have been shown to be lower in infants than those in children and adults. Delayed development of gastrointestinal flora and its metabolic abilities can influence the absorption of certain drugs like digoxin.

Liver is the primary organ for drug metabolism and different hepatic enzyme systems mature of different ages. The cytochrome P-450 mono-oxygenase system appears to mature rapidly, with metabolic activity similar to adults being achieved by 6 months of age. In contrast, glucuronide formation reaches adult values between third and fourth years of life. Although infants are regularly characterized as being slow metabolizers of drugs, some drugs (for example, theophylline, phenytoin, phenobarbitone) are more rapidly metabolized by infants than adults. There are qualitative differences too. A drug may be preferentially metabolized by one pathway during the neonatal period (e.g. theophylline) as compared to adulthood. All these have practical implications. While determining dosages of drugs that undergo hepatic biotransformation, sequence of maturation of process of drug metabolism has to be taken into account. The drugs that are metabolized at a rapid rate are required to be administered in higher dose. Thus, theophylline is administered at much higher dose and frequency during infancy than in adulthood.

Parenteral Routes of Absorption Physiological and physiochemical factors affect the rate and extent of logical drug absorption from parenteral sites. The primary means of extra-vascular drug administration in infants and children, other than the oral route, is the intramuscular route. Blood flow to and from the injection site should be adequate to ensure absorption into the systemic circulation. Premature babies have very little muscle mass and children in whom perfusion is diminished; the drug may remain in the muscle and be absorbed very slowly.

Drug Distribution Knowledge about drug distribution is important while designing an optimal dosage regimen. The distribution characteristics of drugs differ markedly amongst term infants, premature babies and children as compared with adults. These differences are a result of much important age-dependent variables. These include the following:

Composition and Size of Body Water Compartments Neonates have a higher percentage of their body weight in the form of water (70–75%) as compared to adults (50–60%). Similarly, the extra-cellular water compartment accounts 1152 for 40% of the body weight in neonates compared to 20% in adults. The volume of extra-cellular water compartment

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Drug Absorption

Permeability of membrane has an influence on the distri bution of the drugs.

Drug Excretion Kidney is the predominant organ concerned with drug excretion. Drugs are also excreted through the gastro intestinal tract; biliary tract, respiratory tract and sweat glands, but these are important routes of excretion only for miniscule minority of drugs. Renal excretion is dependent upon glomerular filtration rate (GFR), renal blood flow (RBF) and rate of active tubular secretion. These are dependent on age and maturity. A term infant has GFR and RBF that approximate 30% of adult values. In premature neonates, these renal capabilities are only 15% or less, depending on the degree of prematurity. The renal capacity to excrete solutes improves quickly to reach 50% of adult value by 4 weeks and equals that of adults by 9–12 months of age. Thus, the dosages in the neonatal period should be based on age and maturity to avoid accumulation of drugs. ­

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and non-effectiveness. If a particular preparation is taken by child with least degree of fuss, it could also mean that the particular preparation is acceptable to the child in terms of smell, taste and flavor.

Pediatric Drug Dosages Because of the differences in pharmacokinetics in infants and children enumerated above, simple proportionate

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This may have to be resorted to in serious illnesses or when only parenteral form of drug is available or when compliance has to be ensured. Local application to skin and mucous membranes is mainly used for treating local ailments. Drugs administered by subcutaneous route are slowly absorbed. The drug behaves as if it is in a reservoir as the subcutaneous tissue has limited blood supply. Intramuscular injections should be administered in the anterolateral aspect of the thigh rather than in the gluteal muscles. This avoids the risk of injury to the sciatic nerve and the possibility of a part of the dose getting injected in the subcutaneous fat that is abundant in the buttocks. After 5 years of age, when deltoid mass is generally well-developed that site can be used for intramuscular administration. Intravenous (IV) administration of drugs to children requires certain special considerations. Some drugs have to be administered as IV push so that the drug is placed in the circulation with a minimum delay. This is an important factor when rapid onset of action is essential (e.g. adrenaline for

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Depending on age, various drug forms, like drops, suspensions, dry syrups (powder to be mixed with water before use), dispersible tablets, tablets and capsules, are used for oral administration in children. Suspension containing sorbitol base or alcohol base provide uniform drug amount even without shaking but there may be objections on religious or moral grounds for use of alco hol as a base. Syrupy suspensions contain undissolved particles of drug and these may not be evenly distributed throughout the vehicle. Therefore, the bottle should be shaken prior to administration of each drug dose. Proper measurement of the drug dose administered is necessary in terms of milliliter (m ) and not in terms of teaspoonful. The parents should be advised to use calibrated medicine cups or syringe for measuring the dose to be administered. Advent of dispersible tablets has simplified administration of oral medicines. As the tablets can be dissolved in small volume of water, use of dispersible tablets makes the process easier. Children over 8–12 years can be taught to take medicines in tablets or capsule form. This avoids inaccurate measurement, minimizes spills and bypasses bad taste.

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treatment of anaphylaxis, adenosine for managing supraventricular tachycardia). This method should, however, be resorted to only by individuals familiar with acute toxicities of medications. The route carries the risk of sudden cardiac or respiratory collapse, severe anaphylaxis due to sudden antigen-antibody reaction and local venous thrombosis if the drug damages the vascular wall (e.g. crystalline penicillin, cloxacillin). Some drugs are required to be administered over a longer period to avoid acute toxicities or vessel wall irritation. The volume of fluid that can be administered to neonates and young infants or to children with renal failure or congestive cardiac failure is restricted. Hence, novel methods of IV administration are used in pediatrics. Intravenous piggyback (IVPB) route is used to infuse drugs over a period of 1–2 hours. This is common way for administering anti-microbial agents in children. The dose of medication is injected into volumetric chamber inserted between the IV bag and the device controlling the rate of administration. The method is simple, does not require costly equipment like syringe pump and as the medication is diluted in existing IV fluid, no extra fluid is administered. The syringe pump method is the gold standard for administration of drugs intravenously as there is absolute control over drug delivery. But this is not necessary for many medications. The syringe pumps are expensive and entail administration of extra amounts of fluid. The retrograde system is a simpler method mainly used in neonates, as it does not require injection of additional fluids. There are only limited indications for administration of drugs through sublingual, intrathecal and intraperitoneal routes. For example, sublingual administration is used for control of severe hypertension with nifedipine and intra thecal route is used for administering methotrexate in the treatment of childhood leukemia. Anti-diuretic hormone (ADH) is administered with the help of a nasal spray for the control of nocturnal enuresis and diabetes insipidus is selected patients. Use of pulmonary absorption of aero solized drugs has revolutionized the management of childhood asthma. Beta-agonists and steroids are adminis tered through this route. Advantages of this route of administration include almost instantaneous absorption of the drug into the blood, avoidance of hepatic first-pass loss and direct delivery of the drug at the desired site of action and lesser chance of developing systemic toxicity on prolonged use. The cumbersomeness of method of administration that could come in the way of its use in young children has been overcome by using spacer devices or rotahalers.

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reduction in the adult dose is not adequate to determine a safe and effective pediatric dose. Formulae or rules providing calculations based on age or weight of the child are mere approximations. The most reliable pediatric dose information, wherein the dose is given in terms of weight or surface area, is usually that provided by the manufacturer in the package insert, in the pharmacopeia or in pediatric textbooks.

Drugs and Breastfeeding When a mother is on medications, many drugs appear in the breast milk. One must be aware of the side effects of these medications on the neonate (e.g. chloramphenicol and phenobarbitone). When a nursing mother needs medications, the physician must keep in mind the safety profile of the drugs that need to be administered. 1153

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the parents especially when long-term treatment is suggested. Whenever necessary, explain the need for periodical clinical and/or laboratory monitoring when on long-term drug therapy for epilepsy, tuberculosis, renal diseases, etc. to assess the response and prevent serious side effects. Ask the parent to report any worsening, unexplained event or adverse effect immediately Drug combinations must be used with caution, unless the drugs are in the specified dose requirements (e.g. sulfonamide plus trimethoprim, amoxicillin and clavulanic acid, sulfonamide plus pyrimethamine, isoniazid and rifampicin). Avoid fancy but inappropriate combinations like metronidazole plus nalidixic acid or norfloxacin, ampicillin and cloxacillin, etc. Drug interactions between two drugs can happen if administered simultaneously, e.g. penicillin and amino glycoside in the same syringe Be conversant with the ongoing developments and progress in the fields of therapeutics and drug develo pment. Prescribe drugs in a judicious manner to ensure that children do not remain therapeutic orphans and at the same time their safety is not sacrificed while prescribing newer drugs. ­

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1. DeVaries TPGM, Henning RH, Hogerzeil HV, et al. Guide to Good Prescribing, Geneva, World Health Organization, 2000. 2. Loebstein R, Vohra S, Koren G. Drug therapy in pediatric patients In: Carruthers SG, Hoffman BB, Melman KL, Nierenburg DW (Eds). Melman and Morrelli’s Clinical Pharmacology Basic Principles in Therapeutics, 4th edition. New York: McGraw Hill Medical Publishing Division; 2000. pp. 1143-9.



Bibliography



In addition to the usual considerations, it is worthwhile emphasizing the following points that need to be consi dered while prescribing medications for children: • Prescribe drugs only when necessary keeping in mind the risks, benefits and costs involved. Review therapy as and when additional information becomes available • Rather than rushing to know the latest on every new drug, one should be more concerned about the use of proven worthwhile therapies • Prescribe minimum number of appropriate, inexpensive drugs of good quality, one is familiar with. Do not succumb to pressures of prescribing newly marketed drugs, unless a clear indication exists • To ensure compliance, explain to parents the nature of the disease and the likely benefits to be obtained from the therapy. Give clear instruction, preferably in writing to avoid misinterpretation, including the need to complete a given course even if child appears to be asymptomatic • Prescribe doses at a frequency as advised in product insert or as per standard pediatric texts • Prescribe medications for a complete course in appro­ priate formulations, e.g. drops for neonates, liquid preparations or dispersible tablets for infants and young children and tablets and capsules for children older than 8–12 years • Direct parents to discard all remaining doses so as to protect the child from accidental poisoning or improper self-medication at a later date • Explain the adverse effects of the drug, if any, to ­

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Factors such as age, drug allergy, genetic predisposition are intrinsic to the patient. Extrinsic factors like the prescriber and environment influence ADRs. In neonates and infants the drug distribution is affected by lower proportion of fat and higher proportion of water. The blood brain barrier is more permeable. The enzyme systems are immature, conjugation is impaired and elimination by the kidney is lowered, drugs like gentamicin and digoxin have a prolonged half-life. Older children metabolize drugs more rapidly than adults. Heritable conditions like methmoglobinemia and G6PD deficiency can precipitate ADRs.

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Children constitute a vulnerable group since a new drug gets released into the market without adequate trials in them due to ethical reasons, the exceptions being oncology and vaccines. Only a careful post-marketing surveillance detects adverse drug reactions (ADRs) occurring in children. Information about ADRs is scanty in children. An ADR may be defined as any unwanted consequence of administration of a drug during or following a course of therapy. These unpleasant effects occur at doses intended for therapeutic (prophylactic or diagnostic) effect and which necessitate reduction of dose or withdrawal of the drug or predict hazard from future administration. Intolerance denotes a low threshold to the normal pharmacological action of a drug. An idiosyncratic reaction is an inherent qualitative abnormal reaction to a drug. ADRs can cause severe mor bidity and even death. Adverse reactions due to drug overdose (poisoning), drug abuse and therapeutic errors are excluded. ADRs are responsible for 6.8% of admissions and 59% ADRs can be avoided. ADRs are 7th most common cause of death. The administration of a drug may result in the development of side effects, untoward effects, toxic effects or allergic and idiosyncratic effects. ADRs could be either local (irritation, necrosis, thrombophlebitis) or systemic. They are classified as: ype : These are also known as augmented, attenuated or quantitative ADR. They comprise a hyper response to the main action of the drug, e.g. insulin induced hypoglycemia. ype B: They are bizarre or qualitative ADR. Unpredictable or unexpected effects are seen. ype : The effect is time and dose related as in analgesic nephropathy. ype : The ADR is time related as in carcinogenesis. The commonly reported ADRs include • Dermal reactions, erythema multiforme, fixed drug eruptions, Steven Johnson syndrome • Gastrointestinal symptoms namely nausea, vomiting, diarrhea • Hepatotoxicity, elevated enzymes, liver cell failure • Neurological manifestations like tremors, dystonia, impaired cognitive function • Hematological effects like neutropenia, aplastic anemia • Anaphylaxis occurs commonly due to penicillin, vaccines. In clinical practice most ADRs are caused by antibiotics, anticonvulsants and anti-tubercular drugs. Children warrant different attention as they have special issues when ADRs are

detected. Many complaints like poor attention span, visual impairments may go unnoticed; their growth potential may get affected with steroids. Children are more vulnerable to dermal reactions. Our pediatric population represents a wide variety of ethnic and sociocultural groups and may therefore react to drugs in a different manner. Infections are prevalent in Indian children therefore it is worth identifying ADRs to drugs used to treat endemic diseases. Over 50% children are malnourished and malnutrition then affects drug kinetics. This should be given due consideration while pre scribing anti-tubercular drugs. Very often irrational multiple drug prescriptions are commonly given and children are not necessarily treated by pediatricians. Ayurvedic and homeopathic medicines are additionally prescribed and drug interactions may go unnoticed. Ciprofloxacin is not recommended for routine use in children, incidence of ADR is 3.1% but it is used for resistant enteric fever. Additives, coloring agents, sugars, flavorings used in medications induce urticaria, asthma; they are often not mentioned on the labels.

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These factors includes the choice of drug, drug interactions. Side effects of drugs are undesired but are an inevitable part of the pharmacological action of the drug at therapeutic doses, e.g. drowsiness with phenobarbitone. Secondary efects occur due to indirect consequences of a primary drug action, e.g. diuretic induced hypokalemia leading to digoxin intolerance. A high dose of a drug can cause toxicity, e.g. 8th nerve damage with gentamicin. Incorrect technique of administration of drugs can cause adverse reactions. Allergic reactions to drugs result from an interaction of the drug or metabolite with patient and disease. This can happen again from subsequent re-exposure. Most drugs 1155

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Drug interactions (DI) refer to the interface of a drug, food or nutrient in the action of another drug. DI result from the use of two or more drugs, this may lead to an enhanced or diminished effect. The effect may be desired or undesired, beneficial or harmful. A study was conducted in a Brazilian hospital in children where 4 or more drugs were used, the data revealed 5.6% DI, 1.9 interaction/prescription and 0.5 incompatibility/prescription. Pediatric patients have immature systems of eliminating drugs, extended half-life of drugs and therefore behave differently. DI are important in the following situations: • Drugs that have a small therapeutic index or exhibit zero order kinetics • Drugs that are enzyme inducers or inhibitors • Drugs used for the same disorder, e.g. theophylline and salbutamol increase the risk for cardiac arrhythmias • Long-term use of any drugs

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The incidence of ADRs in children is 9.5%, they account for 2.1% of hospital admissions and 39% may be lifethreatening. Practicing doctors must detect ADRs and report to the authorities as a professional responsibility. The National Pharmacovigilance Program was established in 2004, the aim being to collate, analyze and archive data on adverse events and ADRs in children. This is a three tier system with peripheral centers, 5 regional centers and 2 zonal centers at KEM Hospital, Mumbai and AIIMS, New Delhi. The National Pharmacovigilance Center is at the Central Drugs Standard Control Organization, New Delhi.

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Drugs like thalidomide, anticancer drugs affect cell division, protein synthesis or DNA synthesis and can be teratogenic. Indirect action may result from drugs acting on the placenta on the uterus (vasoconstrictors cause fetal anoxia by reducing blood supply). Lipid soluble drugs easily pass into the fetus, drug metabolites persist due to immature excretory processes.



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• Presence of comorbid conditions, multiorgan failure • Use of multiple drugs. Drug interactions are of two types: 1. Pharmacokinetic interaction: These are easy to de tect and quantify. They are related to the absorption, metabolism, distribution and excretion of the drug. They can occur outside the body or in the body. Drug incompatibilities may occur before administering when drugs are mixed, e.g. dopamine with bicarbonate is not compatible. Intravenous solutions must be checked for visible changes like turbidity, color and precipitates. Use of correct vehicle and appropriate pH of the infusion is essential. Concomitant administration of amino glycosides and betalactam antibiotics leads to loss of their effectiveness due to chemical inactivation, it is therefore important to monitor serum levels of amino glycosides and allow an interval of 1–2 hours between the injections. Similarly use of phenobarbitone and valproic acid leads to elevated levels of phenobarbitone and reduced efficacy of valproic acid through enzyme induction. 2. Pharmacodynamic interaction: Effects like synergism and antagonism occur at the action sites of the drugs. They may be mediated through receptors, transport processes or electrolyte levels, e.g. potassium depletion enhances digoxin effect. Synergism results when there is summation or addition with two drugs having the same effect. Potentiation also occurs when one drug increases the action of another, e.g. trimethoprim and sulphonamide. A large number of drugs are introduced every year and new DIs are increasingly reported. Regularly updated manuals of DI and CD ROM formatted programs are avail able for reference.

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a. Immediate which typically begin within 30 minutes of administering of drug. b. Accelerated are IgE mediated, begin in 2–72 hours after the drug use. c. Late reactions occur 72 or more hours later, are often unrelated to IgE mediated mechanisms.

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are simple chemicals and act as incomplete antigens or haptens. Test dose alone at times will be inadequate to rule out any ADR, one must be cautious while using a drug first time when there is a positive family history of drug allergy. Reactions include rashes, angioedema, serum sickness, anaphylaxis, asthma. The reactions can be classified by the time of onset as:

Therapeutic drug monitoring (TDM) was introduced in India in late 1980s and the last 10 years have seen it grow. TDM can be defined as the use of drug measurements in biological fluids as an aid to the management of patients receiving drug therapy for the alleviation or prevention of diseases. Automation and the availability of technically simple methods have made this service available even in rural areas. The assay does not mean only measuring but should be interpreted appropriately. Physicians are not trained to interpret and use the results optimally. Genetic variation in metabolism, elimination rates, disease states, nutritional deficiencies and interactions with other drugs gives rise to a wide range of plasma levels in patients administered the same dose. Ayurvedic, Homeopathic and Unani medicines are often taken together with allopathic medicines. Experimental studies showed that shankhapushpi had both pharmacokinetic and pharmacodynamic interactions with phenytoin and phenytoin levels dropped. Drug levels can

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1. Bavdekar SB, Karande SC. National pharmacovigilance program. Indian Pediatr. 2006;43(1):27-32. 2. Dixit RK, Nayak UV. Drug Interactions. J Applied Medicine. 1997;23(1) 61-5. 3. Gogtay NJ, Khirsagar NA, Dalvi CS. Therapeutic Drug Monitoring in a developing country, an overview. Br J Clin Pharmacol. 1999;48(5):649-54. 4. Gupta A, Waldhauser LK. Adverse drug reactions from birth to early childhood. Pediatr Clin North Am. 1997;44(1):79-92. 5. Karande SC, Khirsagar NA. Adverse drug reactions in deve loping countries. Natl Med J India. 1996;9(3):218-21. 6. Khirsagar NA, Karande SC. Adverse drug reaction monitoring in pediatric practice. Indian Pediatr. 1996;33(12):993-8. 7. Loobstein R, Keren G. Clinical pharmacology and therapeutic drug monitoring in neonates and children. Ped Rev. 1998; 19(12):423-8. 8. Oates JA. The science of drug therapy. In: Goodmasn and Gilmans (Eds). The Pharmacological basis of Therapeutics, 11th edition. New York: Mc Graw Hill; 2006.pp.117-36. 9. Patel KJ, Kedia MS, Bajpai D, et al. Evaluation of the prevalence and economic burden of ADRs presenting to the medical emergency department of a tertiary referral center, a prospective study. BMC Clinical Pharmacol. 2007;7:8. 10. Satoskar RS, Bhandarkar SD, Ainapure SS. Evaluation of drugs in man, drug prescribing and drug interactions. In: Satoskar, Bhandarkar Ainapure (Eds). Text book of Pharmacology and Pharmacotherapeutics, Section 119th edition. Mumbai: Popular Prakashan; 2005.pp.61-75. 11. Uday kumar P, Adhikari P, Periera P. A prospective analysis of ADRs in a South Indian Hospital. Online Journal of Health and Allied Sciences. 2009;3:12.

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concentration above the minimum inhibitory concen tration. The Madras tuberculosis center in South India has developed a urine test to identify noncompliance with isoniazid therapy. TDM for anti-mycobacterial drugs is still not widely available. Therapeutic drug monitoring can also be used as a useful research tool. In developing countries TDM is important where there are spurious poor quality drugs available, drug legislation is inadequate and self-medication is easily practiced. With good prescribing practices and appropriate use of drug monitoring therapeutic concentrations can be achieved in over 70% patients.

Pediatric hera eutics

be altered with a hypoproteinemic state, conditions like AIDS which lead to low levels of anti TB drugs. Nutritional deficiencies are often subclinical and escape detection and they have been shown to affect drug pharmacokinetics. Plasma levels serve as a useful guide when there is a narrow range between therapeutic and adverse effects. Interpopulation variations and ethnic differences also influence plasma drug concentration. Clinical pharmacologists pro vide advice on dosage adjustment, non-responsiveness, compliance, managing and identifying adverse reactions and using anticonvulsants in pregnancy. During estimation of drug level, the actual time that the sample was obtained is important. The levels can be determined anytime during dosing interval for drug with a long half-life, e.g. phenobarbitone. For drugs that have a short half-life, peak and trough concentrations must be measured at specific times. Concentrations measured during the distribution phase are variable and do not correlate with usual therapeutic range. Ideally plasma drug samples should be procured after 4 half lives of the drug, peak concentrations are observed within 1–2 hours after oral administration of a drug, to ensure proper absorption levels must be measured before the next dose (trough). Patients with chronic renal or liver disease, anticonvulsant drugs need TDM to avoid sub therapeutic therapy or toxicity. Patients on theophylline can have increased plasma levels and toxicity when given cimetidine and erythromycin. Cisapride when given with theophylline can induce cardiac arrhythmias. TDM can help to identify noncompliant patients. Quality of products (drug content, bioavailability) is important especially for drugs with a narrow margin of safety for which TDM is relevant. The TDM service can be used to provide an important early indication of substandard drugs. The most common indication for TDM of anticonvulsants has been non-response to a standard dose of drug. This allows differentiation between noncompliance, need for a higher dose and true drug resistance requiring change over to second drug. Other common indications include suspected drug toxicity, dose adjustment in pregnancy and drug interactions (especially common with anti-tuberculous drugs). TDM of anti mycobacterial drugs offers the clinician a chance to ensure that the patient achieves a serum

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Unindicated rugs This is the most commonly occurring irrationality. The most misused drugs are the so-called ‘tonics’, cough mixtures and antibiotics. Very few drug combinations are rational. A child often receives some unnecessary drugs when preparations with drug combinations are used. Combinations of paracetamol-ibuprofen or paracetamolantihistaminic-decongestant are prescribed often. As far as possible preparations containing only one drug should be prescribed and when the proprietary preparation contains multiple drugs, the ingredients and their amounts should be checked.

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The prescription should be written in the standard format (Box 21.3.1). A number of pediatricians in big cities have started giving computerized prescriptions but the majority still writes them by hand and legibility is very important. Doctor’s handwriting is notorious for its illegibility and there is nothing to be proud of it. Writing the prescription legibly does not require lot of effort. Many drugs have similar syntax and pronunciations and serious mistakes have occurred because the chemist could not read correctly and dispensed a wrong medicine. Counseling the parents about administrations of the different medicines is another very important aspect of prescribing drugs. Many doctors indicate symbolically how the different drugs are to be taken and it can be quite confusing. It is better to write the instructions in the language understood by the parents. Many of the patients are illiterate and need to be explained and demonstrated how dry syrups are to be prepared, and how the various quantities of the different drugs are to be administered. At times, an indicated drug is not used either due to oversight or due to ignorance. This type of irrationality is rare.

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In children the dose of the drugs is calculated by weight or surface area and the dose may be different in neonates, in infants and in older children. The dose for parenteral and oral administrations may be different. The doses of certain drugs need readjustment if there is renal or hepatic impairment. 1158 A high dose given inadvertently can be catastrophic. It is

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Medicine is a continuously expanding and improving science and its practitioner must commit to continuous updating and life-long learning. Every year new drugs are in the market. One must know the basic pharmacology of the drug (and not go by what the medical representative said) Box 21.3.1 Standard format for prescriptions  

The drug should not only be effective but also should be affordable and acceptable. When two or more drugs are likely to be equally effective, one which is well known to us, cheap and can be orally administered would be preferable. Even when injections are needed in the acute state, a drug which can be given parenterally as well as orally would be preferable—as the child stabilizes one can switch over to oral administration. Often the latest arrival in the market is prescribed (may be as a result of promotional visit by the medical representative) without knowing its short-term and long-term adverse effects. A drug with which we are familiar is always better. I

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Rational means something sensible, based on reasoning. After about 8 years of experience in the field of clinical medicine, the practicing pediatrician is expected to base the case management on accepted scientific principles and practice guidelines. A practicing pediatrician largely depends on the use of drugs and should use them judiciously. Previous chapters have discussed how the drug therapy of children differs from that of adults. Unfortunately, irrational use of drugs is not uncommon and it is observed at all levels. Irrationality in drug therapy is observed mainly in four areas: 1. Unindicated drugs 2. Improper choice 3. Inappropriate use 4. Inadequate patient counseling

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• Doctor’s name, qualification, address and registration number • Patient’s name, age, sex, weight and date • Names of the drugs (if necessary with the pharmaceutical name) with the recommended strengths, forms and amount to be bought • Clear instructions about the dose, frequency and duration of medication, preferably in a language understood by the parents • Explanation (at least verbally) of the common side effects and their significance (black stools after iron therapy, “red” urine after rifampicin)

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The pediatrician starting his private practice fears that “what is preached cannot be practiced”. Although the circumstances, work conditions and the patient profile in the medical college hospital are different from those existing in private practice, in both circumstances, the pharmacology of the drugs is the same.

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published in print and on electronic media as the gospel truth. There are evidences and evidences. Some are high quality and reliable, others are of low quality and unreliable. A simple hierarchy for the quality of the evidence may be put down as: • Meta-analysis or Systematic reviews of randomized clinical trials (RCTs) • RCTs • Other controlled clinical trials • Observational studies (cohort and case control) • Case studies, anecdotal and personal opinion. Apart from its type, the publication needs to be scrutinized for its methodology and validity of the results. We must then consider whether the valid, important results of the paper are applicable to our patient in the given circumstances. The availability, feasibility, affordability, acceptability and sustainability of the new therapy must be considered in each case. It is said that “half of what we have learned today will in 10 years be shown to be wrong—and no one knows which half”. So the practicing doctor must commit to continuous updating and life-long learning. There is an explosive rise of medical information over the last few decades. The National Library in USA accesses some 11 million papers every year from about 4,300 journals of which only 10–15% are considered to be of lasting value. Searching and appraising papers is a time consuming and laborious work out of bounds for the busy practicing pediatrician.

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before using the drug. Prescribing information (product insert) provided with the proprietary medicine may be useful especially as guidance for the administration of the new drug.

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Many times a young doctor fresh in practice looks at the senior “established” peers as role models and tries to imitate their prescribing behavior without scrutinizing the rationality. In scientific matters, not the person but the scientific facts are important.

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The practice of medicine is a profession and not a business. Our main objective, while earning a decent and comfortable life, must always be the total care of the patient. The pharmaceutical industry is a big business with an objective of earning as great a profit as possible. Some of them give rich gifts and other enticements to doctors and lure them into writing their products. In the interest of the child and his family, the pediatrician must be vigilant and avoid the trap.



Till a few decades ago, patients equated doctors to God and accepted whatever that was advised without any question. The doctor had clinical freedom and the treatment was often guided by one’s experience. Now, the times have changed. Clinical freedom is considered as “at best a cloak for ignorance and at worst an excuse for quackery”. A doctor is accountable and should be able to justify the management. The clinical practice has to be evidence based. The evidence comes from published and unpublished research papers and reports. One cannot take everything

Books give the basic information about drugs and therapy but the information is likely to be 5–10 years old. Yet it is better to possess the latest edition of the standard textbook as a ready reference to start off. Papers published in journals (especially the online issues) give more recent information, but the original papers need critical appraisal. The official journal of Indian Academy of Pediatrics publishes off and on “Management Guidelines” and “Consensus Statements”. These are based on the review (though may not be systematic review) of various publications related to the topic. There are guidelines from various professional and other academic bodies that are based on systematic reviews and give the level of evidence for each recommendation made. The systematic reviews and practice guidelines can be accessed on various websites (Box 21.3.2). There are systematic reviews and metaBox 21.3.2 Some useful websites  

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Life Goals and mbitions

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The young pediatrician is anxious to establish oneself. He feels that curing the patient quickly will increase his clientele and tries to treat every possible cause of the illness simultaneously (poly-therapy). Many patients demand medicines even when they are not necessary (e.g. antibiotics when the child has diarrhea, viral upper respiratory infection or tonics and vitamins fore “debility”). Some demand injections or IV drips under the impression that they bring quick cure. A doctor should not succumb to such demands but spend some time in counseling the parents about the nature of the disease and its management.



Undue Pressures

• www.cochrane.org • www.evidence.nhs.uk • www.clinicalevidence.com • www.nice.org.uk • www.sign.ac.uk • www.tripdatabase.com

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1. Feldman W (Ed). Evidence-Based Pediatrics. Indian Reprint. Banglore; Panther Publishers Private Limited, 2001. 2. Greenhalgh T. How to Read A Paper: The Basics of EvidenceBased Medicine, 3rd edition. London: Oxford Blackwell Publishing Ltd; 2006. 3. Strauss SE, RichardsonWS, Glasziou P, Haynes RB. How to Read A Paper: The Basics of Evidence-Based Medicine, 3rd edition. Edinburgh: Elsevier Churchill Livingstone; 2005. 4. World Health Organization. The Use of Essential Drugs. WHO Technical Report Series. 1990. p.796.



ibliography



• •



•

Make a list of common diseases and disorders that are seen in your practice Look up the guidelines and textbooks and select the essential drugs that you want to use Know the basic pharmacology of the selected drugs Consider the availability and cost of the various proprietary preparations. Box: Keep a basic record of the age group, gender, disease/disorder and the drugs used

and at the end of the year audit your own prescription behavior If you have deviated from the current standard recom mendations, considered the reasons for the deviation and try to correct yourself.



•

C

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Tips for ationalizing the linical Practice

•



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Tex book of Pedia rics

analyses published in the journals off and on. The Archives of Disease in Childhood (ACD) and the ACD-Education and Practice regularly publish clinical problem oriented features like Archimedes, Pickets, Guideline Review. Conferences, lectures seminars, CME sessions are useful but their learning value is limited.

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ssential rugs in Pediatrics

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E

Need for ssential Medicines List for hildren C

Fact 1: The availability of medicines in developing countries is undermined by several factors: poor medicine supply and distribution systems; insufficient health facilities and staff; and low investment in health and the high cost of medicines. The Essential Medicines List can help countries rationalize the purchasing and distribution of medicines, thereby reducing costs to the health system. Fact 2: Pharmaceuticals account for 15–30% of health spending in transitional economies and 25–66% in developing countries. In some developing countries, medicines are the largest health expense for poor households. Fact 3: A 2006 WHO study in China of 41 surveyed medicines—19 of which were essential showed only 10% were available in private pharmacies as branded products and 15% as generics. Fact 4: A 2004 survey in Uganda showed that among 28 nationally listed essential medicines, only 55% could be found in free health facilities. “Out-of-pocket” prices were 13.6 times higher for branded products and 2.6 higher for generics than the international pricing reference. Fact 5: Only about a dozen countries had an essential medicines list or programme in 1977. Today, four out of five countries have adopted national lists. To be selected, medicines must be available through health systems, in suitable amounts and dosage forms. The list is a cornerstone of national medicine policies and the entire pharmaceutical system. Fact 6: By 2015, over 10 million deaths per year could be avoided by scaling up certain health interventions, the majority of which depend on essential medicines. The declaration of Alma-Ata in 1978, a milestone in international

public health—was the first official document to underline the importance of primary care and the role of essential medicines at a global level. Fact 7: Thirty years ago, the concept of a national medicine policy was unknown in most countries. Today, over 100 countries have policies in place or under development. They can act as frameworks to advance pharmaceutical sector reform. Early pioneers in essential medicines include Mozambique, Peru and Sri Lanka. Fact 8: Objective information on rational use of medicines was extremely limited, especially in developing countries. Today at least 135 countries have their own therapeutic manuals and formularies with current, accurate and un biased information. Fact 9: Growing from an international effort started in 1977, a global network of 83 countries now monitors for adverse medicine reactions and potential safety problems. Fact 10: Thirty years ago, there was virtually no publicly available price information for medicines and few countries actively encouraged generic substitution. Today, 33 coun tries collect and make pricing information public. The use of generic medicines has brought down prices through increased demand and competition. The WHO Model List of Essential Medicines 2010, the 16th list (updated) March 2010 is the most recent publication of the much deliberated, edited and updated WHO. EML that was first conceptualized by the WHO. Expert Committee on the use of essential drugs in 1977 the first edition being. The WHO Model Formulary published in August 2002. The WHO Model List of Essential Medicines 2010 contains drug list for adults. It contains monographs of 294 essential drugs used in children (adult doses also incorporated in each drug monograph), 13 drugs not used in pediatrics and 6 drugs for diseases not prevalent in India. Broad treatment guidelines are presented and in comparison to the IAP Drug Formulary, there is significantly more information on antiretroviral drugs, general and local anesthetics, contraceptives and contrast material used for diagnostic procedures.

en Facts about ssential Medical List E

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Essential medicines are those that satisfy the priority health care needs of a population. This WHO definition means that these drugs should satisfy the health care needs of the majority of the target population. The list therefore needs to be country specific and age specific and guided by disease prevalence in a particular country and age group and, most importantly, be evidence based. An essential drug list generated for children in India needs to consider these issues and select drugs which are licensed for use in this age group and are therefore drugs that are detailed in pediatric drug formularies like BNF for Children or our own IAP Drug Formulary. The new edition of the IAP Drug Formulary-IAP Drug Formulary 2009—and its online desktop and PDA version, addresses this issue and contains an Essential Medicines List (EML). Adequate stocks of pediatric presentations of the drugs in this exclusive list need to be always available everywhere in the country at prices that the community can afford. The EML is an inventory of medicines that treat pressing global health concerns. Medicines are identified through an evidence-based process and quality, safety, efficacy and cost-effectiveness are key selection criteria.

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Pediatric hera eutics

21.4

The most important consideration in determining drug of choice and establishing an effective pediatric dosage is the acknowledgment that the pediatric patient is not just a small adult. Pediatric dosages were an extrapolation of therapeutic practice and experience in adults and the use of “scaled down” adult doses. This practice is clinically successful for the majority of drugs which are relatively non-toxic and have a wide margin between therapeutic and toxic doses. Drugs with a narrow therapeutic margin, 1161 such as the aminoglycoside antibiotics and digoxin, require more sophisticated knowledge and individualized dosage regimens. Doses of such agents are decided by weight or allometrically (wt¾), and then modified according to the vip.persianss.ir





­

After deliberations, the broad objectives and outline of the project in India were formulated. It was agreed that the activities would be as follows: Development of a national EMLc by the IAP for inclusion in the National Essential Medicines List (NEML) of India currently being formulated by the Government of India (GOI) with the All India Institute of Medical Sciences (AIIMS) as the lead agency; Activities in two EAG states (Chhattisgarh and Orissa) that include: (1) development of an EMLc with updating of the EML and facilitation of activities to ensure that procurement follows the EML, and (2) undertaking availability and affordability surveys of children’s medicines in these states before and after updating the State EMLc and EML, with at least one procurement cycle using the revised EML. Soon after this meeting a survey of the availability of medicines for children (pediatric formulations) in public health facilities in India was conducted from February 14–21, 2010 at 129 public health facilities in India from across 17 states and three union territories (Pondicherry, Lakshadweep and NCT Delhi). The availability of five medicines meant for use in children, i.e. Vitamin A liquid solution, Syrup Cotrimoxazole, Oral Rehydration Salt, Syrup Paracetamol, and Zinc Sulfate were ascertained. The basis for the selection was that these five medicines have been included in the National Rural Health Mission’s (NRHM) list of medicines to be dispensed at subcenters. It was assumed that therefore, these medicines would also be available at higher levels of health care, i.e. primary health centers and community health centers. Since these medicines were listed in the NRHM, it would also necessarily figure in the EML or on the procurement lists of all the states. The proven impact of each of these medicines for various indications in children was also one of the factors that were considered. When the availability of individual medicines in the centers were analyzed, it was found that 90% of the facilities had ORS, paracetamol and cotrimoxazole. Zinc was poorly available with only one-third of the facilities having it. The availability of Vitamin A also needs to improve. Very few of the centers had photographs of the lists displayed. The survey also revealed that there were very few other pediatric formulation available at these centers and emphasized the need for making available an EML for children to improve health indices of children in our country. A National Consultative Meeting on EML for Children was then held on 17th October 2010 at Mumbai where, for the first time, representatives of virtually all IAP subspecialty chapters united their efforts to formulate a specialty list of Essential Medicines for IAP, WHO was also represented at the meeting. The final IAP/WHO EMLc list for India was released by mid-2011. The EML of the IAP Drug Formulary has been adapted and modified from that WHO Model List of Essential Medicines for Children 2007. It contains 259—26 drugs used exclusively for pediatric illnesses prevalent in India. The drugs are classified into 25 categories with sub categories with lists of commonly used drug and complimentary lists as in the WHO model list. Since the range of disease for which essential drugs are selected is not clear and the criteria for selection of drugs to this list is not acceptable to all academic bodies even today, the choice of essential drugs seems to be based more on experience than evidence and the influence of

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results of serum drug concentration measurements, if these are available. Over the last two decades, there has been an increased recognition of the necessity to perform studies specifically in children and adolescents. Newborns, children and adolescents have different physiological, pharma cokinetic and pharmacodynamic parameters compared to adults. The differences are mainly related to the changes occurring during growth and maturation and require individualized consideration. Thus, guidelines of specific dosages and useful means for calculating pediatric dosages needed to be developed to enhance the effectiveness without causing serious adverse effects. Children are among the most vulnerable individuals in any society. Nowhere is this more true than in their access to appropriate health care. As part of the treatment of children, health care workers need access to drug dosage information. Following the adoption of the World Health Assembly Resolution WHA60.20 in May 2007, WHO launched the “make medicines child size” project on 6 December 2007. This was envisaged as a worldwide campaign to generate awareness and initiate action to ensure availability of and access to safe, child-specific formulations of medications for all common pediatric illnesses to every child in the world. UNICEF and WHO committed itself to work together towards this ambitious goal. By improving access to chil dren’s medicines, the project seeked to directly support and address some of the major issues in Millennium Development Goal 4 (MDG 4). Advocacy for the project was started by promoting the cause of “better medicines for children” to policy-and decision-makers, clinicians and other professionals, repre sentatives of professional associations and drug supply managers. Many countries, supported by these global activities, have developed their own country specific EMLc and are taking steps to make them available at all health facilities in their respective countries. An informal consultation on better medicines for chil dren in India was held on 2–3 February 2010 at the WHO Regional Office for South-East Asia (SEARO). The objectives were to explore the feasibility of implementing the project in a few states of India and to discuss a broad outline of the activities to be carried out under the project at the national and state levels. Prior to the India meeting, the Essential Drug Lists of five Empowered Action Group (EAG) States from central India, namely, Chhattisgarh, Jharkhand, Madhya Pradesh, Orissa and Uttar Pradesh were compared with the WHO Model EMLc in order to document areas of discordance and identify gaps in implementing the lists with special reference to children’s formulations. Representatives from the state health departments, representatives of the Indian Academy of Pediatrics (IAP) from the five states, executive committee members of the IAP, professors of pediatrics and pharmacology from various institutes, experts from WHO Headquarters (HQ), WHOSEARO, the WHO Country Office, and the Bill and Melinda Gates Foundation came together and discussed the road map for the project in India. The report on the EMLs served as a starting point for the country activity in India, and 1162 was extensively discussed during the meeting, because it showed a lack of inclusion of child-friendly formulations for almost every childhood disease.

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6. Anti-infective medicines 6.1 Anthelmintics 6.1.1 Intestinal anthelmintics Albendazole; Mebendazole; Pyrantel pamoate; Praziquantel 6.1.2 Antifilarials Diethylcarbamazine 6.1.3 Antischistosomals and antitrematode medicine Praziquantel 6.2 Antibacterials 6.2.1 Beta Lactam medicines Amoxicillin; Co-amoxiclav; Ampicillin; Benzylpenicillin; Benzathine penicillin; Phenoxymethylpenicillin; Cloxacillin; Cephalexin; Cefixime; Cefotaxime; Ceftazidime 6.2.2 Other antibacterials Azithromycin; Erythromycin; Chloramphenicol; Netilmicin; Gentamicin; Cotrimoxazole; Nitrofurantoin, Ciprofloxacin; Metronidazole 6.2.3 Antileprosy medicines Clofazimine; Dapsone; Rifampicin 6.2.4 Antituberculosis medicines Isoniazid; Rifampicin; Ethambutol; Pyrazinamide; Streptomycin Complementary list—Reserve for MDR TB Cycloserine; Ethionamide; PAS; Ofloxacin or Levofloxacin 6.3 Antifungal medicines Flucanozole; Griseofulvin; Nystatin Complementary list Potassium iodide 6.4 Antiviral medicines 6.4.1 Antiherpes medicines Acyclovir 6.4.2 Antiretrovirals 6.4.2.1 Nucleoside/Nucleotide reverse transcriptase inhibitors Didanosine (ddI); Lamivudine (3TC); Stavudine (d4T); Zidovudine (ZDV or AZT) 6.4.2.2 Non-nucleoside reverse transcriptase inhibitors Efavirenz (EFV or EFZ); Nevirapine (NVP) 6.4.2.3 Protease inhibitors Nelfinavir (NFV) 6.5 Antiprotozoal medicines 6.5.1 Antiamoebic and antigiardiasis medicines Diloxanide; Metronidazole 6.5.2 Antileishmaniasis medicines Paromomycin; Sodium stibogluconate or Meglumine anti moniate 6.5.3 Antimalarial medicines 6.5.3.1 For curative treatment Amodiaquine—may be used alone or in combination with artesunate 50 mg; Artemether (severe malaria); Artesunate in combination with either amodiaquine, mefloquine or sulfadoxine + pyrimethamine; Chloroquine; Mefloquine; Primaquine; Quinine—severe malaria, in combination with doxycycline; Doxycycline 6.5.3.2 For prophylaxis Chloroquine; Doxycycline; Mefloquine; Proguanil



























­











7. Antimigraine medicines 7.1 For treatment of acute attack

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5. Anticonvulsants/Antiepileptics Carbamazepine; Sodium valproate (Valproic acid); Phenobarbitone (Phenobarbital); Phenytoin; Clobazam

6.5.4 Anti-pneumocystosis and antitoxoplasmosis medicines Pyrimethamine; Cotrimoxazole 











 

4. Antidotes and other substances used in poisonings 4.1 Non specific Activated charcoal 4.2 Specific Atropine sulfate; Deferasirox; Deferiprone; Pralidoxime; Naloxone; Calcium gluconate



­



 

3. Antiallergics and medicines used in anaphylaxis Chlorphenamine; Dexamethasone; Epinephrine (adrenaline); Hydro cortisone; Prednisolone



­

 













a

a

 

2. Analgesics, antipyretics, non-steroidal anti-inflammatory drugs (ns ids), disease modifying agents in rheumatoid disorders (dm rds) 2.1 Non-opioids and non-steroidal anti-inflammatory drugs (NSAIDs) Ibuprofen—also IV/oral/rectal in PDA closure; Paracetamol—as antipyretic only; Acetyl salicylic acid—only for use in rheumatic fever, juvenile arthritis, Kawasaki disease 2.2 Opioid analgesics Codeine; Morphine 2.3 Disease modifying agents used in rheumatoid disorders (DMARDs) Methotrexate—most frequently used DMARD and can be used in all types of JIA; Sulfasalazine

















1.1 General anesthetics and oxygen Halothane; Ketamine; Nitrous oxide; Oxygen; Thiopental 1.2 Local anesthetics Bupivacaine; Lidocaine; Lidocaine + epinephrine 1.3 Preoperative medication and sedation for short-term pro cedures Atropine; Diazepam; Morphine





 



1. Anesthetics



 

Table 21.4.1 Essential medicines list for children and adolescents in India IAP drug formulary









Pediatric hera eutics

cost considerations is debatable. There are bound to be problems with implementation. Storage space for this extra load of medicines at large efficient storage and distribution systems at National and State level are issues that need to be addressed. Further, India being a vast country with varying distribution of illness patterns, could mean compilation of an EML separately for every part of the country. A copy of the list prepared by IAP Drug Formulary based on the WHO Model list for children is attached in Table 21.4.1. The core list presents a list of minimum medicine needs for a basic health care system, listing the most efficacious, safe and cost-effective medicines for priority conditions. Priority conditions are selected on the basis of current and estimated future public health relevance, and potential for safe and cost-effective treatment. The complementary list presents essential medicines for priority diseases, for which specialized diagnostic or monitoring facilities, and/or specialist medical care, and/or specialist training are needed. In case of doubt medicines may also be listed as complementary on the basis of consistent higher costs or less attractive cost-effectiveness in a variety of settings.

Ibuprofen; Paracetamol Contd...

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Complementary list Selenium sulfide







8.1 Immunosuppressive medicines

12.2 Anti-infective medicines





Azathioprine; Cyclosporin

Methylrosanilinium chloride (gentian violet); Potassium per manganate; Framycetin; Silver sulfadiazine







8.2 Cytotoxic medicines

Complementary list



­



Allopurinol; Asparaginase; Cyclophosphamide; Cytarabine; Dacarbazine; Daunorubicin; Mercaptopurine; Methotrexate; Vinblastine; Vincristine

Mupirocin



Betamethasone; Hydrocortisone; Calamine lotion





Bleomycin; Chlorambucil; Cisplatin; Dactinomycin

12.3 Anti-inflammatory and antipruritic medicines

Complimentary list

edicines affecting the blood



12.5 Medicines affecting skin differentiation and proliferation Benzoyl peroxide; Coal tar; Podophyllum resin; Salicylic acid; Urea



9.1 Antianemia medicines Ferrous salt; Folic acid; Hydroxocobalamin

Complementary list

9.2 Medicines affecting coagulation

Dithranol















M

9.







Dexamethasone; Hydrocortisone; Prednisolone

12.4 Astringent medicines







8.3 Hormones and antihormones

12.6 Scabicides and pediculicides





Vitamin K

Benzyl benzoate; Permethrin





Complementary List 13.

iagnostic agents

13.1 Ophthalmic medicines

10.1 Plasma substitutes

Fluorescein; Tropicamide



13.2 Radiocontrast media

10.2 Plasma fractions for specific use













10. Blood products and plasma substitutes

D



Heparin sodium; Protamine sulfate; Warfarin

Complementary list





Complementary list

14.

11.1 Antiarrhythmic medicines

isinfectants and antiseptics

14.1 Antiseptics Chlorhexidine; Ethanol; Polyvidone iodine





D







16. Gastrointestinal edicines M

Lisinopril; Amlodipine; Hydralazine



Hydrochlorothiazide; Spironolactone; Mannitol 16.1 Antacids and other antiulcer medicines





11.3 Medicines used in heart failure





Complementary list



Complementary list Lansoprazole



Dopamine

16.2 Antiemetic medicines





11.4 Antithrombotic medicines





Complementary list



Aluminium hydroxide; Magnesium hydroxide; Ranitidine



Digoxin; Frusemide; Captopril; Enalapril; Hydralazine





Domperidone; Promethazine

16.3 Laxatives Milk of magnesia



Complementary list



Unfractionated heparin; Low molecular weight heparin (LMWH); Warfarin; Acetyl salicylic acid; Dipyridamole

Complementary list



Clopidogrel

Lactulose; Sodium picosulfate





11.5 Lipid-lowering agents

Contd...

16.4 Medicines used in diarrhea

Simvastatin





Frusemide Complementary list

Nifedipine; Atenolol; Enalapril





11.2 Antihypertensive medicines





Chloroxylenol; Glutaral

15. iuretics

Diltiazem; Sotalol; Amiodarone; Flecainide



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14.2 Disinfectants



Complementary list





Verapamil; Digoxin; Procainamide; Lidocaine; Phenytoin; Pro pranolol

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11. Cardiovascular medicines

Barium sulfate D



Human normal immunoglobulin; Factor VIII concentrate; Factor IX complex (coagulation factors, II, VII, IX, X) concentrate

­



Miconazole; Clotrimazole







8. Antineoplastic, immunosuppressives and medicines used in palliative care

ermatological medicines (Topical)

12.1 Antifungal medicines





Propranolol

D

12.

7.2 For prophylaxis



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16.4.1 Oral rehydration

21. Peritoneal dialysis solution

Oral rehydration salts 16.4.2 Medicines for diarrhea in children    



Intraperitoneal dialysis solution (of appropriate composition)

22. Psychotherapeutic edicines M



Zinc sulfate

Complementary list

T



   





Contd...

Pediatric hera eutics

Contd...

22.1 Medicines used in disorders of attention and activity

Methylphenidate; Atomoxetine







17.1 Adrenal hormones and synthetic substitutes

Complementary list





Hydrocortisone; Prednisolone; Fludrocortisone

Clonidine 22.2 Medicines used in sleep disorders (insomnia, bedtime refusal, sleep talking, sleep walking, restless leg syndrome) 



Regular (plain) insulin; NPH insulin (intermediate acting insulin); Lispro; Aspart; Glargine









17.2 Insulins and other antidiabetic agents

Melatonin; Clonazepam; Clomipramine







17.3 Thyroid hormones and antithyroid medicines



I

18. mmunologicals

22.4 Medicines used in depressive disorders Fluvoxamine; Fluoxetine





18.1 Diagnostic agents



Nicotine replacement therapy; Topiramate, Bupropion





Lugol’s solution; Potassium iodide; Propylthiouracil

22.3 Medicines used in substance dependence programmes (tobacco, alcohol, illicit drugs)





Complementary list







Levothyroxine

Bupropion

22.5 Medicines used in bipolar mood disorders (Mania/depression) Sodium valproate; Carbamazepine; Risperidone

Fluvoxamine; Sertraline





22.6 Medicines used in anxiety disorders, panic disorder





Complementary list



Clonazepam; Propranolol

22.6.1 Medicines used in post-traumatic stress disorder (PTSD) Sertraline





BCG vaccine; Diphtheria vaccine; Tetanus vaccine; Pertussis vaccine; Poliomyelitis vaccine; Hepatitis B vaccine; Measles vaccine; Mumps vaccine; Rubella vaccine; Typhoid vaccine; Haemophilus influenzae type b vaccine





18.3 Vaccines



­



Blood components and plasma derivatives; Antitetanus immunoglobulin (human); Antivenom immunoglobulin; Diphtheria antitoxin; Rabies immunoglobulin; Hepatitis B immunoglobulin







18.2 Sera and immunoglobulins



Complementary list





Tuberculin, purified protein derivative (PPD)

p



17. Hormones, other endocrine medicines

Complementary list





Complementary list



22.6.2 Medicines used in obsessive compulsive disorders Clomipramine; Fluvoxamine; Fluoxetine

22.7 Medicines used in psychotic disorders, schizophrenia



Chlorpromazine; Haloperidol

23. edicines acting on the respiratory tract



M

20.1 Anti-infective agents



Acyclovir; Tobramycin; Gentamicin; Chloromycetin





Complementary list



Pyridostigmine

20. Ophthalmological preparations

20.2 Anti-inflammatory and antiallergy agents

23.1 Antiasthmatic and medicines for chronic obstructive pulmonary disease Prednisolone; Budesonide; Fluticasone; Salbutamol

Caffeine citrate



24. olutions correcting water, electrolyte and acid-base S

Tetracaine

   

20.4 Mydriatics

disturbances



Oral rehydration salts; Potassium chloride



Complementary list

24.1 Oral



Atropine

Contd...

24.2 Parenteral

Epinephrine (adrenaline)





23.2 Other medicines acting on the respiratory tract



20.3 Local anesthetics







Prednisolone; Betamethasone; Dexamethasone; Olopatadine hydrochloride









Risperidone; Olanzapine



Complementary list



   

 





Neostigmine; Suxamethonium; Vecuronium



M

19. uscle relaxants (peripherally-acting) and cholinesterase inhibitors

Clonazepam





Hepatitis A vaccine; Pneumococcal vaccine; Rotavirus vaccine; Rabies vaccine; Varicella vaccine

Contd...

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Procaine benzylpenicillin Not in neonates/>1 month Promethazine >2 years





Glucose; Glucose with sodium chloride; Potassium chloride; Sodium chloride; Sodium bicarbonate; Sodium lactate, compound solution

Silver sulfadiazine >2 months







24.3 Miscellaneous

Tetracaine not in preterm neonates





Water for injection Ascorbic acid; Cholecalciferol; Iodine; Pyridoxine; Retinol; Riboflavin; Thiamine











Atropine >3 months Azithromycin >6 months Benzyl benzoate >2 years Betamethasone topical preparations Hydrocortisone preferred in neonates Chlorphenamine >1 year Diloxanide >25 kg weight Doxycycline >8 years Efavirenz >3 years or >10 kg weight Emtricitabine >3 months Fluoxetine >6 years Ibuprofen >3 months Mefloquine >5 kg or >3 months





edicines with age restrictions





Ibuprofen; Prostaglandin E; Surfactant





Complementary list



M 

Caffeine citrate



S

27. pecific medicines for neonatal care





Acetic acid; budesonide Nasal spray; ciprofloxacin Topical: 0.3% drops; Xylometazoline



26. Ear, nose and throat conditions in children

1. Better Medicines for Children in India. Report of Informal Consultation, WHO SEARO, New Deldhi, India, 2-3 Feb 2010. http://www.who.int/childmedicines/progress/SEAro_ Feb2010_Meeting.pdf. 2. BNF for Children. 2009. London: BMJ Publishing Group, RPS Publishing, and RCPCH Publications; 2009. 3. Essential medicines. http://www.who.int/medicines/services/ essmedicines_def/en/index.html. (accessed on 8/11/09). 4. Jeeson C Unni, Nair MKC, Menon PSN, Bansal CP editors. IAP Drug Formulary Web Update 2009 (3) Edition 16. IAP Publication. 5. Model formulary for children. Based on second model list of essential medicines for children 2009. WHO. http://apps.who. int/medicinedocs/documents/s17151e/s17151e.pdf. 6. Ten Facts on Essential Medicines. http://www.who.int/ features/factfiles/essential_medicines/essential_medicines_ facts/en/index.html. 7. WHO model formulary: MR Couper and DK Mehta (Editors). Geneva: World Health Organization, 2002. 8. WHO model list of Essential Medicines – 16th list (updated) March 2010. http://www.who.int/medicines/publications/ essentialmedicines/Updated_sixteenth_adult_list_en.pdf. 9. WHO Model List of Essential Medicines for Children 2007 accessed on 10/11/09 from. http://www.who.int/ childmedicines/publications/EMLc%20%282%29.pdf. 10. WHO Model List of Essential Medicines for Children; 2nd List, March 2009. http://www.who.int/selection_medicines/ committees/expert/17/second_children_list_en.pdf.

Calcium gluconate

ibliography



Complementary list



   

B





25. Vitamins and minerals

   

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than 5 US cents per unit) when compared to the fee paid for receiving an injection (50 US cents on average), patients are usually willing to pay a little extra for safety once they personalize the risks.

Managing Waste Safely and Appropriately As waste disposal is frequently not an integral part of health planning, unsafe waste management is common. However, when it is appropriately planned, significant results ensue. National health care waste management strategies require a national policy to manage health care waste, a comprehensive system for implementation, improved awareness and training of health workers at all levels, as well as the selection of appropriate options for the local solutions.

Twenty years into the HIV pandemic, knowledge of HIV among patients and health care workers in some countries has driven consumer demand for safe injection equipment and irreversibly improved injection practices. With growing knowledge of HCV and HBV, similar patterns of consumer demand for safe injections should emerge. HIV prevention programs can be expanded to include injection safety components.

Ensuring Availability of Equipment and Supplies Simply increasing the availability of safe injection equipment can stimulate demand and improve practices. Because the cost of safe disposable syringes is low (less

• • • • •

•

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os and on’ts of njection afety I

Changing behavior of Health Care Workers and Patients

A safe injection, phlebotomy (drawing blood), lancet procedure or IV device insertion is one that: • Does not harm the recipient • Does not expose the provider to any avoidable risk • Does not result in any waste that is dangerous for other people. D

Unsafe injection practices are often viewed as a chronic problem with no easy solution. However, safe and appropriate use of injections can be achieved by adopting a three part strategy:

I

What is a afe njection?

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R

S

R

C

C

I

E

xamples of onditions ausing isk: teps elated to njection Giving

I

S

S

Medical treatment is intended to save life and improve health, and all health workers have a responsibility to prevent transmission of health-care associated infections. Adherence to safe injection practices and related infection control is part of that responsibility—it protects patients and health workers. Injection is defined as a skin piercing event performed by a syringe and a needle to introduce a vaccine or a curative substance into a patient by various routes such as IV, IM, SC, ID, etc. S

I

U

A

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afe and ppropriate se of njections is within Our Grasp

pecifics of afe njection Practices





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Unsafe injection practices are a powerful engine to transmit blood-borne pathogens, including hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV). Because infection with these viruses initially presents no symptoms, it is a silent epidemic. However, the consequences of this are increasingly recognized. • epatitis B virus: HBV is highly infectious and causes the highest number of infections in developing and transitional countries 21.7 million people become infected each year, representing 33% of new HBV infections worldwide. • epatitis virus: Unsafe injections are the most common cause of HCV infection in developing and transitional countries, causing two million new infec tions each year and accounting for 42% of cases. • uman immunodeficiency virus: Globally nearly 2% of all new HIV infections are caused by unsafe injections. In South Asia up to 9% of new cases may be caused in this way. Such proportions can no longer be ignored. HBV, HCV, and HIV cause chronic infections that leads to disease, disability and death a number of years after the unsafe injection. Those infected with HBV in childhood will typically present with chronic liver disease by the age of 30 years, at the prime of their life. This has a dramatic effect on national economies.

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afe njection Practices

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DO carry out hand hygiene (use soap and water or alcohol rub), and wash carefully, including wrists and spaces between the fingers, for at least 30 seconds DO use one pair of nonsterile gloves per procedure or patient DO use a single-use device for blood sampling and drawing DO disinfect the skin at the venipuncture site DO discard the used device (a needle and syringe is a single unit) immediately into a robust sharps container where recapping of a needle is unavoidable, DO use the one-hand scoop technique (see Annexure) 1167 DO seal the sharps container with a tamper-proof lid

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Health workers who give injections or collect blood

Community or other health workers

Unnecessary injections Reuse of injection equipment Nonsterile or reprocessed syringes and needles Poor hand hygiene Cross-contamination through: •  poor hand hygiene •  medication vials Improper injection technique or site Sharps in hospital linen or other unexpected places

Unnecessary injections Two-handed recapping of needles Manipulation of used sharps Lack of sharps box within arm’s reach Poor positioning of patient Poor phlebotomy technique Two-handed transfer of blood Unsafe transport of blood Poor hand hygiene Nonsegregated sharps waste

Increased waste from unnecessary injections Unsafer disposal of sharps waste: •  outside safety boxes •  mixed with hospital linen •  in nonsecure disposal sites Lack of protective clothing (boots, gloves, etc.) for waste handlers Reuse of needles or syringes

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Patients or clients

DO place laboratory sample tubes in a sturdy rack before injecting into the rubber stopper • DO immediately report any incident or accident linked to a needle or sharp injury, and seek assistance; start Post-exposure prophylaxis (PEP) as soon as possible, following protocols • DO NOT forget to clean your hands • DO NOT use the same pair of gloves for more than one patient • DO NOT wash gloves for reuse • DO NOT use a syringe, needle or lancet for more than one patient • DO NOT recap a needle using both hands • DO NOT touch the puncture site after disinfecting it • DO NOT leave an unprotected needle lying outside the sharps container • DO NOT overfill or decant a sharps container • DO NOT inject into a laboratory tube while holding it with the other hand • DO NOT delay PEP after exposure to potentially contaminated material; beyond 72 hours, PEP is NOT effective. The essential steps for safe injection practices are: • Clean work space for injection preparations (free from any blood contamination) • Appropriately done hand hygiene ( described below). Hand hygiene is a general term that applies to either hand washing, antiseptic hand wash, antiseptic hand rub or surgical hand antisepsis. It is the best and easiest way to prevent the spread of microorganisms. Hand hygiene should be carried out as indicated in Figure 21.5.1 either with soap and running water (if hands are visibly soiled) or with alcohol rub (If hands appear clean).

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Putting on gloves (first make sure hands are dry).

Perform Hand Hygiene AFTER • • •

An injection session Any direct contact with patients Removing gloves. You may need to perform hand hygiene between injections, depending on the setting and whether there was contact with soil, blood or body fluids. Avoid giving injections if your skin integrity is compromised by local infection or other skin conditions (e.g. weeping dermatitis, skin lesions or cuts), and cover any small cuts.

Injection Site Preparation •

Apply a 60–70% alcohol-based solution (isopropyl alcohol or ethanol) on a single-use swab or cotton-wool





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Perform Hand Hygiene EFORE

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Starting an injection session (i.e. preparing injection material and giving injections) Coming into direct contact with patients for health care related procedures

Figure 21.5.1 Six steps of hand washing  

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People may have different perceptions and meanings regarding the term “rational drug use”. However, the conference of experts on the rational use of drugs, convened by the World Health Organization in Nairobi in 1985 defined that: “Rational use of drugs requires that patients receive medications appropriate to their clinical needs, in doses that meet their own individual requirements for an adequate period of time, at the lowest cost to them and their community.” A review of essential drug lists and management guidelines of common illnesses shows that injections are recommended only for acute care (emergency setting) and immunization. The reasons given for injection over use are that patients and health workers believe injections are more effective, act fast and course of management is short. These are wrong notions. There is need to promote rational injection therapy among all prescribers. It can be achieved through following steps: • Defining effective and safe protocols • Promoting minimal essential injection practices • Promoting rational drug/injection therapy • Reduction in procurement of injectable drugs at health facilities • Encouraging prescription auditing at all health facilities, public as well as private sectors • Continuing medical education for health workers

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Figure 21.5.2 Prevention of contamination of injection equipment

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Give injections only when indicated Emergency equipment should be kept ready to use in emergency situations like anaphylactic reactions oxygen bag and mask, laryngoscope and endotracheal tubes as well as emergency drugs such as adrenaline, volume expanders, hydrocortisone, dopamine should be available. IV cannulae, syringes and needles are also essential Check the appropriate drug or vaccine and its date Make sure that vial or ampoule contains right medication, its appropriate concentration and doses The drug or vaccine should be kept sterile during the procedure Clean the injection site properly Use disposable or sterile needle and syringe, preferable with reuse prevention feature Do not touch the parts of needle and syringe in which come in contact with injectable drug and body If you accidentally touch these parts, discard the syringeneedle Take care to avoid air bubble in the syringe or bulb While injecting take care to prevent needle stick injury (report immediately if you get injured—this is for your own safety) Used needles and syringes should be disposed as per standard guidelines Observe the child for 15 minutes, after giving injection Talk to the parents regarding drug or vaccine given by injection, necessary precautions, possible adverse reactions, necessary remedial measures in case of adverse reactions Guide them to give information to medical person in case of major problems.

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Contamination of injection equipment should be prevented by not touching certain parts as shown in Figure 21.5.2 The used needles and syringes should be disposed as per biomedical waste management rules.

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Preventing njection quipment from ontamination •

Community awareness regarding harmful effects of injections.

Pediatric hera eutics

ball. DO NOT use methanol or methyl-alcohol as these are not safe for human use • Wipe the area from the center of the injection site working outwards, without going over the same area • Apply the solution for 30 seconds then allow it to dry completely. DO NOT pre-soak cotton wool in a container—these become highly contaminated with hand and environmental bacteria. DO NOT use alcohol skin disinfection for administration of vaccinations.

mportant Points

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DO NOT allow the needle to touch any contaminated surface • DO NOT reuse a syringe, even if the needle is changed • DO NOT touch the diaphragm after disinfection with the 60–70% alcohol (isopropyl alcohol or ethanol) • DO NOT enter several multidose vials with the same needle and syringe • DO NOT re-enter a vial with a needle or syringe used on a patient if that vial will be used to withdraw medication again (whether it is for the same patient or for another patient) • DO NOT use bags or bottles of IV solution as a common source of supply for multiple patients (except in pharmacies using laminar flow cabinets).

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Muscles commonly used for intramuscular injections are: • Vastus lateralis • Deltoid • Gluteus medius. Children do not have well-developed gluteus medius and therefore it is not the site of preference for IM injections in children. It has been documented that some vaccines like hepatitis B and anti-rabies vaccines administered at gluteal region produce very poor antibody response. The vastus lateralis (anterolateral aspect of thigh) is preferred site in infants. The specific site in vastus lateralis is the middle third of the area between the greater trochanter and lateral femoral condyle. In case of deltoid, the site for injection is midway between acromion process and deltoid insertion, it comes to 3–5 cm below the acromion process. This site may be used in children above 5 years and adults. The quantity of drug should be less than 5 ml. Only watery injections with less viscosity should be injected at deltoid region.

Figure 21.5.4 Technique for IM injection

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The site of injection should be exposed well For anterolateral aspect of thigh, the child may be laid supine or be held in mother’s lap For deltoid, child may be held in mother’s lap or may sit The muscle selected for injection should be relaxed The skin over injection site should be cleaned with spirit. A circular motion of swab is used proceeding from puncture site and extending outward for 5 cm et the spirit evaporate and skin become dry, otherwise spirit entering into tissues is painful The syringe is filled with the medicine In children usually 23G needle with 25 mm length is used for IM injections Stretch the skin flat and push the needle down at 90° Aspiration before injecting the vaccine is not required Inject the vaccine at the rate of 1 ml per 10 seconds The needle is withdrawn and injection site is pressed for few seconds Do not rub the injection site

Figure 21.5.5 Technique for SC injection  

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echnique (W O echnique) ( igs 21.5.3 to 21.5.6)

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Figure 21.5.6 Technique for ID injection

• B Figures 21.5.3A and B Positioning of the child for IM injection (vastus lateralis)  

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Needle should be withdrawn smoothly with steady movement • Discard the needle and syringe as per standard guidelines. Alternative to WHO technique, ACIP technique may be used. It is also called bunching technique. In this technique,

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Indications for intradermal (ID) injections are: • BCG vaccination • Mantoux test • Skin tests for allergy • Test for sensitization of certain drugs like penicillin, etc.

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The risks of transmission of infection from an infected patient to the HCW following an NSI are Hepatitis B 3–10%; Hepatitis C 3% and HIV 0.3%.

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The exposure site should be cleaned immediately. This is the most important part of PEP. Puncture wounds and other cutaneous injury sites should be washed with soap and water. Exposed oral and nasal mucous membranes should be vigorously flushed with water. Eyes should be irrigated with clean water or saline. There is no evidence that antiseptics for wound care reduces the risk of blood borne pathogen transmission. The use of bleach or other caustic agents that cause local tissue trauma are not recommended.

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Technique Ventral (volar) aspect of forearm is commonly used for ID injection Skin is cleaned with spirit or clean water A measured amount of antigen (usually 0.1 ml) is drawn into the syringe 26 or 27G needle with 1/4 to 1/2 inch (6.35–12.7 mm) length needle is used for ID injection The skin is held taut between thumb and index finger of the left hand. The syringe is held at an angle of 10–15° with the skin Needle is inserted for about 2 mm, so that entire needle bevel penetrates the skin and the injected solution raises a small bleb of about 5 mm in diameter. The development of perifollicular puckering (Peau de orange) indicates successful ID injection The needle is withdrawn The site is circled and it is recorded in patient’s chart The reaction is observed in defined time.

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Overuse of injections and unnecessary sharps Lack of supplies: Disposable syringes, safer needle devices, and sharps-disposal containers ack of access to and failure to use sharps containers immediately after injection Inadequate or short staffing Recapping of needles after use ack of engineering controls such as safer needle devices Passing instruments from hand to hand in the operating suite ack of awareness of hazard and lack of training. T

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Needle stick injuries (NSIs) can be defined as an accidental exposure through needles which may occur before, during or after the process of injection giving. It might place health care professional or worker (HCP/HCW) at risk of blood borne infections like Hepatitis B, Hepatitis C or HIV and many others. Globally, NSIs are the most common source of occupational exposures to blood and the primary cause of blood-borne infections of HCWs. The two most common causes of NSIs are two handed recapping and the unsafe collection and disposal of sharps waste.

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Drugs or vaccines are injected subcutaneously when slow absorption and long duration of action are desired. Another indication of subcutaneous injection (SC) route is a coagulopathy which makes IM injection hazardous, for fear of development of intramuscular hematoma. Insulin and heparin like drugs as well as measles, varicella, MMR, etc. vaccines are given by SC route.

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bunch the muscle and direct needle inferiorly along long axis of leg at an angle of 45°. It stabilizes leg and increases the muscle mass.

If the HCP/HCW is vaccinated and his serum antibody titer is more than 10 IV/ml, no further treatment is required If antibody titer is less than 10 IV/ml and HCP/HCW is HbsAg negative or the source is unknown, then one course of three doses of vaccine is repeated and then antibody titer is rechecked

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If HCP/HCW is HbsAg positive then both Hepatitis B vaccine is repeated and HBIG is given within hours of exposure If HCP/HCW is not vaccinated then vaccination series is started within 7 days.

 

Flow chart 21.5.1 Management of HCP/HCW exposed to hepatitis B injection

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Biomedical waste management (BWM) is a process starting from the point of use of a device till its final disposal. It is not only an issue of technology but also requires lot of changes in the way we think. Health care waste is hazardous both to the HCP, patients and public at large. Government of India under the provision of Environ mental Act, 1988 notified the BMW Rules in 1988, which regulates the disposal of all biomedical waste with an

harp Waste Minimization

As far as possible minimize the use of sharps. Emphasize the rational use of injections in the treatment of illness. The use of disposable syringes and needles has increased considerably, generating potentially infectious waste with limited options for treatment and disposal. The use of plastic disposables should be limited as far as possible because plastics are not degradable and more likely to cause reuse.

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Indian Academy of Pediatrics (IAP) endorses the NACO (National AIDS Control Organization) guidelines. These should be implemented all over India • If any HCP/HCW or citizen reports with NSI to emergency services in a public health facility, it is recommended that immediate care, free testing and free PEP medicines should be provided • A nodal contact person should be in place in all facilities with 24 hours access to deal with immediate management of NSIs/other exposures • Health care workers (HCWs) should ensure that a startup pack of PEP medication is available in their place of work. For HIV PEP, as per NACO guidelines, first define exposure code (EC) indicating degree of exposure to infectious materials, then decide HIV status of exposure source (ES) and follow PEP regimen as per recommendations (Flow chart 21.5.1).

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objective to ensure safety of health and environment. All health care facilities are required to segregate, disinfect, transport and dispose off the biomedical waste in an environmental friendly manner. Biomedical waste shall not be mixed with other wastes. As per the schedule-I, Rule 5 of BMW Rules, sharp wastes are classified in Category 4, which says, sharp wastes means needles, syringes, scalpel blades, glass, etc. that may cause puncture and cuts. This includes both used and unused sharps, which should be treated. As per Schedule-II, color coding of the container for disposal sharps is a must. Blue/ White translucent colored puncture proof container has to be used and disposed as per the schedule. Section 4 of the Act has given policy statement. The following steps should be followed: Minimization, segre gation, handling, storage of hospital waste, and disposal.

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The following are recommendations for follow-up of occupational HCV exposures: • For the source, perform anti-HCV • For the person exposed, to HCV positive source: – Perform baseline testing for anti-HCY and A T activity – Perform follow-up testing at 4–6 months for antiHCY and A T activity – If earlier diagnosis of HCY infection is desired, testing for HCV RNA may be performed at 4–6 weeks • Confirm all anti-HCV results reported positive by enzyme immunoassay, using supplement anti-HCV testing • Immunoglobulins and antiviral agents are not recommended • Post-exposure prophylaxis (PEP) after exposure to HCV positive blood. –

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Sharps should be segregated at source. The clinical staff is responsible for segregating the waste at source. Blue/ White translucent puncture proof containers should be placed at strategic and easily accessible locations. Needles should not be recapped, removed and transported by hand. Sharps should be disinfected. Hub-cutters or needle and syringe destroyer should be used at the site of generation to reduce the bulk, to disinfect and to prevent reusing.

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These are disposable syringes that lock once the medication has been injected and hence physically cannot be reused, since these syringes prevent reuse and they present the lowest risk of patient-to-patient transmission of blood borne pathogens. These are available as prefixed 0.5 ml syringes and are presently available for immunization only. Syringe with different mechanisms are commercially available. These can be broadly divided into two types of auto-disable mechanisms:

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Passive Mechanism •

The device is disabled as soon as the drug is fully injected out. The user has no control over the mechanism • No chance of reuse as user has no control over mechanism. WHO-UNICEF-UNFPA joint statement issued in 1999 on the use of AD syringes in immunization services has urged countries to use only AD syringes for immunization after 2003. It is also recommended that in the curative sector also, injection devices with re-use prevention mechanisms should be used (Fig. 21.5.7).

Prefilled Vaccine evices or Pouch and Needle evices ( igs 21.5.8 and B) A

Prefilled vaccine devices or pouch and needle devices were also developed by PATH and are used by the pharmaceutical companies and vaccine manufacturers to fill vaccines into them and supply. They combine the benefit of prefilled device with that of auto-disable technologies. Minimally trained volunteers can use them. Several vaccines are now available with this technology.

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It is necessary to treat certain waste before disposal to prevent hazards to human health and environment. Immediately after use, syringes with needles should be dropped into sharp decontaminating unit so that both parts are completely immersed in disinfectant. When SDU is one-third full, after contact time of 30 minutes the inner perforated container contents are drained into puncture proof containers for shredding. Heat disinfection, encapsulation, smelting, burial, incineration are modes for disposal of sharp wastes in mass. The education and awareness of HCW and public is important. The general public coming to hospital and in the community should know the medical risks of hospital waste so that they keep away from risks and also to demand the proper care, services from the hospital.

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Requires the user to “actively” disable the syringe/ device after use Disadvantage—chances of reuse if mechanism is not activated.

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Types of waste required to be mutilated are needles, syringes, plastic disposables, etc. Shredders are equipment to cut the waste into small pieces to reduce the volume. They must have safety provisions to prevent contamination. They must be placed in a separate room. Waste must be properly disinfected before feeding into shredder.

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Sharps decontaminating units (SDU) for syringes and needles are made of plastic and are puncture proof, they can be foot operated with an inner perforated container with secured handles. They should be filled one-third with 1% hypochlorite solution (refer to the recent central pollution board guidelines). Sharps in inner containers after treatment with hypochlorite solution should be transferred to puncture proof containers for shredding. They should be labeled as sharps only.

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Figure 21.5.7 Auto disable syringes  

Technology plays a supportive role in enhancing the quality of patient care in our day-to-day working. This has over a period of time helped health care professionals to deliver services effectively and efficiently. Most of the technological advances have happened as a response to the demands of the health care provider. These technologies for ease of understanding can be divided into three different kinds: Auto-disable (AD) syringes, prefilled AD devices and health care worker safety devices.

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Figures 21.5.8A and B (A) Needle shields; (B) Safety cannula

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Bibliography

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Keep hands clean before giving injections Always use “sterile injection equipment”. Always use sterile syringe and needle for each injection and to reconstitute each unit of medication Prevent contamination of injection equipment and medicines Prepare each injection in a clean designated area where blood or body fluid contamination is unlikely Clean skin prior to injection with water and wait for it to dry. Do not use cotton balls stored wet in a container If multidose vials are used, always pierce the septum with a sterile needle. DO NOT leave a needle in place in the stopper of the vial Follow product-specific recommendations for use storage and handling of a medication or vaccine Discard a syringe if the needle has touched any nonsterile surface Ensure safe containment of sharps immediately after use: in a sharp safety box after use, without recapping or manually mutilating/handling the sharps/needles. Practice safe disposal for all medical sharps waste Prevent needle stick injuries to the provider: Anticipate and take measures to prevent sudden patient movement during and after injection. Do not recap or touch needles. Collect used syringes and needles at the point of use in a sharps container that is puncture-proof and leak-proof. The container should be sealed when three-fourth full Prevent public access to used needles: Seal sharps containers before carrying to a secure area in preparation for disposal. After dosing and sealing sharps containers, do not open, empty or reuse them. Manage sharps waste in an efficient, safe and environmentally friendly way to



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1. Abdel-Aziz F, Habib M, Mohamed MK, et al. Hepatitis C virus (HCV) infection in a community in the Nile Delta: population description and HCV prevalence. Hepatology. 2000;32(1):111-5. 2. Centers for Disease Control and Prevention. National Institute for Occupational Safety and Health (NIOSH) NIOSH Alert: Preventing Needle stick Injuries in Health Care Settings, 1999. Publication No. 2000-108. . 3. Frank C, Mohamed MK, Strickland GT, et al. The role of parenteral antischistosomal therapy in the spread of hepatitis C virus in Egypt. Lancet. 2000;355(9207):887-91. 4. Hutin YJ, Hauri AM, Armstrong G . Use of injections in healthcare settings worldwide, 2000: literature review and regional estimates. BMJ. 2003;327(7423):1075-8. 5. Indian academy of pediatrics Workshop on Safe Injection Practices: recommendations and IAP plan of action. Indian Pediatr. 2005;42:155-61. 6. Kamath SS, Bhave S, Shah RC (Eds). IAP Guide Book on Safe Injection Practices. Published by IAP National Task Force on Safe Injection Practices, 2005. 7. akshman M, Nichter M. Contamination of medicine injection paraphernalia used by registered medical practitioners in South India: an ethnographic study. Soc Sci Med. 2000;51(1):11-28. 8. Lala KR, Lala MK. Intramuscular Injection: review and guidelines. Indian Pediatr. 2003;40(9):835-45. 9. Management of wastes from immunization campaign activities. Practical guidelines for planners and managers. [online] www.healthcarewaste.org. (Accessed Nov 2004). 10. Pruss-Ustun A, Rapiti E, Hutin Y. Sharps injuries: global burden of disease from sharps injuries to health-care workers. Geneva, Switzerland: World Health Organization, 2003 (WHO Environmental Burden of Disease Series, No. 3). 11. Royal College of Pediatrics and Child Health, Position Statement in Injection Technique, March 2002. 12. World Health Organization. Aide-Memoire for a Strategy to Protect Health Workers from Infection with Blood borne Viruses. Geneva, Switzerland: WHO; November 2003.

safety and prevention act passed in the US in 2000, the trend, globally, is shifting towards use of safety engineered products. Now a range of products which help prevent accidental NSIs are available. These products are now widely available in India.

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cetazolamide: Epilepsy: as adjunct. Starting dose up to 12 years 2.5 mg/kg and 12–18 years 250 mg 2–3 times daily and increase every 4–5 days to maintenance dose of 5–7 mg/kg/dose 2–3 times daily up to 750 mg/day in less than 12-year-old and 1 g/day in 12– 18 year olds. The IV bolus dose is 6–7 mg/kg 2–3 times daily in less than 12 year and 250 mg 2–4 times in 12–18 year. Edema: oral or IV starting dose. Starting dose—up to 12 years 2.5 mg/kg and 12–18 years 250 mg 2–3 times daily. Raised intracranial pressure: oral/IV 8 mg/kg thrice daily and gradually increased. Hydrocephalus: due to communicating IVH Neonates—25 mg/kg/24 hour. Glaucoma: oral/IV 5 mg/kg in less than 12 years and 250 mg in 12–18 years 2–4 times daily to a maximum of 750 mg/day in less than 12 years and 1 g/day in 12–18 years. If creatinine clearance is 10–20 mL/mt/1.73 sqm, reduce to twice daily and if less than 10 avoid. A

cetylcysteine: Paracetamol poisoning: initial IV infusion over 15 min (less than 12 years 150 mg/kg in 100 mL, 12–18 years 150 mg/ kg in 200 mL) followed by IV infusion over 4 hours (less than 12 years 50 mg/kg in 250 mL, 12–18 years 50 mg/kg in 500 mL) and then IV infusion over 16 hours (less than 12 years 100 mg/kg in 500 mL, 12–18 years 100 mg/kg in 1,000 mL).

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Herpes simplex prophylaxis: 100 mg 1 month to 2 years; 200 mg. 2–18 years 4 times daily. Double dose for immunocompromised. dapalene: Topical: wash and dry affected area and apply a thin film before bedtime. Assess for improvement after 3 months treatment. denosine: Up to 12 years—0.05 mg/kg IV push and then increase bolus doses by 0.05 mg/kg every 2 min till clinical response occurs or a maximum dose of either 0.3 mg/kg or 12 mg, 12–8 years—3 mg IV bolus, increase after 2 min to 6 mg and to 12 mg if SVT not controlled after another 2 min. drenaline ( pinephrine): Cardiopulmonary resuscitation (CPR) 1). Neonates: IV or intratracheal initially 0.1 mL/kg followed by 0.1–0.3 mL/kg of 1:10,000 solutions 2). One month to 12 years SC 0.01 mL/kg of 1:1,000 solution, IV 0.1 mL/kg of 1:10,000 solution and similar subsequent doses if required or intratracheal 0.1 mL/ kg of 1:1,000 solution to maximum of 5 mL of 1:1,000 solution. 3). 12–18 years IV 1–5 mg every 3–5 min, intratracheal 1 mg initially to maximum of 12.5 mg/dose, continuous infusion 1–10 µg/min. Acute anaphylaxis: up to 12 years 0.01 mL/kg and 12–18 years 0.5–1 mL of 1:1,000 solution deep IM. Repeated every 5 min if required. Low cardiac output: Continuous IV infusion of 10 ng to 1 µg/kg/min. Croup: Nebulize 1–5 mL of 1:1,000 solutions. Observe with ECG and oxygen saturation monitoring. IV infusion at a low dose of 0.05– 0.3 µg/kg/min, adrenaline exerts only beta 1 and 2 effect, thereby increasing cardiac output and heart rate without vasoconstriction. It may produce vasodilation due to its effect on B2 receptors. At a higher dose, 0.3–1.0 µg/kg/min, both alpha and beta effects are seen. At further higher dose (more than 1.0 µg/kg/min) the alpha effect predominates resulting in vasoconstriction. Bolus dose is used for anaphylactic reaction and for acute bronchial asthma. A



Meconium ileus: 20% injection given orally diluted 1:4 at 1–2 mL in newborn.

Children—orally 100 mg less than 2 years and 200 mg 2–18 years 5 times daily; IV infusion 10 mg/kg less than 3 months, 250 mg/sqm 3 months to 12 years and 5 mg/kg 12–18 three times daily. Double dose for immunocompromised.

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carbose: Oral—12–18 years initially 25–50 mg daily and gradually increased to 23–50 mg thrice daily. Maximum after 6–8 weeks could be 100–200 mg thrice daily.

cyclovir: The cream and ophthalmic ointment may be used 5 times daily for herpes simplex infection and herpes simplex keratitis respectively of the skin. Continue the eye ointment for 3 days after healing. Newborn—IV infusion at 10 mg/kg 3 times daily for 10 days.

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bciximab: 0.25 mg/kg intravenous bolus, followed by 0.125 µg/ kg/min infusion for 12 hours. Platelet counts and coagulation time must be monitored. Preferably used by specialist experienced in its use.

ctivated charcoal: Dose related more to dose of poison (10 times weight of poison is given) than age/weight of child. If amount of toxin unknown, give either as single dose within 1 hour of ingestion of poison or as multiple doses 4th hourly till toxicity abates or side effects of charcoal become evident by weight 1 g/ kg or by age 25–50 g in 2–12-year-old.

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For adolescents, the initiation of antiretroviral therapy is recommended in any patient: with a history of an AIDS-defining infection; with a CD4 less than 350/mm3; who is pregnant; who has HIV-associated nephropathy; or who is being treated or hepatitis B (HBV) infection. For children, the initiation of antiretroviral therapy is recommended in any symptomatic patient. For asymptomatic or mildly symptomatic children more than or equal to 5 years, the initiation of antiretroviral therapy is recommended or patients with HIV RNA more than or equal to 100,000 copies/mL and CD4 less than 350/mm3. For asymptomatic or mildly symptomatic children 1–5 years, the initiation of antiretroviral therapy is recommended for patients with HIV RNA more than or equal to 100,000 copies/mL and CD4 less than 25%. For infants, the initiation of antiretroviral therapy is recommended in any infant regardless of clinical status, CD4 percentage or viral load.

daily. Occasionally up to 1 mg/kg needed (maximum 35 mg daily for short periods).

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bacavir: HIV infection in combination with at least two other antiretroviral medicines, by mouth, adolescent—300 mg twice daily; 3 months to 16 years, 8 mg/kg twice daily (maximum 600 mg daily).

galsidase beta: IV 16–18 years—1 mg/kg once in 2 weeks.

lbendazole: Whipworm, trichuriasis, pinworm, threadworm, hookworm, roundworm, ascariasis: less than 2 years 200 mg, more than 2 years 400 mg. Single dose. May be repeated after 2–3 weeks for pinworm, threadworm. Ankylostomiasis—400 mg single dose. A

Mucolytic: as 10% solution for inhalation— infants 2–4 mL 3–4 times, children 6–10 mL 3–4 times, adolescents 10 mL 3–4 times. A

citretin: Maximum duration of continuous treatment is 6 months. Given orally in 12–18-year-old at 500 µg as single dose

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lfacalcidol):

lprazolam: Anxiety: orally for 12–18 years old 200–500 µg 3 times daily (maximum 4 mg/day in divided doses) use minimum effective dose. Panic disorder: orally for 12–18 year olds 500 µg 3 times daily, increase once in 4 days to maximum of 10 mg/day in divided doses.

lendronate: Experience of the use of bisphosphonates in children is limited and expert advice should be sought. Their use is only justified when the potential benefits outweigh any risk. 5 mg/ day or 35 mg/week for less than 30 kg, 10 mg/day or 70 mg/week for 30 kg. Mean dosage is 0.37 ± 0.069 mg/kg/day.

Hyperphosphatemia: Oral—1 month to 1 year 2.5–5 mL 3–4 times daily; 1–5 year 5–10 mL 3–4 times daily; 5–12 years 10–20 mL 3–4 times daily dose may be increased or decreased as required within the ranges given. 12–18 years—tab containing 840 mg; 1–3 tabs; 4–5 times daily.

lendronic acid ( odium alendronate): Experience with bispho sphonates in children is limited; expert advice required and use only in specialist centers experienced in its use.

mantadine: Influenza A virus infection: Oral—Children more than or equal to 10 years 5 mg/kg/day PO in 2 divided doses, not to exceed 200 mg/day (100 mg PO twice daily in children who weigh more than or equal to 40 kg). Children less than 10 years 5 mg/kg/ day PO (up to 150 mg/day) in 2 divided doses. Primary influenza prophylaxis (influenza virus type A only). Oral—Adults less than 65 years and adolescents: 200 mg/day PO as a single dose or 2 divided doses; begin as soon as possible after initial exposure and continue for at least 10 days after exposure. Elderly: No more than 100 mg PO once daily; begin as soon as possible after initial exposure and continue for at least 10 days after exposure. HIVinfected adults, adolescents, and children more than or equal to 10 years: as an alternative to influenza vaccination amantadine 100 mg PO twice daily be considered for primary prophylaxis during outbreaks of influenza A. Monitor these patients closely. Children more than or equal to 10 years: 5 mg/kg/day PO in 2 divided doses; begin as soon as possible after initial exposure and continue for at least 10 days after exposure. Do not exceed 200 mg/day. Children less than 10 years: 5 mg/kg/day PO (up to 150 mg/day) given in 2 divided doses; begin as soon as possible after initial exposure and continue for at least 10 days after exposure. In all above mentioned scenarios, prophylaxis may be continued for up to 90 days for repeated or suspected exposures if influenza virus vaccine is unavailable. If used with the influenza virus vaccine, continue amantadine for 2–3 weeks until vaccine protection develops.

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Monitor carefully for hypercalcemia. In renal bone disease, main tain parathyroid hormone level at or slightly above the normal range. Over suppression can result in a dynamic bone disease. Hypophosphatemic rickets: up to 2 years and less than 20 kg 25–50 ng/kg; more than 20 kg 1 µg IV/oral daily once. Neonatal hypocalcemia: 50–100 ng/kg oral/IV. Up to 2 µg/kg in severe cases. 100 ng/kg/day for prophylaxis in premature. Prophylaxis of vitamin D deficiency in renal failure: up to 2 years and less than 20 kg 15–30 ng/kg and more than 20 kg 250–500 ng daily once orally/IV. A

lfentanil: Used only by trained anesthetist/interventionist as assisted ventilation required. Initially 20–50 µg/kg followed by 15 µg/kg both as IV bolus over 30 seconds. Alternatively, loading dose 50–100 µg/kg IV over 10 min followed by IV infusion at 500 ng to 1 µg/kg/min. A

lginate: Dosage description: give infants sachets with or after feeds—less than 4.5 kg half sachet and more than 4.5 kg 1 sachet. More than 2 years give liquid or tablet after meals and at bedtime 2–12 years 1 tab or 5–10 mL liquid and 12–18 years 2 tabs or 10–20 mL liquid.

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luminum chloride: Hyperhidrosis: Apply 1–2 mL of aluminum chloride hexahydrate in the affected areas (armpits, palms, legs) only at night. This can be washed off in the morning. This has to be applied initially for every night in the first week and once the sweating comes down this can be brought down to thrice weekly and then twice weekly and then weekly. Eventually the patient can be maintained with a weekly dosage. Bromhidrosis and prevention of tenia pedis—apply powder to the dry affected skin areas. A

luminum hydroxide: Antacid 4% w/w 6–12 years—5 mL 3 times daily; 12–18 years—5–10 mL 4 times daily and as required between meals and at bedtime.

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Hydatid disease, echinococcosis: 15 mg/kg daily for 4 weeks. In hydatid disease, a large dose of mebendazole is required (400– 600 mg 3 times a day for 21–30 days). This large dose may cause bone marrow aplasia and hence albendazole is a preferred drug nowadays for hydatid disease. Repeat the dose after 14 days, if required for next such three doses. Cutaneous larva migrans: less than 2 years 10 mg/kg twice daily for 5 days; 2–12 years 400 mg daily once for 5 days. Toxocariasis: 2–12 years 10 mg/kg up to maximum of 400 mg; 12–18 years 400 mg twice daily for 5 days. Steroid cover in symptomatic cases; especially if there is ocular involvement. Albendazole 400 mg bid for 5 days is also used for all the ages. Therapy may be adjuncted with corticosteroid if inflammatory symptoms with ocular involvement persist. Filariasis: It has adjuvant value to DEC or ivermectin in lymphatic filariasis. A single dose in combination has been used in mass programs.

lfacalcidol (1 lpha-hydroxycholecalciferol): Indices of res ponse—plasma calcium (ideally corrected for protein binding), alkaline phosphatase, parathyroid hormone, as well as radiological and histological investigations.

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Trichinosis: 2–12 years 400 mg daily once for 5 days. Repeat if necessary. Tapeworm: 400 mg daily once for 3 days. Neurocysticercosis: In neurocysterosis—albendazole is used in dose of 15 mg/kg for 3–4 weeks. A short course of 8 days is also found to be effective depending upon location of cyst. A dose of 7.5 mg/ kg up to maximum of 400 mg twice daily for 14–28 days. Take with food. Repeat if necessary. Under steroid and anticonvulsant and in readiness for shunting for raised intracranial pressure.

llopurinol: Hyperuricemia due to tumor lysis syndrome: IV/oral 100 mg/sqm 3 times daily to be commenced 24 hours before starting cytotoxic drugs. GSD and MMA: 10–15 mg/kg (maximum 400 g) as single daily dose if serum uric acid more than 0.36 mmol/L. PRPP synthetase superactivity and Lesch-Nyhan syndrome: 10–20 mg/kg (maximum 400 mg) daily once at minimum dose to maintain normal uric acid levels. APRT deficiency: 10 mg/kg (maximum 400 mg).

mikacin: Newborn: IV—less than 35 weeks up to 14 days 10 mg/kg once daily and more than 14 days 10 mg/kg loading dose followed by 7.5 mg/kg/dose 2 times daily; more than 35 weeks less than A

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Strongyloidosis (Strongyloides stercoralis): 2–12 years 400 mg daily once for 3 days. May repeat after 3 weeks, if necessary. 400 mg twice daily for 3 days, repeated after 3 weeks. More effective than mebendazole. Enterobiasis: 100–200 mg single dose, repeated after 4 weeks.

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minophylline: Neonatal apnea: IV 6 mg/kg (loading) followed 24 hours later by maintenance of 2.5 mg/kg IV twice daily (long half-life and so continuous infusion not required). Give slowly over 20 min (undiluted or diluted in NaCl 0.9% or glucose 5%). Monitor theophylline level, if possible—therapeutic range 8–12 mg/L. Bronchial asthma and bronchospasm of anaphylaxis: IV loading dose of 5 mg/kg (maximum 500 mg) over 20–30 min if no theophylline given in prior 24 hours followed by IV infusion at 0.5 mg/kg/hour in 6 weeks to 6 months, 0.7 mg/kg/hour in 5 months to 1 year, 1 mg/kg/hour in 1–12 years and 0.7 mg/kg/hour in more than 12 years. Oral dose of 6 mg/kg for 1 week and then 12 mg/kg 3–12 years and 100–200 mg initially and then 200–450 mg

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mitriptyline: Nocturnal eneuresis: 6–12 years 10–25 mg, 12–18 years 25–50 mg at bedtime daily for up to 3 months. Review before deciding on need for further courses. Depression: more than 12 years 25 mg 2–3 times or 50 mg at bedtime, initially at lower dose and increased if tolerated/required. Usual maintenance is 50–150 mg/day. Neuralgic pain: 30 mg bedtime; increased if required/ tolerated up to 150 mg/day. Idiopathic musculoskeletal pain syndromes: 10–50 mg bedtime, starting at lower dose. A

mlodipine: Oral 100–200 µg/kg daily once increased if required to maximum of 10 mg (6–15 kg 1.25 mg, 15–25 kg 2.5 mg, more than 25 kg 5 mg). A

morolfine: Cream: apply once daily after cleansing in the evening for at least 2–3 weeks (up to 6 weeks for foot mycosis) continuing for 3–5 days after lesion has healed. Nail lacquer: apply to infected nails 1–2 times weekly after filing and cleaning; allow to dry (approximately 3 min). Treat finger nails for 6 months; toe nails for 9–12 months. Review 3 monthly. A

moxicillin: Oral 20–50 mg/kg/day in 2 or 3 divided doses. Higher dose of 80–90 mg/kg in acute suppurative otitis media. (maximum of 500 mg 2–3 times daily). In uncomplicated gonorrhea 3 g with 1 g probenecid. A

mphotericin: No dose reduction is generally required in pre-existing renal failure. Dose reduction may be advisable if amphotericin is suspected of causing nephrotoxicity. Lipid complex formulations should also be considered in such situations. In renal dialysis patients, administration of amphotericin should commence only when dialysis is completed. Children: 2.5–5 mg/ kg IV infused over 1–2 hours once a day. May use higher doses of 7.5–10 mg/kg/24 hour if indicated and tolerated. mpicillin: Neonate: 50 mg/kg/dose less than 7 days 12th hourly, 7–21 days 8th hourly, more than 21 days 6th hourly. 100 mg/kg/ dose for suspected meningitis and Gr B Streptococcal infection. Children: Oral 1 month to 2 years 12.5 mg/kg/dose, 2–12 years 250 mg/dose and 12–18 years 500 mg/dose; IV/IM 25 mg/kg/ dose (maximum 1 g/dose); IV infusion 100 mg/kg/dose (maximum 3 g/dose) all given 4 times daily. A

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minoglycosides: Dose—many dose regimens exist for aminoglycosides depending on target concentration aimed for and patient groups treated. The dose regimens shown here are generally accepted initial doses and dose adjustments should be made in the light of serum concentration measurement. Gentamicin—Neonates IV/IM less than 7 days 1,200–2,000 g 2.5 mg/kg once in 12–18 hours and more than 2,000 g 2.5 mg/kg once in 12 hours; more than 7 days 1,200–2,000 g 2.5 mg/kg once in 8–12 hours and more than 2,000 g 2.5 mg/kg once in 8 hours. Children—less than 12 years 7.5 mg/kg/day and 12–18 years 3–6 mg/kg/day in 3 divided doses. Plasma levels done after 3–4 doses to achieve predose level of less than 2 mg/L and 1 hour post dose peak of 5 mg/L. Alternatively 5–7.5 mg/kg/24 hour IV once daily. Plasma levels done 18–24 hour after first dose to achieve predose level of less than 1 mg/L and 1 hour post dose peak of 16–20 mg/L. Intrathecal/ventricular preservative free preparation—newborn 1 mg/24 hour; children 1–2 mg/24 hour; 16–18 year. Netilmicin—newborn—IV 3 mg/dose 12th hourly. Increase to 8th hourly after 1 week age postnatal. Monitor after 3rd dose for 1 hour post dose peak of 8–12 mg/L and a trough of less than 3 mg/L. Prolong dose interval in PDA, prolonged hypoxia and indomethacin therapy. Children—IV/IM less than12 year 7.5 mg/ kg/day and more than 12 year 6 mg/kg/day in 3 divided doses or 1 month to 18 year 7.5 mg/kg as single dose daily. Intraperitoneal 7.5–10 mg/L in peritoneal dialysis fluid. Tobramycin—newborn— IV less than 32 weeks 4–5 mg/kg 36 hourly and more than 32 weeks 4–5 mg/kg once in 24 hours. PDA, prolonged hypoxia, indomethacin treatment necessitate increased dose intervals. Child—IV/IM 2.5 mg/kg/dose 3 times daily or 7 mg/kg as single daily dose. Intraventricular—newborn 1 mg/day, child 1–2 mg/ day, adolescent 2–4 mg/day. Amikacin—children (1 month to 18 years): IV/IM 7.5 mg/kg/dose 2 times daily up to maximum of 500 mg/dose. Child more than 12 years with life-threatening infection—1.5 g/day in 3 divided doses for up to 10 days may be given.

miodarone hydrochloride: Given under the direct supervision of cardiologist. The minimum effective dose used at all times. Oral loading dose of 5 mg/kg (maximum 200 mg) 2–3 times daily for 5 days followed by maintenance dose of 5 mg/kg (maximum 200 mg) once daily. IV loading dose of 5 mg/kg (in rare cases up to maximum of 15 mg/kg may be given) slowly over 30 min followed by maintenance continuous infusion at 5–15 µg/kg/min (maximum 1.2 g in 24 hours). Central line preferred. In cardiopulmonary resuscitation (CPR) for shock resistant ventricular fibrillation and pulseless tachycardia rapid IV bolus of 5 mg/kg may be given. Amiodarone has a long duration of action and may exert effect for weeks or months after discontinuing. Since it is metabolized in liver, its dose must be adjusted in hepatic dysfunction.

ntiperspirants: Preparations containing aluminum chloride hexahydrate are among the most effective. Aluminum chloride hexahydrate concentrations of 10–15% are recommended for excessive sweating of the underarms. For the hands or feet, higher concentrations are needed usually around 30%. Apply on dry skin at bedtime when sweating is minimal. Use the antiperspirant every night until sweating is reduced. Once that is achieved, reduce frequency of application. A

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miloride: Oral. Prophylaxis of drug induced hypokalemia less than 12 years 100–200 µg/kg and more than 12 years 5–10 mg twice daily. Nephrogenic diabetes insipidus along with hydrochlorothiazide 100 µg/kg 3 times daily.

in more than 12 years given 2 times daily. Diuresis in ICU: IV over 20–30 min 2–4 mg/kg (up to 6 mg/kg in critically ill) 30 min before IV frusemide.

Pediatric hera eutics

14 days 15 mg/kg as single dose daily and more than 14 days 10 mg/kg loading dose followed by 7.5 mg/kg/dose 2 times daily. Extended interval dose regimen by slow intravenous injection or intravenous infusion 15 mg/kg every 24 hours. Children (1 month to 18 years): IV/IM 7.5 mg/kg/dose 2 times daily up to maximum of 500 mg/dose. Child more than 12 years with life-threatening infection—1.5 g/day in 3 divided doses for up to 10 days may be given. Aim for 1 hour post dose (peak) of 15–30 mg/L. Once daily dose regimen (not for endocarditis or meningitis). Child 1 month to 18 years—initially 15 mg/kg, then adjusted according to serumamikacin concentration.

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Kawasaki disease: 25 mg/kg/dose 4 times daily for 14 days followed by 5 mg/kg once daily for 6–8 weeks. If no evidence of coronary lesions discontinue. Anti-platelet dose: 3–5 mg/kg/day, given as a single dose (maximum 75 mg). Rheumatic fever: 25 mg/kg/dose for 4 doses/day for 2–3 weeks. Then 60 mg/kg/day for total period of 9–12 weeks. Aspirin resistance, as seen in adults is prevalent in children also; 26% in one study. tenolol: Renal failure: No dose adjustment is required in patients with a creatinine clearance more than 35 mL/min/1.73 sqm. If creatinine clearance is 10–35 mL/min/1.73 sqm give 50% dose, less than 10 mL/min/1.73 sqm give 30–50% dose and adjust according to response. In hemodialysis and CAPD give 30–50% of dose and adjust according to response. 1–2 mg/kg once daily. Adjust according to pulse and BP. May be given 2 times daily up to maximum of 100 mg/24 hours. A

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rginine: CPS and OCT deficiency: oral 25–35 mg/kg 3–4 times daily, IV 200 mg once given over one and half hour, IV continuous infusion 200 mg/kg/24 hour. Citrullinemia and ASA: oral 100–175 mg/kg 3–4 times daily up to 700 mg/day, IV 600 mg once given over one and half hour, IV continuous infusion 600 mg/kg/24 hour (25 mg/kg/hour). Growth hormone stimulation test: IV infusion 500 mg/kg as single dose over 30 min. A

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rgipressin ( rginine vasopressin, Vasopressin): A continuous infusion administered when no alternative measures available and discontinued at earliest. Treatment should not normally continue for more than 72 hours. Monitor carefully. IV over 20–30 min— birth to 18 years 0.3 units/kg. Continuous infusion: 0.3 units/kg/ hour or 0.0003–0.006 units/kg/min (maximum 1 unit/kg/hour). A

rtemisinin and its derivatives: Expert advice should be sought for optimum treatment including choice of preparation and dosage. A

sparaginase: Always consult the current treatment protocol for details of dosage and scheduling. As part of combination therapy—6,000 units/sqm, 3 times/week for 3 weeks. High-dose IM therapy—25,000 units/sqm/dose weekly once for doses. IV therapy—1,000 units/kg/24 hour for 10 days; or 200 units/kg/24 hour for 28 days. spirin: Fever: 10–15 mg/kg/dose 4–6 times daily (maximum

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tropine sulfate: Premedication: Neonates (never give IM) 15 µg/kg and children: SC/IM 1 month to 12 year 20 µg/kg (minimum 100 µg to maximum 600 µg); 12–18 year 300–600 µg as single dose 45 min before procedure. Less than 5 kg 0.2 mg/ kg 30 min preoperatively and then 4–6 hourly. More than 5 years 0.1–0.2 mg/kg 30 min preoperative. IV bolus over 1 min 15 µg/ kg; 1 month to 12 year 20 µg/kg (minimum 100 µg to maximum 600 µg); 12–18 year 300–600 µg as single dose at induction in the unpremedicated patient. Sinus bradycardia: Neonates (never give IM) and children IV/intratracheal/SC/IM 15 µg/kg may be repeated once 5 min later. Adolescent 0.5–1 mg every 5 min (maximum 2 mg). Organophosphorus poisoning: 0.02–0.05 mg/kg every 10–20 min till atropine effect (mydriasis, tachycardia) and then once in 1–4 hour for at least 24 hours. zathioprine: During the first 4 weeks of therapy, full blood count (including platelets) should be performed at least weekly and monthly thereafter. More frequent monitoring may be indicated if high dosage is used or in the presence of severe renal or hepatic impairment. Dosage should be reduced in renal failure. In transplantation, dose depends on the immunosuppressive regimen employed; always follow the protocol and seek expert advice before prescribing. In organ transplantation to prevent rejection initially 2–5 mg/kg/24 hour IV or oral; maintenance 1–3 mg/kg/24 hour. Autoimmune disease like lupus arthritis or nephritic syndrome 1 mg/kg/24 hour for 6–8 weeks. A

Note local tourniquet should not be released unless full dose of anti-snake venin is administered.

tracurium besylate: Single IV bolus dose: neonate 300–500 µg/ kg; 1 month to 18 years 300–600 µg/kg. Continuous IV infusion: neonate 300–400 µg/kg/hour; 1 month 18 years 300–600 µg/kg/ hour.

zelaic acid: Wash affected area with water alone, dry and apply cream sparingly. Rub in well. Use twice daily (morning and evening), but once daily for the first week to check if skin is sensitive to the drug. Reduce the amount of cream per application if marked skin irritation. Distinct improvement apparent after 4 weeks. Should not be applied for more than 6 months. A

Some centers use for minimal envenomation: 20–40 mL; moderate envenomation: 50–90 mL; severe envenomation: 100–150 mL; if systemic symptoms increase in severity or new manifestations appear, administer an additional 10–50 mL. Sea snake and pit viper specific antivenin is not available. However, due to paraspecificity of venom and antivenin same polyvalent antivenin is recommended. No more test dose is indicated. Intramuscular adrenaline is given before administering the anti-snake venin as prophylaxis.

tomoxetine: Children and adolescents may be started at 0.5 mg/ kg/day and dose may be increased after a minimum of 3 days to a target dose of 1.2 mg/kg/day, given once daily or in 2 divided doses in the morning and late afternoon. No additional benefit is seen in doses more than 1.2 mg/kg/day. Do not exceed 1.4 mg/kg/ day or 100 mg/day.

zithromycin: Six months to 12 years 10 mg/kg/day once daily for 3 days up to maximum of 200 mg (3–7 years), 300 mg (8–11 years, 400 mg (12–14 years) and 500 mg more than 14 years. Alternatively, 10 mg/kg/day once on first day followed by 5 mg/kg/day once A

nti-snake venom polyvalent: Prior to administering the snake antivenin, it is obligatory to observe precautions and carry out sensitivity test. The usual mode of administration to snake antivenin is either by intramuscular or intravenous route. The actual dose of snake antivenin, to be administered to the patient varies according to site of bite, severity of bite, age and physical status, degree of envenomation, involvement of systematic organs and time factor of initiation of treatment. A suitable dosage schedule recommended 100 mL given over 30–60 min by intravenous route (avoid bolus administration which may rapidly activate the compliment system and result in severe reaction). 50 mL to be repeated after 30 min of the initial dose, if active bleeding persists. This may be followed by 100 mL given by slow intravenous route over 24 hours to counteract the venom absorbed into the circulation from the site of bite which act as a depot. This is especially so for krait, cobra, Russell’s viper bites. Echis carinatus bites require less than 50 mL of the initial dose. A

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nti-scorpion venom serum: The usual mode of administration of scorpion antivenin IP is either by intramuscular or intravenous route. Generally, 10 mL of the reconstituted scorpion antivenin IP is sufficient for the treatment. However, if the patient continues to show clinical signs of envenomation for more than 3 hours or if the signs aggravate further, 10 mL of the antiserum may be administered by the intravenous route. In very rare cases, further 10 mL will have to be given.

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eclomethasone dipropionate: Aerosol inhaler: 6 months to 2 years 50–200 µg and 2–18 years 100–400 µg 2 times daily as preventor for regular use. Dry powder inhalers: 5–18 years 100–400 µg 2 times daily as preventor for regular use. Intranasal for allergic rhinitis 6–12 years 50–100 µg (1–2 sprays) into each nostril twice daily. B

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endroflumethiazide ( endrofluazide): Orally 1 month to 12 years 50–100 µg/kg, 12–18 years 2.5–5 mg once daily. B

enzathine penicillin: Infants and children—Gr A streptococcal URI—25,000–50,000 units/kg as single dose, maximum 12 L units/ dose or child less than 27 kg—3–6 L units as single dose and more than 27 kg—9 L units as single dose. Adolescents—12 L units as single dose Prophylaxis of rheumatic fever—IAP recommends—children less than 27 kg 6 lakh units every 15 days; more than or equal to 27 kg—1.2 lakh units every 21 days. Congenital syphilis—50,000 units/kg/dose (maximum 24 L units) once a week for 3 weeks. Early syphilis in adolescents—24

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enzylpenicillin (Penicillin G): Newborn: 25 mg/kg/dose 2 times daily up to 7 days age and 3 times daily thereafter. Dose doubled if meningitis diagnosed. Child: 25 mg/kg/dose 4 times daily. In severe infection and meningitis 50 mg/kg/dose 6 times daily to maximum single dose of 2.4 g and daily dose of 14.4 g/day. In moderate renal failure (creatinine clearance 10–50 mL/min/1.73 m2), dosage interval may be increased to 8–12 hours and in severe renal failure (less than 10 mL/min/1.73 m2) to every 12 hours. B

eta carotene: Once daily orally—1–4 year 60–90 mg, 5–8 years 90–120 mg, 9–12 year 120–150 mg, 13–15 year 150–180 mg and more than 16 year 180–300 mg—protection not total and 2–6 weeks treatment should result in yellow discoloration of palms and soles before exposure to sunlight is attempted. B

etaine: Orally 50 mg/kg/dose 2 times daily—increase according to response—maximum 20 g/day. Dosage in renal impairment/ liver failure: no information available. B

etamethasone sodium phosphate: Ear: 2–3 drops into the affected ear (s) 2–3 hourly, reduce frequency when relief obtained. Nose: 2–3 drops into each nostril 2–3 times daily. B

ezafibrate: Oral: 200 mg/day has been used in adolescents, adjusted according to response to a maximum of 200 mg 3 times daily but experience in children is limited; refer to an expert. B

iotin: Oral/IV bolus—initially single dose of 5–10 mg followed by maintenance of 10–50 mg daily once. B

isacodyl: Constipation: orally less than 10 year 5 mg, more than 10 year 5–10 mg daily bedtime (maximum 15–20 mg). Rectal suppositories less than 10 years 5 mg, more than 10 years 5–10 mg daily once in the morning. Preparation for surgery, labor or radiological investigation—orally less than 10 years 5 mg and more than 10 years 5–10 mg at bedtime for 2 days prior to procedure and rectally, if necessary, 1 hour before procedure. leomycin: 10–20 units/sqm/dose IV, IM or 0.25–0.50 mg/kg SC 1–2 times/week in combination regimens. Always consult the current treatment protocol for details of dosage and scheduling. otulinum toxin-hemagglutinin complex: Only those who have been trained in its use should administer this drug. It can be an effective tool for reducing muscle tone in the appropriately selected patient. The “ideal” patient is the one who has hypertonia that interferes with function, is expected to develop fixed contractures, and requires treatment of only a few muscles at any given time. The effect is seen within days—a couple of weeks and lasts for 3–8 months. Use 23–26 gauge needle and administer on 2 sites of each muscle (used mainly for gastronemius muscles) up to a total dose of 4 units/kg. If more than one muscle group needs to be injected at the same time, this total dose is divided between these muscles. Dose may be repeated when clinical effect diminishes but not within 2 months of previous injection. A

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acillus almette-Guérin ( G) vaccine: For intradermal use, the dose is 0.1 mL (0.05 mL for infants less than 12 months).

enzoyl peroxide: Topical 2.5% 1–3 times daily sparingly for 15 min. Increase strength and duration of exposure as tolerated. If excessive peeling or redness occurs, decrease to alternate day.

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aclofen: Initial dose for 1–12 years is 2.5 mg and for 12–18 years is 5 mg 3 times daily and increase gradually every 3 days. Maintenance dose is 5–10 mg (1–2 year), 10–15 mg (2–6 years), 15–30 mg 6–10 years (twice daily) and 10–20 mg 3 times daily. Dosage adjustment in renal impairment: Reduce oral doses by at least 50% (maximum dose 5 mg) in patients with impaired renal function and the frequency to 3 times daily (mild), twice daily (moderate) or daily (severe).

enzatropine ( enztropine): Oral—3–12 years 20 µg/kg and 12–18 years 1–2 mg as single dose. Dose can be repeated up to maximum of 6 mg/day depending on clinical response. IV/IM 3–12 years 20–100 µg/kg (maximum 2 mg), 12–18 years 1–2 mg as single dose—followed, if necessary, with oral treatment.

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ztreonam: IV over 3–5 min or IV infusion less than 7 day old is 30 mg/kg 12th hourly; rest of neonatal period and up to 12 years is 30 mg/kg 6–8th hourly. In severe infection and cystic fibrosis in 2–12 year olds it may increase up to 50 mg/kg 6–8th hourly (maximum 2 g 6th hourly); 12–18 years 1 g or 8th hourly 2 g 12th hourly (severe infection with P. aeruginosa or pulmonary infection in cystic fibrosis). Renal impairment: CrCl 10–30 mL/min/1.73 m2 no change in first dose but subsequent doses to be halved; CrCl less than 10 mL/min/1.73 m2 no change in first dose but subsequent doses to be reduced to one fourth of the usual dose.

L units as single dose in 2 injection sites. If present for more than 1 year—24 L units as single dose in 2 injection sites once weekly for 3 doses.

Pediatric hera eutics

daily from day 2 to day 5. Group A beta-hemolytic streptococcal (GAS) pharyngitis and tonsillitis (primary prophylaxis of rheumatic fever): 12.5 mg/kg/day single dose for 5 days (not recommended for secondary prophylaxis of rheumatic fever). Chlamydial infection such as non-gonococcal urethritis (NGU) or cervicitis due to susceptible strains of Chlamydia trachomatis: Adolescents: single dose of 1 g orally. Bacterial endocarditis prophylaxis: 15 mg/ kg (single dose maximum 500 mg) 30–60 min before procedure in children and adolescents allergic to penicillin. Treatment and postexposure pertussis prophylaxis (for postexposure prophylaxis, administer to close contacts within 3 weeks of exposure, especially in high-risk patients (e.g. women in 3rd trimester, infants less than 12 months). Oral dosage for Infants more than 6 months and for children 10 mg/kg/day (maximum 500 mg) on day 1, then 5 mg/ kg/day (maximum 250 mg) on days 2–5. Infants less than 6 months: 10 mg/kg/day for 5 days. Monitor for infantile hypertrophic pyloric stenosis in infants less than 1 month old. Uncomplicated typhoid fever: Orally—Adolescent 8–10 mg/kg/day once daily for 7 days, 1,000 mg on first day, followed by 500 mg once daily for 6 days. Children: 10 mg/kg/day once daily for 7 days or 5 day regimen of 20 mg/kg/day. Continued treatment may be needed to prevent relapse in cryptosporidiosis. STD caused by chlamydia trachomatis: 12–18 years 1 g as single dose.

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upivacaine hydrochloride: Caudal block—children 1–3.7 mg/kg; adolescent 15–30 mL of 0.25% or 0.5%. Epidural block— children 1.25 mg/kg/dose; adolescent 10–20 mL of 0.25–0.5%. Peripheral nerve block: 5 mL of 0.25% (12.5 mg) or 0.5% (25 mg); maximum 400 mg/24 hour. Sympathetic nerve block: 20–50 mL of 0.25% (no epinephrine). The dosage of bupivacaine will depend upon the site of injection and the procedure used. Expert advice should be obtained. Epidural administration should be carried out by, or under the supervision of a consultant anesthetist. B

upropion: Orally 150–300 mg (usually 150 mg) once in the morning.

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affeine citrate: Birth—3 months IV/oral loading dose 20 mg/kg followed by maintenance dose 24 hours later at 5–10 mg/kg/day once or twice daily. alamine lotion: Apply to external affected area as needed.

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alcitriol (1, 25-dihydroxycholecalciferol): Premature 0.05 µg/ kg/ 24 hour IV or 1 µg/24 hour orally; children 0.01–0.08 µg/kg/24 hour; adolescent 0.25–1 µg/24 hour. O

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alcium ( ral supplements): Orally—birth to 4 years 0.25 mmol/ kg/dose; 5–12 years 0.2 mmol/kg/dose; 12–18 years—10 mmol/ dose—4 times daily. C

alcium carbonate: 50–75 mg/kg/day in 2–3 divided doses and adjusted according to plasma phosphate and calcium levels. F

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alcium folinate ( olinic acid): Oral/IV 15 mg once daily. At the methotrexate dosages used in most protocols folinic acid rescue will be required. IV folinic acid is commenced 24 hours or 36 hours after the start of the methotrexate and continued until plasma methotrexate levels are 0.1–0.2 micromol/L (depending on protocol). See protocol for details of folinic acid rescue. Folinic acid may be given orally if the child is not vomiting. C

alcium gluconate: Hypocalcemia: urgent correction – 2 mL/kg of 10% solution IV bolus over 5–10 min. (0.3 mL/kg/dose), followed by oral maintenance. If IV maintenance desired for a few days, be careful to avoid extravasation and administer 10% solution at 0.1 mL/kg/hour in neonates, 0.2 mL/kg/hour up to 2 years and 40 mL/24 hour in 2–18 years. Cardiopulmonary resuscitation: 0.3 mL/ kg of 10% solution as single IV bolus. Parenteral nutrition regimen: approximate doses to maintain normal serum calcium – 1 mmol/ kg in neonates, 0.2–1 mmol/kg up to 2 years, 0.2 mmol/kg in 2–12 years and 5–10 mmol/24 hour continuous IV over 12–24 hours. Hyperkalemia: 1–2 mL/kg intravenously. I

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alcium polystyrene sulfonate ( on exchange resin): Rectally and orally 125–250 mg/kg 4 times daily. Not given orally in neonates. Must monitor electrolytes. aptopril: IAP “Working group on management of congenital heart disease in India”: The starting dose is 0.1 mg/kg/dose; it is gradually increased to 0.5–1 mg/kg/dose 3 times a day (increase after every 4–5 doses). Maximum dose is 2 mg/kg/dose. BP and renal parameters should be monitored when up titrating the dose. arbamazepine: Children less than 6 years (use in neonates limited) initially 5 mg/kg/day in 1–2 divided doses; increase by 5 mg/kg/day every 5–7 days till response obtained/toxicity develops/serum levels attained. 6–12 years initially 10 mg/kg in 2–4 divided doses; increase by 100 mg or 5 mg/kg/day weekly till effect obtained (usually 800–1,200 mg/24 hour). 12–18 years initially 200 mg twice daily; increase by 200 mg/day once in a week till effect obtained (usually 1.6–2.4 g/day in 3–4 divided doses). C

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uspirone hydrochloride: Orally 2–12 years 5 mg and 12–18 years 5–10 mg 2–3 times daily (maximum dose in adolescent 45 mg in divided doses).

alcitonin ( almon/ alcatonin): There is very limited experience of use in children; dose depends on the condition being treated.

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udesonide: Prophylaxis and management of BPD: For ventilated babies 400 µg/kg inhaled 2 times daily. For non-ventilated babies 500 µg 2 times daily inhaled with nebulizer. May be increased to 1 mg 2 times daily in babies more than 2.5 kg with severe symptoms. Asthma prophylaxis: Aerosol 1 month–12 years 50–400 µg, 12–18 years 200–400 µg and Turbohaler in 6–18 years old 100–400 µg twice daily to be used regularly. Can use up to 800 µg/day in severe asthmatics. Nebulizer in 3 months to 12 years 250–500 µg and 12–18 years 500 µg—1 mg 2 times daily—higher doses may be used. Croup: 1 month to 18 years 2 mg with nebulizer when required Bumetanide: oral 1 month to 12 year—0.015–0.05 mg/ kg/dose (maximum 2 mg); 12–18 years 1–2 mg 1–4 times daily. IV bolus—12–18 years—1–2 mg repeated after 20 min if required. IV infusion over 30–60 min—1 month to 12 years—0.025–0.050 mg/ kg; 12–18 year 1–5 mg.

alcipotriol: All preparations: apply to affected area morning and evening. Do not apply to face. Wash hands after use to avoid inadvertent transfer to other body areas. Cream/ointment: weekly maximum to be applied—6–12 years, 50 g; adolescents more than 12 years, 75 g; adults, 100 g. Scalp solution: weekly maximum to be applied—adults, 60 mL. When used with the cream/ointment, weekly maximum of total calcipotriol 5 mg.

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Blepharospasm: Initially, 1.25–2.5 U injected into the medial and lateral orbicularis occuli of the upper lid and the lateral orbicularis occuli of the lower lid. Subsequently, the dose may be increased up to twofold. Initial dose should not exceed 25 U per eye. Total dose should not exceed 100 U every 12 weeks. Hemifacial spasm: Treat as for unilateral blepharospasm (as above). Inject other affected facial muscles as needed. Cervical dystonia: Inject using a 25, 27 or 30 gauge needle (for superficial muscles) or 22 gauge (deeper musculature). Tailor dosing to individual patient based on the head and neck position, location of pain, muscle hypertrophy, body weight and response. Do not inject sternocleidomastoid muscle bilaterally. Maximum total dose usually not more than 200 U. Hyperhidrosis of the axillae: Inject using a 30 gauge needle. Inject 50 U intradermally to each axilla, evenly distributed in multiple sites 1–2 cm apart. Pediatric cerebral palsy: Inject using a 23–26 gauge needle into the medial and lateral heads of the affected gastrocnemius muscle. Recommended total dose: 4 U/kg. Divide dose between two limbs if injected on same occasion. Repeat dose not more frequently than every 2 months. Focal spasticity associated with infantile hemiplegia: Inject using a 25, 27 or 30 gauge needle (superficial muscles) or longer needle for deeper musculature. Multiple injection sites may facilitate more uniform contact with the innervation areas of the muscle, especially in larger muscles. Tailor dose and number of sites based on size, number and location of muscles involved, the severity of spasticity, and the presence of local muscle weakness.

arbamylglutamate: Orally 12.5–25 mg/kg/dose 4 times daily.

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arbapenems: Meropenem—newborn – 40 mg/kg/day in 2 divided doses less than 7 days and in 3 divided doses more than 7 days. Double dose in meningitis and severe infection. Children— UTI, gynecological infections, skin and soft tissue infection—30 mg/kg in 3 divided doses (maximum 500 mg/dose). Pneumonia, peritonitis, neutropenia, septicemia—60 mg/kg/day in 3 divided

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arvedilol: Oral—0.1 mg/kg/day in 2 divided doses; increase at 1–2 weekly interval to 1 mg/kg/day with a maximum of 2 mg/ kg/day. Patients with hepatic impairment: not recommended for patients with clinically evident hepatic impairment. Patients with renal impairment: no dosage adjustments are needed. Intermittent hemodialysis: due to its high degree of plasma protein-binding, carvedilol is not likely to be significantly removed by hemodialysis. No supplemental dosage is needed. C

efaclor: Orally less than 1 year 62.5 mg, 1–5 year 125 mg, 6–18 years 250 mg/dose 3 times daily. Dose doubled in severe infection with susceptible organisms.

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efadroxil: Children—Orally 30 mg/kg/24 hours in 2 divided doses (maximum 2 g/day); adolescent 250–500 mg 8th–12th hourly. efdinir: 14 mg/kg/day in 2 divided doses.

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efepime: Neonates less than 14 days 30 mg/kg/dose twice daily IV/IM. Neonates more than 14 days 50 mg/kg/dose twice daily IV/IM. Children IV 50 mg/kg every 8 hours (maximum 2 g/dose). Intraperitoneal 15 mg/kg/dose. In peritoneal dialysis associated with peritonitis 1,000 mg/24 hours. However, not yet licensed for use in children less than 12 years of age in the UK and the US. C

efixime: 8 mg/kg/24 hours in 1–2 divided doses; adolescent: 400 mg/24 hours in 1–2 divided doses. C

efoperazone: 50–200 mg/kg/day in 2 or more divided doses (maximum in adolescent 1–2 g IM/IV 12th hourly). C

efotaxime: Newborn (severe infections like meningitis) 50 mg/ kg/dose—less than 7 day 2 times, 7–21 days 3 times, 21–30 days 3–4 times. One month to 12 years 50 mg/kg/dose and 12–18 years

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arnitine (Levocarnitine): Premature—8–16 mg/kg/24 hour IV infusion; Children—Orally 50–100 mg/kg/24 hour in 2–3 divided doses or IV 50 mg/kg/dose 4th–6th hourly (maximum 300 mg/ kg/24 hour); adolescent 0.33–1 gm/dose 2–3 times daily orally.

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arboplatin: Always consult the current treatment protocol for details of dosage and scheduling. Total cumulative doses vary with protocol. An increasing number of protocols employ doses based on glomerular filtration rate (GFR) (e.g. UKCCSG GC2, MMT 98) or EDTA half-life (e.g. UKCCSF CNS 2000 01). Children: Solid tumor—300–600 mg/sqm IV once in 4 weeks; brain tumor 175 mg/sqm IV once a week for 4 weeks. Adolescent: 360 mg/sqm IV once in 4 week.

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arbimazole: Orally up to 12 years 250 µg/kg/dose and 12–18 years 10 mg thrice daily (maximum 40 mg). Give until euthyroid and then taper to once daily dose barely enough to sustain normal thyroid function.

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arbaryl: Topical—gently rub into dry hair and scalp until all the hair is fully soaked. Allow the hair to dry naturally away from heat or sun in a well-ventilated room. After 12 hours wash in ordinary shampoo, remove dead lice and eggs with comb while the hair is still wet. Repeat after 1 week if lice are still present.

1–3 g 2 times daily. Dosage adjustment in renal impairment. Due to extrarenal elimination it is only necessary to reduce dose in severe renal impairment (creatinine clearance less than 10 mL/ min/1.73 sqm). A normal single dose should be given as a loading dose then the daily dose should be halved without a change in frequency. efpodoxime: 9 mg/kg/day in 2 divided doses (maximum single dose—200 mg). The dose frequency should be reduced in renal impairment. Creatinine clearance 10–40 mL and less than 10 mL/ min/1.73 sqm—frequency of dosing once in 24 hours and once in 48 hours respectively. eftazidime: Neonates less than 7 days and more than 7 days less than 1,200 g 100 mg/kg/24 hour in 2 divided doses IV/IM, more than 7 days more than 1,200 g 150 mg/kg/day divided 8th hourly IM/IV. Children 150 mg/kg/24 hour divided 8th hourly. Maximum 6 g/day. Single dose more than 1 g to be given IV only. Dose adjustment in renal failure—in mild impairment give a dose every 12 hours, in moderate impairment (creatinine clearance 10–50 mL/min/1.73 m2) give a dose once daily and in severe impairment (creatinine clearance less than 10 mL/min/1.73 m2) give 50% of dose once daily. Levels may be monitored if clinically indicated. In hemodialysis: the appropriate maintenance dose should be repeated after dialysis. In peritoneal dialysis: 125–250 mg may be added to 21 of dialysis fluid, and given in addition to the IV dose. eftriaxone: Neonates 50–75 mg/kg once daily IM/IV. Infuse over 10–30 min. Avoid in premature, acidotic or hyperbilirubinemic neonates. Children 50–75 mg/kg once daily IV/IM. Meningitis loading dose 75 mg/kg followed by 80–100 mg/kg/24 hour once or divided 12 hourly. Maximum 4 g/day. In severe renal failure reduce dose to a maximum of 2 g or 50 mg/kg. No dose adjustment required in hepatic impairment. If both hepatic and severe renal impairment monitor serum concentrations. In patients undergoing dialysis no supplemental dose required but serum concentration monitoring advisable. efuroxime: Neonates; 40–100 mg/kg/24 hour divided 12th hourly IM/IV. Children 200–400 mg/kg/24 hour divided 8th hourly IM/IV; 20–30 mg/kg/day divided 8th hourly orally. Maximum of 1.5 g/dose IV or 6 g/24 hour. ephalexin: Children 25–100 mg/kg/24 hour in 3–4 divided doses; adolescent 250–500 mg 4 times daily (maximum 4 g/24 hour. Reduce dose in severe renal impairment (creatinine clearance less than 10 mL/min/1.73 sqm) by reducing dose frequency. Removed by dialysis thus an additional dose may be required after dialysis. ephalosporins: 1st generation cephalosporins: Dose—Cepha lexin—children 25–100 mg/kg/24 hour in 3–4 divided doses and 12–18 years 250–500 mg 4 times daily (maximum 4 g/ day). Cefadroxil—children 30 mg/kg/24 hour in 2 divided doses maximum 2 g/day) and in 12–18 years 250–500 mg 8th–12th hourly. 2nd generation cephalosporins: Dose—Cefuroxime— neonates 40–100 mg/kg/day IM/IV given 12th hourly; children 200–400 mg/kg/day 8th hourly IM/IV and 20–30 mg/kg/day 3 times a day orally. Maximum dose not to exceed 1.5 g/dose IV or 6 g/24 hour. Cefaclor—orally less than 1 year 62.5 mg, 1–5 years 125 mg, 6–18 years 250 mg/dose 3 times daily. Dose doubled in severe infection with susceptible organisms. 3rd generation cephalosporins: Dose—Cefixime—Children—8 mg/kg/24 hour in 1–2 divided doses. In adolescent: 400 mg/24 hour in 1–2 divided doses. Cefpodoxime—Children—9 mg/kg/24 hour in 2 divided doses (maximum single dose – 200 mg. In adolescent: 200 mg 2 times daily. Cefdinir—Children—7 mg/kg/dose 2 times daily. 12– 18 years – 300 mg/dose 2 times daily. 4th generation cephalosporins: Cefpirome—Children 12–18 years IV injection or infusion 1 g 12th

Pediatric hera eutics

doses (maximum 1 g/dose). Meningitis and life threatening infections—120 mg/kg/day in 3 divided doses (maximum 2 g/ dose). In renal impairment CrCl (mL/min/1.73 m2) 25–50—give full dose but at 12 hours intervals, 10–25—50% dose at 12 hours intervals less than 10–50% dose at 24 hours interval. Imipenem with cilastatin—Newborn IV 20 mg/kg/dose in the frequency— less than 7days, 7–21 days and more than 21 days at 2 times, 3 times and 4 times daily respectively. Children—IV less than 3 months 80 mg/kg/day, 3 months—12 year 60 mg/kg/day, 12–18 years 2 g/day in 4 divided doses (maximum/dose less than 12 years 500 more than 12 years 1 g).

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etirizine: 2–6 years 5 mg and 6–18 years 10 mg as single or 2 divided doses. In renal impairment give 50% of above dose.

years 25–50 mg/dose 3–4 times daily. Nausea and vomiting of terminal illness—2–12 years 500 µg/kg/dose (maximum 40 mg/ day; 12–18 years 10–25 mg/dose (maximum 75 mg/day)—4 times daily.

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henodeoxycholic acid: Cerebrotendinous xanthomatosis 5 mg/ kg/dose 3 times daily; Bile acid synthesis defects initially 5 mg/kg/ dose 3 times daily then 2.5 mg/kg 3 times daily; others 7 mg/kg/ dose in 1 or divided doses. hloral hydrate: Sedation for procedures less than 12 years 25–50 mg/kg 12–18 years 1–2 g 45–60 min prior to procedure (maximum single dose 100 mg/kg); long-term sedation 20–30 mg/kg/dose 4 times daily. Night sedation less than 12 years 30–50 mg/kg, 12–18 years 500 mg to 1 g single dose at bedtime.

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holestyramine: Cholesterol reduction—oral 240 mg/kg/24 hour in 3 divided doses. 12–18 years 1 sachet (4 g) start at 1 daily and usually require 4 times daily but up to 9 sachet/day in adults according to cholesterol levels. Cholestatic pruritus—oral less than 6 years half sachet (2 g), 6–12 years 1 sachet (4 g) and 12–18 years 1–2 sachet once daily. Diarrhoea in ileal resection, Crohn’s disease, vagotomy, radiation—same as for cholesterol reduction but alternate treatment to be instituted if no response in 3 days. holine salicylate: Children more than 4 months: apply quarter of an inch of gel to the dried area of affected oral mucosa, no more frequently than once every 3 hours to a maximum of 6 applications in 24 hours. More than 12 years: apply half an inch of gel with massage not more often than every 3 hours.

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hlorothiazide: 20–40 mg/kg/day in 2 divided doses oral; 2–8 mg/kg twice a day IV. C

hlorpheniramine: Oral less than 2 years 1 mg 2 times (maximum 2 mg), 2–5 years 1–2 mg 3 times (maximum 6 mg), 6–12 years 2–4 mg 3–4 times (maximum 12 mg), 12–18 years 4 mg 4–6 times daily (maximum 2–4 mg) IM/IV/SC less than 1 year 250 µg/kg; 1–5 years 2.5–5 mg, 6–12 mg 5–10 mg, 12–18 10–20 mg once. Repeated up to 4 times daily (maximum 49 mg in adults).

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hlorpromazine: Withdrawal symptoms in baby born to drug abuser: Orally 1 mg/kg/day 3 times or orally/IV 500–750 µg/kg/ dose 4 times (maximum 6 mg/kg/day)—dose doubled if withd rawal is severe. Children with schizophrenia, violent behavior, agitation less than 6 years 500 µg/kg/dose 4 times daily (maximum 40 mg/day); 6–12 years 10 mg/dose (maximum 75 mg/day) and 12–18 years 25 mg/dose 4 times daily (maximum 300 mg/day). Intractable hiccup—6–12 years 10 mg/dose 1–3 times daily; 12–18

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iprofibrate: Oral: 2–4 mg/kg (maximum 200 mg) has been used in adolescents but experience in children is limited; refer to an expert. iprofloxacin: Neonates 10 mg/kg 12 hourly orally or IV; children 15–30 mg/kg/24 hour in 2 divided doses oral or IV (Maximum single dose IV 400 mg and oral 750 mg). Dose adjustment in renal or liver failure: In severe impairment (creatinine clearance less than20 mL/ min/1.73 sqm) total daily dosage may be reduced by half, although monitoring serum levels provides the most reliable basis for dose adjustment. No adjustment in impaired hepatic function. Corneal ulcers—apply throughout the day and night. First day—2 drops every 15 min for 6 hour followed by 2 drops every 30 min for the rest of the day. 2nd day—2 drops every hour and from 3rd to 14th day—2 drops 4th hourly. Superficial infections of eye—1–2 drops 4 times daily till 48 hours after the eye is clinically normal (use for maximum of 21 days). C

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hloroquine: Doses expressed as chloroquin base—malaria prophylaxis—1 month–12 years 5 mg/kg, 12–18 years 300 mg once weekly. Start 1 week before entering and 4 weeks after leaving endemic area. Malaria treatment (P. vivax, P. ovale and sensitive P. falciparum). Oral/IV—1 month to 12 years—initially 10 mg/kg followed by 5 mg/kg 6–8 hours later and then daily once for 2 days. 12–18 years. Initially 600 mg followed by 300 mg 6–8 hours later and then daily once for 2 days.

imetidine: Oral/IV less than 1 month 5 mg/kg/dose and less than 12 years 5–10 mg/kg/dose 4 times daily; 12–18 years 400 mg/ dose 2–4 times/day. Cinnarizine: Vestibular disorders—oral—5– 12 years—15 mg 3 times daily, 12–18 years 30 mg 3 times daily. Motion sickness—oral—5–12 years—15 mg 2 hours before travel then 7.5 mg 8th hourly during journey if necessary, 12–18 years 30 mg 2 hours before travel then 15 mg 8th hourly during journey if necessary.

isapride: Orally birth to 12 year 0.15–0.3 mg/kg/dose; 12–18 year 10 mg/dose 3–4 times daily. Doses to be given 15–30 min before meals. C

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hlorhexidine gluconate: Dental gel: 1 inch of gel brushed around the teeth and gums once or twice daily for 1 min. For gingivitis, apply for 1 month. Mouth wash 0.12%: 15 mL for 30 seconds twice daily. Mouth wash 0.2%: 10 mL for 1 min twice daily. Oral spray: up to 12 actuations to be used twice daily, morning and night. For the prevention of gingivitis, use for 1 month. In aphthous ulcertation and oral infections use for 48 hours after the infection has cleared. Postoral surgery/trauma on the advice of the supervising clinician.

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iclopirox ( opical anti-fungal): Apply once a day with an applicator brush to all affected nails and immediately adjacent skin. Daily applications should be made over the previous coat and removed every 7 days. Up to 48 weeks of daily applications, weekly trimming by the patient, and monthly professional removal of the unattached, infected nail, are needed. C

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hloramphenicol: Neonates less than 14 days 12.5 mg/kg/dose twice daily; more than 14 days 12.5 mg/kg/dose 2–4 times daily— monitor levels. Children 50 mg/kg/day (maximum 1 g/day) 4 divided doses—double dose for meningitis, septicemia). Ear drops: 2–3 drops 2–3 times daily. Eye ointment may be used in the ear. Eye drops: 1 drop 4–6 times daily (1–2 hourly in severe infections). In addition, a small amount of ointment may be applied at bedtime. Eye ointment: apply 4 times daily (1–2 hourly in severe infections). Continue treatment till 48 hours after the eye is clinically normal.

holestipol hydrochloride: Oral: 12–18 years initially 5 g once daily. May be increased at intervals of 1 month to a maximum of 30 g daily in 1–2 divided doses.

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hlorambucil: Hodgkin’s disease and non-Hodgkin’s lymphoma— consult the current treatment protocol for details of dosage and scheduling. Systemic amyloidosis and severe JIA—all ages: 100– 120 µg/kg orally once daily.

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holecalciferol (Vitamin 3): Orally less than 6 months 3,000 units, 6 months to 12 years 6,000 units and 12–18 years 10,000 units. Check biochemistry after 6 weeks therapy. Stop once serum alkaline phosphatase (ALP) and parathyroid hormone (PTH) are normal. Routine supplementation: 400 IU/day. Rickets: IM 5,000– 50,000 IU daily or 1 single dose of 3–600,000 units once in 3 weeks.

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extbook of Pediatrics T

hourly and increased to 2 g 12th hourly in severe infections and infections in immunocompromised children. Cefepime—Children IV 50 mg/kg every 8 hours (maximum 2 g/dose).

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lonazepam: 1 month to 12 years: Start with 25 µg/kg (0.25 mg less than 5 years and 0.5 mg 6–12 years) as single bedtime dose and increasing every 4 days over 2–4 weeks to maintenance of 80 µg/kg/dose (0.1–0.3 mg less than 1 year, 0.3–1 mg 1–5 year and 1–2 mg 6–12 year) 3 times daily. 12–18 years: start with1 mg bedtime to maintenance of 1–2.5 mg/dose 3 times daily.

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lonidine: Hyperactivity and Tourette syndrome: ral initially 0.05 mg/24 hour once daily increase by 0.05 mg once in 5–7 days up to maximum of 0.4 mg/kg/day in 3–4 divided doses. Hypertension: oral 5–10 µg/kg/day in 2–4 divided doses (maximum 0.9 mg/ kg/day); IV 2–6 µg/kg as single dose sedation, pain and narcotic withdrawal— ral initial test dose 1 µg/kg, monitoring for hypotension and escalate in steps of 1-3-5 µg/kg/day if required, 3 times daily (maximum 5 µg/kg 4 times daily). Growth hormone stimulation test: oral 150 µg/m2 as single dose. lopidogrel: 0.2 mg/kg/day is sufficient to achieve platelet inhibition level similar to that in adults taking the standard dose of 75 mg/day. 80% of children would also be taking aspirin. When appropriate, tablets were rounded to the nearest one half, onethird, or one-fourth tablet. lotrimazole: Apply 2–3 times daily continuing for 14 days after lesions have healed. Oral thrush: 10–20 drops gently apply to buccal mucosa (covering all lesions) 4 times daily for 5–7 days. Vaginal candidiasis: apply 2% vaginal gel 5 gm deep into vagina at bedtime for 6 consecutive nights (not to be used during menstruation). Or alternatively – 100 mg vaginal pessaries for 6 days, 200 mg for 3 days or 500 mg single dose at bedtime. Scalp seborrhea: apply to liquid with selenium to scalp, massage gently, leave for 5 minutes and then rinse well with water: 2–3 times/week. Otomycosis: instill 4–5 drops in ear 3–4 times daily till 2 weeks after infection subsides. C

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larithromycin: Oral 15 mg/kg/24 hour in 2 divided doses up to maximum of 500 mg twice daily for 5–10 days. H. Pylori—1–2 years 125 mg, 2–6 years 250 mg, 6–9 years 375 mg, 9–12 years 500 mg and 12–18 years 1 g/day in 2 divided doses along with amoxicillin and omeprazole or amoxicillin and lansoprazole or metronidazole and omeprazole. CAP and pharyngitis in children due to Chlamydophila pneumoniae, Mycoplasma pneumoniae, or Streptococcus pneumoniae give for 10 days. Bacterial endocarditis prophylaxis: 15 mg/kg (single dose maximum 500 mg) 30–60 minutes before procedure in children and adolescents allergic to penicillin. Treatment and postexposure pertussis prophylaxis— (For postexposure prophylaxis, administer to close contacts within 3 weeks of exposure, especially in high-risk patients (e.g. women in 3rd trimester, infants less than 12 months). Oral dosage: infants more than 6 months and children: 15 mg/kg/day up to maximum of 500 mg twice daily for 7 days. Not used in neonates. patients with renal impairment: CrCl more than 60 mL/min: no dosage adjustment needed. CrCl 30–60 mL/min: no dosage adjustment needed except in patients receiving concurrent ritonavir. In these patients, reduce the recommended clarithromycin dose by 50%. CrCl less than 30 mL/min: reduce recommended dose by 50%. In patients receiving ritonavir, decrease the recommended clarithromycin dose by 75%.

lomipramine: Start with 25 mg/day and gradually increase up to 250 mg/day according to response usually as single dose at bedtime (may give in divided doses).

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itrulline: Birth to 18 years 42.5 mg/kg/dose 4 times daily.

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italopram: 12–18 years 20 mg in the morning increased to maximum of 60 mg.

lomiphene: Male adolescent gynecomastia: on a trial basis at a dose of 50–100 mg per day for up to 6 months. Approximately 50% of patients achieve partial reduction in breast size, and approximately 20% of patients note complete resolution. Patients with hepatic impairment: Clomiphene is contraindicated for use in those patients with hepatic disease or hepatic impairment. Patients with renal impairment: No dosage adjustments are needed.

Pediatric hera eutics

isplatin: 37–75 mg/sqm once in 2–3 weeks or 50–150 mg/sqm once in 21–28 days given over 4–6 hours. Renal failure: creatinine clearance 10–50 mL/min—75% of dose and if less than 10 mL/min 50% of dose. Always consult the current treatment protocol for details of dosage and scheduling.

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lobetasone: Apply thin layer 2–3 times daily on affected area for a maximum of 2 weeks. C

lofazimine: Multibacillary leprosy (in combination with dapsone and rifampicin), by mouth; Adolescent, 50 mg once daily and 300 mg once a month; Child 10–14 years, 50 mg on alternate days and 150 mg once a month; Children less than 10 years: 1 mg/kg PO once daily plus an additional 6 mg/kg PO once per month in combination with dapsone and rifampin; continue treatment for 12 months. Type 2 lepra reaction (erythema nodosum leprosum), by mouth, Adolescent and Child, 200–300 mg daily in 2 or 3 divided doses for a maximum of 3 months; 4–6 weeks treatment may be required before any effect is seen.

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lozapine: Oral 12–18 years Initial dose on first day given as inpatient 12.5 mg/dose 1–2 times daily and from second day 25 mg/dose 1–2 times daily and if tolerated gradually increased in steps of 25–50 mg over 14–21 day to maintenance dose of 300 mg/day in divided doses (maximum 900 mg/day if necessary). C

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lobazam: Initially orally less than 12 years 125 µg/kg/dose, 12–18 years 10 mg/dose 2 times daily followed by maintenance of 250 µg/dose (maximum 500 µg)/dose in less than 12 years and 10–15 (maximum 30) mg/dose in 2 doses.

loxacillin: Newborn IV/oral less than 7 days 50–100 mg/kg/day in 2 divided doses; 7–21 days 75–150 mg/kg/day in 3 divided doses, more than 21 days 100–200 mg/kg/day in 4 divided doses. May be increased to 100 mg/kg/dose in severe infection (meningitis, cerebral abscess, staphylococcal osteitis). Oral used only for minor infections. Children—IV/IM 50–100 mg/kg/day in 4 divided doses (maximum single dose 1 g—may be doubled in severe infection) Oral less than 1 year 250 mg/day, 1–5 year 500 mg/day, 5–18 years 1 g in 4 divided doses. Doses may be doubled in severe infection. In renal failure—if creatinine clearance less than 10 mL/min/1.73 sqm, increase dosage interval to 8th hourly.

oal tar: Topical: Bath 60–90 mL of a 5–20% solution or 15–25 mL of 30% solution is added to bath water. Soak for 5–20 minutes, and then pat dry. Use once every 3 days. Shampoo—apply 2 times C

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lindamycin: Neonates—less than 7days less than 2,000 g 10 mg/kg/day divided 12th hourly IV/IM; less than 7 days more than 2,000 g 15 mg/kg/day divided 8th hourly IV/IM; more than 7 days less than 1,200 g 10 mg/kg/day divided 12th hourly IV/IM; 1,200–2,000 g 15 mg/kg/day divided 8th hourly, more than 2,000 g 20 mg/kg/day divided 8th hourly IV/IM. Children10–40 mg/ kg/day divided 8th hourly IV/IM or orally. 12–18 years 150–300 mg up to maximum of 450 mg/dose 4 times daily. Falciparum malaria (alternate therapy) with 20 mg/kg/day for 5 days. Acne Topical application as thin film 2 times daily with lotion and once with gel. Dose adjusted in hepatic failure: Dose reduced and liver function monitored. Not readily removed by dialysis or peritoneal dialysis.

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odeine phosphate: Children: pain 0.5–1 mg/kg/dose 4–6th hourly (maximum 60 mg/dose) and for dry cough 1–1.5 mg/ kg/24 hour divided 4th–6th hourly. Adolescent: pain 15–60 mg/ dose 4–6th hourly and for cough 10–20 mg/dose 4–6th hourly (maximum 120 mg/24 hour). C

olchicine: Children—Prophylaxis of Mediterranean fever less than 5 years 0.5 mg/24 hour and more than 5 years 1–1.5 mg/24 hour in 2–3 divided doses.

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o-trimoxazole: Children: orally 6–20 mg TMP/kg/24 hour divided 12th hourly. (Maximum 160 mg TMP 12th hourly). P. Carinii pneumonia Oral/IV15–20 mg TMP/kg/24 hour divided 12th hourly. P. Carinii prophylaxis orally 5 mg TMP/kg/24 hour or 3 times/week. The use of co-trimoxazole is not generally recommended under 6 weeks of age, but some neonatologists feel that there is no specific reason for this caution other than the risk of hemolytic anemia in babies with G6PD deficiency and the risk of kernicterus because sulfamethoxazole competes for the protein binding sites usually available to bilirubin in babies with jaundice. If co-trimoxazole is used in newborn infants it is given in the same dosage as for 6 weeks to 5 months but trimethoprim on its own is now usually preferred to co-trimoxazole. C

rotamiton: Topical: after patient has a warm bath and dried well, the preparation should be rubbed into the entire body surface excluding face and scalp. The application should be repeated once daily preferably in the evening for a total of 3–5 days. Children less than 3 years of age should not apply crotamition more than once a day. C

yclizine: Children: 6–12 years orally 25 mg/dose up to 3 times/24 hour as required and older. Adolescents: 50 mg up to 4th–6th hourly 30 min before travel (maximum 200 mg/24 hour; IM 50 mg 4–6 times. yclopentolate: 1–2 drops or as required. Its effect lasts 24 hours.

yclophosphamide: Children: Induction IV 40–50 mg/kg (1.5–1.8 g/sqm) in divided doses over 2–5 days; Orally 1–5 mg/kg/24 hour followed by maintenance IV 10–15 mg/kg (350–550 mg/sqm) once in 7–10 days or 3–5 mg/kg twice in a week. SLE 500–750 mg/sqm/ month. Juvenile rheumatoid arthritis/vasculitis IV 10 mg/kg once in 2 weeks. Bone marrow transplant conditioning IV 50 mg/kg/24 hours for 3–4 days. Nephrotic syndrome—orally 2–3 mg/kg/24 hour— when steroids fail use up to 12 weeks. Adjust doses for 1. Renal failure—CrCl 25–50 mL/min give half dose and if less than 25 mL/ min avoid 2. Decreased bone marrow function gives 33–50% of dose. ycloserine: Children: 10 mg/kg/day in 2 divided doses. Adolescent: 250–500 mg twice daily for 2 weeks and then increased to 500 mg to 1 g in divided doses. C

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olestipol hydrochloride: Oral: 12–18 years initially 5 g once daily. May be increased at intervals of 1 month to a maximum of 30 g daily in 1–2 divided doses.

orticotropin ( orticotrophin) ( ): IM/SC 1 month to 18 years 20–80 units once daily. Duration and frequency of doses depend on individual child.

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o-careldopa: Metabolic disorders: start with 250–500 µg/kg/dose of levodopa 4 times daily. Increase every 4–5 days to maintenance of 2.5–3 mg/kg/dose of levodopa. Review dose every 3–6 months in early childhood and adjust if needed according to weight and CSF amine metabolic concentration. Dystonia: 3 months to 18 years start with 250 µg—1 mg/kg/dose of levodopa 2–3 times daily and increase every 2–3 days.

steroid, hydrocortisone. Apply sparingly to the affected areas once or twice a day.

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o-amoxiclav ( moxicillin and clavulanic acid): Dosed on amoxycillin content. Neonates: 30 mg/kg/day in 2 divided doses. Children 20–45 mg/kg in 2–3 divided doses. Higher doses of 80 mg/kg/day may be required in otitis media. Administration: Oral: give at the start of a meal. Dispersible tablets should be stirred into a little water before taking. IV: reconstitute a 600 mg vial with 10 mL Water for injections (final volume 10.5 mL) and a 1.2 g vial with 20 mL (final volume 20.9 mL). Give by slow IV injection (over 3–4 minutes, within 20 min of reconstitution) or infuse over 30–40 minutes and complete infusion within 4 hours of reconstitution. For infusion the reconstituted injection can be diluted to 5 times its volume in NaCl 0.9%. Do not infuse in glucose solutions as coamoxiclav is less stable in infusions containing glucose. C

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in a week for first 2 weeks and then once weekly or more often if needed. Skin—apply to affected areas 1–4 times daily. Decrease frequency to 2–3 times/week once condition is controlled. Atopic dermatitis: 2–5% coal tar cream once daily or every other day to reduce inflammation. Scalp psoriasis: Tar oil bath or coal tar solution. may be applied sparingly to lesions 3–12 hours before each shampoo. Psoriasis of body, arms and legs—apply at bedtime. If thick scales are present, use a product containing salicylic acid and apply several times during the day.

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oloxyl: Oral: up to 6 months to 10 drops 3 times daily. 6–18 months: 15 drops 3 times daily. D

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o-phenotrope ( iphenoxylate + atropine): Oral 2–4 years half tablet, 4–12 years 1 tablet, 13–16 years 2 tablet, 16–18 years initially 4 tablets followed by 2 tablets—3–4 times daily. Avoid in treatment of diarrhea in children. C

opper histidine: Dosage tailored to individual patient requirements. SC 50–150 µg elemental copper/kg daily once; IM 200 µg elemental copper, increase monthly to maximum of 1 g. Daily once. orticosteroids ( opical): Initial treatment, certainly in infants T

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1184 less than 12 months, should always be with the weakest topical

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yclosporin: Juvenile idiopathic arthritis, collagen disease, vasculitis, uveitis—orally 1–2 mg/kg per dose 2 times daily increased gradually up to 3 mg/kg/dose twice daily. Organ transplant orally 5–7 mg/kg/dose 2 times daily starting 12 hours before transplant and continued for 1–2 weeks postoperatively gradually reducing to maintenance dose of 1–3 mg/kg/dose 2 times daily. OR 1.5–4 mg/kg/dose 2 times daily when given with other immunosuppressants as part of triple or quadruple regime. Bone marrow transplant 6–7.5 mg/kg/dose 2 times daily starting on day prior to transplant. Psoriasis/atopic dermatitis 1.25 mg/kg/ dose 2 times daily—increased, if no response, after 2 weeks for dermatitis and 4 weeks for psoriasis till 2.5 mg/kg/dose 2 times daily. Severe ulcerative colitis orally 3–4 mg/kg 2 times daily. Crohn’s disease 2.5–4.5 mg/kg/dose 2 times daily. yproterone acetate: Seek expert advice on use in MAS or testotoxicosis. One tablet daily for 21 days starting on first day of menstrual cycle and repeated after a 7-day interval, usually for several months. C

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olistin: Nebulized along with oral ciprofloxacin for pseudomonas lung infection in cystic fibrosis—less than 1 year 500,000 units, 1–10 years 1 million units, more than 10 years 2 million units 2 times daily. IV for early pseudomonas infections not cleared by ciprofloxacin and nebulized colistin or moderate—severe infection or multiresistant strains along with aminoglycoside where other regimens fail (IV preparation not available in India).

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antrolene: Spasticity—more than 5 years 500 µg/kg/day once daily and increase once in 7 days in increments of 500 µg/kg/ dose till response achieved and in 12–18 years 25 mg daily once and increased gradually till response. Malignant hyperthermia— IV bolus of 1 mg/kg as single dose repeated as required at 5–10 minutes intervals to maximum cumulative dose of 10 mg/kg. D

apsone: Leprosy: oral 1–2 mg/kg/day as single dose in combination with rifampicin. Blistering skin conditions: start at 500 µg/kg/day and increase or decrease as necessary in 12.5 mg increments. D

aunorubicin: Always consult the current treatment protocol for details of dosage and scheduling. Children: remission induction in ALL (combination therapy) 25–45 mg/sqm on day 1 of every week for 4 cycles (maximum: total dose 300 mg/sqm). D

eferasirox: Start with 20 mg/kg orally once daily calculated to nearest whole tablet. Adjust dose in increments of 5–10 mg/kg every 3–6 months based on ferritin levels (maximum 30 mg/kg/ day since there is limited experience at higher doses. D

eferiprone: Oral more than 6 years 25 mg/kg/dose rounded to the nearest 250 mg dose 3 times daily (maximum 100 mg/kg/day). D

eflazacort: Oral 1 month to 12 years 250 µg to 1.5 mg/kg; 12–18 years 2–18 mg once daily. Up to 2.4 mg/kg may be used. 2 days dose could be taken as single dose on alternate days. D

esferrioxamine mesilate: Acute iron poisoning: oral (injection given orally through NG tube as very bitter) 1 month to 12 years 5 g and 12–18 years 5–10 g in 50–100 mL water. IM 1 month to 12 years 1 g and 12–18 years 2 g repeated 8th hourly if necessary. IV continuous infusion: initially 15 mg/kg/hour reducing after 4–6 hours as indicated so that total maximum dose does not exceed 80 mg/kg/day. Continue until serum iron is less than TIBC. Pathological iron overload—IV or SC infusion using pump over 8–24 hours – 1 month to 12 years 20 mg/kg and 12–18 years 500 mg—give 4–5 days in a week. Maintenance doses proportional to iron excretion rate. Not to exceed 50 mg/kg/dose. IV infusion over 24 hours for high dose therapy if cardiac damage due to iron overload is present—up to 180 mg/kg in 1 month to 12 years. Aluminum overload in dialysis patients—IV infusion at 5

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examethasone: Croup: oral 150 µg/kg/dose twice a day or 600 µg/kg as single daily dose up to maximum of 12 mg/day. Antiemetic with chemotherapy: IV/oral per dose less than 1 year 250 µg—1 mg, 1–5 years 1–2 mg, 6–12 years 2–4 mg and 12–18 years 4 mg thrice daily until 48 hours after chemotherapy. Headache of increased ICT: IV/oral 250 µg/kg/dose 2 times daily for 5 days and then reduce the dose to 62.5–125 µg/kg/dose twice daily. Brain tumor edema: IV/oral 125–500 µg/kg/dose 2 times daily. Replacement—IV/oral 250–500 µg/m2/dose 2 times daily. Fetal lung maturation: given to mother IM 12 mg repeated once after 24 hours and orally 6 mg twice daily for 4 doses. Bronchopulmonary dysplasia: 250 µg/kg IV/oral twice daily for 3 days, course repeated once every 10 days until baby is no longer oxygen dependent or 500 µg/kg once daily for 3 days and tapered over 6 weeks to 100 µg/ kg on alternate day during the last week. Post intubation laryngeal edema—200 µg/kg IV/oral 8th hourly for 3 doses starting 4 hours before extubation. Cerebral edema: initially less than 35 kg 20 mg and more than 35 kg 24 mg, followed by 1–3rd day 4 mg q3h (less than 35 kg) and 4 mg q2h (more than 35 kg), 4th day 4 mg q6h (less than 35 kg) and 4 mg q4h (more than 35 kg), 5–8th day 2 mg q6h (less than 35 kg) and 4 mg q6h (more than 35 kg), and thereafter taper. Eye drops: 1 drop 4th–6th hourly. Severe conditions—apply hourly till condition improves and then reduce to 4–6th hourly. Eye ointment: Small amount into conjunctival sac 3–4 times daily or only at bedtime along with drops during daytime. Congenital adrenal hyperplasia: 0.25 to 0.5 mg once daily. The drug should be used only after epiphyseal fusion so as to avoid adverse effects on growth. D

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alteparin sodium: Treatment—SC 200 units/kg/24 hour in 2 divided doses in less than 12 years and as single dose in 12–18 years not to exceed 18,000 units/24 hours; Prophylaxis—SC 100 units/kg up to 12 years and 2,500–5,000 units as single dose in 12–18 years.

esmopressin: Nocturnal enuresis: intranasal in children more than 5 years 20 µg once at night half dose in each nostril for 3 months and then reassess by stopping for 1 week. Increase if necessary to 40 µg (20 µg in each nostril). Assessment of ADH secretion: intranasal 1–5 µg as single dose. Infants with congenital ADH deficiency are very sensitive to desmopressin and dose may need to be reduced to 1/10th of mentioned dose. Test dose for suspected diabetes insipidus: intranasal 1 month to 2 years 5–10 µg, 2–12 years 10–20 µg and 12–18 years 20 µg. Restrict fluid input to maximum 1.5 times the urine volume from start of hydration phase to the test. Please refer to an expert for testing. Established diabetes insipidus: birth to 1 month 1.25–5 µg, 1 month to 2 years 2.5–5 µg, 2–12 years 5–20 µg, 12–18 years 10–20 µg 1–2 times daily. Individual dose titration required. Mild to moderate hemophilia A and Von Willebrand disease—intranasal more than 1 year 4 µg/ kg as single dose preoperatively—2 hours before procedures. IV more than 1 year 300 ng/kg diluted in 30–50 mL of 0.9% NaCl over 20 minutes, immediately before surgery—repeated after 12 hours if there is no tachycardia.

examphetamine sulfate: Oral initially 3–5 year 2.5 mg, more than 6 years 5–10 mg 1–2 times daily. Increase if required less than 6 years 2.5 mg a day at weekly intervals (maximum 20 mg/day) more than 6 years 5 mg a day at weekly intervals (maximum 40 mg/day). Give maintenance in 2–3 divided doses. D

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actinomycin ( ctinomycin ): Always consult the current treatment protocol for details of dosage and scheduling. Children more than 6 months age—15 µg/kg/24 hours or 400–600 µg/ sqm/24 hours for 5 days; repeated once in 3–6 weeks.

esloratadine: Oral 2–5 years 1.25 mg; 6–11 years 2.5 mg; 12–18 years 5 mg once daily.

extromethorphan: Oral 1.25–2 mg/kg/dose 4 times daily 15 min before food. Oral long acting suspension 2.5 mg/kg/dose 2 times daily. D

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acarbazine: Always consult the current treatment protocol for details of dosage and scheduling. Children: solid tumors—200–470 mg/sqm/24 hours over 5 days once in 21–28 days; Neuroblastoma: 800–900 mg/sqm on day 1 of combination therapy once in 3–4 weeks. Hodgkin’s disease: 375 mg/kg/sqm on day 1 and 15 of combination therapy and repeat once in 28 days.

mg/kg once weekly via fistula over last hour of hemodialysis or hemofiltration for 3 months. Reassess aluminum levels 4–8 weeks after completing course. Give IV, IM, SC or IP prior to last exchange of the day for CAPD or CCPD.

Pediatric hera eutics

ytarabine ( ytosine arabinoside, ra- , rabinosylcytosine): Doses depend on individual protocols. Typically induction: IV 100– 200 mg/sqm/24 hour for 5–10 days or until remission followed by maintenance70–200 mg/sqm/24 hour for 2–5 days/month. Always consult the current treatment protocols for details of dosage and scheduling maximum intrathecal dose is 30 mg. Consider dosage reduction when liver function is poor.

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idanosine ( ): Oral more than 1 month age 120 mg/sqm/ dose 2 times daily and if given with zidovudine 90 mg/sqm/dose 2 times daily. In renal impairment—creatinine clearance (mL/ min/1.73 sqm)/ dose/frequency—30–59/60% of normal total dose/2 divided doses, 10–29/40% of normal total dose/ once daily, less than 10/30% of normal total dose/once daily. Total daily dose may be given once daily to improve compliance. Dose reduction is better when reintroducing following discontinuation due to pancreatitis/neuropathy/hepatic impairment. D

iethylcarbamazine: Filariasis and loiasis—oral 300 µg/kg/dose on day 1 and increase over 3 days to 2 mg/kg/dose 3 times daily for 3 weeks. Tropical pulmonary eosinophilia—oral 6 mg/kg/day in 3 divided doses for 21 days. Toxocariasis (visceral larva migrans)— oral 160 µg/kg/dose on day 1 and 2 and increased over 3 days to 2 mg/kg/dose 3 times and given for further 7–10 days. D

igoxin: The doses stated are for patients who have not received cardiac glycosides in the preceding 2 weeks. If cardiac glycosides have been given in the 2 weeks preceding commencement, it should be anticipated that optimum loading doses will be less than those stated (levels should be checked before loading). The dosage schedules are meant as guidelines and careful clinical observation and monitoring of serum digoxin levels should be

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iltiazem: Oral 12–18 years 30–60 mg/dose 2–3 times daily. E

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inoprostone (Prostaglandin 2): Oral initially 20–25 µg/kg hourly doubled if required. If treatment continues for more than 1 week, dose/frequency to be reduced. IV infusion initially 5 ng/ kg/min increased to 10–2 ng/kg/min in 5 ng/kg/min increments till effect or side effects develop. Monitor HR, RR, BP and temp in arms and legs. iphenhydramine hydrochloride: Oral 2–12 years 10–25 mg and 12–18 year 25–50 mg once at bedtime. D

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icyclomine hydrochloride: Oral 6 months to 2 years 5–10 mg/ dose 3–4 times 15 min before feeds, 2–12 years 10 mg/dose and 12–18 years 10–20 mg/dose 3 times daily.

iloxanide furoate: Oral 2–12 years 20 mg/kg/day and 12–18 years 1.5 gm in 3 divided doses.

iphtheria and tetanus vaccine (adsorbed): Given at 10 year, 16 year and every 10 years thereafter. D

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iclofenac: Oral/rectal more than 6 months age 300 µg – 1 mg/ kg/dose 3 times daily (maximum 150 mg/day). IM/IV more than 6 months age 300 µg – 1 mg/kg/dose 1–2 times daily (maximum 150 mg/day for maximum 2 days). Topical 2–18 years small amount 3–4 times daily.

iphtheria antitoxin: Differs with site. Half dose in children less than 10 years. Nasal—IM 10–20,000 units, Tonsillar IM/IV 15–25,000 units, Pharyngeal or laryngeal IM/IV 20–40,000 units, combined types or delayed diagnosis IV 40–60,000 units, Severe diphtheria, e.g. with extensive membrane and or severe edema (bull neck diphtheria) IV or part IV and IM 40–100,000 units. D

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ichloroacetate: Oral 12.5 mg/kg/dose 4 times daily (up to 200 mg/kg/day used).

iphtheria, tetanus and pertussis (acellular) vaccine (adsorbed): 3 primary doses at 6, 10 and 14 weeks or 2, 3 and 4 months age followed by boosters at 1.5 year and between 41/2–5 years age. D

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iazoxide: Intractable hypoglycemia: Oral 1.7–5 mg/kg/dose 3 times daily. Establish response and then gradually increase (maximum 15 mg/kg/day—up to 20 mg/kg/day used in hyperinsulinemia of infancy). Higher doses are unlikely to be beneficial. Resistant hypertension—oral 1.7 mg/kg/dose 3 times daily (maximum 15 mg/kg/day). Severe hypertension—IV bolus 1 month to 18 years 1–3 mg/kg (maximum 150 mg). Repeat after 5 to 15 minutes if necessary. Monitor BP. Maximum 4 doses/day.

used as a basic for adjustment of dosage. In myocarditis, halve loading and maintenance doses, as the myocardium is more sensitive to cardiac glycosides. Check the doses carefully because an overdose can cause death. Maintenance dose should start 12 hours after loading ends. More than 10 years use doses at the lower end of the range in early adolescence and/or in underweight children. Neonate—10–30 µg/kg IV load then 5–10 µg/kg/24 hour maintenance dose orally. 1 month to 2 years—30 µg/kg oral load then 10–15 µg/kg/24 hour maintenance dose orally. 2–10 year— 30 µg/kg oral load then 5–10 µg/kg/24 hour maintenance dose orally. 10–18 years—10 µg/kg oral load then 2–5 µg/kg/24 hours maintenance dose orally. Impaired renal function—CrCl 10–50 mL/min reduce dose to 25–75%, less than10 mL/min reduce dose to 10–25% of normal. Age total digitalizing dose µg/kg/24 hour. Daily maintenance dose µg/kg/24 hour. Premature newborn: PO: 20 mg IV: 15 mg PO: 5 mg IV: 3–4 mg. Full term newborn: PO: 30 mg IV: 20 mg PO: 8–10 mg IV: 6–8 mg less than 2 years: PO: 40–50 mg IV:30–40 mg PO: 10–12 mg IV: 7.5–9 mg 2–10 years PO: 30– 40 mg IV:20–30 mg PO: 8–10 mg IV: 6–8 mg more than 10 years/ adults: PO: 0.75–1.5 mg IV: 0.5–1.0 mg PO: 0.125–0.5 mg IV:0.1– 0.4 mg. The half-life of digoxin is markedly prolonged in preterm babies and in those with renal dysfunction. Digoxin-specific antibody fragments (Fab): Each vial will bind to approximately 500 µg of digoxin. Acute ingestion of known quantity—use following formula. Dose (number of vials) = total amount ingested (mg) x 0.8 0.5. Acute ingestion of unknown quantity—less than 20 kg— clinical judgment; more than 20 kg start with 10 vials followed by another 10 vials if required. Toxicity during chronic therapy— steady conc. known—use formula. Dose (number of vials) = serum digoxin conc. (ng/mL) x body wt. (kg). 100. Toxicity during chronic therapy—steady conc. Unknown—less than 20 kg 1 vial; more than 20 kg 6 vials as single dose should reverse toxicity.

iphtheria, tetanus and pertussis (whole cell) vaccine (adsorbed): 3 primary doses at 6, 10 and 14 weeks or 2, 3 and 4 months age followed by boosters at 1.5 year and between 41/2–5 years age. Part of Universal Immunization Program. D

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iazepam: Sedation—IV slowly 100–200 µg/kg (maximum 5 mg less than 12 years and 10–20 mg more than 12 years. Oral 200–300 µg/kg 45–60 min before procedure. Rectal 1–3 years 5 mg, 3–12 years 5–10 mg and 12–18 years 10 mg. Premedication—oral 1 month to 1 year 250 µg/kg, 1–5 years 2.5 mg, 5–12 years 5 mg and 12–18 years 10 mg. Status epilepticus: IV bolus birth to 12 years 300– 400 µg/kg; 12–18 years 10–20 mg slowly. Repeat after 10 minutes if required. Start with the smaller dose and increase to higher dose. IV infusion Birth–1 month 50 µg/kg/hour (maximum 300 µg/kg/ hour), 1 month to 12 years 100 µg/kg/hour (maximum 125 µg/ kg/hour but up to 400 µg/kg/hour have been used in ICU), 12–18 year 125 µg/kg/hour. Rectal Birth to 1 month 1.25–2.5 mg, 1 month to 2 year 5 mg, 2–12 year 5–10 mg, 12–18 year 10 mg—repeat if required after 5 minutes. Anxiolytic (short term)—oral 2–12 years 2–3 mg/dose and 12–18 years 2–10 mg/dose thrice daily. Not very effective less than 12 year. Suppression of stage IV sleep in parasomnias—oral 2–18 year 1.5 mg at bedtime. Relief of muscle spasm (postoperative, initial dose for tension and irritability in cerebral spasticity)—less than 1 year 250 µg/kg, 1–5 years 2.5 mg, 5–12 years 5 mg and 12–18 years 10 mg (all per dose 2 times daily).

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ipyridamole: Antiplatelet—oral 1 month to 12 years—1–2 mg/ kg per dose 3 times a day and 12–18 years 100–200 mg/dose 3 times daily before food (avoid antacids). Kawasaki disease—oral 1 month to 12 years 3 mg/kg in 3 divided doses.

conazole: Apply 2–3 times daily continuing for 14 days after lesions have healed. E

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iphtheria, tetanus, pertussis (whole cell) and ib vaccine (adsorbed): Given at 6, 10 and 14 weeks. If Hib vaccine not given in infancy it may be given at 1.5 year.

mg/m2/dose repeat every 21 days; or 20–30 mg/m2 repeat every week; or 60–90 mg/m2 given as continuous infusion over 96 hours once in 3–4 weeks. Hepatic impairment—reduce dose. If bilirubin 1.2–3 mg reduce by 50% and if bilirubin more than 3 mg reduce dose by 75%.

Pediatric hera eutics

iphtheria, tetanus, acellular pertussis and inactivated poliomyelitis vaccine (adsorbed): Given at 6, 10 and 14 weeks and 1.5 and 4.5–5 years boosters.

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ocusate sodium: ess than 3 year 10–40 mg/24 hours in 1–4 divided doses, 3–6 years 20–60 mg/24 hours in 1–4 divided doses, 6–12 years 40–150 mg/24 hours, more than 12 years 50–400 mg/24 hours. D

omperidone: Gastroesophageal reflux and gastric stasis—oral 1 month to 12 year 200–400 µg/kg/dose 3–4 times daily before food and at night. Not often used less than 2 years. Radiotherapy/ chemotherapy induced vomiting—oral 1 month to 12 years 200– 400 µg/kg as single dose. Could be given once in 4–8 hours. D

opamine hydrochloride: Continuous low dose IV infusion for renal effect 2–5 µg/kg/min. IV infusion in newborn—start at 3 µg/kg/min and increase as clinically indicated to maximum of 20 µg/kg/min IV infusion; 1 month to 18 years 5–20 µg/kg/min. Continuous low dose IV infusion exerts effect on dopaminergic receptors, which are present in renal, splanchnic, and coronary vascular beds producing vasodilatation. These effects are not antagonized by beta blockers. The increased renal blood flow results in diuresis and natriuresis. At higher doses, 5–10 µg/kg/ min, it is a pure b agonist, producing positive inotropic effect on the heart. At doses of more than 10 µg/kg/min, it exerts alpha agonistic action, resulting in vasoconstriction. The usual starting dose is 5 µg/kg/min; increased gradually, if required, up to a maximum of 20 µg/kg/min. D

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othiepin ( osulepin hydrochloride): Oral 12–18 years 50–75 mg at bedtime or in divided doses. Increase gradually as needed up to 150 mg/day. In hospital setting maximum 225 mg/day may be used.

mollients: All ages—apply on affected areas as needed to prevent skin from drying out. 250–500 g required weekly for generalized dry skin in child.

noxaparin: Prophylaxis—SC less than 2 months 1.5 mg/kg/ day and more than 2 months 1 mg/kg/day in 2 divided doses E

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oxorubicin hydrochloride: Always consult the current treatment protocol for details of dosage and scheduling. Children—35–75

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oxapram: IV loading dose 2.5 mg/kg over 5–10 min IV infusion 300 µg/kg/hour (maximum 1.5 mg/kg/hour—side effects if infused for more than 36 hours) Oral 6 mg/kg per dose 4 times daily after an IV dose.

nalapril: Neonate—oral 0.1 mg/kg/24 hours in 1–2 doses (maximum 0.4 mg/kg/24 hours); IV 5–10 µg/kg/dose every 8–24 hours. 1 month to 12 years—oral 0.1–0.5 mg/kg/24 hours in 1–2 doses; IV 5–10 µg/kg/dose every 8–24 hour. 12–18 years Oral 2.5–5 mg/24 hour and titrate to maximum 40 mg/24 hour in 2 divided doses; IV 0.625–1.25 mg/dose 4 times daily (maximum 20 mg/24 hour).

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favirenz: Children less than 3 years: There are no pharmacokinetic data available on the appropriate dose of efavirenz in children less than 3 years. Treatment of HIV infection: Children PO more than= 3 years, 32.5–39.9 kg: 400 mg, 25–32.4 kg: 350 mg, 20–24.9 kg: 300, 15–19.9 kg: 250 mg, 10–14.9 kg: 200 mg, more than or equal to 40 kg: 600 mg PO once daily at bedtime. For children who can swallow capsules combine efavirenz with either (1) zidovudine plus lamivudine, emtricitabine, or didanosine or (2) didanosine plus lamivudine or emtricitabine. Adolescents more than 40 kg: 600 mg PO once daily at bedtime. Combine efavirenz with either lamivudine or emtricitabine plus either zidovudine or tenofovir. HIV post exposure prophylaxis: The CDC recommends that efavirenz once daily at bedtime (or nelfinavir, indinavir, or abacavir) be added to the basic 2-drug regimen in situations where exposure is associated with an increased risk of HIV transmission (e.g. severe percutaneous exposure (e.g. large-bore hollow needle, deep puncture, visible blood on device, or needle used in patient’s artery or vein) from a Class 1 or 2 HIV+ source; or a large volume exposure to mucous membranes or nonintact skin exposures from a Class 2 HIV+ source); or if the source person’s virus is known or suspected to be resistant to one or more antiretrovirals. In all cases, therapy should be initiated as soon as possible and continued for 4 weeks. Although animal studies suggest postexposure prophylaxis started more than 24–36 hours following exposure is substantially less effective, the interval after which no benefit is derived for humans is undefined. Therefore, if appropriate for the exposure, prophylaxis should be started even when the interval following exposure is more than 36 hours. The dose is the same as foe treatment of HIV given above. Patients with hepatic impairment: Dosing in patients with hepatic impairment has not been studied. Patients with renal impairment: No dosage adjustment is required. E

obutamine hydrochloride: Continuous IV infusion 5–15 µg/kg/ min increased to a maximum of 20 µg/kg/min in newborn (side effects more) and rarely up to 40 µg/kg/min in older children if necessary. Correct hypovolemia prior to administration. Adjust the rate of infusion to desired response. Dose may be increased every 10–30 minutes if necessary, up to a maximum dose of 40 µg/kg/min. Titrate to discontinue. Infusion should be gradually tapered after 48–72 hours of administration. In cases with low BP, dopamine or noradrenaline infusion may be used concomitantly with dobutamine.

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ithranol: Topical: apply on a daily basis, leaving on for 20–30 min depending on the preparation being used then remove by washing off. Always commence treatment with 0.1% continuing for at least 1 week increasing if necessary to 0.25%, 0.5%, 1% and 2%. Build up gradually over 4 weeks to the highest tolerated strength that gives the best effect. Apply evenly and sparingly to lesions.

drophonium chloride: Myasthenia gravis—for diagnosis—IV birth—12 years 20 µg/kg followed 30 sec later (if no adverse reaction noted) by remaining dose of 80 µg/kg; 12–18 years 2 mg and then 8 mg. Cholinergic drug—to differentiate between under/ overdosing—IV given 1 hour after chlenergic1 month—12 years 20 µg/kg and 12–18 years 2 mg. In underdosing muscle strength increases transiently and in overdosing muscle strength decreases transiently. Nondepolarizing muscular blockade antagonist—IV 1 month to 18 years 500–700 µg/kg slowly over several min along with 7 µg/kg of atropine.

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phedrine hydrochloride: Intranasal 1–2 drops in each nostril 3–4 times daily (15 min before feeds) for maximum of 7 days. E

pirubicin hydrochloride: Always consult current treatment protocols for details of dosage and scheduling. E

poprostenol (Prostacyclin): Neonate—IV infusion 20 ng/kg/min (maximum 40 ng/kg/min)—monitor for systemic hypotension. Children IV infusion 2 ng/kg/min (maximum 40 ng/kg/min)— monitor for systemic hypotension. D

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rgocalciferol ( alciferol, Vitamin 2): Oral less than 6 months 3,000 units, 6 months to 12 years 6,000 units and 12–18 years 10,000 units as single dose.

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rythromycin: General indications: Neonates—orally/IV less than 7 days age 20 mg/kg/day 2 times daily; more than 7 days less than 1,200 g 20 mg/kg/day 2 times daily; more than 7 days more than 1,200 g 30 mg/kg/day 3–4 times daily. Children: Orally—30–50 mg/ kg/day in 3–4 divided doses maximum 250 mg 4 times daily may be given. 12–18 years—250–500 mg 4 times daily. IV – 1 month to 18 years 12.5 mg/kg/dose 4 times daily or as a continuous infusion. Maximum dose—4 g/day. Replace by oral dosage as soon as possible. Special indications: Topical (acne vulgaris)—wash and apply twice daily directly to the affected area. Secondary prevention of rheumatic fever – when child is sensitive to penicillin—oral 20 mg/kg/day maximum 500 mg twice daily (Contraindicated in liver disorder). Chlamydia trachomatis pneumonia in infants and neonates: Oral—50 mg/kg/day (erythromycin base) in 4 divided doses for 14 days. Ophthalmia neonatorum caused by Chlamydia trachomatis: Neonates—oral—50 mg/kg/day in 4 divided doses for 14 days. If chlamydial conjunctivitis recurs after discontinuing therapy, the erythromycin dosage regimen should be repeated. A beta-hemolytic streptococcal (GAS) pharyngitis (primary rheumatic fever prophylaxis as an alternative to penicillin in children allergic to penicillin)—40 mg/kg/day in 4 divided doses × 10 days. Cardiology Sub Chapter of IAP does not recommend using erythromycin for this indication. Uncomplicated urethral, endocervical, or rectal gonorrhea, penicillinase-producing Neisseria gonorrhea, or for gonorrhea during pregnancy—Adolescent: 500 mg PO 4 times per day for 7 days. Treatment and postexposure pertussis prophylaxis—(for postexposure prophylaxis, administer to close contacts within 3 weeks of exposure, especially in highrisk patients (e.g. women in 3rd trimester, infants less than 12 months). Oral dosage: Infants, children and adolescents: 40–50 mg/kg/day PO (maximum 2 g/day) in 4 divided doses for 14 days. For neonates: Azithromycin is the preferred. If azithromycin is unavailable, erythromycin 40–50 mg/kg/day PO in 4 divided doses may be used. Monitor for infantile hypertrophic pyloric stenosis. Pneumococcal prophylaxis – 1 month to 2 years 250 mg/day, 2–8 years 500 mg/day, more than 9 years 1 g/day in 2 divided doses. Gastric stasis—oral/IV—1 month to 18 years—3 mg/kg 4 times daily. E

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(maximum 40 mg/day). Treatment—less than 2 months 3 mg/kg/ day and more than 2 month 2 mg/kg/day in 2 divided doses.

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rythropoietin ( ecombinant human epoetin): 25–100 units/ kg SC/IV 3 times in a week. Monitor the hemoglobin (Hgb) at least twice weekly after drug initiation until the Hgb stabilizes. In addition, monitor the Hgb twice weekly for 2–6 weeks following any dosage adjustment. Any clinically significant change in Hgb or hematocrit (HCT) following a dosage adjustment of epoetin alfa may take 2–6 weeks. someprazole: For the treatment of symptomatic gastro

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Oral dosage: Adolescents and children 12–17 years. 20 mg or 40 mg PO once daily, taken 1 hour before meals, for up to 8 weeks. Children less than 12 years: Limited data from a small pharmacokinetics study in 31 children ages 1–11 years with a diagnosis of GERD suggests that a 10 mg PO daily dose results in similar medication exposure compared to a 20 mg PO daily dose in adult patients. A 10 mg dose in this study provided a mean daily dose of 0.71 mg/kg in 1–5 year-old and 0.34 mg/kg in 6–11 year-old. Infants: Safe and effective use has not been established. For short-term treatment of gastric esophageal reflux (GERD) associated with a history or erosive esophagitis in patients unable to take oral therapy. Intravenous dosage: Adolescents more than or equal to 17 years and children: Safe and effective use have not been established. For the treatment of pathological hypersecretion associated with Zollinger-Ellison syndrome: Adolescents and children: Safe and effective use has not been established. For the treatment of gastric acid hypersecretion associated with cysteamine therapy for nephropathic cystinosis: Oral dosage: Children ages 2–10 years: A small, prospective, open-label study of 12 children aged 2–10 years receiving cysteamine therapy reports mean doses of esomeprazole 2.1 mg/kg/day PO and 1.24 mg/kg/day PO in children less than 5 years (n=6) and more than or equal to 5 years (n=6), respectively. Initial doses used in the study for the 2 age groups were a mean of 1.1 mg/kg/day PO and 1.7 mg/kg/day PO divided twice daily, and doses were increased during the study if necessary based on upper GI symptoms. A maximum dose of 20 mg PO twice daily was used. The authors report a significant decrease in basal gastric acid output and significant improvement in symptom scores. Infants and Children less than 2 years: Safe and effective use has not been established. For the active treatment of Helicobacter pyloriassociated duodenal ulcer, gastric ulcer, or dyspepsia: NOTE: Two weeks of a triple-drug regimen containing a proton pump inhibitor (PPI), clarithromycin, and either amoxicillin or metronidazole are recommended and continue to be first line therapy according to the 2006 global updates from the Maastricht III Consensus Report. In populations where H. pylori infection is common (more than or equal to 10%), patients presenting with non-ulcer dyspepsia should be tested for H. pylori; those found to be H. pylori positive should be started on combination eradication therapy. If the patient has an active peptic ulcer at the time therapy is initiated, additional weeks of esomeprazole may be needed to achieve ulcer healing. Oral dosage: Children more than or equal to 2 years and adolescents: Limited data from a prospective, pilot study of 58 patients ages 2–17 years (mean 11.5 years) suggest a dose of 0.8–1.3 mg/kg/day PO for 1 week in combination with appropriate antimicrobial therapy. The total daily dose was divided and given as a morning and evening dose, and doses were rounded to the nearest 10 mg. The maximum dose given was 20 mg PO twice daily. Infants and children less than 2 years: Safe and effective use has not been established. For NSAIDinduced ulcer prophylaxis (gastric): Adolescents more than 17 years: 40 mg/day PO/IV. Adolescents less than or equal to 17 years: 40 mg/day PO. Children more than or equal to 12 years: 40 mg/ day PO. Children less than 12 years: Safe and effective use has not been established; doses up to 2.1 mg/kg/day with a maximum of 40 mg/day PO have been reported. Infants: Safe and effective use has not been established. Patients with hepatic impairment: No dosage adjustment is recommended for mild to moderate hepatic impairment. However, in patients with severe hepatic insufficiency, do not exceed 20 mg/day. Patients with renal impairment: No dosage adjustment is necessary. Intermittent hemodialysis: No dosage adjustment is necessary. Due to high protein binding, esomeprazole is not expected to be removed by hemodialysis.

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luconazole: Newborn—Systemic candidiasis and cryptococcosis— oral/IV 6–12 mg/kg every 72 hours in less than 14 day, every 48 hours in 14–28 day and every 24 hours in more than 28 day olds. Mucosal candidiasis 3 mg/kg in same intervals. Children: Mucosal candidiasis—oral/IV loading dose 6 mg/kg followed by 3 mg/kg once daily for 7–14 days. Systemic candidiasis and cryptococcosis—6–12 mg/kg daily once (maximum 400 mg)—dose dependent on severity of infection Prophylaxis of fungal infection in immunocompromised 3–12 mg/kg once daily (maximum 400 mg) dose dependent on extent and duration of neutropenia. F

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luoride (sodium fluoride, stannous fluoride): Oral drops and tablets (where water fluoride concentrations less than 0.3 ppm//300 µg/L) 6 months to 3 years 250 µg F/day, 3–6 year 500 µg F/day, more than 6 years 1 mg F/day. Doses are expressed as fluoride ion (F). If water fluoride concentrations. 0.3–0.7 ppm use half dose in more than 3-year-old and no fluoride required inless than 3-year-old. Gel (for children more than 3-year-old) applied with toothbrush over all surfaces of tooth after normal cleansing with toothpaste. Then gently rubbed over tooth surface for 1 minute before spitted out excess. No food/drink for 30 minutes after use for best effect. luoxetine: Depression—oral 6–18 years 10 mg once daily, gradually increase over 3 weeks to 20 mg once daily. Bulimia— oral 12–18 years 60 mg once daily. Obsessive compulsive disorder (OCD) and Anxiety—oral 6–8 years 10 mg and 8–18 years 20 mg once daily. Gradually increase by 10–20 mg increments once in 2 weeks if required (maximum 60 mg/day). Idiopathic musculoskeletal pain—8–12 years 10 mg and 12–18 years 20 mg once daily (must be given in the morning). F

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lecainide acetate: Flecainide is available with difficulty in India. The tablet strength is 50 mg and 100 mg. Flecainide is available with difficulty in India. The tablet strength is 50 mg and 100 mg.

lunisolide: Intranasal 5–12 years 1 spray in each nostril up to 3 times daily and 12–18 years 2 spray in each nostril up to 2–3 times daily.

luticasone propionate: Inhaled—2–4 years 50–100 µg, 4–16 years 50–200 µg, more than 16 years 100 µg—1 mg 2 times daily. Starting dose appropriate for severity of disease adjusted to attain control and then reduced to minimal effective dose according to individual response. Nebulized—1 mg 2 times daily for acute exacerbation of asthma. Intranasal—4–12 years 50 µg (1 spray) in each nostril, 100 µg (2 sprays) in each nostril twice daily for allergic rhinitis. Treatment of alopecia areata, atopic dermatitis, discoid lupus erythematosus, eczema (including hyperkeratotic eczema, nummular eczema, and severe eczematous conditions of the hands or feet), generalized exfoliative dermatitis, cutaneous lichen planus, lichen simplex chronicus, lichen striatus, nodular prurigo, pompholyx (dyshidrosis), pemphigus, polymorphous light eruption, psoriasis, seborrheic dermatitis, severe contact dermatitis, and xerosis: NOTE: Occlusive dressings may be F

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lunarizine: Oral 3–12 year 5 mg and more than 12 years 10 mg daily once. Dose reduction required in liver impairment

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exofenadine hydrochloride: Seasonal allergic rhinitis—tablets more than 6 years, susp 2–11years, Dose—2–11 years 30 mg, 12– 18 years 60 mg 2 times daily/120 mg daily once. Chronic idiopathic urticaria—tabs more than 6 years, susp 6 months to 11year Oral 6 months to 2 year—15 mg, 2–11 years 30 mg twice daily and 12–18 years—180 mg once daily. For pediatric patients with decreased renal function, the recommended starting dose of fexofenadine is 30 mg once daily for patients 2–11 years of age and 15 mg once daily for patients 6 months to less than 2 years of age. The pharmacokinetics of fexofenadine in subjects with hepatic disease did not differ substantially from that observed in healthy subjects.

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lumazenil: Dosage description: IV bolus over 15 seconds less than 12 years 10 µg/kg (maximum 200 µg) and more than 12 years 200 µg as single dose, repeated every minute to maximum total dose of 40 µg/kg. IV infusion less than 12 years 2–10 µg/kg/hour (maximum 400 µg/hour) and more than 12 years 100–400 µg/kg/ hour.

elbamate: Children 2–14 years with Lennox-Gestaut syndrome: Adjunct therapy—initially 15 mg/kg/day in 3–4 divided doses and to increase in 15 mg/kg/day increments at weekly intervals till response is obtained; maximum 45 mg/kg/day or 3,600 mg/day whichever is less. Children more than 14 years: Adjunct therapy— initially 1,200 mg/day in 3–4 divided doses and increase daily dose by 1,200 mg once every week to maximum of 3,600 mg/day. Conversion to monotherapy: Initially 1,200 mg/day in 3–4 divided doses and from week 2 increase daily dose by 1,200 mg once every week to maximum of 3,600 mg/day. Decrease dose of other anticonvulsants by one-third original dose when felbamate is started and at week 2, when felbamate dose is increased. Continue to reduce other anti-convulsants as clinically indicated. entanyl: For pain relief: Neonates and infants—IV 1–4 µg/kg/ dose, repeat every 2–4 hours or continuous infusion 0.5–5 µg/kg/ hour. 1–12 year IM/IV 1–3 µg/kg/dose, repeat every 30–60 min or continuous infusion 1–5 µg/kg/hour. 12–18 years 0.5–1 µg/kg/ dose, repeat every 30–60 minutes. Anesthesia: IV/IM 2–50 µg/kg.

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ludrocortisone acetate: Adrenal insufficiency—oral replacement therapy 50–200 µg once daily according to potassium and/or plasma rennin activity levels. Higher doses are usually required in the neonatal period (start with 100 µg once daily and increase up to 200 µg daily). Sweat test—3 mg/m2 single dose on 2 consecutive days prior to sweat test. Cerebral salt wasting: Start with 100 µg daily and increase up to 200–300 µg according to response.

thambutol: Following oral administration, absorption is approximately 80%. The drug is well distributed throughout the body with high concentrations in kidneys, lungs, saliva and red blood cells. Half-life is approximately 2.5–3.6 hours but this can be up to 7 hours or longer with renal impairment. Twenty percent metabolism in the liver to inactive metabolite. Approximately 50% excreted in the urine and 20% in the feces as unchanged drug.

enofibrate: Experience in children is limited; refer to an expert.

Pediatric hera eutics

lucytosine: Newborn—IV/oral 100 mg/kg/day less than 7 days and 100–200 mg/kg/day more than 7 days in 4 divided doses. Children: IV/oral 200 mg/kg/day (100–140 mg/kg/day if organism sensitive) in 4 divided doses. In renal impairment—CrCl in mL/ min/1.73 sqm—20–40, 50% daily dose in 2 divided doses; 10–20, 25% of daily dose once daily; less than 10, 50 mg/kg as single dose and adjust dose according to serum levels.

tanercept: All patients should have their varicella antibody status measured before commencing the treatment. Siblings should be considered for varicella immunization prior to commencement of treatment of the patient. Patients in contact with varicella should be considered for treatment with varicella zoster immunoglobulin (VZIG) if their varicella titers are negative. Patients with a significant exposure to varicella should have their etanercept therapy temporarily discontinued. SC more than 4 years 400 µg/kg twice weekly at 72–96 hours interval (maximum 25 mg/dose).

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luvoxamine maleate: Dosage description: Oral 6–18 years—25–50 mg after food twice daily or 12–18 years 100 mg once daily—increasing to maximum doses of 300 mg/day needs to be under expert supervision as Indian children tolerate lesser doses than in the West.

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ormaldehyde: Lotion: apply topically at night as a soak. Gel: apply twice daily directly to the wart and cover with plaster. Remove the outer dead layers with an emery board or pumice stone as the treatment progresses. F

ormoterol fumarate: Dosage description: Aerosol inhaler/ turbohaler more than 6 years 6–12 µg 1–2 times daily; dry powder inhaler—12 µg 1–2 times daily. For regular prophylactic use. Increase up to 24 µg twice in a day in severe obstruction. F

oscarnet sodium: Dosage description: Usually in combination with ganciclovir—IV more than 1 month to 18 years. Induce therapy for CMV rhinitis with 180 mg/kg/day in 3 divided doses and for mucocutaneous HSV with 120 mg/kg/day in 3 divided doses and follow it up with maintenance therapy of 90 mg/kg as single dose. F

osphenytoin: Generalized, convulsive status epilepticus or acute tonic clonic seizures—IV (Avoid IM for status epilepticus since therapeutic concentrations are not reached as fast as with the IV route. The full antiepileptic effect of phenytoin is not immediate; IV benzodiazepines (e.g. lorazepam or diazepam) should be given initially or concurrently. Adolescents: In patients with unknown,

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ramycetin sulfate: Eye drops—1–2 drops 2 hourly and reducing gradually as infection gets controlled to 48 hours after the eye is clinically normal. Eye ointment—3 times daily when given alone or at bedtime along with eye drops given during the day. Cream— apply 1–3 times daily. F

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olic acid: Supplementation in folate deficiency in child; cofactor in metabolic disorders, e.g. homocyctinuria—birth—12 years 250 µg/kg and 12–18 years 5–10 mg, once daily for 6 months if cause correctable and lifelong if uncorrectable. Megaloblastic anemia due to folate deficiency—oral newborn—1 mg, less than 1 year 500 µg/ kg, 1–18 year 5 mg daily once for 4 months. Hemolytic anemias— oral less than 12 years 2.5 mg and 12–18 years 10 mg once daily. To limit methotrexate associated side effects when it is used for JIA— oral 2–18 years—1 mg once daily. Dose may be omitted on day methotrexate is given. May be given 5 mg weekly or twice weekly. Newborn infant (birth to 1 month): Preterm babies fed heat-treated human milk may benefit from a 500 µg supplement once a week unless a suitable breast milk fortifier is used. Supplementation has no impact on the risk of anemia developing in other term or preterm breast or formula fed babies.

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rusemide: Oral Newborn 1–2 mg/kg/day in 2 divided doses; 1 month to 12 years 1–2 mg/kg/dose and 12–18 years 20–40 mg/ dose 2–3 times daily. IV bolus Birth—12 years 0.5–1 mg/kg and 12– 18 years 20–40 mg as single dose (maximum 4 mg/kg). Dose could be repeated every 8 hours. Continuous infusion may be better and safer in acute heart failure and in postoperative setting. The dose does not need to be adjusted in renal or hepatic impairment. F

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luticasone/ almeterol: Aerosol inhaler starting with 125 µg and taper to 50 µg of fluticasone and double dose of dry powder inhaler.

undetectable or low (i.e. less than or equal to 10 µg/mL) phenytoin concentrations, the usual loading dose of fosphenytoin is 15–20 mg PE/kg IV, not to exceed 150 mg PE/min IV rate. If seizures are not terminated after the initial loading dose, consider additional anticonvulsants. Some experts give an additional dose of 5–10 mg PE/kg IV if the initial loading dose fails to terminate seizures; maximum total loading dose 30 mg PE/kg. The initial maintenance dose is 4–6 mg PE/kg/day IV or IM, divided into 2 or more doses. Children less than 12 years and infants: In patients with unknown, undetectable or low (i.e. less than or equal to 10 µg/mL) phenytoin concentrations, the usual loading dose of fosphenytoin is 15–20 mg PE/kg IV, not to exceed 3 mg PE/kg/min (maximum: 150 mg PE/ min) IV rate. If seizures are not terminated after the initial loading dose, consider additional anticonvulsants. The initial maintenance dose is 4–6 mg PE/kg/day IV or IM, divided into 2 or more doses. Some experts have used this protocol for infants as young as 6 weeks of age. As phenytoin substitute when oral phenytoin administration is not possible or when oral phenytoin dosing is inappropriate for the maintenance treatment of tonic-clonic seizures or for partial seizures with complex symptomatology— adolescents: Fosphenytoin, given IV or IM, can be substituted for oral phenytoin sodium at the same total daily dose and frequency. If IV, give no faster than 150 mg PE/min (no faster than 3 mg PE/ kg/min—maximum: 150 mg PE/min in children less than 12 years). The daily dose may need to be divided into 2 or more doses to maintain seizure control. Seizure prophylaxis or for seizure treatment during neurosurgery—adolescents: The loading dose is 10–20 mg PE/kg IV or IM; if IV give no faster than 150 mg PE/min. The rate of IV administration should not exceed 150 mg PE/min. The initial maintenance dose is 4–6 mg PE/kg/day IV or IM, divided into 2 or more doses. In controlled clinical trials, IM fosphenytoin was administered as a single daily dose using 1 or 2 injection sites, but study was limited to 5 days of treatment. Children less than 12 years: The loading dose of fosphenytoin is 10–20 mg PE/kg IV or IM. If IV, give no faster than 3 mg PE/kg/min (maximum: 150 mg PE/min). The initial maintenance dose is 4–6 mg PE/kg/day IV or IM, divided into 2 or more doses.

urazolidone: Oral 1 month to 12 years 6 mg/kg/day in 4 divided doses and 12–18 years 400 mg/day in 4 divided doses. 7–10 days for giardiasis and for 4–6 days after defervescence in typhoid fever. F

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required for chronic or severe cases of lichen simplex chronicus, psoriasis, eczema, atopic dermatitis or chronic hand eczema. More potent topical corticosteroids and/or occlusive dressings may be necessary for the treatment of discoid lupus erythematosus, lichen planus, granuloma annulare, psoriatic plaques, and psoriasis of the palms, soles, elbows, or knees. Adolescents: 0.005% ointment or 0.05% cream applied sparingly to the affected area twice daily. Each treatment course may continue for up to 4 weeks. In the treatment of psoriasis, studies suggest that patients respond preferentially to the 0.005% ointment. In the treatment of eczema, fluticasone cream 0.05% applied once daily is as effective as twice daily application. Children and infants 3 months of age or more: Fluticasone cream 0.05% applied sparingly to the affected area once daily or twice daily. Only fluticasone cream 0.05% has been approved for the treatment of atopic dermatitis in this population. In clinical trials, the 0.05% cream has been applied once daily to children for the treatment of atopic dermatitis for up to 4 weeks.

Gabapentin: Dosage description: Oral 2–12 years 10 mg/kg/dose initially once, twice on day 2 and 3 times on day 3 followed by maintenance of 10–20 mg/kg/dose 3 times daily. Some children tolerate weekly increments better. 12–18 years initially 300 mg once daily gradually increase as described to maintenance of 300–800 mg/dose 3 times daily. For renal impairment (creatinine clearance in mL/min/1.73 sqm) adjusted frequency of administration of maintenance doses for less than 12 years—30–40 = twice daily; 15–30 mL = once daily; less than 15 mL = once on alternate days.

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Ganciclovir: CMV retinitis—induction therapy 10 mg/kg/24 hours IV (over 1–2 hours) divided into 2 doses given 12th hourly for 14– 21 days followed by maintenance of 5–6 mg/kg/24 hours IV once daily. CMV disease and prophylaxis (solid organ transplant)— induction 10 mg/kg/24 hours IV divided into 2 doses given 12th hourly for 7–14 days followed by maintenance of 5–6 mg/kg/24 hours IV once daily. Gastrografin: Oral or rectal less than 2 years 15–30 mL; 15–25 kg 50 mL; more than 25 kg 100 mL. Dilute well with water. Keep child well hydrated. CSF

G(Granulocyte-colony stimulating factor, filgastrim): Prevention of febrile neutropenia—5 µg/kg/day, commencing the day after chemotherapy and finishing after 10–14 days, when the post-nadir neutrophil level has reached 10 × 109/L. G-CSF is repeated with each cycle of chemotherapy. Bone marrow transplantation: starting dose of 20–30 µg/kg/day, commencing within 24 hours of the marrow infusion, and tapering the dose according to neutrophil levels during the post-nadir neutrophil recovery. Severe chronic congenital neutropenia—6 µg/kg SC twice daily. Titrate dose based on child’s ANC. The target ANC is 1,500– 10,000/mm3; however, children may experience clinical benefit below this range. Reduce dose if ANC is persistently greater than 10,000/mm3. Rarely may require doses more than or equal to 100 µg/kg/day. Severe chronic cyclic neutropenia or idiopathic neutropenia—5 µg/kg SC once daily. Titrate dose based on individual’s ANC. The target ANC is 1,500–10,000/mm3; however, patients may experience clinical benefit below this range. Reduce dose if ANC is persistently greater than 10,000/mm3. Usually a median dose of 2.1 µg/kg/day is required for cyclic neutropenia and 1.2 µg/kg/day for idiopathic neutropenia. HIV-induced or drug therapy-induced neutropenia (e.g. ganciclovir-induced neutropenia or zidovudine-induced neutropenia) in patients with HIV disease to decrease the risk of bacterial infections—5–10 µg/ kg/day (300–600 µg/day) SC 1–3 times weekly to maintain absolute neutrophil counts of 2,000–10,000/mm3—decreased incidence of severe neutropenia and bacterial infection and allows tolerance of myelosuppressive agents (e.g. ganciclovir or zidovudine). Gelatin: In hypovolemic shock 10–20 mL/kg bolus as rapidly as possible. Repeat as necessary. In trauma these requirements may increase up to 40 mL/kg. At this level, replacement with whole blood should be considered. Gemfibrozil: Limited experience of use in pediatrics. Gemfirosil is tried by specialists only if statins, bile acid sequestrants and fibrates like bezafibrate and fenofibrate are unsuccessful/contraindicated.

Gentamicin: Neonates IV/IM less than 7 days 1,200–2,000 g 2.5 mg/kg once in 12–18 hours and more than 2,000 g 2.5 mg/kg once in 12 hours; more than 7 days 1,200–2,000 g 2.5 mg/kg once in 8–12 hours and more than 2,000 g 2.5 mg/kg once in 8 hours. Extended interval dose regimen by slow intravenous injection or intravenous infusion—less than 32 weeks gestation 4–5 mg/kg every 35 hours; more than 32 weeks gestation 4–5 mg/kg every 24 hours. Children—less than 12 years 7.5 mg/kg/day and 12–18 years 3–6

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Glucagon: Hypoglycemia—severe occurring during diabetes treatment—IM/SC/IV bolus newborn 20 µg/kg; 2 year and up to 25 kg 500 µg; more than 25 kg 500 µg—1 mg as single dose. 25% glucose IV if no response in 15 minutes. Hyperinsulinemia: IV infusion at 1–10 µg/kg/hour; IM/IV in less than 2-year-olds 1 mg/ kg as single dose (stimulates insulin release). GH testing—more than 1 month 100 µg/kg (maximum 1 mg). Eat before discharge to avoid death due to rebound hypoglycemia. Beta blocker poisoning: 0.05–0.15 mg/kg IV bolus, then 0.05–0.1 mg/kg/hour infusion.

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Gamma benzene hexachloride: Scabies: Apply to whole body surface below neck. Scrub baths after 12–24 hours. If required one more application may be repeated after a week. Pediculosis: Massage scalp with emulsion at night & cover with a piece of cloth. Following morning, head bath should be taken ensuring that medication does not enter eyes.

Pediatric hera eutics

mg/kg/day in 3 divided doses. Plasma levels done after 3–4 doses to achieve predose level of less than 2 mg/L and 1 hour post dose peak of 5 mg/L. Alternatively 5–7.5 mg/kg/24 hours IV once daily. Plasma levels done 18–24 hours after first dose to achieve predose level of less than 1 mg/L and 1 hour post dose peak of 16–20 mg/L. Once daily dose regimen (not for endocarditis or meningitis) by intravenous infusion—Child 1 month to 18 years—initially 7 mg/ kg, then adjusted according to serum-gentamicin concentration. Intrathecal/ventricular—preservative free preparation—newborn 1 mg/24 hours; children 1–2 mg/24 hours; 16–18 years. Pseudomonal lung infection in cystic fibrosis—By inhalation of nebulized solution—Child 1 month to 2 years 40 mg twice daily; Child 2–8 years—80 mg twice daily; Child 8–18 years—160 mg twice daily. Bacterial infection in otitis externa—gentamicin 0.3% (as sulfate) 3 times daily (avoid prolonged use). Eye—Eye drops—gentamicin 0.3% (as sulfate)—Apply 1 drop at least every 2 hours in severe infection then reduce frequency as infection is controlled and continue for 48 hours after healing. For less severe infection 3–4 times daily is generally sufficient (1.5% eye drops for severe eye infection).

On hemodialysis give loading dose of 8–12 mg/kg followed by 6–8 mg/kg after every 4 hours dialysis period.

Glutamine: Child: 250–500 mg/kg/day of L-glutamine have been used. Up to 2 mL/kg can be used in adults; it has been used in children and 2 mL/kg is approximately equivalent to 300 mg/kg L-glutamine. Glutaraldehyde: Topical: remove dead skin by gentle rubbing with pumice stone before applying twice daily. Allow each drop to dry before next is applied. Glycerol (Glycerin): Rectal less than 1 year 1 qm, 1–12 year 2 g; 12–18 years 4 g after moistening as single dose. Glyceryl trinitrate (Nitroglycerine): IV infusion—The initial dose is 0.5 µg/kg/min IV, it is up titrated depending on the response, to a maximum of 10 µg/kg/min. Monitor BP and heart rate. Tolerance may develop. Glycine: 50 mg/kg/dose 3 times daily. Dose may be increased to 200 mg/kg 3 times a day during acute episodes. Glycopeptides: Dose—Vancomycin—Newborn—IV 15 mg/kg/ dose less than 28 weeks once daily, 29–35 weeks twice daily and more than 35 week 3 times daily. Intrathecal all newborn 2.5–5 mg once daily. Child IV 15 mg/kg loading dose followed by 10 mg/kg/ dose 4 times daily (maximum 2 gm/day). Intrathecal 1 month to 4 years 5 mg, 4–15 years 10 mg and more than 15 years 20 mg once daily. Children with enlarged ventricles need higher doses. Adjust dose according to CSF levels aiming for a trough level of less than 10 mg/L. Teicoplanin—Newborn—loading 16 mg/kg and 24 hours later start maintenance 8 mg/kg/day as single dose; children 10 mg/kg/dose 2 times daily X 3 doses and then once daily in same dose for severe infection and 6 mg/kg/day once for mod infection. Orally for pseudomembranous colitis 10 mg/kg/dose 2 times daily. May be given intraventricular and intraperitoneal. Glycopyrrolate (Glycopyrronium bromide): Premedication and intraoperative use—IM/IV more than 1 month 4–8 µg/kg as

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uman chorionic gonadotrophin ( G): Short stimulation test IM 1,500–2,000 units daily once for 3 days (testosterone and androgen profile at base line and on 4th day). Prolonged simulation test IM 1,500–2,000 units twice weekly for 3 weeks (testosterone and androgen profile at base line and 4–6 days after final dose). Hypogonadotropic hypogonadism IM 1,000–2,000 units twice weekly in addition to testosterone. Prepubertal cryptorchidism 1,000–2,000 units/m2/dose 3 times a week for 3 weeks or 500 units 3 times a week for 4–6 weeks. uman cytomegalovirus ( MV) immunoglobulin: Doses of CMV immunoglobulin G need to be individualized to suit the patient. Typical dosage regimens are shown below. Prophylaxis: 200 mg/kg pretransplant; 100 mg/kg on days 7, 21, 42 and 63. Treatment: 200 mg/kg on days 1 and 7, given with appropriate antiviral therapy. C

uman normal immunoglobulin ( N G): Measles and polio—IM less than 1 year 250 mg, 1–2 years 500 mg, 3 years or more 750 mg; Hepatitis A less than 10 years 250 mg more than 10 years 500 mg; Rubella in pregnancy 750 mg. I

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eparin ( tandard or unfractionated): Thromboembolic disease and ECMO—50 units/kg IV bolus and 15–35 units/kg/hour continuous IV infusion maintenance dose (adjust to target APTT or heparin level). Catheter patency—0.5–1 unit/mL as heparin lock. An IV bolus dose of 75–100 units/kg of heparin results in a therapeutic aPTT in 90% of children. Maintenance dose (as IV infusion) less than 2 months of age 28 units/kg/hour 2 months to 1 year 25 units/kg/ hour more than 1 year 20 units/kg/hour Older children 18 units/ kg/hour (same dose as for adults) Dosage in catheterization lab: 50–100 units/kg bolus IV or through arterial sheath. Monitoring— Heparin dosing monograms have been validated in children. Many physicians use anti Xa levels for infants or in critically ill children as aPTT may not be very predictive. In relatively stable infants and in older children, aPTT is used for monitoring as it is more easily

uman albumin solution: In hypovolemic shock 10–20 mL/ kg bolus as rapidly as possible. Repeat as necessary. In trauma these requirements may increase up to 40 mL/kg. At this level, replacement with whole blood should be considered. H

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eparin (Low molecular weight heparin): Majority of data in children is with enoxaparin. Other LMWHs are reviparin, dalteparin and tinzaparin. Dose of enoxaparin is 1.5 mg/kg 12 hourly for less than 2 months (less than 5 kg) and 1 mg 12 hourly for older infants and children. For preterm babies a higher dose, up to 1.5–2 mg/kg 12 hourly, may be required.

epatitis vaccine: Either given at 6–8, 10–12 and 14–16 weeks of age (if HbsAg negativity of mother is certain) or 0, 4–6 weeks and 14 weeks or 0, 4–6 weeks and 6 months. Post exposure prophylaxis might require 4 doses 0, 1 month, 2 months and 1 year (accelerated) or 0, 7 and 21 days and 1 year (superaccelerated).

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aloperidol: Schizophrenia, mania and tic disorders including tourette syndrome—2–12 years 25–50 µg/kg/day (maximum 10 mg/day) and 12–18 years 0.5–30 mg/day (maximum 60 mg/day) in 2 divided doses. Intractable hiccup—12–18 years 1.5 mg 3 times daily. Adjust according to response. Nausea—12–18 years 0.5–2 mg 2–3 times daily.

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Hemophilus influenzae type b vaccine (Hib): Given at 6–8, 10– 12 and 14–16 weeks of age. Children 13–48 months and older children with asplenia who have not received the vaccine need receive only one dose to develop immunity.

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Griseofulvin: 1 month to 12 years 10 mg/kg and 12–18 years 500 mg once daily.

epatitis immunoglobulin ( G): Baby to be given 200 IU or 40 IU/kg of HBIG immediately after birth. Accelerated course of Hepatitis B vaccine to be started on opposite arm—0, 1 month, 2 months and 1 year doses given. Other post exposure prophylaxis: treatment depends on immunization status and whether exposure is significant, e.g. percutaneous needle prick, bite, mucocutaneous exposure to blood, unprotected sexual intercourse, etc.

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Granisetron: Oral – 1 month to 12 years – 20 µg/kg/dose to a maximum of 1 mg; 12 to 18 years – 1 mg administered 1–2 times with the first dose given 1 hour prior to starting chemotherapy. IV—1 month to 12 years – 40 µg/kg/dose to a maximum of 3 mg; 12–18 years – 3 mg as a single dose just before administering chemotherapy. 1 more dose may be given within a 24-hour period.

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epatitis vaccine: Primary vaccination schedule. This consists of 2 doses, the second being administered 6 months to 1 year after the first dose (a dose is 0.5 mL of the pediatric preparation for children 1–15 years. An adult preparation is for those more than 16 years). Once initiated, the primary course of vaccination should be completed with the same preparation. H

Goserelin: 3.6 mg every 4 weeks or 10.8 mg every 12 weeks. Injections may need to be given more frequently (e.g. every 3 weeks or every 10 weeks) if patients show signs of failure of hormone suppression.

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Gonadotrophin-releasing hormone (Gn µg/kg (maximum 100 µg) as single dose.

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epatitis and epatitis vaccine (combined): Primary vaccination schedule. This consists of 3 doses, the second being administered 1 month after the first dose and the third 6 months after the first dose (a dose in 0.5 mL of the pediatric preparation for children 1–15 years and 1 mL of the adult preparation for those more than 16 years). Once initiated, the primary course of vaccination should be completed with the same preparation. Booster dose: There is increasing evidence that once a satisfactory serological response had been attained after hepatitis B vaccine, no boosters are necessary. Booster vaccination with the combined vaccine can be recommended from 5 years after initiation of the primary course. If the monovalent vaccines are used as boosters they can be administered 5 years after initiation of the primary course for hepatitis B and 10 years after initiation of the primary course for hepatitis A.

GM(Molgramostim): Newborn—very limited studies— IV infusion over 2 hours 5 µg/kg as single dose, cytotoxic chemotherapy—SC 5–10 µg/kg starting 24 hours after last dose of chemotherapy and continue for 7–10 days. Bone marrow transplant—IV infusion over 4–6 hours 10 µg/kg starting 24 hours the day after BMT and continue daily once till absolute neutrophil count is more than 1 X 109/L, maximum duration of therapy 30 days. Adjunct to ganciclovir therapy—SC 5 µg/kg daily once. After fifth dose to adjust dose to maintain desirable absolute neutrophil count. CSF

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performed and is widely available. If aPTT is less than 60 seconds, dose of heparin should be increased by 10% every 4–6 hours till aPTT is over 60 seconds. If aPTT exceeds 85 seconds, heparin dose should be decreased and if aPTT is more than 95 seconds, the heparin infusion should be stopped.

single dose (maximum 200 µg. Larger dose greater and prolonged antisialogogue effect. Antagonism of neostigmine muscarinic effect—IV more than 1 month 10 µg/kg as single dose with 50 µg/kg neostigmine to reverse residual non-depolarising neuromuscular block. Controlling upper airway secretions—Oral 40–100 µg/kg/ dose 3–4 times daily (oral dose is 10 times parenteral dose).

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ydrochlorothiazide: Neonates and infants—Oral 2–4 mg/kg/24 hour in 2 divided doses more than 6 months to 12 years 2 mg/ kg/24 hours in 2 divided doses; 12–18 years 12.5 to 100 mg/24 hours. Nephrogenic diabetes insipidus—Oral less than 12 years 3 mg/kg and more than 12 years 37.5–75 mg/day in 3 divided doses.

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ydroxychloroquine: Oral 5–6.5 mg/kg (maximum 400 mg) once daily. Adjusted according to plasma levels in severe renal and hepatic impairment. H

ydroxyethyl starches: Use in children is probably best restricted to an intensive care setting. Consult a consultant intensivist for dosage details. Has been tried in controlled trial in pediatric cardiac surgery. Administration is by IV infusion.

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ydroxytryptophan: Given orally at a starting dose of 250–500 µg/kg 4 times daily and increased according to patient response, weight and CSF amine metabolic conc. Up to maintenance dose of 2–2.5 mg/kg 4 times daily. H

ydroxyzine: Pruritis—Oral 6 months to 6 years 5–15 mg; 7–12 years 10–15 mg and 12–18 years 25 mg at bedtime. Increase if required to maximum dose of 50 mg/day in 6 month-6 years, 50– 100 mg/day in 7–12 years and 100 mg/day in 12–18 years in 3–4 divided doses. Anxiety—Oral 12–18 years 50–100 mg/dose 4 times daily in renal impairment dose needs to be reduced by half. H

yoscine butylbromide: Oral 5–12 years 10 mg/dose and 12–18 years 20 mg/dose 3–4 times daily. IM/IV less than 6 years 5 mg/ dose, 6–12 years 5–10 mg/dose and more than 12 years 20 mg/ dose 3–4 times daily. H

yoscine hydrobromide: Oral 2–12 years 10 µg/kg and 12–18 years 300 µg 4 times daily. I

buprofen: Pain/fever—5–10 mg/kg/dose 3–4 times daily (maximum 20 mg/kg/day up to 2.4 gm/day). Juvenile idiopathic arthritis and other rheumatic disorders—30–50 mg/kg/24 hours in 3–4 divided doses—higher doses in systemic JIA. Closure of PDA in newborn (IV preparation) Dose as ibuprofen base and given at 24 hours interval—First dose 10 mg/kg, 2nd and 3rd dose 5 mg/ kg. If PDA dose not close 48 hours after last dose or reopens, a 2nd course of 3 doses may be given. fosfamide: Always consult the current treatment protocol for details of dosage and scheduling. Children IV – 1,200–1,800 mg/ m2/24 hours for 5 days every 21–28 days; or 5 gm/m2 as single IV infusion. I

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ydralazine: Oral less than 12 years 0.75 mg/kg/day in 2–3 divided doses and 12–18 years 50 mg in 2 divided doses. Increase if needed to maximum dose of 7.5 mg/kg/day or 200 mg/day. IV bolus over 20 min—less than 12 years 100–500 µg/kg and more than 12 years 5–10 mg as single dose. May be repeated up to 4–6 times daily. IV infusion—less than 12 years 12.5–50 µg/kg/hour and more than 12 years 3–5 mg/hour. In hepatic and renal impairment start with small doses or increase interval between doses.

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ydroxocobalamin (Vitamin 12): Vitamin B12 deficiency—IM 250 µg—1 mg 3 times weekly for 2 weeks followed by 250 µg once weekly till blood counts are normal and then 1 mg once in 2–3 months as maintenance dose. Hydroxocobalamin responsive inborn errors of metabolism—IM initially 1 mg daily for 5 days and assess response. If responsive continue maintenance at 1 mg once or twice a week. Oral up to 10 mg once or twice weekly. Oral may be started as soon as response to IM is confirmed but some patients do not respond to oral administration.

loprost: 12–18 years IV infusion start with 0.5 ng/kg/min over 6 hours daily once for 3–5 consecutive days followed by maintenance dose of 1–2 ng/kg/min/day. I

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ydrocortisone, neomycin and polymyxin: Ear: place 3 drops into the ear 3–4 times daily.

matinib mesylate: 260 mg and 350 mg/m2 equivalent to the adult dose of 400 mg chronic phase and 600 mg/day accelerated/ blast phase crisis respectively. Dose adjustment for hepatotoxicity:

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ydrocortisone and gentamicin: Ear: 2–4 drops 3–4 times daily and at night. Alternatively, wicks medicated with the drops may be placed in the ear or mastoid cavity.

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yaluronidase: Infants and children—IV extravasation—SC or intradermal—reconstitute 150 unit vial of lyophilized powder in 1 mL NS; dilute 0.1 mL of this solution. With 0.9 mL of NS to prepare a 15 unit/mL solution—with a 25 or 26 gauge needle, five 0.2 mL injections are made SC or intradermally into the extravasation site at the leading edge, changing the needle as after each injection. In older adolescents, 150 units of hyaluronidase may be added to the vehicle containing the drug given IM or SC to increase its absorption and dispersion. Hypodermolysis—SC 15 units added to each 100 mL of IV fluid administered. In premature infants and neonates, the volume of a single clysis should not exceed 25 mL/kg and the rate of administration should not exceed 2 mL/ min. In children less than 3 years and in more than 3 years up to adolescents the volume of a single clysis should not exceed 200 mL and maintenance IV fluid volume, respectively.

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ydrocortisone: Adrenocortical insufficiency: Adrenocortical crisis: 50 mg/m2/day stat followed by 100 mg/m2/day in 4 divided doses. Reduce to 75 mg/m2/day on day 2 and 50 mg/m2/day on day 3. Maintenance dose 8–15 mg/m2/day.

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uman Papillomavirus Vaccine, Quadrivalent ( PV vaccine, quadrivalent): General information on immunization against human papilloma virus (HPV): The vaccine can be given to females with abnormal Pap tests, a positive Hybrid Capture II high risk test, or genital warts; data from clinical trials do not indicate that the vaccine will have any therapeutic effect on existing Pap test abnormalities, HPV infection, or genital warts. However, the vaccine should be given to these patients as it will provide protection against infection with vaccine HPV types not already acquired. Lactating females and females who are immunocompromised can receive the HPV vaccine. Females 9–12 years: Routine vaccination with 3 doses of the quadrivalent HPV vaccine is recommended for all females 11–12 years of age. The vaccination series can be initiated in females as young as 9 years of age. Females 13–18 years: Catch-up vaccination is recommended for females 13–18 years old who have not been vaccinated previously or who have not completed the full series. Ideally, the vaccine should be administered prior to exposure to HPV through sexual contact. The vaccine is not indicated for the treatment of HPV infection; cervical neoplasia; or cervical, vulvar, and vaginal precancers and lesions including genital warts. The vaccine is not indicated for use in males. Although it is recommended for immunocompromised females, the human papillomavirus vaccine, quadrivalent may not elicit an effective immune response in patients with immunosuppression such as people with acquired immunodeficiency syndrome (AIDS) or other clinical manifestations of human immunodeficiency virus (HIV) infection. As with other vaccines, concomitant use of immunosuppressive therapies including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and high-dose corticosteroid therapy may reduce the immune responses. Intramuscular dosage: Female children, adolescents and adults aged 9–26 years: 0.5 mL/dose IM. Give the first dose at an elected date, the second dose 2 months after the first, and the third dose 6 months after the first dose.

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miglucerase: IV infusion Type I disease 60 units/kg and Type III disease 120 units/kg given every 2 weeks. mipenem with cilastatin: Newborn IV 20 mg/kg/dose in the frequency—less than 7days, 7–21 days and more than 21 days at 2 times, 3 times and 4 times daily respectively. Children—IV less than 3 months 80 mg/kg/day, 3 months to 12 years 60 mg/kg/ day, 12–18 years 2 g/day in 4 divided doses (maximum dose less than 12 years 500 more than 12 years 1 g). Children—IV less than 3 months 80 mg/kg/day, 3 months to 12 years 60 mg/kg/day, 12–18 years 2 g/day in 4 divided doses (maximum dose less than 12 years 500 more than12 year 1 g).

ndomethacin: Pain/inflammation in rheumatic disease and nephrogenic diabetes insipidus—Oral 1– 2 mg.kg in 2 divided doses. Closure of PDA in newborn – 3 IV doses at 12–24 hours intervals (µg/kg). 1st dose is for 200; 2nd and 3rd doses are 100, 200 and 250 for the age groups less than 48 hours, 2–7 days and more than 7 days, respectively. I

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nfliximab: Severe active crohn’s—IV infusion 5 mg/kg single dose over 2 hours. If recurrence occurs readminister within 14 weeks after 1st dose. Beyond this point chances of delayed hypersensitivity are high.

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mipramine hydrochloride: Nocturnal eneuresis—6–12 years 25 mg and 12–18 years 25–75 mg half an hour before bedtime. Maximum period of treatment 3 months. Review before giving further courses. Hyperactivity—6–12 years 25–75 mg; 12–17 years 50–75 mg once daily. Start at lower doses. Doses more than 1.5 mg/kg given in 2 divided doses. Depression—12–18 years 25 mg/dose 1–3 times daily. Increase up to 150–200 mg/day and maintained till improvement noted. Usual maintenance—50–150/ day Neuropathic pain—Start at 0.2–0.4 mg/kg and gradually increase to 1–3 mg/kg at bedtime.

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At Birth: Zero Dose OPV 6 Weeks: OPV Only 10 Weeks: OPV + IPV 14 Weeks: OPV Only 18 Weeks: IPV Only 15–18 months: OPV + IPV 5 Years: OPV. If child has received OPV primary series—2 primary doses of IPV at 8 weeks interval Booster of IPV, 6–12 m after the second primary dose; OPV at 5 years and OPV at all NIDs and sNIDs. Immunocompromised child—OPV is C/I in immunocompromised child and contacts. 3 primary doses of IPV at 6, 10, 14 weeks or 2 primary doses of IPV at 8 & 10 weeks; 1st booster of IPV at 15–18 months and 2nd booster of IPV at 5 years.

If elevation in bilirubin more than 3 times upper limit of normal or in liver enzymes more than 5 times upper limit of normal then stop imatinib. When bilirubin levels have returned to less than 1.5 times upper limit of normal and transaminases levels to less than 2.5 times upper limit of normal, treatment of imatinib can be continued at a reduced daily dose.

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nactivated poliomyelitis vaccine ( PV): IM or deep SC: 0.5 mL. Each dose of 0.5 mL replaces a single dose of OPV. A basic course consists of 3 injections at monthly intervals. OPV and IPV are interchangeable and the same schedule should be followed whichever vaccine is used. It is not necessary to use the same vaccine throughout the course. Indian Academy of Pediatrics’ Recommendations on use of IPV for the Individual practice by its members: Option 1: At Birth: Zero Dose OPV 6 Weeks: OPV + IPV 10 Weeks: OPV + IPV 14 Weeks: OPV + IPV 18 Weeks: 15–18 months: OPV + IPV 5 Years: OPV, OPV at all NIDs & sNIDs. Option 2:

nsulins: Dosage should be adjusted according to response. Dose may need to be increased as patients reach the pubertal growth spurt. Usual dose of insulin is 0.7 unit/kg/day if prepubertal children and 1.0 unit/kg/day in midpuberty and 1.2 unit/kg/day by the end of puberty. At the time of diagnosis, larger doses are required up to 2.0 units/kg/day or higher for a few days to enable restoration of body glycogen, protein and fat stores by increased caloric intake. This period rapidly ends within 7–10 days when the child enters the ‘honeymoon period’ with some residual ß-cell function. Exogenous insulin dose will then reduce up to 0.5 units/kg/day or even lower. The honeymoon period ends in a few months and this will manifest itself by increased insulin requirements triggered by wider fluctuations of blood glucose levels. The optimal insulin dose can be arrived at only by frequent home blood sugar monitoring and insulin adjustment by the parents with help from the diabetes team. Insulin Regimens Although the new insulin preparations are very effective, in the Indian scenario, these insulins should be recommended with care, depending on the family’s financial status. In general, a combination of short (regular) and intermediate acting (NPH or lente) insulins is recommended. In the morning before breakfast approximately one half to two-thirds of the total daily dose of insulin is given with a 2:1 ratio of intermediate to short acting. The remaining one-third of the insulin dose is given before the evening meal again in the same proportion of 2:1 intermediate to short acting insulins. The insulin doses can be refined and adjusted according to the blood sugar profiles obtained subsequently by home blood glucose monitoring using a glucometer. Two or more daily injections of insulin are often given for infants and children. Three or more daily injections of insulin may be required in highly motivated older adolescents based on frequent blood glucose monitoring. Such intensive therapy improves glycogenic control toward normal, and diminishes the risk of complications. IV in diabetic emergencies—Neonate 0.01–0.1 units/kg/hour adjusted according to blood glucose concentration. 1 month to 18 years 0.025–0.1 units/kg/hour adjusted according to blood glucose concentration. Hyperkalemia: 5–10 units in 25–50 g dextrose (e.g. 500 mL 5% dextrose with 10 units insulin; 500 mL push then 100– 250 mL/hour).

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mmunoglobulin ( ntravenous): ITP—IV infusion 400 mg once daily for 1–5 days. May stop if he platelet counts are normal after the 2nd dose. Repeated if symptoms warrant and not according to platelet count. Kawasaki syndrome—IV infusion 2 g/kg given over 8–12 hours period. The treatment should be given within 10 days of onset of illness, preferably within 7 days (Class I). If active inflammation persists beyond 10 days in the form of persistent fever, raised ESR and C reactive protein, or presence of coronary aneurysms, IVIg can be given (Class IIa). IVIg is not indicated in Kawasaki after 10 days if there are no signs of ongoing inflammation or coronary aneurysms (Class III). IVIg is also indicated in incomplete Kawasaki disease with echocardiographic demonstration of coronary aneurysms (Class I) or with normal echo (Class IIb). In non-responders or partial responders, a second course of IVIg may be given after 48 hours. Immunodeficiency syndromes IV infusion 400 mg/kg once in 3 weeks. Dose depends on severity, infection frequency and serum IgG. Intractable epilepsy—IV infusion 400 mg/kg once in 3 weeks for 3 doses. If 75% reduction achieved, continue therapy for 9–12 months and review. JIA – IV infusion 1 g/kg once daily for 2 days. Repeat if clinically needed. GuillainBarré syndrome – 400 mg/kg once daily for 3–5 days depending on severity and rate to recover. Myocarditis – 2 g/kg, however it is generally given over 2 days as the volume of fluid is too much in the presence of ventricular dysfunction.

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nfluenza vaccine (inactivated): More than 6 months—those receiving it for first time will need a 2nd dose after 4 weeks. Vaccine given yearly for those at continuing risk.

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nterferon alfa: SC less than 12 years 3 million units/m2; more than12 years 3–10 million units/m2 usually 3 times/week (daily for hemangioma) for 4–6 months.

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min, less than 12 years 20 ng to 1 µg/kg/min and 12–18 years 1–4 µg/min.

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traconazole: Oral less than 12 years 3–5 mg/kg and 12–18 years 100 mg once daily for 15 days in tenia corporis, tenia cruris and oropharyngeal candidiasis and 30 days for tenia pedis and tines manuum. Aspergillosis—allergic bronchopulmonary 3–5 mg/kg in 2 divided doses.

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odine: Thyrotoxicosis—neonatal—1 drop 3 times daily Thyro toxicosis (preoperative)—0.1–0.3 mL 3 times daily. I

pratropium bromide: Inhaled 20–120 µg 4 times daily. Dry powder inhaler 40 µg (1 cap) 3–4 times daily. Nebulized newborn 25 µg/kg, less than 1year 62.5 µg, 1–5 years 125–250 µg, 5–12 years 250–500 µg and 12–18 years 500 µg every 20–30 min in first 2 hours and then tapered according to response. I

ron: All mg doses are expressed as elemental iron. Newborn infant (birth to 1 month) for prophylaxis of iron deficiency in low birth weight and breast fed babies—5–6 mg of elemental iron once daily. Children treatment of iron deficiency anemia—3 month to 12 years 5–6 mg/kg in 2 divided doses and 12–18 years 180 mg of elemental iron in 3 divided doses. Iron chloride injection 1 mL/kg as part of a balanced PN regimen. Isoniazid 5 mg/kg/day. I

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soproterenol ( soprenaline): ECG monitoring required during administration IV infusion as HCl salt—newborn 20–300 ng/kg/

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vermectin: 5–18 years 0.15 mg/kg as single dose to repeat every 6–8 months. Strongyloidosis—5–18 years 0.2 mg/kg for 2 days as single dose and repeat every 6–12 months if necessary. Filariasis— Ivermectin has no lethal effects against adult worms and therefore it is to be given in dose of 150 µg/kg once a year for 10 years. If symptoms recur, then dose is given every 3 months instead of once a year. Ivermectin is also effective against lymphatic filaria caused by W. bancrofti. In endemic areas, for mass treatments single dose of albendazole 400 mg + Ivermectin 200 mg/kg every 12 months is highly effective in controlling filiaria. Its effect is more sustained than diethylcarbamazine for elimination of microfilaria from skin and ocular tissues. Ivermectin is not used against filiaria caused by Loa loa due to risk of encephalopathy (in Loa loa diethylcarbamazine and albendazole are first & second line drug of choice). Scabies and pediculosis—Recently single dose of ivermectin (200 µg/kg) has been found to be highly effective in treatment of scabies and head lice. Ivermectin is typically helpful in treatment of crusted scabies found in patient with immunosuppression (e.g. HIV and Leukemia, etc.). It is used to prevent and cure the outbreak of scabies in institution.

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Japanese encephalitis vaccine (inactivated): Two dose schedule for those residing in endemic areas – 1 mL (0.5 mL if less than 3 year) at 0 and 7 days and booster after 6 month 3 dose schedule for those not residing in endemic areas – 1 mL (0.5 mL if less than 3 year) at 0, 7 and 30 days and booster (optional) after 2 years. etamine: Intermittent IV less than 12 years 1–2 mg/kg and 12–18 years 1–4.5 mg/kg as induction followed by maintenance as required—usually half induction dose or as IV infusion. IV infusion induce with 0.5–2 mg/kg followed by maintenance newborn 0.5 mg/kg/hour and 1 month—18 years 0.6–2.7 mg/ kg/hour. Neuropathic pain for palliative care 0.1–0.3 mg/kg/hour (maximum 1.5 mg/kg/hour) will suffice. IM 4 mg/kg for diagnostic/ pain causing procedures. K

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spaghula husk: Child 2–12 years 1 level 5 mL spoonful in water once or twice daily, preferably at mealtimes. Child 12–18 years 2 level 5 mL spoonful in water once or twice daily, preferably at mealtimes.

etoconazole: Pityriasis versicolor: use daily for a maximum of 5 days. Seborrheic dermatitis and dandruff: use twice weekly for 2–4 weeks Candidiasis, candiduria, or chromomycosis: Oral: Adolescent: 200 mg PO once daily. Serious infection may require 400 mg PO once daily. Children more than or equal to 2 years of age: 3.3–6.6 mg/kg PO once daily. Children less than 2 years of age: Safety and efficacy have not been established. Oropharyngeal candidiasis (thrush) in HIV-infected children: Oral: Children: 3–7 mg/kg/day for 5–49 days till cured vulvovaginal candidiasis: Nonpregnant adolescent females: 200–600 mg PO once daily for 3–6 days. For recurrent vulvovaginal candidiasis, topical or oral therapy daily for 2 weeks, then 6 months of therapy that could include ketoconazole 100 mg PO everyday. Not recommended in pregnancy. Tinea K

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ntralipid 10%/ ntralipid 20%: The ability to eliminate Intralipid 10%/20% should govern the dosage and infusion rate. 1 g triglycerides corresponds to 10 mL Intralipid 10% or 5 mL Intralipid 20% Neonates and Infants: The recommended dosage range in neonates and infants is 0.5–4 g triglycerides/kg body weight/ day. The rate of infusion should not exceed 0.17 g triglycerides/ kg body weight/hour (4 g in 24 hours). In prematures and low birthweight neonates, Intralipid 10%/20% should preferably be infused continuously over 24 hours. The initial dosage should be 0.5–1 g/kg body weight/day followed by a successive increase by 0.5–1 g/kg body weight/day up to 2 g/kg body weight/day. Only with close monitoring of serum triglyceride concentration, liver tests and oxygen saturation may the dosage be increased to 4 g/ kg body weight/day. The rates given are maximum rates and no attempt should be made to exceed these in order to compensate for missed doses. The ability to eliminate fat should be tested regularly in neonates and infants. Measuring serum triglyceride levels is the only reliable method. Essential Fatty Acid Deficiency (EFAD): To prevent or correct essential fatty acid deficiency, 4–8% of the nonprotein energy should be supplied as Intralipid 10%/20% to provide sufficient amounts of linoleic and linolenic acid. When EFAD is associated with stress, the amount of Intralipid 10%/20% needed to correct the deficiency may be substantially increased. Adolescent: The recommended maximum dosage is 3 g triglycerides/kg body weight/day. Within this upper limit, Intralipid 10%/20% can be given to contribute up to 70% of the energy requirements, also in patients with highly increased energy requirements. The infusion rate for Intralipid 10%/20% should not exceed 500 mL in 5 hours. The ability to eliminate fat should be closely monitored in patients with conditions mentioned under Contraindications and warnings and in patients given Intralipid 10%/20% for more than 1 week. This is done by collecting a blood sample after a fat-free clearance period of 5–6 hours. Blood cells are then separated from plasma by centrifugation. If the plasma is opalescent, the infusion should be postponed. The sensitivity of this method is such that hypertriglyceridemia can pass undetected. Therefore, it is recommended that serum triglyceride concentrations should be measured in patients who are likely to have impaired fat tolerance.

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sotretinoin: Oral 0.5 mg/kg daily once for 4 weeks and if response is good continue for further 8–12 weeks; if response poor, give up to 1 mg/kg for 8–12 weeks. If intolerant, reduce to 0–0.2 mg/kg/ day. Topical apply 1–2 times daily over affected area.

nterferon gamma-1b ( mmune interferon): SC surface area less than 0.5 m2 1.5 µg/kg/dose and surface area more than 0.5 m2 50 µg/kg/dose 3 times in a week. Avoid in children less than 6 months.

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etotifen: Adolescents: 1–2 mg once daily with food. Initial treatment is 0.5 –1 mg at night. Children: Over 2 years: 1 mg once daily with food. Not recommended for children below 2 years. K

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capitis, tinea corporis, tinea cruris, tinea pedis, tinea manuum, tinea unguium (onychomycosis) caused by Trichophyton sp., Microsporum sp. or Epidermophyton sp., and tinea versicolor: Adolescent: 200 mg PO once daily. Serious infection may require 400 mg PO once daily. Children more than= 2 years of age: 3.3–6.6 mg/kg PO once daily.

Labetalol: Oral start with 4 mg/kg/24 hour in 2 divided doses and gradually increase (maximum 40 mg/kg/24 hour) IV 0.2–1 mg/kg/ dose (maximum 20 mg/dose). Continuous IV infusion 0.4–1 mg/ kg/hour (maximum 3 mg/kg/hour). Lactitol monohydrate: Administer oral once daily along with evening meals – the dose may also be given in the morning if that is more convenient. Constipation: 2–6 year age – 10 mL; more than 6 years 10–15 mL. Prevention of hepatic encephalopathy: 30 mL once in the evening. Acute phase of hepatic encephalopathy: 45– 90 mL divided into 3 doses along with main meals. Lactulose: Constipation—initial dose less than 1 year 5 mL, 1–5 years 10 mL, 5–10 years 20 mL, more than 12 years 30 mL in 2 divided doses. Then adjust according to response. Hepatic encephalopathy—initially 30–50 mL/dose 3 times daily. Then adjust to produce 2–3 soft stools/day. Lamivudine: Adolescents (weight more than or equal to 40 kg): 300 mg/day. Safe and effective use has not been established in adolescent less than 40 kg and in children. Patients with renal impairment: CrCl less than or equal to 50 mL/min: Lamivudine requires dose adjustment in the presence of renal insufficiency.

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Lamotrigine: Individualized based on age and additional anticonvulsants. Adults 150–500 mg/day; bid Children: 5–15 mg/kg/day (1–5 mg/kg/dL with Valproate). Dosing guidelines for patients 2–12 years of age. The initial weight-based dosing guide for lamotrigine for patients 2 to 12 years taking valproate (weeks 1 to 4) with epilepsy. If the patient’s weight is greater than 6.7 kg and less than 14 kg. Give this daily dose, using the most appropriate combination of LAMICTAL 2-mg and 5-mg tablets. Weeks 1 and 2: 2 mg every other day. Weeks 3 and 4: 2 mg every day. The initial weight-based dosing guide for lamotrigine for patients 2–12 years taking valproate (weeks 1 to 4) with epilepsy. If the patient’s weight is greater than 14.1 kg and less than 27 kg. Give this daily dose, using the most appropriate combination of LAMICTAL 2-mg and 5-mg tablets. Weeks 1 and 2: 2 mg every day. Weeks 3 and 4: 4 mg every day. The initial weight-based dosing guide for lamotrigine for patients 2–12 years taking valproate (weeks 1–4) with epilepsy. If the patient’s weight is greater than 27.1 kg and less than 34 kg. Give this daily dose, using the most appropriate combination of LAMICTAL 2-mg and 5-mg tablets. Weeks 1 and 2: 4 mg every day. Weeks 3 and 4: 8 mg every day. The initial weight-based dosing guide for lamotrigine for patients 2–12 Years Taking Valproate (Weeks 1–4) with epilepsy. If the patient’s weight is greater than 34.1 kg and less than 40 kg. Give this daily dose, using the most appropriate combination of LAMICTAL 2-mg and 5-mg tablets. Weeks 1 and 2: 5 mg every day. Weeks 3 and 4:10 mg every day. Escalation regimen for lamotrigine in patients 2–12 years of age with epilepsy. Weeks 1 and 2: For patients taking valproate (see Table 2 for weight-based dosing guide) for patients taking 0.15 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see table below for weight-based dosing guide). AEDs other than carbamazepine,

phenytoin, phenobarbital, primidone, or valproate 0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet. For patients taking carbamazepine, phenytoin, phenobarbital, primidone and not taking valproate 0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet. Weeks 3 and 4: For patients taking valproate (see Table 2 for weight-based dosing guide). For patients taking 0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see table below for weight-based dosing guide). AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate 0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet. For patients taking carbamazepine, phenytoin, phenobarbital, primidone and not taking valproate 1.2 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet. Weeks 5 onwards to maintenance: For patients taking valproate (see table 2 for weight-based dosing guide). For patients taking the dose should be increased every 1–2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose. AEDs other than carbamazepine, phenytoin, phenobarbital, primidone or valproate. The dose should be increased every 1–2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose. For patients taking carbamazepine, phenytoin, phenobarbital, primidone and not taking valproate. The dose should be increased every 1–2 weeks as follows calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose. Usual maintenance dose: For patients taking valproate (see table 2 for weight-based dosing guide) for patients taking 1–5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses). One to three mg/kg/day with valproate alone AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate. 4.5–7.5 mg/kg/day (maximum 300 mg/ day in 2 divided doses). For patients taking carbamazepine, phenytoin, phenobarbital, primidone and not taking valproate. 5–15 mg/kg/day (maximum 400 mg/day in 2 divided doses). Maintenance dose in patients less than: 30 kg. For patients taking valproate (see Table 2 for weight-based dosing guide) for patients taking. May need to be increased by as much as 50%, based on clinical response. AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate may need to be increased by as much as 50%, based on clinical response. For patients taking carbamazepine, phenytoin, phenobarbital, primidone and not taking valproate. May need to be increased by as much as 50%, based on clinical response. Lansoprazole: Gastroesophageal reflux disease (GERD), acid related dyspepsia, duodenal and benign gastric ulcer including those following NSAID therapy: children less than 30 kg—0.5–1 mg/kg (maximum 15 mg) once daily; Children more than 30 kg – 15–30 mg once daily for 8–12 weeks. Leuprorelin acetate (Leuprolide): 3.75 mg every 4 weeks or 11.25 mg depot preparation every 12 weeks. Injections may need to be given more frequently (e.g. every 3 weeks or every 10 weeks) if patients show signs of failure of hormone suppression. Levamisole: Roundworm (ascariasis)—less than 12 years 2.5–3 mg/kg and 12–18 years 150 mg as single dose. Hookworm (ankylostomiasis)—less than 12 years 2.5 mg/kg and 12–18 years 150 mg as single dose. Repeat after 7 days if severe infection. Adults 300 mg for 1–2 days. Nephrotic syndrome—2.5 mg/kg on alternate days.

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Levetiracetam: Oral—16–18 years old—initiated at 500 mg twice daily. The dose may be titrated based on patient response with 500 mg/day increments every 2 weeks, up to 1,500 mg/day (maximum 3 g/day). When levetiracetam is withdrawn, it should be tapered slowly over 2–4 weeks to prevent withdrawal seizures. In adolescents with moderate to severe renal impairment, reduce dose by half and give twice daily. Hemodialysis removes approximately 50% of a levetiracetam dose in one 4-hour session. Those undergoing hemodialysis should therefore receive a supplemental dose of half their standard maintenance dose after dialysis. No dosage adjustment is needed in presence of hepatic impairment. But if hepatic impairment is associated with renal impairment with CrCl less than 70 mL/min/1.73 m2, half the usual dose is recommended.

Linezolid: The usual oral dose is 400–600 mg every 12 hours. Patients treated initially with IV linezolid may be switched to oral therapy without dosage adjustment when clinically appropriate.

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Levothyroxine ( hyroxine) sodium: Oral; initial dose—newborn: 10–15 µg/kg, late neonatal period: 6–8 µg/kg, 3 months–2 years: 5–10 µg/kg, 2–12 years: 5 µg/kg, 12–18 years: 50–100 µg.

Lincosamines and streptogramins: Dose—Clindamycin— Neonates—less than 7days less than 2,000 gm 10 mg/kg/day divided 12th hourly IV/IM; less than 7 days more than 2,000 g 15 mg/kg/day divided 8th hourly IV/IM; more than 7 days less than 1,200 g 10 mg/kg/day divided 12th hourly IV/IM; more than 7days 1,200–2,000 g 15 mg/kg/day divided 8th hourly IV/IM; more than 7 days more than 2,000 g 20 mg/kg/day divided 8th hourly IV/ IM; children 10–40 mg/kg/day divided 8th hourly IV/IM or orally; 12–18 years 150–300 mg up to maximum of 450 mg/dose 4 times daily. Falciparum malaria (alternate therapy) 20 mg/kg/day for 5 days. Quinopristin with dalfopristin—IV into central vein – 1 month to 18 years 7.5 mg/kg 8th hourly 7 days in skin and soft

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Lithium: Oral 12–18 years 200–800 mg/dose 3 times daily. Higher dose with citrate—citrate 509 mg = 200 mg carbonate. Maintain plasma level of 0.4–1 mmol/L 12 hours after last dose. Monitor once in 3 months.

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Lisinopril: Hypertension: Oral - adolescent: Initially, 10 mg PO once daily. The usual dosage range is 20–40 mg PO once daily. Lower dosage may be necessary in patients with renal impairment and in those receiving diuretics. In patients with a creatinine clearance of less than 30 mL/min, initiate therapy with 5 mg PO once daily. Maximum daily dose is 80 mg/day. Children more than or equal to 6 years: starting dosage is 0.07 mg/kg PO once daily (up to 5 mg/day). Adjust dosage based on blood pressure response. Doses more than 0.61 mg/kg/day PO or more than 40 mg/day have not been studied in pediatric patients. Lisinopril is not recommended in children with glomerular filtration rate less than 30 mL/min/1.73 m2. Children less than 6 years: Not recommended. The doses for heart failure in children are not defined. Lisinopril is removed by hemodialysis. For patients receiving dialysis, the initial recommended dosage is 2.5 mg PO once daily. Maximum 40 mg/day.

Levonorgestrel: Oral 30 µg.

Lignocaine: Antiarrhythmic – Loading dose IV bolus less than 12 years 0.5 mg–1 mg/kg and 12–18 years 50–100 mg (50 mg for thin build or those with severely impaired circulation) followed by maintenance dose IV infusion with ECG monitoring less than 12 years 0.6–3 mg/kg/hour and 12–18 years start with 4 mg/min for 30 min then 2 mg/kg for 2 hours than 1 mg/min for the rest of the day. Lower concentration. further if continued beyond 24 hours. Ventricular fibrillation or pulse less tachycardia—IV less than 12 years 1 mg/kg repeat every 5 min to maximum of 3 mg/kg and 12–18 years 50–100 mg. Local anesthetic—Local infiltration less than 12 years 3 mg/kg and 12–18 years up to 200 mg—not more frequently than once in 4 hours. Intraurethral 3–4 mg/kg prior to catheterization.”

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Liquid paraffin: Oral 3–12 years 0.5–1 mL/kg and 12–18 years 10–30 mL once daily. Topical application apply 2 times daily while skin is still moist after wash.

Levobupivacaine hydrochloride: Ilioinguinal/iliohypogastric nerve block—local infiltration 1.25–2.5 mg/kg single adminis tration.

The goal of therapy is to maintain the total thyroxine (TT4) in the upper normal range of 10–15 µg/dL and normalize elevated TSH. Adjust dose to correct free thyroxine (FT4) to more than 20 pmol/L and TSH to less than 1–3 mU/L within 4 weeks of therapy. TSH levels take at least 4 weeks to show any change following therapy. Monitor thyroid hormone levels 4–6 weekly at onset till target levels are attained and then according to progress. It is ideal to test 6–8 weeks after any change in dose and every 3–4 monthly intervals during the second year and biannually or annually as the child grows. It is preferable to monitor total thyroxine levels to free thyroxine levels. FT4 is preferred in special circumstances like pregnancy or inappropriately elevated TSH, and to cross check central hypothyroidism if T4 level is borderline as TSH will not be useful.”

Pediatric hera eutics

tissue infection, 10 days in hospital acquired pneumonia; duration for E. faecium infection depends on site of infection.

Loperamide: Chronic diarrhea, e.g. short bowel syndrome—less than 1 year 0.2 mg/kg 30 min before feeds (up to 2 mg/kg/day may be required); 1–12 year 0.1–0.2 mg/kg/dose and 12–18 years 2–4 mg 3–4 times daily. Acute diarrhea—not recommended in children. 12–18 years—may be used—start with 4 mg and then give 2 mg after each loose stool up to 6–8 mg/day (maximum 16 mg/day). Not given for more than 5 days. Loratadine: Oral less than 6 years 5 mg, more than 6 years 10 mg once daily. Lorazepam: Antiemetic—IV 0.4–0.8 mg/kg/dose 6th hourly as needed. Anxiety/sedation—Neonates 0.1–0.4 mg/kg/dose 6th hourly as needed. Children 0.05–0.1 mg/kg/dose 4th–8th hourly, adolescents. Orally1–10 mg/24 hour in 2–3 divided doses. Status epilepticus—Neonates IV 0.05–0.2 mg/kg/dose over 2–5 min; may repeat in 10–15 min, children 0.1 mg/kg loading over 2–5 min and if required, another 0.05 mg/kg bolus in 10–15 min, adolescent 0.07 mg/kg/dose over 2–5 min and may repeat after 10–15 min. Losartan potassium: Hypertension—adolescents: Initially, 50 mg PO once daily, unless the patient is volume-depleted. The maintenance dosage range is 25–100 mg/day PO, given in 1–2 divided doses. Maximal effects generally occur within 3–6 weeks. The addition of a diuretic has a greater effect on lowering blood pressure than increasing the losartan dosage beyond 50 mg/ day. The addition of hydrochlorothiazide 12.5 mg to losartan 50 mg daily results in an additional 50% reduction in diastolic and systolic BP. A modest reduction in blood pressure (up to 3 mm Hg) is achieved by increasing the daily dose of losartan from 50–100 mg. When volume-depletion is suspected (e.g. patients taking diuretics), initiate therapy with 25 mg PO once daily. Children more than or equal to 6 years: the usual recommended starting dose is 0.7 mg/kg PO once daily (up to 50 mg/day). Individualize dosage to attain blood pressure goals. Doses more than 1.4 mg/kg/day (or more than 100 mg/day) PO have not been studied. Losartan

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Macrolides: Erythromycin: Dose—Neonates—Orally less than 7 days age 20 mg/kg/day 2 times daily; more than 7 days less than 1,200 g 20 mg/kg/day 2 times daily; more than 7 days more than 1,200 g 30 mg/kg/day 3 times daily. Children: 30–50 mg/kg/day in 3–4 divided doses. Pneumococcal prophylaxis – 1 month to 2 years 250 mg/day, 2–8 years 500 mg/day, more than 9 years 1 g/day in 2 divided doses. Clarithromycin: Dose—Oral 15 mg/ kg/24 hour in 2 divided doses up to a maximum of 500 mg twice daily. H. Pylori—1–2 years 125 mg, 2–6 years 250 mg, 6–9 years 375 mg, 9–12 years 500 mg and 12–18 years 1 g/day in 2 divided doses along amoxicillin and omeprazole or metronidazole and omeprazole. Azithromycin: Dose—Children – 6 months – 12 years 10 mg/kg once daily for 3 days up to a maximum of 200 mg/dose in 3–7 years, 300 mg/dose in 8–11 years 400 mg/dose in 12–14 years and 500 mg/dose in more than 14 years. Continued treatment may be required to prevent relapse of cryptosporidiosis. For STD caused by chlamydia trachomatis in 12–18 years 1 g as single dose.

Mebeverine hydrochloride: Oral—3–4 years 75 mg/day, 4–8 years 150 mg/day, 9–10 years 300/day and more than 10 years 450 mg/day in 3 divided doses 10–20 min before meals. Mefenamic acid: Adolescents: 250–500 mg thrice daily, preferably after food. Children: 9.5 mg–25 mg/kg/day in divided doses. Except for Still’s disease therapy should not exceed 7 days. Mefenamic acid should be used with extreme caution in children younger than 14-years-old; safety and effectiveness in these children have not been confirmed. Mefloquine: Treatment—Oral 15 mg/kg followed by 10 mg/kg 8–12 hours later (maximum 1.25 g). Prophylaxis—Oral first dose 1 week before entering malarious area (may be started earlier to make sure drug is tolerated) and given weekly on same day for 6 weeks and continued for 4 weeks after return from malarious area. 3 months to 3 years 6–16 kg 62.5 mg (1/4th tab), 4–7 years 16–25 kg 125 mg (1/2 tab), 8–12 years 25–45 kg 187.5 mg (3/4th tab) and more than 13 years more than 45 kg 250 mg (1 tablet).

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polysaccharide vaccine: IM/deep SC—

Meningococcal , , W135 & Y polysaccharide vaccine: Deep SC or IM: 0.5 mL pf reconstituted vaccine. Meningococcal conjugate vaccine: IM or deep SC—0.5 mL. Number of doses depends on age of recipient. When given as primary immunization—3 doses at 4 weeks intervals starting at 6–8 weeks, if started after 16 weeks age—2 doses at 4 week intervals and if started more than 1 year age—only 1 dose is required.

Mannitol: A test dose may be given to assess renal function – 200 mg/kg (maximum 12.5 g) over 3–5 min to produce urine output of 1 mg/kg/hour for 1–3 hours. Then follow-up with cerebral and ocular edema—IV over 30 min 0.5–1 gm/kg initially followed by maintenance of 0.25–0.5 g/kg every 4–6 hours as required. Peripheral edema and acites—IV infusion over 2–6 hours 1–2 g/kg.

Mercaptopurine: Always consult the current treatment protocol for details of dosage and scheduling. The dosage should be carefully adjusted according to blood counts. Leukemia/ lymphoma/T-NHL—Oral induction 2.5–5 mg/kg once daily followed by maintenance of 1.5–2.5 mg/kg/day. Inflammatory bowel disease—2–18 years 1–1.5 mg/kg once daily (maximum initially 50 mg/day may be increased up to 75 mg/day).

Mebendazole: Oral more than 6 months 100 mg as single dose for all members of the family, may be repeated after 2 weeks: all other susceptible worm infestation – 100 mg 2 times daily for 3

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Malathion: Topical: medical supervision is required for children less than 6 months of age. Scabies—apply to whole body excluding head and neck, allow to dry, wash off after 24 hours. Children less than 2 years should have a thin film applied to scalp, face and ears, avoiding eyes and mouth. If hands or any other part are washed the treatment must be reapplied. Head lice-rub liquid gently into dry hair until all hair is thoroughly moistened. Comb and allow to dry naturally, away from heat or sunshine. A contact time of 12 hours or overnight is recommended. Repeat after 7 days only if live lice are found again.

Measles vaccine: 1 single dose amp. SC at 9 completed months of age. In case of an outbreak, however, the vaccine may be given to infants as young as 6 months with a recommendation for an additional MMR/Measles at 12–15 months. Commonly used strain is the Edmonston Zagreb strain grown in human diploic cell culture. Other strains used are Schwarz, Moraten and Edmonston B.

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Melphalan: Always consult the current treatment protocol for details of dosage and scheduling. IV 10–35 mg/m2/dose once in 21–28 days. High dose: 140–220 mg/m2 before bone marrow transplant. Oral 4–20 mg/m2/day for up to 21 days.

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Magnesium sulfate: Neonatal hypocalcemia—IM 100 mg/kg/ dose 2 doses will suffice. A third dose is required in some babies. Hypomagnesemia in newborn—IM/IV 1 dose of 100 mg/kg. Repeat more than 6–12 hours if needed. Persistent pulmonary hypertension in newborn—IV loading dose 200 mg/kg followed by IV infusion maintenance 20–75 mg/kg/hour to maintain plasma magnesium between 3.5–5.5 mmol/L. Can give for 2–5 days. Child—slow IV over 10 min less than 1 year 50 mg/kg 12–18 years 1 g (4 mmol)—may be repeated once in 12 hours.

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Meloxicam: Oral/rectal 12–18 years less than 50 kg 7.5 mg and more than 50 kg 15 mg once daily. In renal failure, dose of 7.5 mg not to be exceeded.

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Magnesium salts: 5–10 mL bedtime daily, reducing dose gradually until constipation is relieved.

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Magnesium glycerophosphate: Oral less than 12 years 0.6 mmol/ kg/day; 12–18 years 12–24 mmol/day in 3 divided doses.

Melatonin: Oral 2–3 mg 20–30 min before bedtime. May be increased to 4–6 mg if benefit not achieved in 1–2 weeks. Maximum of 10 mg tried. If still no response in 2 weeks, drug is stopped.

Mepacrine hydrochloride: Oral 100 mg 1–2 times daily. Mercaptamine ( ysteamine): Oral Initially less than 12 years 2–3 mg/kg/dose and more than 12 years 100 mg 4 times daily followed by maintenance of 12.5 mg/kg/dose and more than 12 years 500 mg 4 times daily. Eye—1 drop in each eye 4–6 times daily. C

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consecutive days. Better than albendazole for trichuris infestation. Hytatid disease 200–400 mg bid or tid for 3–4 weeks, less effective than albendazole. Reduction in dose for hepatic impairment.

can be prepared extemporaneously as an oral suspension. Children less than 6 years: not recommended. Chronic congestive cardiac failure—75 to 1.4 mg/kg/day other drugs in this group are Candesartan, Valsartan. Studies in children are in progress, primarily for treatment of hypertension.

Meropenem: Newborn – 40 mg/kg/day in 2 divided doses less than 7 days and in 3 divided doses more than 7 days. Double dose in meningitis and severe infection. Children UTI, gynecological, skin and soft tissue infection – 30 mg/kg in 3 divided doses (maximum 500 mg/dose). Pneumonia, peritonitis, neutropenia, septicemia – 60 mg/kg/day in 3 divided doses (maximum 1 g/dose). Meningitis and life threatening infections—120 mg/kg/day in 3 divided doses (maximum 2 g/dose). In renal impairment—CrCl (mL/min/1.73 m2)

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Methylene blue: Methemoglobinemia—1–2 mg/kg or 25–50 mg/m2; may be repeated after 1 hour if necessary. NADPHmethemoglobin reductase deficiency—Oral—1–1.5 mg/kg/day (maximum 300 mg) given with 5–8 mg/kg/day ascorbic acid.

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Mesalazine [5-aminosalicylic acid (5)]: Acute cases—15–20 mg/kg/dose 3 times daily followed by maintenance of 10 mg/kg/ dose 2–3 times daily. S

Methionine: Oral less than 6 years 1 g 4th hourly (maximum 4 g/day) more than 6 years 2.5 g 4th hourly (maximum 10 g/day) started within 8 hours of overdosage. Not effective if given after activated charcoal.

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Metoclopramide hydrochloride: Oral, IM or slow IV less than 12 years 0.3 mg/kg/day (maximum 10 gm/day) in 3 divided doses. 12– 18 years, 5–10 mg/dose 3 times daily. Dosage is renal impairmentsee contraindications and warnings. Metolazone: 2.5–5 mg/day for adolescents, 0.2–0.4 mg/kg/day in children. Electrolytes must be monitored closely. Intermittent doses of metolazone may help to overcome diuretic resistance which may occur due to fluid overload, mesenteric congestion (inadequate absorption) and low renal blood flow. Patients with hepatic impairment: no specific dosage adjustment is specified due to limited data. Use with caution in patients with hepatic disease since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. Patients with renal impairment: no dosage adjustment is needed; however, higher doses may be needed to achieve clinical goals in some patients with end-stage renal disease. Intermittent hemodialysis: no dosage adjustment is needed.

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Methylprednisolone: Dosage may have to be reduced in patients with hepatic impairment. The lowest effective dose should be used. Prophylactic antacid administration may be required with high dose, short–term IV therapy. If a patient is receiving oral steroids then these are usually stopped on the days that methylprednisolone is given. Severe JIA, connective tissue disorders—IV 30 mg/kg once daily for 3 days (maximum 1 g/day) Graft rejection—IV 10–20 mg/ kg once daily. Demyelinating disorders—IV less than 12 years 500 mg and more than 12 years 1 g once daily.

Metformin hydrochloride: 500 mg/dose 2–3 times daily (maximum 1 gm/dose 2 times).

Methoxsalen: Psoriasis—Oral—12–18 years 600 µg/kg (maxi mum 70 mg) once daily—given 2–3 hours before UVA 1–3 times in a week (not to be more frequent than an alternate day schedule). Vitiligo—Adolescent—Vitiligo is reversible but not equally reversible in every patient. Repigmentation will vary in completeness, onset time, and duration. Repigmentation occurs more rapidly in fleshy areas such as the face, abdomen, and buttocks and less rapidly over less fleshy areas such as the dorsum of the hands or feet. Apply the topical preparation to a well-defined area and then expose the area to UVA. Initial exposure time should be conservative and not exceed that which is predicted to be onehalf the minimal erythema dose. Determine the treatment interval by the erythema response; generally once a week treatment or less is recommended. Pigmentation may begin after a few weeks, but significant repigmentation may require 6–9 months of treatment. Periodic retreatment may be necessary to retain all of the new pigment. Patients with hepatic impairment: specific guidelines are not available; however, patients should be treated with caution, as methoxsalen undergoes significant hepatic metabolism. Patients with renal impairment: specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

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Methylphenidate hydrochloride (controlled drug): (0.5–1 mg/ kg/day before food). More than 6 years 5 mg/dose 1–2 times daily. Increase at weekly increments of 5–10 mg daily. Maximum 60 mg/ day given in 2–4 divided doses. Avoid dosing in the evenings.

Mesna ( odium mercaptoethane sulfonate): Uroprotectant— Injection: Mesna doses vary but in practice doses greater than 100% (mg:mg) of the total daily oxazaphosphorine dose are used. May be given in 5 divided doses, 15 min before and 3, 6, 9 and 12 hours after alkylating agent dose. Always consult the current treatment protocols for details of dosage and scheduling. Mucolytic—Nebule: 3–6 mL of a 20% solution twice daily. Maximum of 24 mL per day.

Methotrexate: Severe acute Crohn’s disease—SC/IM—Child 7–18 years—15 mg/m2 (maximum 25 mg) once weekly followed by maintenance of remission dose—Oral/SC/IM—Child 7–18 years—15 mg/m2 (maximum 25 mg) once weekly; dose reduced according to response to lowest effective dose. JIA, juvenile dermatomyositis, vasculitis, uveitis, SLE, localized scleroderma, sarcoidosis—Oral/SC/IM—Child 1–18 years—10–15 mg/m2 (increased to maximum 25 mg, if needed) once weekly. For all malignant conditions—early stage Burkitt’s lymphoma, nonHodgkin’s lymphoma, osteogenic sarcoma, some CNS tumors including infant brain tumors, acute lymphoblastic leukemia (IV inj./infusion); maintenance and remission of acute lymphoblastic leukemia, lymphoblastic lymphoma (oral); and meningeal leuke mia, treatment and prevention of CNS involvement of leukemia (intrathecal)—use doses prescribed in respective protocols. Severe uncontrolled psoriasis unresponsive to conventional therapy—oral—child 2–18 years—initially 200 µg/kg (maximum 10 mg) once weekly increased according to response to 400 µg/kg (maximum 25 mg) once weekly.

Pediatric hera eutics

Methyldopa: 10 mg/kg/day in 2–4 divided doses. Maximum 3 g/day.

25–50—give full dose but at 12 hours intervals, 10–25—50% dose at 12 hours intervals less than 10–50% dose at 24 hours interval.

Metoprolol: Oral children 0.2–0.4 mg/kg/day initially, gradually increase to a maximum of 1 mg/kg/day in 2 divided doses and adolescents 100–450 mg/24 hour in 3–4 divided doses. IV 5 mg every 2 min for 3 doses. Metronidazole: Newborn—IV 15 mg/kg as loading dose followed 24 hour later by 7.5 mg/kg/dose 2 times daily. Anaerobic infections and propionic and methylmalonic academia—Oral/IV 7.5 mg/kg/ dose (maximum 400–500 mg) 3 times daily. Giardiasis—Oral 40 mg/kg (maximum 2 g) once daily for 3 days. Trichomoniasis – 5 mg/kg/dose (maximum 300–499 mg/day) 3 times daily for 7 days. Amebiasis (5–10 days). Balantidiasis (5 days)—Oral 10 mg/kg (maximum 400–800 g. H. pylori Oral 1–6 years 100 mg, 6–12 years 200 mg and 12–18 years 400 mg/dose 3 times daily for 14 days with either amoxicillin/omeprazole or clarithromycin/omeprazole. Increase dose interval to 12 hours in renal impairment (CrCl less than 20 mL/min/1.73 m2. Reduce dose in hepatic impairment and avoid in hepatic encephalopathy. Miconazole: Topical on skin apply on affected area 2 times daily for 10 days after lesions have healed. Oral thrush less than 1 month 1.25 mL, up to 2 years 2.5 mL, 2–12 years 5 mL and 12–18 years 5–10 mL 2–4 times daily. Use in the mouth after food and retain as long as possible. Midazolam: Newborn—sedation IV infusion 1 µg/kg/min for 1st 24 hours followed by 0.5 mg/kg/min. Children: premedication: IM 1–18 years 70–100 µg/kg or orally 500 µg/kg (maximum 15 mg)

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Mycophenolate mofetil: Given along with cyclosporin or tacrolimus and steroids. Renal—Oral 600 mg/m2/dose 2 times daily—first dose within 72 hours after transplant (maximum 2 g/ day). Liver—Oral 10 mg/kg/dose 2 times daily increasing to 20 mg/ kg/dose 2 times daily—first dose within 72 hours after transplant (maximum 1 g/day).

as a single dose 30–60 min before surgery. Monitor from time of administration. Sedation for procedures—IV less than 12 years 50–100 µg/kg (maximum 300 µg/kg) and more than 12 years 2 mg (if sedation not adequate, incremental doses of 0.5–1 mg may be given—maximum 5 mg); oral 0.5 mg/kg (maximum 15 mg); rectal 500–700 µg/kg; intranasal 200–300 µg/kg, half in each nostril. Sedation in intensive care: 30–300 µg/kg IV bolus over 3–5 min followed by continuous IV infusion of 500 ng – 3.3 µg/kg/min. (may not be needed if child has received morphine or post-op sedation. Reduce dose in hypovolemia, vasoconstriction and hypothermia. Low doses if child receiving opiates. Adjust according to response). Induction of anesthesia: Slow IV bolus—more than 7 years up to 12 years 150 µg/kg; 12–18 years 200–300 µg/kg as single dose. Status epilepticus—IV bolus initial bolus of 0.15–0.2 mg/kg followed by 1 µg/kg/min and increase by 1 µg/kg/min every 15 min until seizures stop (maximum 5 µg/kg/min). Buccal/intranasal less than 6 months 300 µg/kg, 6 months to 1 year 2.5 mg, 1–4 years 5 g, 5–9 years 7.5 mg, more than 10 years 10 mg as single dose. Intractable seizures in palliative care: 5 mg/24 hour IV/SC continuous infusion (can be titrated up to 40 mg/24 hour). Dose must be reduced in severe renal impairment and renal failure. Milrinone lactate: IV as 25–50 µg/kg bolus over 10 min, followed by infusion at 0.25–0.75 µg/kg/min.

Nalidixic acid: Urinary tract infection (UTI) due to susceptible organisms: Oral: Adolescents: 1 gram suspension or tablet PO every 6 hours for 1–2 weeks. Maintenance dose of 500 mg PO every 6 hours. Children and infants more than or equal to 3 months: the recommended total daily dosage for initial therapy is 55 mg/kg/ day PO, administered in 4 equally divided doses. For prolonged therapy, the total daily dose may be reduced to 33 mg/kg/day PO. Urinary tract infection (UTI) prophylaxis in children: Oral: Children and infants more than or equal to 2 months to 2 years: A dose of 30 mg/kg/day PO in 2 divided doses has been recommended. Maximum Dosage Limits: Adolescents: 4 g/day PO. Children and infants more than or equal to 3 months: 55 mg/kg/day PO. Infants less than 3 months: Safe and effective use has not been established. Patients with hepatic impairment: Exercise caution when using nalidixic acid in patients with liver disease; however, no specific dosage adjustments are indicated. Patients with renal impairment: Decrease the dose by half in patients with a CrCl less than or equal to 20 mL/min.

Minocycline: Oral: 50 mg/dose 2 times daily for minimum of 6 weeks. Minoxidil: Less than 12 years 0.2 mg/kg (maximum 1 mg/kg/day) and 12–18 years 5 mg (maximum 100 mg/day—rarely need to give more than 50 mg/day. The dose may be given 1–2 times daily. Androgenic alopecia – Apply 12 hourly not exceeding 2 mL/day for at least 45 days – usually more than 4 months to arrest hair fall.

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Misoprostol: Prophylaxis of NSAID induced GI complications— 12–18 years 200 µg/dose taken with NSAID along with or after meals 4 times daily. Treatment of NSAID induced GI complications—2–12 years 5 µg/kg/dose 2 times daily and 12–18 years 200 µg/dose 2–4 times daily with breakfast or main meal and at bedtime. To improve fat absorption in cystic fibrosis—2–18 years 400 µg/day in 4 divided doses.

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Mitoxantrone (Mitozantrone): Always consult the current treatment protocol for details of dosage and scheduling. Careful supervision is recommended when treating patients with severe hepatic insufficiency. Acute non-lymphocytic leukemias in children—less than 2 years 0.4 mg/kg/day for 3–5 days; more than 2 years 8–12 mg/m2/day for 5 days. Solid tumors in children—18–20 mg/m2 once in 2–3 weeks or 5–8 mg/m2 weekly. R

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MM (Measles, Mumps and ubella) vaccine: IM or deep SC: 0.5 mL of reconstituted vaccine at 15 months. Mometasone: A thin film to be applied to affected skin once or twice daily. Montelukast: Oral 2–5 years 4 mg, 6–14 years 5 mg and more than 14 years 10 mg once daily in the evening. ­

Morphine sulfate (controlled drug): Neonates—IM/IV/SC Anal gesia—0.05–2 mg/kg/dose every 2–4 hours or continuous infusion 0.025–0.05 mg/kg/hour. Infants and children—IM/IV/SC 0.1–0.2 mg/kg/dose every 2–4 hours; oral 0.2–0.4 mg/kg/dose every 4–6 hours. Adolescents more than 12 years—IV 3–4 mg may repeat after 5 min if required.

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Mupirocin: Dosage description: topical cream -apply to affected area 3 times daily for up to 10 days; nasal ointment apply to the inner surface of each nostril 2–3 times a day for 5–7 days; ointment apply to affected area 2–3 times daily for up to 10 days.

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Naloxone: Newborn infant—Do not administer to newborns whose mother is suspected of narcotic abuse as a withdrawal syndrome may be precipitated. Ensure establishment and maintenance of adequate ventilation before administering naloxone. Specifically indicated for reversal of respiratory depression on newborn of mother who has received narcotics within 4 hours of delivery. IM preferred because it affords more prolonged effect. 0.1 mg/kg may be repeated after 3–4 min. In older children with suspected narcotic depression same dose (maximum 2 mg) may be given IV. Repeat doses to maintain opioid reverse. If no response seen after 2 doses, diagnosis of opioid toxicity must be reviewed. Naproxen: Oral 10–20 mg/kg in 2 divided doses (maximum 1 g/ day). In severe cases up to 15 mg/kg may be used for a few weeks. Nedocromil: Asthma prophylaxis: Nedocromil sodium is intended for regular maintenance treatment and should not be used for relief of symptoms in an acute asthmatic attack. For maintenance therapy in the treatment of mild to moderate chronic asthma: Oral inhalation dosage (metered dose inhaler): Adolescents and children more than or equal to 6 years: 2 sprays (1.75 mg/spray) inhaled orally 4 times per day. Dosage may be reduced to 2–3 times per day once desired clinical response obtained. Safe and effective use has not been established in children less than 6 years. Prevention of exercise-induced bronchospasm: Oral inhalation dosage (metered dose inhaler): Adolescents and children more than 12 years: A dose of 2 sprays (1.75 mg/spray) inhaled orally 10–15 min prior to exercise. Allergic conjunctivitis: Ophthalmic dosage: Adolescents and children more than 3 years: 1–2 drops in each eye twice daily at regular intervals. Maximum Dosage Limits: Adolescents: Dependent on route of administration and indication for therapy; 8 sprays (14 mg)/day via MDI. Children more than or equal to 6 years: Dependent on route of administration and indication for therapy; 8 sprays (14 mg)/day via MDI. Children less than 6 years: Dependent on route of administration and indication for therapy. Patients with hepatic impairment: Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed. Patients with renal impairment: Specific guidelines for dosage adjustments

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Neostigmine: Newborn myasthenia gravis—Oral 1–2 mg initially half hour before feed followed by 1–5 mg/dose (adjusted according to response) 6 times daily. IM 0.1 mg initially followed by 0.05–0.25 mg IM or SC (2–3 mg IM/SC is equal to 30 mg orally). Reversal of nondepolarizing neuromuscular blockade—IV bolus over 1 min to 80 µg/kg with 20 µg/kg of atropine (for drugs other than atracurium) and 50 µg/kg with 20 µg/kg of atropine (for atracurium). Children myasthenia gravis—Oral 1 month to 5 years 7.5 mg/dose, 6–12 years 15 mg/dose and 12–18 years 15–30 mg/ dose repeated at suitable intervals according to response. IM 1 month to 12 years 0.2–0.5 mg and 12–18 years 1–2.5 mg repeated at suitable intervals. B

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Nesiritide (h NP; human -type natriuretic peptide): Infusions starting at 0.01 µg/kg/min and up titrated to a maximum of 0.03 µg/kg/min. Calculate the required bolus volume based on the patient’s weight as follows: bolus volume (in mL) = 0.33 x patient weight (kg). Then withdraw the appropriate bolus volume from the nesiritide infusion bag, and inject it over about 60 seconds through an IV port in the tubing. Immediately following the administration of the IV bolus, infuse nesiritide solution at a flow rate of 0.1 mL/kg/hour. The calculation for the infusion flow rate (mL/hour) = 0.1 x patient weight (kg). This will deliver the initial recommended nesiritide maintenance infusion rate of 0.01 µg/ kg/min. Nesiritide is generally administered at a fixed IV infusion rate. Due to a long onset and offset of action, nesiritide should be titrated upward no more frequently than every 3 hours. Do not titrate infusion rate at frequent intervals as is done with other IV agents that have a significantly shorter half-life (e.g. dobutamine, dopamine, nitroglycerin, nitroprusside).

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Nevirapine: Treatment of HIV infection in combination with other antiretroviral agents. For adolescents, the initiation of ART is recommended in any patient: with a history of an AIDS-defining infection; with a CD4 less than 350/mm3; who is pregnant; who has HIV-associated nephropathy; or who is being treated for hepatitis B (HBV) infection. For children, the initiation of ART is recommended in any symptomatic patient. For asymptomatic or mildly symptomatic children more than or equal to 5 years, the initiation of ART is recommended for patients with HIV RNA more than or equal to 100,000 copies/mL and CD4 less than 350/ mm3. For asymptomatic or mildly symptomatic children 1–5 years, the initiation of ART is recommended for patients with HIV RNA more than or equal to 100,000 copies/mL and CD4 less than 25%. For infants, the initiation of ART is recommended in any infant regardless of clinical status, CD4 percentage, or viral load.

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Netilmicin: Newborn IV 3 mg/dose 12th hourly. Increase to 8th hourly after 1 week age post natal. Monitor after 3rd dose for 1 hour post dose peak of 8–12 mg/L and a trough of less than 3 mg/L. Prolong dose interval in PDA, prolonged hypoxia and indomethacin therapy. Children—IV/IM less than 12 years 7.5 mg/ kg/day and more than 12 years 6 mg/kg/day in 3 divided doses or 1 month to 18 years 7.5 mg/kg as single dose daily. Intraperitoneal 7.5–10 mg/L in peritoneal dialysis fluid.

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Neomycin sulfate: Adolescents: 0.25–1 g 4 times. Children: 12.5 mg/kg/dose oral in diarrhea and 3 g/m2/ day q 6 hours. Oral in hepatic coma. Eye drops—Superficial eye infection—1 drop 2–4 times daily, severe infection 1 drop every 15–20 min initially then reducing frequency as infection gets controlled. Eye ointment—3–4 times daily. Treatment to continue till 2 days after condition is cured.

Adolescents: 200 mg PO once daily for the first 14 days, then 200 mg PO twice daily. If mild to moderate rash with constitutional symptoms is observed during the first 14 days of therapy, do not increase the dose until the rash has resolved; if the rash does not resolve by treatment day 28, discontinue nevirapine and use an alternative treatment regimen. Permanently discontinue treatment if severe hepatotoxicity, severe cutaneous reactions, or hypersensitivity reactions occur. Adolescents in early puberty (Tanner I-II) should be dosed using pediatric schedules. Neonates more than or equal to 15 days old, infants, and children: 150 mg/ m2 (not to exceed 400 mg) PO once daily for the first 14 days, then 150 mg/m2 (not to exceed 400 mg) twice daily. Alternatively, the following volume recommendations per dose of nevirapine 50 mg/5 mL oral suspension, based on body surface area, can be used: more than 1.25 m2, 20 mL; 1.08–1.25 m2, 17.5 mL; 0.92–1.08 m2, 15 mL; 0.75—0.92 m2, 12.5 mL; 0.58–0.75 m2, 10 mL; 0.42– 0.58 m2, 7.5 mL; 0.25–0.42 m2, 5 mL; 0.12–0.25 m2, 2.5 mL; and 0.06–0.12 m2, 1.25 mL. Same rules as for adolescent in case of rash or appearance of indication for discontinuation of therapy. Neonates less than 15 days old: Dosing information is unavailable. (HIV) prophylaxis—to prevent perinatal transmission of HIV to neonates born to HIV-infected women in labor who have had no prior antiretroviral therapy: Oral dosage (nevirapine single agent):- Pregnant females—intrapartum: The addition of singledose maternal/infant nevirapine to an ongoing highly active combination antiretroviral therapy regimen does not provide additional efficacy in reducing perinatal transmission and may result in nevirapine resistance in the mother, and is therefore not recommended. In patients who are not receiving any antiretroviral treatment prior to labor, administer 200 mg PO as a single dose at the onset of labor. Neonates more than or equal to 34 weeks gestation: The CDC recommends 2 mg/kg PO as a single dose 48–72 hours after birth. If the mother received nevirapine less than 1 hour prior to delivery, the infant should be given 2 mg/ kg PO as soon as possible after birth and again at 48–72 hours. Oral dosage (nevirapine and zidovudine combination): Pregnant females—intrapartum: Due to synergistic inhibition of HIV with the combination in vitro, the following regimen has been suggested: nevirapine 200 mg PO as a single dose at the onset of labor plus zidovudine (2 mg/kg IV bolus followed by 1 mg/kg/hour IV continuous infusion until delivery). During or immediately after intrapartum treatment with nevirapine and zidovudine, consider initiation of maternal zidovudine and lamivudine, continuing for 3 to 7 days, to potentially reduce development of nevirapine resistance. Neonates more than or equal to 34 weeks gestation: Due to synergistic inhibition of HIV with the combination in vitro, the following regimen has been suggested: nevirapine 2 mg/ kg PO as a single oral dose at age 48–72 hours plus zidovudine (2 mg/kg PO every 6 hours for 6 weeks). Maximum dosage limits: Adolescents: 400 mg/day PO. Children: 300 mg/m2, up to 400 mg, per day PO. Infants: 300 mg/m2, up to 400 mg, per day PO. Neonates more than or equal to 15 days old: 300 mg/m2, up to 400 mg, per day PO. Neonates less than 15 days old: Safe and effective use not established.

Pediatric hera eutics

in renal impairment are not available; it appears that no dosage adjustments are needed.

Nicardipine: Continuous IV infusion initially 500 ng/kg/min followed by maintenance infusion of 1–3 µg/kg/min. Niclosamide: Tenia solium (pork) Tenia saginata (beef), Diphyllobothrium latum (fish)—Oral less than 2 years 500 mg, 2–6 years 1 g, more than 7 years 2 g once daily. Give the dose in 2 divided doses one before breakfast and the rest 1 hour later. Hymenolepis nana (dwarf tapeworm)—Oral single dose on first day followed by half that dose daily once for the next 6 days. Initial

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Nortriptyline: Nocturnal eneuresis: Nocturnal eneuresis—Oral more than 6 years 20–25 kg 10 mg, 25–35 kg 10–20 mg, more than 35 kg 25–35 mg once daily (bedtime). Maximum duration of treatment 3 months. Review before further courses are given. Depression—Oral 12–18 years 30–100 mg once daily at night or in divided doses. Use low dose initially and increased if required up to 100 mg.

Nimesulide: 5 mg/kg/day in 2 or 3 divided doses.

N [2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3 cyclohexane dione] (nitisinone): Oral 0.5–0.75 mg/kg as single dose initially. May require up to 2 mg/kg/day. Daily dose may be given in 2 divided doses.

Nitazoxanide: Amebiasis, Giardiasis, Cryptosporiodiosis and Helminthiasis—12–47 months – 100 mg 12 hourly for 3 days; 4–11 years – 200 mg 12 hourly for 3 days; adolescents – 500 mg 12 hourly for 3 days.

Nystatin: Newborn—Treatment and prophylaxis against oral candidia -1 mL 3–4 times daily. Children—Intestinal and oral candida1 mL 3–4 times daily; oral candida in immunocompromised 1 mL 4–6 times, esophageal/intestinal candida 5 mL or 1 tab 4–6 times daily.

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Nitroglycerine (Glyceryl trinitrate): IV infusion 200 ng—5 µg/ kg/min (maximum 10 µg/kg/day). Monitor BP and heart rate. Tolerance may develop. Nitrous oxide: Inhalation: nitrous oxide is administered with oxygen to avoid the hypoxia which would otherwise occur. Doses may be self-regulated in most cases by the use of a face-mask connected through a demand valve to the cylinder. The valve is operated by the act of inhalation by the patient and closes when the patient ceases to inhale. This will generally only be possible with children aged about 5 years and over. It should be administered only by personnel trained in its use. Dose adjustments are not necessary in renal or hepatic disease. Noradrenaline (Norepinephrine): IV infusion 0.3–2 µg/kg/min. Monitor ECG and hemodynamic parameters.

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Norethisterone: Induction of sexual maturity Oral: 5 mg once daily for the last 7 days of a 28 day cycle. (Norethisterone is added after 1 1/2-2 years of estrogen therapy or when breakthrough bleeding occurs to regularize menstrual cycles by adding progesterone in last 7 days of the cycle.) Postponement of menstruation. Oral: 5

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lanzapine: 12–18 years 5–20 mg once daily. Usual dose is 10 mg daily. lopatadine: Allergic conjunctivitis, including ocular pruritus: Adolescents, and Children more than or equal to 3 years: 1 drop in each affected eye 2 times per day at an interval of 6–8 hours (this is the maximum dosage allowed) Children less than 3 years: Safety and efficacy have not been established. No dosage adjustment is necessary for ocular administration in patients with renal or hepatic impairment. O

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floxacin: Eye drops - More than 1 year 1 drop 2–4 hourly for 1st 48 hours and then 4 times daily till 2 days after healing is achieved (maximum 10 days). Ear drops—Otitis externa—1–12 years 5 drops and 12–18 years 10 drops to affected ear(s) 2 times daily for 10 days. CSOM—more than 12 years 10 drops to affected ear(s) 2 times daily for 14 days. AOM with perforation or with tympanostomy tubes 1–12 years—5 drops to affected ear(s) 2 times daily for 10 days. IV and oral—10–15 mg/kg/day in a single dose or divided twice daily. Systemic use—it is replaced by levofloxacin which is an S-isomer of ofloxacin and has less side effects.

lsalazine: Oral—Adolescents and children (2–18 years): 30 mg/kg/day (not exceeding 3 g/day), in two or 3 divided doses. May initiate with 500 mg twice daily and increase over 1 week up to a maximum of 3 g/day (a single dose not exceeding 1 g). Maintenance dose is 250–500 mg 2 times daily. Patients with hepatic impairment: Specific guidelines for dosage adjustments in hepatic impairment are not available. Patients with renal impairment: Specific guidelines for dosage adjustments in renal impairment are not available. Olsalazine should be used cautiously in patients with preexisting renal impairment or renal disease due to possibility of renal tubular damage. Monitoring BUN, serum creatinine and urinalysis. O

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Nitrofurantoin: Contraindicated in infants less than 3 months age. UTI treatment – 3 months to 12 years 5–7 mg/kg/day and in 12–18 years 200–400 mg/day in 4 divided doses. UTI prophylaxis—1–2.5 mg/kg/day in at bedtime or in 2 divided doses (maximum 100 mg/24 hour).

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ctreotide: Varices—IV infusion 1 µg/kg/hour initially may be increase to 3 µg/kg/hour till bleeding is controlled. Then taper over 24 hours to avoid rebound bleeding Hyperinsulinemia—SC 1 µg/kg 4 hourly initially and increased up to 40 µg/kg/24 hour depending on response. No change in dose required for renal impairment. O

Nitrazepam: Oral initially 0.25 mg/kg in 2 divided doses followed by maintenance of 0.5 mg/kg in 2 divided doses (maximum 1 mg/ kg/day). Total daily dose may be given in 3 divided doses. Achieve target maintenance dose in 2–3 weeks. Dosage reduction required for renal and hepatic impairment. Nitric oxide: Delivered along with oxygen through the ventilator circuit in a dose of 5–80 ppm. More than 33 weeks gestation: start at 20 ppm. If this produces a raise in post ductal pO2 of at least 3kPa (while ventilator parameters remain unchanged), reduce the dose after an hour to the lowest dose capable of producing a sustained response. Less than 33 weeks gestation: start with a dose of 5 ppm and consider increasing in stages to a maximum of 40 ppm. If this produces no response return to 5 ppm and give this for 12 hours. If still no response-stop. Tailing off: always try to use the lowest effective dose; failure to do so may result in increasing dependency. Try to reduce the dose further every 12 hours. Drop the concentration by 10% every 3 min but reverse any reduction that causes the arterial saturation to drop by more than 2%. Nitric oxide should not be used for long term, as it results in methemoglobinemia. BP, pulmonary artery pressure, and arterial oxygen saturation should be monitored during therapy with nitric oxide.

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Nifedipine: Hypertensive crisis/angina—Sublingual/oral pierce the capsule and pour contents sublingually/into mouth—250–500 µg/kg as single dose. Hypertension/angina—less than 12 years 0.2–0.3 mg/kg/dose and 12–18 years 5–20 mg/kg/dose 3 times daily (maximum 3 mg/kg/day). Raynaud’s phenomenon—2–18 years 2.5–10 mg 2–4 times daily. Start with low dose at bedtime and gradually increase to avoid postural hypotension.

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mg 3 times a day, starting 3 days before the expected onset of menstruation.

meprazole: Oral less than 12 years initially 0.7 mg.kg and increased to 3 mg/kg/day and 12–18 years 20–40 mg initially as single dose and at higher doses in 2 divided doses. H. Pylori—Oral 1–12 years 1–2 mg/kg rounded to nearest 10 mg and maximum 40 mg and in 12–18 years 40 mg as single dose for 14 days with O

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day dose for less than 2, 2–6 and 7–18 years are 500 mg, 1 g and 2 g, respectively. No purgative is needed.

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Paraldehyde: Rectal less than 12 years 0.4 mL/kg and 12–18 years 5–10 mL diluted in equal volume of olive or sunflower oil before administration. IM Newborn 0.2 mL/kg; 1 month to 12 years 0.1– 0.15 mL/kg and 12–18 years 5–10 mL as single dose. Deep IM with Z injection [maximum 1 mL (newborn) and 5 mL (older children) per site].

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l: 1 drop in each nostril twice daily or when

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xytetracycline: Acne—Oral 12–18 years 250–500 mg/dose 12th hourly. Infections—250–500 mg/dose 6th hourly. Palivizumab: 15 mg/kg once monthly starting just prior to the beginning of the RSV season, for a total of 5 doses. Not used in India as of now. Pamidronate disodium: Experience of the use of bisphosphonates in children is limited and expert advice should be sought. Their use is only justified when the potential benefits outweigh any risk. Children - 1 mg/kg/24 hour for three consecutive days once in 3 months or 10–40 mg/m2 over 5–8 hours once a month. Dose adjusted according to serum calcium levels. Pancreatin: Dose varies widely and should be tailored to each individual patient according to symptoms, stool type and abdominal findings; should not exceed 10,000 lipase units per kg body weight per day. Pancuronium bromide: Newborn—IV loading 0.1 mg/kg followed by maintenance IV 0.05 mg/kg/dose 4–6 times daily as needed. Children—IV 1 month to 18 years 0.06–0.1 mg/kg initially followed by 0.01–0.02 mg/kg as required.

Penicillinase-resistant penicillins ( lucloxacillin/ loxacillin): Dose—Newborn—IV or orally less than 7 days 50–100 mg/kg/ day in 2 divided doses; 7–21 days 75–150 mg/kg/day in 3 divided doses; more than 21 days 100–200 mg/kg/day in 4 divided doses. Children—IV/IM 50–100 mg/kg/day in 4 divided doses (maximum single dose 1 g—may be doubled in severe infection). Oral less than 1 year 250 mg/day, 1–5 years 500 mg/day, 5–18 years 1 g in 4 divided doses. Doses may be doubled in severe infection. C

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xymetazoline required.

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xygen: Dependent on condition. In some conditions (e.g. bronchopulmonary dysplasia), very low flow rates (e.g. 0.1 L/min.) may maintain oxygen saturation.

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xandrolone: Oral: 1.25–2.5 mg once daily, generally for about 3–6 months, but has been used occasionally for up to 1 year; evidence suggests using doses as low as 625 µg for Turner syndrome, in combination with growth hormone—seek expert advice before prescribing.

Penicillamine: Full blood count (FBC), platelet count and urinaly sis should be performed prior to treatment with penicillamine. Urinalysis and FBC should be carried out monthly during treatment. Caution should be exercised in patients with renal insufficiency, and modification of the dosage may be necessary. Renal function should be assessed monthly. An immediate blood count should be carried out if neutropenia or thrombocytopenia is suspected due to symptoms such as a sore throat, glossitis, buccal ulceration, easy bruising or bleeding. If any abnormal results are found, treatment should be withheld and discussed with the clinician responsible for the child’s care. Severe dyspepsia or taste disturbances may necessitate dosage reduction. Wilson disease—adjust dose to maintain urinary copper excretion more than 1 mg/24 hours. Orally 20 mg/kg/24 hour in 2–4 divided doses (maximum 1 g/24 hour). Lead intoxication—Orally 30–40 mg/kg/24 hour in 2–3 divided doses (maximum 1.5 g/24 hour). Juvenile idiopathic arthritis—3 mg/kg/24 hour in 2 divided doses; increasing once every 3 months by 3 mg/kg/24 hour up to maximum of 10 mg/ kg/24 hour. Systemic sclerosis—Oral less than 12 years 2.5–5 mg/ kg/day in 2 divided doses increased 4 weekly to maximum of 15– 20 mg/kg/day and 12–18 years 125–250 mg/day increased slowly to 250–375 mg in 2 divided doses.

Penicillins ( enzylpenicillin/Penicillin G): Given IV. In newborn— 25 mg (approximately 40,000 units)/kg/dose 2 times daily up to 7 days of age and 3 times daily thereafter. Dose is doubled in meningitis. In children 25 mg/kg/dose 4 times daily. Double dose is given in meningitis 6 times daily to a maximum single dose of 2.4 g (approximately 40 L units) and a maximum daily dose of 14.4 g (approximately 2.3 crore units). B

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P : Adolescents: 14–16 g/day in 2–3 divided doses. Children: 275– 420 mg/kg/day in 3–4 divided doses.

seltamivir: Prevention of influenza—Oral 13–18 years – 75 mg once daily for at least 7 days after exposure or for up to 6 weeks during an epidemic. Treatment of influenza—Oral—for children above 1 year age—up to 16 kg – 30 mg, 16–23 kg – 45 mg, 23–40 kg - 60 mg and more than 40 kg – 75 mg—every 12 hour for 5 days.

xybutynin: Oral 2–5 years 1.25– 2.5 mg, 5–12 years 2.5–5 mg and 12–18 years 5 mg 2–3 times daily (maximum in 12–18 years 5 mg 4 times daily).

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Paroxetine: Obsessive compulsive disorder (OCD)—Oral 12–18 years 20 mg (maximum 60 mg) once daily in the morning. Increase weekly by 10 mg/day to maximum dose. Panic disorder—Oral 12– 18 years 12.5 mg of Cr Tab/day. Higher doses under supervision of specialist (maximum 40 mg) once daily in the morning. Increase weekly by 10 mg/day to maximum dose. Idiopathic musculoskeletal pain—Oral 8–12 years 10 mg and 12–18 years 20 mg once daily.

ral rehydration salts ( ): According to fluid loss—less than 1 year 1–1.5 times daily fluid requirement or 150 mL/kg/day; 1–12 years 200 mL after each stool; adolescent 200–400 mL after each stool.

xcarbazepine: Oral 6–12 years 8–10 mg/kg/day in 2 divided doses—increase by 5 mg/kg/dose twice daily weekly till maximum of 30 mg/kg/dose for adjunctive therapy and 46 mg/kg/day for monotherapy. 12–18 years 8–10 mg/kg/day (maximum initial dose 300 mg/dose) in 2 divided doses. Increase over 2–4 weeks to 1,200 mg/24 hour in 2 divided doses (maximum 2,400 mg/24 hour).

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ndansetron: Nausea and vomiting—chemotherapy induced— IV less than 12 years 5 mg/m2 and 12–18 years 8 mg as single dose just before chemotherapy and repeated 8–12 hourly during therapy and for 24 hours after. Oral following initial IV dosing to get control—less than 12 years 4 mg and 12–18 years 8 mg 2–3 times daily for up to 5 days after a course of chemo. Post-op nausea and vomiting—IV slow infusion 2–12 years 0.1 mg/kg (maximum 4 mg) and 12–18 years 4 mg. Pruritis—Oral 2–12 years 2–4 mg/dose and 12–18 years 4–8 mg/dose 2 times daily. Palliative for nausea/ vomiting and pruritis: IV/SC 5 mg/m2 continuous over 24 hours. O

Paracetamol: Oral or suppository less than 12 years 15 mg/kg/ dose every 4–6 hourly; 12–18 years 325–650 mg every 4–6 hourly.

Pediatric hera eutics

amoxicillin and clarithromycin or amoxicillin and metronidazole or clarithromycin and metronidazole.

Pentazocine: Adolescents: Injection: 30–60 mg IM or 30 mg IV. May be repeated 3–4 hourly. Doses in excess of 30 mg IV or 60 mg SC or IM not recommended. Maximum daily dose: 360 mg. in labor. 30 mg IM or 20 mg IV 2–3 hourly. Maximum: 2–3 doses. Tab: 25–100 mg repeated when necessary. Maximum 600 mg daily. Children: Not for children below 12 years.

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1 mmol/kg, less than 2 years 0.7 mmol/kg, more than 2 years 0.4 mmol/kg. Phosphocysteamine: Oral more than 2 years 6 mg/kg 4 times daily. Increase every 2–3 weeks by 25 mg/kg/day up to maintenance of 125 mg/kg/day. Pimozide: Schizophrenia—Oral 12–18 years 1–20 mg usually once daily but may be given in divided doses. Tourette syndrome—Oral 2–12 years 1–4 mg, 12–18 years 2-10 mg usually once daily but may be given in divided doses. Do annual ECG to monitor QT interval.

Pethidine hydrochloride (controlled drug): SC/IM Newborn 0.5–1 mg/kg, less than 12 years 0.5–2 mg/kg, 12–18 years 25–100 mg as single dose—repeated if required once in 4–6 hour IV bolus less than 12 years 0.5–1 mg/kg and 12–18 years 25–50 mg repeated if required once in 4–6 hours IV infusion loading dose of 1 mg/kg followed by 0.1–0.4 mg/kg/hour—ventilated babies may require higher doses. Newborn and infants are prone to respiratory depression. Avoid in severe renal impairment, sickle cell crisis and prolonged infusions as accumulation of metabolite norpethidine can cause seizures. May precipitate coma in children with liver disease.

Piperacillin with tazobactam: Newborn IV 90 mg/kg/dose 3 times daily. Children IV 90 mg/kg/dose 4 times daily (maximum single dose 4.5 g).

Phenobarbitone (Phenobarbital): Anticonvulsant—Loading dose 15–20 mg/kg .Orally, IV or IM; then maintenance newborn 3–4 mg/ kg/24 hour oral or IV in 2 divided doses or as single daily dose, children 5–6 mg/kg/24 hour oral or IV in 2 divided doses or as single daily dose and in adolescents 1–3 mg/kg/24 hour oral or IV in 2 divided doses or as single daily dose. Sedation—children 2 mg/kg/dose. Hyperbilirubinemia—newborn 5–8 mg/kg/day orally for 2–7 days. Not widely used as phototherapy usually suffices.

Piperazine: Round worm: 4 g once daily for 2 days—Children .75 g/year, maximum 4 g. Because of its capacity to relax worms mainly useful for intestinal obstruction caused by round worms. Enterobiasis; 50 mg/kg OD for 7 days consecutively or 75 mg/kg single dose.

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Phenoxymethylpenicillin (Penicillin V): Oral 250 mg/day, 1–5 years 500 mg/day, 6–12 years 1 g/day and 12–18 years 2 g/ day (severe infection 3 g/day) in 4 divided doses. Pneumococcal infection prophylaxis—Half the above daily dose in 2 divided doses. Rheumatic fever prophylaxis - 500 mg/day in 2 divided doses.

Phenytoin: Status epilepticus—Loading dose—neonate 15–20 mg/kg IV (not to exceed 0.5 mg/kg/min) and in children and adolescents 15–18 mg/kg IV (not to exceed 1–3 mg/kg/min). Antiepileptic—Oral/IV Newborn 5 mg/kg/24 hour once daily or in 2 divided doses, less than 6 years 8–10 mg/kg/24 hour, 7–9 years 6–8 mg/kg/24 hour once daily or in 2 divided doses, 10–16 years 6–7 mg/kg/24 hour once daily or in 2 divided doses, more than 16 years 300–600 mg/24 hour once daily or in 2 divided doses. Arrhythmias—loading dose 1.25 mg/kg IV once in 5 min until desired effect or total dose 15 mg/kg. Maintenance children 8–10 mg/kg/day in 2–3 divided doses and in adolescents, 250 mg 3–4 times daily. Pholcodine: Oral 1 month to 6 years 2 mg/dose, 6–12 years 2.5 mg/dose, 12–18 years 5–10 mg/dose 3–4 times daily.

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Phosphates: Hypercalcemia—Oral: newborn 1 mmol/kg, less than 5 years up to 48 mmol, more than 5 years up to 96 mmol. Hypophosphatemia—Oral: newborn 1 mmol/kg, less than 5 years up to 36–48 mmol, more than 5 years up to 64–96 mmol. May be given in 3 divided doses in hypophosphatemic rickets. IV newborn

Piroxicam: Oral less than 15 kg 5 mg, 16–25 kg 10 mg, 26–45 kg 15 mg and more than 46 kg 20 mg once daily.

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Phenoxybenzamine hydrochloride: Oral 1–2 mg/kg/24 hour in 2 divided doses. IV infusion 1 mg/kg bolus given IV over 30 min, followed by 0.5–1 mg/kg/day infusion.

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Piracetam: Learning difficulties: 3 g/day in 3 divided doses for 1 school year. Children: 50 mg/kg in 3 divided doses. Once the desired result has been obtained reduce the initial dose by half up to 6–8 weeks.

Pneumococcal conjugate vaccine: Deep SC or IM injection: 0.5 mL. The number of doses for a primary course depends on the age of the child. For routine immunization 3 doses at 1 month interval from 6 weeks of age, if given below 6 months age, 2 doses at 1 month interval if given between 6 months and 1 year and 1 dose if given after 1 year with a booster at 1.5 year age. For these highrisk groups, three doses at monthly intervals for children less than 2-years-old and two doses at a month apart for those of more than 2 years. The course should then be followed by a single dose of the plain polysaccharide vaccine to increase the breadth of cover. This should be administered at more than 2 years with a minimum interval of 8 weeks after the conjugate vaccine. Pneumococcal polysaccharide vaccine: Deep SC or IM: 0.5 mL as single dose. Booster doses of the plain polysaccharide vaccine are not normally recommended and should certainly not take place within 3 years of the first dose as marked local reactions can occur. As the vaccine could be used in conjunction with the conjugate vaccine in children, one must ensure an 8 week gap between the last conjugate pneumococcal vaccine and the polysaccharide vaccine. Podophyllum: Topical: applied twice weekly. Leave on affected area for not more than 6 hours then wash off. Protect surrounding area with soft paraffin. Continue applying till eradication of wart or a maximum of 6 weeks. Poliomyelitis vaccine, live oral ( PV): Oral: 3 drops (0.135 mL). The primary course is usually given at birth, 8, 12 and 16 and 20 weeks of age. This is followed by a booster at 1.5 year and 4.5 years age. Given on National immunization days to all children less than 5 years of age for poliomyelitis eradication. O

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Permethrin: Scabies (dermal cream). Single topical application of up to: 1 tube for children more than 12 years. Half a tube for children aged 6–12 years. A quarter of a tube for children aged 1–5 years. An eighth of a tube for children aged 2 months to 1 year. Medical supervision required for children less than 2 years of age. If necessary a second application may be given not less than 7 days after the initial application. Apply to whole body excluding head. Wash off after 8–12 hours. Children less than 2 years old should also have the cream applied to the face, neck, scalp and ears. If hands or any part are washed, the treatment must be reapplied. Pediculosis: Head lice (cream rinse) Apply to clean damp hair, leave on for 10 min, rinse and dry. Not affected by chlorine in swimming pools.

Polyethylene glycol 3350: Polyethylene glycol 3350 powder—1 sachet or 1 heap tablespoon once daily—mix with a liquid and give orally once a day as needed for up to 2 weeks. It may take 2–4 days for polyethylene glycol 3350 to produce a bowel movement. Potassium chloride: Potassium supplementation—Oral/IV 0.5–1 mmol/kg 2 times daily or 0.5–1 mEq/kg 2 times daily. Acute

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Potassium permanganate: Cleansing and deodorising suppurating eczematous reactions and wounds. For wet dressings or baths, use approximately, 0.01% (1 in 10 000) solution OR 1 granule dissolved in 300 mL (2 1/2 glasses) of water.

Primaquine: Oral 1–12 years 0.25 mg/kg/day and 12–18 years 15 mg once daily for 14 days. For G6PD patients—1–12 years 0.5–0.75 mg/kg and 12–18 years 30 mg once in a week for 8 weeks.

Prochlorperazine: Oral/rectal more than 1 year 0.1–0.25 mg/kg/ dose 2–3 times daily. IM 0.1–0.15 mg/kg/24 hour divided in 2–3 doses.

Pravastatin sodium: Oral 2–12 years: 5 mg, 12–18 years: 10 mg once daily. Increase if needed over 6–12 weeks.

Prednisolone: Acute asthma—Oral 1–2 mg/kg in 2–3 divided doses (maximum 40 mg/day) for 1–5 days and stop without tapering if the episode is controlled. Croup requiring intubation—Oral 2 mg/ kg/day in 2 divided doses soon after intubation and continued for 24 hour after extubation. Nephrotic syndrome—Oral Initially for 4–6 weeks 60 mg/m2 (maximum 80 mg/day) as single morning dose and after proteinuria is absent for 3 days, maintenance for 4–8 weeks of 40 mg/m2 (maximum 60 mg) on alternate days. Then taper and stop. Repeat for relapses. Autoimmune hepatitis - 2 mg/kg (maximum 40 mg) once daily Inflammatory bowel disease—1–2 mg/kg (maximum 60 mg/day)—taper and stop over a few weeks JIA, connective tissue disorder, vasculitis—up to 2 mg/kg single morning dose or alternate day at lowest dose that controls disease. Avoid if possible as weaning would be difficult. Ulcerative colitis, Crohn’s disease—Rectal (enema) at bedtime for 2–4 weeks and continued if response is good. Infantile spasms and intractable seizures—2 mg/kg/day—higher doses in infantile spasms Chemotherapy regimens—follow doses recommended for given protocol. Transplant programs—each unit has its own

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Procyclidine: Oral 7–12 years 4 mg/kg/day and 12–18 years 7.5 mg/kg/day in 3 divided doses. Proguanil: Oral 0–12 weeks less than 6 kg 25 mg 1/4th tab; 12 weeks to 11 months 6–10 kg 50 mg ½ tab; 1–3 years 10–16 kg 75 mg 3/4th tab; 4–7 years 16–24 kg 100 mg 1 tab; 8–12 years 25–44 kg 150 mg 1 ½ tab; more than13 years more than45 kg 200 mg 2 tab. To be given once daily starting 1 week before entering endemic area and continue till 4 weeks after return.

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Procarbazine: Always consult the current treatment protocol for details of dosage and scheduling. Hodgkin’s disease - Oral 1.5–3 mg/kg/24 hour (50–100 mg/m2) once daily for 14 days per 28 day cycle. Bone marrow transplant preparation—12.5 mg/kg/dose. Neuroblastoma and medulloblastoma—100–200 mg/m2/dose as part of protocol.

Pralidoxime: Adolescents: Following resuscitation measures, and 2–4 mg atropine inj., 1–2 g IM or IV as 5% soln. over 5–10 min or infusion in 100 mL sodium chloride over 15–30 minutes. Repeat therapy if required. Children: 20–40 mg/kg once daily.”

Prazosin: Hypertension—Oral 1 month to 12 years 10–15 µg/kg/ dose 2–4 times daily (maximum 0.5 mg/kg/day) and 12–18 years 0.5 mg/dose 2–3 times daily (maximum 20 mg/day). Congestive cardiac failure - Oral 1 month to 12 years 0.5 µg/kg/dose 2 times daily (maximum 0.1 mg/kg/day) and 12–18 years 0.5 mg/dose 2–4 times daily (maximum 20 mg/day).

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Prilocaine hydrochloride: Children less than10 years 1 mL, more than 10 years 1–2 mL.

Povidone-iodine: Antiseptic paint: apply twice daily. Dry powder: use for minor wounds and infections. Ointment: apply once or twice daily for up to 14 days. Shampoo: use as shampoo twice weekly until improvement noted then once weekly. Skin cleanser: retain on infected skin for 3–5 min before rinsing. Repeat twice daily. Solutions, tinctures and scrub: use undiluted for skin disinfection.

Praziquantel: Schistosomiasis hematobium (S mansoni)—Oral 4–18 years 40 mg/kg/day as single dose or in 2 divided doses with food for 1 day. S. japonicum—Oral 4–18 years 60 mg/kg/day in 3 divided doses with food for 1 day. Liver fluke—Oral 4–18 years 60 mg/kg/day in 2 divided doses with food for 3 days. Lung fluke (Paragonimus westermani)—Oral 4–18 years 75 mg/kg/day in 3 divided doses with food for 3 days. Intestinal fluke (Fasciolopsis buski)—Oral 4–18 years 75 mg/kg/day in 3 divided doses with food for 1 day. Beef, pork and fish tapeworm—Oral 4–18 years 10– 20 mg/kg/day as single dose with light breakfast for 1 day. Dwarf tapeworm—Oral 4–18 years 25 mg/kg/day as single dose with light breakfast for 1 day. Neurocysticercosis: Oral 4–18 years 50 mg/ kg/day in 3 divided doses with food for 15–21 days. Give steroids to reduce severity of adverse reactions. Echinococcosis: Oral 4–18 years 40 mg/kg/day once in a week with food in combination with albendazole as adjunct to surgery and for inoperable cysts. No dosage adjustment for renal failure and hepatic failure.

Pediatric hera eutics

protocol. Adrenal insufficiency including congenital adrenal hyperplasia: 2.5–5 mg/m2 in 2 divided doses. Thyroid storm: 1–2 mg/kg/day in 2 divided doses for 2 weeks. Hypercalcemia due to vitamin D excess: 2 mg/kg/day in 2 divided doses for 4–6 weeks.

hypokalemia—0.08–0.2 mmol/kg/hour or mEq/kg/hour. Check dose carefully as overdose could be fatal. Recheck potassium levels after 3 hours. 1 g KCl = 13.4 mmol or 13.4 mEq.

Promethazine hydrochloride: Symptomatic relief of allergy—Oral less than 1 year 2.5–5 mg, 1–6 years 5–10 mg, 6–12 years 10–15 mg and 12–18 years 10–20 mg 2–3 times daily. Vomiting and nausea— Oral 1 mg/kg/24 hour in 4 divided doses. Sedation—Oral 1–2 mg/ kg as single dose. Sedation in ICU—Slow IV/Oral/deep IM less than 12 years 2–4 mg/kg/day and more than 12 years 100–200 mg in 4 divided doses. Start with lower dose and increase gradually depending on response. May use along with chloral hydrate. Propafenone hydrochloride: Oral 10–20 mg/kg/day in 2 divided doses; starting at lower dose. IV bolus followed by IV infusion 0.2 mg/kg slowly over 10 min repeated every 15 minutes up to maximum 2 mg/kg followed by IV infusion with ECG monitoring of 4 µg/kg/min increasing to 8 µg/kg/min (if required). 20–30% of this total dose if hepatic function is impaired. Propantheline bromide: Oral less than 12 years 0.9–1.2 mg/kg/ day in 3–4 divided doses (maximum 3 mg/kg/day—larger doses in eneuresis) and more than 12 years 15 mg before meals and 20 mg at bedtime. Propofol: Sedation—IV 1.5–3 mg/kg/dose over 1–2 min. Continuous sedation (mechanical ventilation—5.5 mg/kg for 30 min, increase to 6 mg/kg for 30 min, increase to 8 mg/kg for 1 hour, increase to 10 mg/kg for 1 hour, increase to final infusion rate of 12.5 mg/kg/hour. Induction of general anesthesia—1.5–2.5 mg/kg (larger doses in children less than 8 years) and maintain anesthesia with 9–15 mg/kg/hour. Propranolol: Hypertension—Oral newborn 0.25–0.5 mg/kg, less than 12 years 0.25–1 mg/kg 3 times daily and more than 12 years 80–160 mg 2 times daily. Maximum in newborn 2 mg/kg/day and in children increase weekly as required to usual dose 1–5 mg/kg/ day. Migraine prophylaxis and essential tremor- Oral 2–12 years 20 mg/dose and 12–18 years 20–40 mg/dose 2–3 times daily. Dysarrhythmias—Oral less than 12 years 0.25–0.5 mg/dose and more than 12 years 10–40 mg/dose 3–4 times daily. IV bolus—less than 12 years 25–50 µg/kg and more than 12 years 1 mg/kg as

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Propylthiouracil: Oral less than 1 year 2.5 mg/kg/dose, 1–4 years 25 mg/dose, 5–12 years 50 mg/dose and 12–18 years 100 mg/dose 3 times daily. Dose gradually tapered after child is euthyroid. Protamine sulfate: All ages: 1 mg (0.1 mL) for each 100 units mucous heparin (or low molecular weight heparin (LMWH) or 80 units lung heparin given at last dose, Maximum dose 50 mg. Administer within 15 min-if the delay is longer less protamine is required, as heparin is rapidly excreted (after 30 min give approximately half dose).

Pyrimethamine with sulfadoxine: Oral 2 months to 4 years half tab, 5–6 years 1 tab, 7–9 years 1.5 tab, 10–14 years 2 tabs and more than 14 years 3 tabs as a single dose after quinine therapy. Pyritinol: Children: 100–200 mg daily according to age. Continue therapy for several weeks. Infants: 2.5–5 mL 1–3 times daily.

Psoralen: Adults: Tab: 0.6–0.7 mg/kg body wt. daily.

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Pyrimethamine: Toxoplasmosis in pregnancy: if toxoplasma infection is diagnosed in early pregnancy and the fetus is not infected, spiramycin is given (see spiramycin monograph). If the fetus is found to be infected then pyrimethamine 50 mg once daily, sulfadiazine 1 g 3 times daily and calcium folinate (folinic acid) 15 mg 3 times per week are given until delivery. Toxoplasmosis in infants: Pyrimethamine along with sulfadiazine (50 mg/kg 2 times daily) and calcium folinate (folinic acid) (15 mg/kg three times in a week) are given for 12 months. Pyrimethamine is started with

abies vaccine: Pre-exposure: 1 mL on days 0, 7 and 28. Two doses 4 weeks apart may be adequate in those not expecting to handle animals if postexposure treatment will be readily available. In this case, if exposure continues, a further dose after 6–12 months will be necessary. Boosters may be given every 2–3 years if there is continuing risk and postexposure treatment is not readily available. After 2–3 boosters, expert advice should be sought before giving more. Post exposure: When an individual has been exposed via a break in the skin or contamination of a mucosal surface to a potentially rabid animal, consideration should be given to post exposure treatment. Advice should always be sought before starting treatment. Unimmunized/incompletely immunized (received less than 3 doses or had intradermal)—low risk 1 mL on 0, 3, 7, 14 and 30 day and in high risk 1 mL on 0, 3, 7, 14 and 30 day plus rabies immunoglobulin. Fully immunized individual—1 mL on 0, 3 and 7 day. amipril: Oral—Children—1.5 mg/m2/24 h once daily. Adoles cents—2.5 mg once daily. Adjust dosage to achieve proper blood pressure response, up to maximum of 20 mg/day. But more studies are required in children before it is used in pediatrics. ­

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Pyearidoxine (Vitamin 6): Metabolic indications—50–250 mg/ dose 1–2 times daily. Higher doses in partially responsive cases and for Wilson disease. Pyridoxine dependent seizures—Newborn Oral try test dose of 50–100 mg 1–2 times daily for 2 days and if responsive, maintenance of 25–100 mg 2 times daily lifelong. Increased dose may be required with intercurrent illness and with growth. IV bolus/IM 50–100 mg as test dose; may give for 2 days and then change to oral. If seizures persist, commence conventional anticonvulsant therapy. Children 20–50 mg 1–2 times daily—up to 500 mg twice daily may be required. IV bolus—1 month to 12 years 25–100 mg as test dose for 2 days and then change to oral.

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abies immunoglobulin, human ( G): 20 IU/kg IM and infiltration: half infiltrated around wound with the rest IM. Give at a different site to the vaccine. R

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Pyearidostigmine bromide: Oral initially 1.5 mg/kg/dose (maximum newborn 10 mg, 1 month to 2 years 30 mg and 2–12 years 60 mg) and in 12–18 years 30–120 mg. The dose is increased in increments of 25–50% daily till maximum improvement is obtained and given in divided doses at suitable intervals. Usual total daily dose less than 12 years is 30–360 mg and more than 12 years 300 mg to 1.2 g.

Quinolones: Ciprofloxacin—Neonates—10 mg/kg 12 hourly orally or IV; Children 15–30 mg/kg in 2 divided doses oral/IV (maximum single dose IV 400 mg and oral 750 mg). Ofloxacin— Oral: Adolescents 200–800 mg/day. Not recommended for children less than 12 years age. IV: Adolescents 200 mg infusion over 30 minute 2 times daily. May be increased to 400 mg twice in severe infections.

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Pyrantel Pamoate: 11 mg/kg/day as single dose. Repeat after 2 weeks (maximum 1 g). In heavy hookworm infestation gives for two successive days. Pyrazinamide: Oral children 15–40 mg/kg/24 hour as single dose or in 2 divided doses (maximum 2 g/day) for the first 2 months of the standard 6 months regimen. 12–18 years less than 50 kg 1.5 g/day and more than 50 kg 2 g/day as single dose or in 2 divided doses (maximum 2 g/day) for the first 2 months of the standard 6 months regimen.

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Quinine: Oral birth-12 years 30 mg/kg/day (sulfate) and 12–18 years 1.8 g/day (sulfate) in 3 divided doses for 7 days. IV infusion over 4 hours initial loading dose of 20 mg/kg (maximum 1.4 g), then 10 mg/kg (maximum 0.7 g) every 12 hours for 48 hours and then maintenance of 5–7 mg/kg once in 8 hours if IV is needed after 48 hours. As soon as possible change to oral.

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Pseudoephedrine hydrochloride: Oral (not used in newborn) 1 month to 2 years 7.5 mg/dose, 2–12 years 15–30 mg/dose and 12–18 years 60 mg/dose 3 times daily.

Quinidine: Adolescents: 200–400 mg 3–4 times daily. Initially give test dose. Children: 2 mg/kg test dose to exclude idiosyncrasy. PO: 30 mg/kg/24 hour in divided doses every 4–6 hours.

anitidine: Newborn—Oral/IV 1 mg/kg 3 times daily (studies with oral treatment in newborn is limited) and IV infusion 30–60 µg/ kg/hour (maximum 3 mg/kg/day). Child Oral 6 months to 12 years 2–4 mg/kg/dose (maximum 150 mg) 12–18 years 150 mg/dose R

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loading dose of 1 mg/kg/dose 2 times daily for 2 days, then 1 mg/ kg/dose once daily for 6 months followed by 1 mg/kg/dose thrice in a week for 6 months. Prednisolone at 0.5/kg/dose 2 times daily is also given until signs of CNS inflammation (CSF protein more than 10 g/L) or active chorioretinitis have settled and then tapered. Ocular toxoplasmosis, reactivation of toxoplasmosis during HIV infection and toxoplasmosis in imunocompromised child with protracted or incapacitating illness – 2 mg/kg loading dose for 2 days followed by 1 mg/kg in less than 12 years and 25–100 mg in 12–18 years olds for 6 weeks to prevent relapse in HIV patients followed by maintenance of a quarter to half of starting dose indefinitely.

single dose slowly over 5 min with ECG monitoring. Repeat dose as required up to 4 times daily. Hyperthyroidism and neonatal thyrotoxicosis—Oral 0.25–0 75 mg/kg/dose 3 times daily. Increase according to response. May require 1 mg/kg/dose 3 times daily. Tetralogy of Fallot—Oral less than 12 years 0.25–1 mg/kg/dose 2 times daily in newborn and 3–4 times in more than 1 month age. IV bolus up to 0.1 mg/kg over 5 min under ECG control 2 times daily in newborn and 4 times in more than 1 month age. Hypertrophic obstructive cardiomyopathy—Oral less than 12 years 0.25–1 mg/ kg/dose and more than 12 years 10–40 mg/dose 3–4 times daily (8 mg/kg/day in 4 divided doses).

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elenium sulfide: Use as shampoo twice weekly for 2 weeks then once weekly for 2 weeks then as necessary. Administration: Use as shampoo twice weekly for 2 weeks then once weekly for 2 weeks then as necessary. S

enna: Oral tabs 6–12 years 1–2 tabs, 12–18 years 2–4 tabs. Liquid less than 2 years 0.5 mg/kg 2–6 years 2.5–5 mL, 6–12 years 5–10 mL, 12–18 years 10– 20 mL.

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erratiopeptidase: 5–10 mg thrice a day after meals to be swallowed whole without chewing. ertraline: Oral 6–12 years 25 mg, 12–18 years 50 mg once daily.

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ildenafil: 0.5–5 mg/kg/day in 3 or 4 divided doses. Dose reduction is required in renal and hepatic disease. S

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ilver sulfadiazine ( ulfadiazine): Burns: after cleaning the wound apply over all affected areas to a depth of 3–5 mm, using a sterile gloved hand or sterile spatula. Where necessary, re-apply to any area from which it has been removed by patient activity. Reapply at least every 24 hours or more frequently if the volume of

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odium bicarbonate: Renal tubular acidosis Oral 2 years 1–2 mmol/kg/day more than 2 years 70 mmol/m2/day; Renal hyperkalemia IV 1 mmol/kg/day; Cardiopulmonary resuscitation 1 mL/kg of 8.4% solution initially followed by 0.5 mL/kg 8.4% if needed.

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odium chloride: IV: 2–4 mmol/kg/24 hour in continuous IV infusion. Oral: 2–4 mmol/kg/24 hour in 2–4 divided doses. Note: (1) Adjust dose according to clinical requirements for sodium. (2) Higher doses may be required in very premature infants because of significant renal loss of electrolytes. odium chloride drops: 1 drop 2–3 times.

odium cromoglycate: Inhaler 4 times daily. Intranasal 1 spray 2–4 times daily. Oral less than 14 years 100 mg and more than 14 years 200 mg/dose 4 times daily—increased if required to 40 mg/ kg and then reduced according to response. S

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almeterol: Less than 4 years 25 µg, 4–12 years 50 µg and 12–18 years 50–100 µg 2 times daily as preventer.

odium benzoate: Hyperammonemia—Oral 250 mg/kg/day in 4 divided doses; IV 250 mg/kg as single infusion over 90 min. Nonketotic hyperglycinemia—Newborn 250 mg/kg/day in 4 divided doses; more than 1 month 500 mg/kg/day in 4 divided doses.

odium nitrite: 3% injection (30 mg/mL) in water for injection— give IV over 5–20 minutes. 1 month to 18 years—4–10 mg/ kg (maximum 300 mg) or 0.13–0.33 mL/kg (maximum 10 mL) followed immediately by 25% injection (250 mg/mL) sodium thiosulfate in water for injection given 400 mg/kg (maximum 12.5 g) or 1.6 mL/kg (maximum of 50 mL) over 15 min. Recommended dose of both drugs vary with hemoglobin levels of the child. If Hb level is known. Sodium nitrite 3% soln. and sodium thiosulfate 25% soln. Hb 8 g%—Sodium nitrite 6.6 mg/kg (0.22 mL/kg); sodium thiosulfate 1.1 mL/kg. Hb 10 g%—Sodium nitrite 8.7 mg/kg (0.27 mL/kg); sodium thiosulfate 1.35 mL/kg. Hb 12 g%—Sodium nitrite 10 mg/kg (0.33 mL/kg); sodium thiosulfate 1.65 mL/kg. Hb 14 g%—Sodium nitrite 11.6 mg/kg (0.39 mL/kg); sodium thiosulfate 1.95 mL/kg. If Hb is not known. Sodium nitrite 10 mg/kg (0.33 mL/ kg); sodium thiosulfate 1.6 mL/kg – 400 mg/kg IV repeated every 30–60 min to maximum of 50 mL. S

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alicylic: Topical: remove dead skin by gentle rubbing with pumice stone or emery board before applying daily.

odium (cromoglycate): Inhaler 4 times daily. Intranasal 1 spray 2–4 times daily. Oral less than 14 years 100 mg and more than 14 years 200 mg/dose 4 times daily—increased if required to 40 mg/ kg and then reduced according to response.

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albutamol: Oral: 1 month to 2 years 0.3–0.4 mg/kg/day; more than 2 years 0.3–0.7 mg/kg/day. Aerosol inhaler up to 100–200 µg single dose on demand. Nebulizer soln. 1.25–2.5 mg 1–2 hourly initially and then 4–6 hourly.

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otavirus vaccine: Live attenuated human rota virus vaccine— Oral—more than 6 weeks 2 doses of 1 mL each, separated by an interval of at least 4 weeks; course to be complete less than 24 weeks age (preferably less than 16 weeks). Live pentavalent reassortment vaccine (human and bovine strains)—3 doses orally starting at 6–12 weeks, with subsequent doses at 4–10 week intervals—3rd dose latest by 32 weeks age.

ubella vaccine, live: IM or deep SC: 0.5 mL. Booster doses of single antigen rubella vaccine are not recommended.

ilymarin: 70–140 mg bid/tid.

imvastatin: Dosage: 5–10 years: 5 mg at night increased at 4 week intervals to 20 mg per night if required. Reduced dose required with concomitant cyclosporine, danazol, fibrates, amiodarone, diltiazem or verapamil—seek specialized advice.

isperidone: Aggressive behavior, Tourette syndrome—Oral 0.5– 2 mg once daily or in 2 divided doses. Schizophrenia—Oral 0.5–2 mg once daily or in 2 divided doses.

oxithromycin: Dosage: Adolescents: 150 mg twice daily at least 15 min before meals. Children: 5–8 mg/kg/day in 2 divided doses for not more than 10 days.

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ifampicin: Tuberculosis in combination with other drugs— Oral 10 mg/kg (maximum 600 mg/day) as single morning dose. Meningococcal infection prophylaxis and staphylococcal infections—Oral less than 5years 5 mg/kg/dose and more than 1 year 10 mg/kg/dose (maximum 600 mg/dose) 2 times daily for 2 days for meningococcal infection prophylaxis and for 10–14 days for staphylococcal infections. H. influenza prophylaxis—Oral less than 3 months 10 mg/kg and more than 3 months 20 mg/kg/ dose (maximum 600 mg/dose) once daily for 4 days. Cholestasis— pruritis—5–10 mg/kg (maximum 600 mg) once daily. Dose adjustment in liver failure. Avoid altogether or reduce doses for tuberculosis and prophylaxis to 8 mg/kg daily.

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iboflavin (Vitamin 2): Oral 50 mg once daily. May be given in frequent smaller doses. Doses up to 300–400 mg/day have been used.

Pediatric hera eutics

exudates is large. Hand burns: apply to the burn and enclose the whole hand in a clear plastic bag or glove which is then closed at the wrist. The patient should be encouraged to move the hand and fingers and the dressing should be changed when an excessive amount of exudates has accumulated in the bag. Leg ulcers/pressure sores: the cavity of the ulcer should be filled with cream to a depth of at least-3–5 mm, followed by application of an absorbent pad or dressing, with further application of pressure bandaging as appropriate. Dressings should be changed daily, but if less exudates every 48 hours may be sufficient. Finger-tip injuries: hemostasis of the injury should be achieved prior to the application of a 3–5 mm layer of cream, and then the finger covered with a finger dressing or the finger of a plastic glove. Dressings should be changed every 2–3 days. In all cases, use the contents of the tube or pot on one person only. Discard 50 g tubes 7 days after opening. Discard 250 g and 500 g pots 24 hours after opening.

2 times daily. Up to 9 mg/kg may be used. IV bolus 1 mg/kg 2–4 times daily IV infusion 125–250 µg/kg/hour. Reduce dose to 50% in severe renal failure.

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days. Local therapy may be better for catheter induced thrombosis, if the catheter is already in situ. Monitor Fibrinogen, TCT, PT, aPTT. S

treptomycin: Adolescents: 0.75–1 g daily by IM route. Children: 20–40 mg/kg/day IM. S

ucralfate: Oral less than 2 years 250 mg; 1–12 years 500 mg; 12– 18 years 1 g 4–6 times daily.

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odium perborate: For oral hygiene measures 1 sachet to be dissolved in 30 mL water 3 times daily after meals. As a bleaching agent, a small quantity of granules to be mixed to a thick paste with a few drops of 30 vols hydrogen peroxide. odium phenylbutyrate: Oral 250 mg/kg/day in 4 divided doses; IV 250 mg/kg over 50 min; IV infusion 250–600 mg/kg/day as continuous infusion.

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ulfadiazine: 12 years 100–200 mg/kg/day and 12–18 years 4–6 g/day in 4 divided doses.

odium picosulfate: 2–5 years 2.5 mL, 5–19 years 2.5–5 mL, more than 10 years 5–15 mL as single dose at bedtime.

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umatriptan: Oral 6–10 years 25 mg; 10–12 years 50 mg; 12–18 years 50–100 mg as single dose. May be repeated if migraine recurs (maximum 300 mg/day). If there is no response, do not repeat for same attack. SC more than 10 years 6 mg single dose. May repeat once not less than 1 hour later for a recurrence (maximum 12 mg/ day). If there is no response, do not repeat for same attack.

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odium stibogluconate: IV/IM 1 month to 18 years – 20 mg/kg (maximum 850 mg) daily once for 20–30 days. Total daily dose may be given in 2 divided doses 12 hours apart.

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pironolactone: Oral 1–3 mg/kg/day in 2 divided doses. In resistant ascites, up to 9 mg/kg/day have been given with careful serum potassium monitoring. Hirsutism: Start with 50 mg in 2 divided doses, gradually increasing to 100 mg; maximum up to 200 mg daily can be given. tilbestrol: Oral: 1 mg twice a day, for 2 days before the test.

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treptokinase: The optimal dose for pediatric patients is not known. IV infusion over 30 min insitially 2,000 units/kg (less than 12 years) and 2.5 lakh units (12–18 years) followed by continuous infusion of 500–2,000 units/kg/hour (less than 12 years) and 1 lakh unit/hour (12–18 years) till vascular flow returns or maximum of 3

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estosterone and esters: Androgen replacement—Orally: test osterone undecanoate starting dose 40 mg alternate days, increasing slowly up to 120 mg daily. Delayed puberty—Dose/ dose schedule depends on the product. An example is given but ­

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piramycin: Pregnant women with suspected or confirmed toxoplasma infection: 1.5 g (4.5 million international units) orally twice daily until term if the fetus is not infected.

acalcitol: 12–18 years apply sparingly at bedtime. acrolimus: Liver transplant renal transplant—IV/oral. Atopic dermatitis—2–16 years 0.03% for 3 weeks and then once till clearance, more than 16 years 0.1% twice 3 weeks, then 0.03% twice, then once till clearance. eicoplanin: Newborn—loading 16 mg/kg and 24 hours later start maintenance 8 mg/kg/day as single dose; children 10 mg/kg/ dose 2 times daily X 3 doses and then once daily in same dose for severe infection and 6 mg/kg/day once for mod infection. Orally for pseudomembranous colitis 10 mg/kg/dose 2 times daily. May be given intraventricular and intraperitoneal. erbinafine: Topical 1–2 times daily 1–2 weeks, Oral 3–6 mg/kg 4–5 weeks. erbutaline: Oral less than 7 years 0.25 mg/kg/day in 3 divided doses; 7–12 years 2.5 mg/dose and 12–18 years 2.5–5 mg/dose 3 times daily. Aerosol inhaler 250–500 µg/dose 4–6 times daily. Turbohaler 500 µg/dose 4 times daily. Nedulized 1 month to 5 years 2.5–5 mg, 5–12 years 5 mg and 12–18 years 10 mg/dose up to 8 times daily. SC/IM/slow IV 2–12 years 10 µg/kg/dose (maximum 300 µg/dose) 12–18 years 250–500 µg/dose of nebulizer not available. IV loading dose of 2–4 µg/kg followed by IV infusion of 1–10 µg/kg/hour. T

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otalol: Oral less than 12 years 1–4 mg/kg/dose (maximum 8 mg/ kg/day or 40–80 mg) and 12–18 years 40 mg/dose (maximum 80– 160 mg) 2 times daily. According to Shi J et al. body surface area is the better predictor for sotalol dosing; the recommended dose is 30–70 mg/m2/day.

urfactants (synthetic): 67.5 mg/kg or 5 mL/kg.

uxamethonium chloride: Newborn—for 5–10 min muscular paralysis 2 mg/kg IV; for full neuromuscular blockade 3 mg/kg IV; IM 4 mg/kg provides 10–30 min muscle paralysis after 2–3 min delay. Children IV less than 12 years 1–2 mg/kg; 12–18 years 1 mg/ kg; IM less than 1 year up to 4–5 mg/kg; more than 1 year up to 4 mg.

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omatropin (Growth hormone): SC Growth hormone deficiency 25–35 µg/kg once daily; Turner syndrome 50 µg/kg once daily; chronic renal failure 50 µg/kg once daily; Prader-Willi syndrome 70 µg/kg once daily; Noonan syndrome 35 µg/kg once daily; Intrauterine growth retardation (IUGR) 70 µg/kg once daily.

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odium valproate: Oral start with 10–15 mg/kg/day in 2 divided doses and maintain at 12.5–15 mg/kg/day. Even doses of 30–40 mg/kg/day have been used in infantile spasms.

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urfactants (natural): Survanta - Intratracheal 100 mg/kg or 4 mL/ kg over 4 min; repeat after 8–12 hours if necessary. If birth weight is less than 1,250 g, give first dose within 15 min of birth. Curosurf— Intratracheal 100 mg/kg or 1.25 mL/kg over 4 min; repeat after 12 hours if necessary. If birth weight is less than 1,250 g, give first dose within 15 min of birth. S

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odium thiosulfate: 25% injection (250 mg/mL) in water for injection given 400 mg/kg (maximum 12.5 g) or 1.6 mL/kg (maximum of 50 mL) over 15 min. It is given after IV sodium nitrite. Recommended dose of both drugs vary with hemoglobin levels of the child. If Hb level is known. Sodium nitrite 3% soln. and sodium thiosulfate 25% soln. Hb 8 g%—Sodium nitrite 6.6 mg/kg (0.22 mL/kg); sodium thiosulfate 1.1 mL/kg. Hb 10 g%—Sodium nitrite 8.7 mg/kg (0.27 mL/kg); sodium thiosulfate 1.35 mL/kg. Hb 12 g%—Sodium nitrite 10 mg/kg (0.33 mL/kg); sodium thiosulfate 1.65 mL/kg. Hb 14 g%—Sodium nitrite 11.6 mg/kg (0.39 mL/kg); sodium thiosulfate 1.95 mL/kg. If Hb is not known. Sodium nitrite 10 mg/kg (0.33 mL/kg); sodium thiosulfate 1.6 mL/kg – 400 mg/kg IV repeated every 30–60 min to maximum of 50 mL.

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ulfasalazine ( ulfasalazine): JIA oral 10 mg/kg/day 1st week, 20 mg/kg/day 2nd week, 40 mg/kg/day 3rd week, 40–50 mg/kg/day maintenance (maximum 2 g/day less than 12 and 3 g/day 12–18 years). Ulcerative colitis/Crohn disease less than 12 years 10–15 mg/kg/dose 4–6 times daily (maximum 50 mg/kg/day) and 12–18 years 1–2 g/kg/dose 4 times daily and half dose as maintenance. May be used as rectal suppository and enema if these preparations are available.

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odium nitroprusside: Advisable to start with a low dose—IV infusion 500 ng/kg/min, increased in increments of 200 ng/kg/ min according to improvement in symptoms, status of BP, filling pressures, to maximum of 10 µg/kg/min. In general, invasive monitoring of blood pressure is recommended when sodium nitroprusside infusion is being administered. Pediatric data on sodium nitroprusside is not available, however due to its potent action on blood pressure, it is preferable to have invasive pressure monitoring in children also.

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Pediatric hera eutics

for 3 weeks in newly diagnosed MSUD to determine thiamine responsiveness.

expert advice should be sought from a pediatric endocrinologist. IM injection: 1 mL by deep IM injection every month for 3 doses. Priming—IM injection: 1 mL by deep IM injection 3–5 days before the test of growth hormone secretion.

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etanus immunoglobulin (human): Prevention—a single dose of 250 international units. If there is a risk of heavy contamination or following burns, or more than 24 hours have elapsed since injury, 500 international units should be given. Treatment of tetanus—150 IU/kg IM in multiple sites or by IV infusion.

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hioguanine: Always consult the current treatment protocol for details of dosage and scheduling. Thiopental (thiopentone) sodium IV bolus 4 mg/kg maximum 10 mg/kg (facilities for ventilation must) followed in ventilated babies only with IV infusion 2.5 mg/kg/hour (newborn) and 2–8 mg/kg/hour (1 month to 18 years). Reduce dose in hepatic disease.

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etracycline: Acne—topical application 2 times daily for maximum 10–12 weeks. May be repeated after 12 weeks interval. Aphthous ulceration—Local mouth wash with contents of 250 mg cap of tetracycline in water 3–4 times daily for 2–3 min each time (do not swallow) for 3 days. etrahydrobiopterin: Oral 1–3 mg/kg once daily. Some require up to 5–20 mg/kg/day.

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hiamine (Vitamin 1): Congenital lactic acidosis—Oral 100– 300 mg once daily. MSUD—Oral 10–300 mg once daily. A trial

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iagabine: Doses are for patients receiving enzyme-induced antiepileptic drugs. Lower doses and slower titration may be required when used in patients not receiving enzyme-induced antiepileptic drugs. Children 12–18years—Initially 4 mg once daily for 1 week, then 8 mg/day given in 2 divided doses for 1 week, then increase weekly by 4–8 mg/day once (given in 2–4 divided doses, preferably thrice in a day) to a maximum of 32 mg/day or till response is obtained. Doses more than 32 mg/day have been used in some adolescents for short periods of time. inidazole: Oral 1 month to 12 years 50–60 mg/kg and 2–12 years 2 g—single dose for trichomonas vaginitis and amebiasis, 3 days for amebiasis and colitis and 5 days for liver abscess. T

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hiabendazole: Cutaneous larva migrans—25 mg/kg (maximum 1.5 g), 2 times daily for 2 days. Repeat for 2 days if active lesions persist 2 days after completion of 1st course. 10–15% suspension is applied topically to lesions 4–6 times per day for 2–5 consecutive days. Dracunculiasis (Guinea worm)—1–2 visible worms: 25 mg/ kg (maximum 1.5 g), 2 times daily for 1 day; 3–9 visible worms: 50 mg/kg (maximum 1.5 g), 2 times daily for 1 day; more than 9 visible worms: 50 mg/kg (maximum 1.5 g), 2 times daily for 1 day, repeat once after 5–8 days. Trichinosis - 25 mg/kg (maximum 1.5 g), 2 times daily for 2–4 days—up to 7 days if required. Strongyloidiasis - 25 mg/kg (maximum 1.5 g), 2 times daily for 2 days. For disseminated infection—5–7 day course may be given. Toxocariasis (Visceral larva migrans)—Efficacy is limited. A course of 25 mg/kg (maximum 1.5 g), 2 times daily for 7 days may be tried. Trichuriasis and hookworm – 25 mg/kg (maximum 1.5 g), 2 times daily for 2 days. Thiabendazole is not usually first-line therapy for pinworm; other agents are better tolerated and more effective. However, if pinworm infection occurs concurrently with any of the other listed indications for thiabendazole, thiabendazole therapy alone is usually adequate for most patients. May repeat the course after 1 week. There is limited study of its use in infants and children with weight of less than 13 kg for any of the indications mentioned Patients with renal impairment: Dosage should be modified depending on clinical response and degree of renal impairment, but no quantitative recommendations are available.

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obramycin: Newborn—IV less than 32 weeks 4–5 mg/kg 36 hourly and more than 32 weeks 4–5 mg/kg once in 24 hours. PDA, prolonged hypoxia, indomethacin treatment necessitate increased dose intervals. Extended interval dose regimen by intravenous injection over 3–5 min or by intravenous infusion— Neonate less than 32 weeks postmenstrual age 4–5 mg/kg every 36 hours; Neonate 32 weeks and over postmenstrual age 4–5 mg/ kg every 24 hours. Child—IV/IM 2.5 mg/kg/dose 3 times daily or 7 mg/kg as single daily dose. Once daily dose regimen by intravenous infusion—Child 1 month to 18 years—initially 7 mg/ kg, then adjusted according to serum-tobramycin concentration Intraventricular—newborn 1 mg/day, child 1–2 mg/day, adolescent 2–4 mg/day. Pseudomonal lung infection in cystic fibrosis—Child 1 month to 18 years—8–10 mg/kg/daily in 3 divided doses. Once daily dose regimen by intravenous infusion over 30 min—Child 1 month to 18 years—initially 10 mg/kg (maximum 660 mg), then adjusted according to serum-tobramycin concentration. Chronic pulmonary Pseudomonas aeruginosa infection in patients with cystic fibrosis—By inhalation of nebulized solution—Child 6–18 years—300 mg every 12 hours for 28 days, subsequent courses repeated after 28-day interval without tobramycin nebulizer solution Eye drops—1 drop 2 hourly and then reduce frequency as infection is controlled. To continue till 2 days after healing. T

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etracosactide ( etracosactrin): Infantile spasm—1 month to 2 years 500 µg IM as depot injection. Standard dose test—IV/IM (not depot preparation) less than 6 months 62.5 µg, 6 months to 2 years 125 µg and 2–18 years 250 µg.

heophylline: Oral more than 6 months 5 mg/kg/dose 3–4 times daily—adjust according to response and plasma levels. Sustained release preparations 8–12 years 10 mg/kg/dose and 12–18 years 8 mg/kg/dose (maximum 500 mg/dose).

hyroxine: Oral; Initial dose—newborn: 10–15 µg/kg, late neonatal period: 6–8 µg/kg, 3 months to 2 years: 5–10 µg/kg, 2–12 years: 5 µg/kg, 12–18 years: 50–100 µg. The goal of therapy is to maintain the total thyroxine (TT4) in the upper normal range of 10–15 µg/dL and normalize elevated TSH. Adjust dose to correct free thyroxine (FT4) to more than 20 pmol/L and TSH to less than 1–3 mU/L within 4 weeks of therapy. TSH levels take at least 4 weeks to show any change following therapy. Monitor thyroid hormone levels 4–6 weekly at onset till target levels are attained and then according to progress. It is ideal to test 6–8 weeks after any change in dose and every 3–4 monthly intervals during the second year and biannually or annually as the child grows. It is preferable to monitor total thyroxine levels to free thyroxine levels. FT4 is preferred in special circumstances like pregnancy or inappropriately elevated TSH, and to cross check central hypothyroidism if T4 level is borderline as TSH will not be useful. T

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etanus vaccine (adsorbed): IM/deep SC 0.5 mL.

M ( rometamol) [ ris ( ydroxymethyl) minomethane]: Dose in mL of 0.3 M solution = weight (kg) x base deficit, or 1–2 mEq/kg/dose. Blood gases should be checked before, during and after administration. Only half the base deficit should be corrected initially. Blood gases should be checked before further correction.

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hiotepa: Children—IV 25–65 mg/m2 every 3–4 week; high dose 300 mg/m2/24 hour for 3 doses. Always consult the current treatment protocol for details of dosage and scheduling.

etanus toxoid and reduced dose diphtheria: Contains Tetanus toxoid 5LF units and 2 LF units of diphtheria toxoid. 0.5 mL deep IM on anterolateral thigh for children above 7 year age and routinely at 10 and 16 years (Td to replace TT boosters at 10 and 16 years).

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years) and 2 g (more than 12 years). T

rifluoperazine: Schizophrenia and severe behavior disorders— 3–5 years 1 mg/day in divided doses; 6–12 years 2–5 mg in divided doses as required; 12–18 years start with 5 mg 2 times daily and increased by 5 mg/week up to 15–20 mg/day. Severe anxiety disorder—Oral—3–5 years up to 1 mg/day; 6–12 years up to 4 mg/ day; 12–18 years 4 mg/day and increased if required up to 6 mg/ day. Vomiting not responding to other medication—Oral—3–5 years up to 1 mg/day in divided doses; 6–12 years up to 4 mg/ day in divided doses; 12–18 years 2–4 mg/day in divided doses (maximum 6 mg).

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olnaftate: Apply evenly to affected area and rub gently 2–3 times daily. T

olterodine: Oral 2–18 years 1 mg once daily—may increase up to 2 mg twice daily according to response. Usually effective within 4 weeks. opiramate: Oral initially 0.5 mg/kg (1 month to 12 years) and 25 mg (12–18 years) followed by maintenance of 2–4.5 mg/kg (1 month to 12 years) and 100–200 mg (12–18 years). Doses up to 6 mg/kg twice daily have been used. Use starting dose for 2 weeks then increase dose every 2 weeks taking at least 6 weeks to reach maintenance dose. Use with caution in renal failure, titrating dose and intervals between dose adjustments to efficacy and sideeffects. Supplemental doses required after dialysis. T T

retinoin: Topical: apply 1–2 times daily thinly. The skin should be thoroughly washed first. Cream is recommended for dry or fair skin, gel for oily or dark skin. T

riamcinolone: Intra-articular—more than 1 year 1 mg/kg for large joints (maximum 40 mg), 0.5 mg/kg for small joints (maximum 20 mg but maximum 10 mg for finger and toe joints). T

riclofos sodium: Oral 30–50 mg/kg as single dose. Doses up to 100 mg/kg used for level 4 sedation required prior to doing procedures. Most used in children less than 12 years—cholral hydrate preferred more than 12 years. rientine dihydrochloride: Oral more than 2 years initially 300– 750 mg/dose 2 times daily to a maximum of 1.5 g/day (less than 12 T

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yphoid (strain y21a), live (oral): One capsule administered on alternate days until all three have been taken. When exposure is repeated or continuous, protection is likely to last for at least 3 years. For those normally living in nonendemic areas and traveling to endemic areas infrequently, the course should be repeated if more than a year has elapsed since the previous course. T

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yphoid vaccine (Polysaccharide): IM or deep SC: 0.5 mL.

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rea cream: Topical: wash affected area, rinse off all traces of sap and apply sparingly twice daily. U

rokinase: Thromboembolic disease—loading dose of 4,400 IU/ kg in 15 mL solution over 10 min followed by IV infusion 4,400 IU/kg/hour over 6–12 hours. Blocked arteriovenous shunts, IV cannulas/central lines – 5,000 IU/kg directly into the catheter and clamp off and retain for 2–4 hours. If not cleared, instill 10,000 IU and clamp. Monitor with Fibrinogen, TCT, PT, aPTT estimations. rsodeoxycholic acid: Oral 5–10 mg/kg/dose 2–3 times daily (maximum 45 mg/kg/day).Cystic fibrosis – 10 mg/kg/dose 2 times daily. Vancomycin: Newborn—IV 15 mg/kg/dose less than 28 weeks once daily, 29–35 weeks twice daily and more than 35 weeks 3 times daily. Intrathecal all newborn 2.5–5 mg once daily. Child IV 15 mg/kg loading dose followed by 10 mg/kg/dose 4 times daily. (maximum 2 g/day). Intrathecal 1 month to 4 years 5 mg, 4–15 years 10 mg and more than 15 years 20 mg once daily. Children with enlarged ventricles need higher doses. Adjust dose according to CSF levels aiming for a trough level of less than 10 mg/L. Varicella-Zoster immunoglobulin (VZ G): IM 0–5 years 250 mg (1 vial), 6–10 years 500 mg (2 vials), 11–14 years 750 mg (3 vials), more than 15 years 1 g (4 vials). I

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ranexamic acid: Oral 25 mg/kg/dose 3 times daily. Menorr hagia—1–1.5 g/dose 3–4 times daily for 3–4 days (maximum 4 g/ day). Initiate treatment after heavy bleeding starts.

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ryptophan (L- ryptophan): 100 mg/kg in 3 divided doses.

uberculin purified protein derivative (PP ): 10 TU 1:1,000 solution 0.1 mL intradermal on right forearm.

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rimipramine: Oral 6–12 years 50–100 mg and 12–18 years 75– 300 mg at bedtime.

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orsemide: On a weight to weight basis torsemide is twice as potent as frusemide, and provides a longer duration of action at lower urinary concentrations - allows for a 24-hour dosage interval and avoids the paradoxical antidiuresis seen with frusemide. Dosage: Edema associated with congestive heart failure or CRF: Oral or intravenous dosage: Adolescent: Initially, 10–20 mg PO or IV once daily. If needed, titrate by doubling the dose up to 200 mg PO or IV to achieve a satisfactory diuretic response. The safe use of a single dose more than or equal to 200 mg has not been evaluated. Adjunctive treatment of ascites (e.g. due to hepatic cirrhosis) either alone or in combination with spironolactone or amiloride: Oral or intravenous dosage: Adolescent: Initially, 5–10 mg PO or IV once daily. If needed, titrate upwards by doubling the dose up to 40 mg PO or IV to achieve a satisfactory diuretic response. Doses more than or equal to 40 mg have not been evaluated in patients with hepatic cirrhosis. Chronic use in hepatic disease has not been evaluated. Hypertension: Oral dosage: Adolescent: Initially, 5 mg PO once daily. May increase to 10 mg PO once daily if the desired reduction in blood pressure is not achieved in 4–6 weeks. If this dose is insufficient an additional antihypertensive agent should be added to the regimen. Patients with hepatic impairment: No dosage adjustment is needed; see the dosage for the treatment of ascites. Diuretics should be used with caution in patients with hepatic disease since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. Patients with renal impairment: No dosage adjustment is needed; however, high doses may be effective in patients with end-stage renal disease. Intermittent hemodialysis: Torsemide is not removed by hemodialysis; no dosage adjustment is needed. Torsemide can be safely used, and appears to be effective for treatment of heart failure in children (Archives of Disease in Childhood. 2008;93:76871). Future clinical trials are warranted to verify the results of this study.

rihexyphenidyl ( enzhexol): Extrapyrimidal symptoms and dystonia - 2 mg as single or divided doses. Antispasmodic—Initial dose of 0.5 mg in less than 7 years and 2 mg more than 7 years and increased by 0.5–2 mg/day every 10 days till response and given in 3–4 divided doses.

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olazoline: Newborn—IV bolus 1 mg/kg as single dose. Best result when blood p H more than 7.2. IV infusion 0.2 mg/kg/hour.

Varicella-Zoster vaccine, live: SC 1–12 years single dose of 0.5 mL if immunocompetent, otherwise 2 doses at least 6 weeks apart. More than 13 years 0.5 mL 2 doses at least 6 weeks apart. Vecuronium bromide: IV bolus—80–100 µg/kg as single dose and adjust dose and interval as required. IV infusion 1 month to 18 years 50–80 µg/kg/hour. Verapamil hydrochloride: Oral newborn 1–2 mg/kg/dose, 1 month to 2 years 20 mg/dose and 2–18 years 40–120 mg/dose 3 times daily. Slow IV bolus newborn – 1 year 100–200 µg/kg (maximum 2 mg), more than 1 year 100–300 µg/kg (maximum 5 mg) as single dose with ECG monitoring. May repeat after 30 min usually lower doses suffice.

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Vigabatrin: Oral less than 12 years 15–20 mg/kg/dose more than 12 years 1 g/dose 2 times daily as initial dose followed by maintenance of less than 12 years 30–40 mg/kg/dose, more than 12 years 1–1.5 g/dose 2 times daily. Increase to maintenance dose over 2–3 weeks except for infantile spasms when the maintenance dose should be reached in 5–7 days. Reduce dose in impaired renal function.

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Vitamin (retinol): Oral less than 1 year 500 IU and more than 1 year 10,000 IU daily. Prophylaxis of Vitamin A deficiency 1 lakh IU once in 6 months as a National Program.

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Yellow fever vaccine, live: Deep SC: 0.5 mL repeated every 10 years while still at risk. Zidovudine (azidothymidine or Z ): Newborn—Prevention of fetomaternal transmission. Oral 2 mg/kg/dose 4 times daily started within 12 hours of birth and continued for 6 weeks. IV 1.5 mg/kg/ dose 4 times daily. Child—Oral 180 mg/m2 2 times daily (maximum 250 mg/dose). IV 120 mg/m2 4 times daily. T

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ylometazoline hydrochloride: Intranasal 3 months to 12 years 1–2 drops 1–2 times of 0.05% and 12–18 years 0.1% 2–3 drops or 1 spray 2–3 times daily.

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Vitamin : Neonates and babies: vitamin K deficiency bleeding. Prophylaxis: current practice continues to vary widely. Exclusively breast-fed babies are at risk of late onset vitamin K deficiency bleeding in the first 3 months of life. Those with undiagnosed liver disease are at increased risk. If oral prophylaxis is used, repeated dosage throughout this period is probably the wisest course. Bottle-fed babies are not at risk because all formula milks are fortified with vitamin K giving an average dose of 50 µg per day. If IM/IV dose is giving at birth usually no further doses are required. 1 mg can be given IM to healthy neonates more than 36 weeks gestation, at birth or shortly after. Healthy neonates more than 36 weeks gestation: 2 mg orally at birth and at 4–7 days. Exclusively breast-fed babies should receive a further 2 mg oral dose 1 month after birth. Further monthly 2 mg oral doses until mixed feeding is introduced have been advised but no safety or efficacy data exist for these additional doses. Preterm neonates less than 36 weeks gestation and more than 2.5 kg and term neonates at special risk: 1 mg IM or IV at birth or soon thereafter. The frequency of further doses should depend on coagulation status. Preterm neonates less

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Vitamin ( lpha tocopheryl acetate): Oral less than 1 year 50 mg, 1–12 years 100 mg and 12–18 years 200 mg once daily. Rophylaxis of Vitamin E deficiency in newborn. Oral: 0.25 mL (29 mg) daily for all premature infants. herapy of symptomatic deficiency/prevention of RLF, BPD, IVH. Oral: 75–100 mg daily in 3 or 4 divided doses. Note: (1) 1 mg of d-alpha tocopheryl acetate is equivalent in activity to 1.36 i.u. of vitamin E. (2) Folic acid status is also important in hemolytic anemia.

Warfarin: Newborn infant (birth to 1 month)—There is very little experience of the use of warfarin in the neonatal period. Always seek expert advice before starting anticoagulation. Initial loading dose is 0.2 mg/kg. Infants less than 1 year usually need higher maintenance dose compared to older children. The dosage schedule is as per INR value. Average dose of warfarin in infants and young children is 0.33 mg/kg/day to achieve an INR of 2.0–3.0. For teenagers, the dose is 0.09 mg/kg/day and for adults, 0.04–0.08 mg/kg/day. Monitoring: Frequent dose adjustments warrant close supervision of INR. Vitamin K antagonists have extensive crossreactivity with several commonly used drugs and dietary agents. Certain “point-of-care” monitors are commercially available, which are considered reliable and acceptable for checking INR in home setting. These are somewhat similar to “glucometers”. INR level is affected by cumulative dose of warfarin taken over the last 5–7 days, so testing INR just after a day of change in dose is not useful. Dosing of Warfarin. Loading dose (Day 1). 0.2 mg/kg (maximum 10 mg); 0.1 mg/kg in presence of hepatic dysfunction. Days 2–4. INR 1.1–1.3, repeat loading dose. INR 1.4–1.9, give 50% of initial loading dose. INR 2.0–3.0, give 50% of initial loading dose. INR 3.1– 3.5, give 25% of initial loading dose. INR more than 3.5, hold until less than 3.5, restart at 50% of previous dose. Maintenance dose (day 5 and beyond). INR 1.1–1.4, increase dose by 20% of previous dose. INR 1.5–1.9, increase dose by 10% of previous dose. INR 2.0–3.0, no chance. INR 3.1–3.5, decrease dose by 10% of previous dose. INR more than 3.5, hold until less than 3.5, restart at 20% of previous dose. INR: international normalized ratio.

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Vitamin ( scorbic acid): Scurvy—Oral initially 500 mg then 100 mg/day for 1 week then 50 mg/day for prophylaxis. Metabolic indications—200–400 mg/day. Transient tyrosinemia—50–200 mg/day for 1–2 weeks. Hawkinsuria, Tyrosinuria III—up to 1 g daily for several weeks until symptoms subside.

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Vitamins and : Infants 0–6 months: 2.5 mL of emulsion daily, orally. 6 months-adults: 5 mL of emulsion of 1 capsule daily, orally.

Vincristine sulfate: Children less than 10 kg 0.05 mg/kg once a week, more than 10 kg 1–2 mg/m2 once a week. Always consult the current treatment protocol for details of dosage and scheduling. Maximum dose in adults is 2 mg weekly. Small infants may be unexpectedly sensitive to vincristine. Dosage reductions may be necessary if toxicity is unacceptable. An increase in the severity of side-effects may be seen in patients with liver disease sufficient to decrease biliary excretion. A 50% dosage reduction is recommended in patients with a serum bilirubin level more than 50 mmol/L.

Vitamin complex: Infants – 5 mL daily. 1–12 years – 5 mL twice daily. 12–18 years – 5 mL thrice daily. Therapeutic - Infants – 5 mL thrice daily. 1–12 years 10 mL thrice daily. 12–18 years—10–15 mL thrice daily.

Pediatric hera eutics

Vinblastine sulfate: Hodgkin’s in children—IV 2.5–6 mg/m2/24 hours 1–2/week for 3–6 weeks (maximum 12.5 mg/m2/week). Always consult the current treatment protocol for details of dosage and scheduling. Maximum single dose 10 mg. A 50% dose reduction has been suggested in patients with serum bilirubin more than 50 mmol/L.

than 36 weeks gestation and less than 2.5 kg: 400 µg/kg IM or IV at birth or soon thereafter. The frequency of further doses should depend on coagulation status. Treatment: 1 mg IV repeated 8th hourly if necessary. At risk babies are those at increased risk of hemorrhagic disease, e.g. birth asphyxia, bleeding problems, maternal liver disease or mother receiving anticonvulsant or antituberculosis drugs. Neonates and babies: biliary atresia and liver disease, 1 mg daily by mouth.

Zinc sulfate: As zinc base. Acrodermatitis enteropathica—Oral 0.5–1 mg/kg/dose 2 times daily. Wilson’s disease—Oral 2–12 years 25–37.5 mg/dose 12–18 years 50 mg/dose 2–4 times daily. Do not give at same time as penicillamine. Zinc deficiency—Oral newborn 1 mg/kg once daily, 10–30 kg 22.5 mg once or twice daily. More than 30 kg 45 mg 1–3 times daily. Adjust according to response. Zinc sulfate injection: 2–5 micromol/kg depending on age and deficiency state. Zonisamide: 4–8 mg/kg/day should be administered once or twice daily, using 25 mg, 50 mg or 100 mg capsules. Given orally and can be taken with or without food.

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Zopiclone: Oral 12–18 years 3.75 mg once daily at bedtime.

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