2006, Vol.24, Issues 1, Brain Injury and Cardiac Arrest

Neurol Clin 24 (2006) xi–xii

Foreword

Brain Injury and Cardiac Arrest We use many terms to describe brain injury after cardiac arrest: global cerebral ischemia (complete or incomplete), global ischemia, hypoxic brain injury, hypoxic-ischemic brain injury, and post–cardiac arrest syndrome, to name a few. Yet however we vary our lexography, the single literal translation is a seriously injured brain without a treatment or good functional outcome. Great progress has been made in the treatment of cardiac arrest, particularly reanimating the heart and circulation; however, little has changed with respect to ‘‘reanimating’’ or protecting the brain. Three decades beyond the discovery of cardiopulmonary resuscitation (CPR), predicting neurologic recovery is based almost entirely on what we have learned from the pathologic evaluation of brain tissue following cardiac arrest/CPR death. In the living patient, the clinician is taught the clinical examination at the bedside to determine coma, prognosis, and brain death statusdtasks satisfactory for identifying the poor prognosis patient; but there has been little effort or success developing predictive assessments to select (or not select) treatment for the questionable-outcome patient, the one who escapes brain death or emerges from a coma. In the past few years, slow but thoughtful changes offer new opportunities for neurologists and others interested in the emergent care of acute brain injuries. This issue of Neurologic Clinics offers an excellent window into the changing outlook of brain injury after cardiac arrest. Romer Geocadin has assembled a group of physician-scientists who are improving the clinical picture of brain function after cardiac arrest. It is clear that, within the first decade of the twenty-first century, we will have the experience to assess the comatose cardiac arrest survivor and the know-how to optimize return to brain health. Within this time, we can look forward to guidelines for optimal return of circulatory function; brain tissue protection; early prognostication; early monitoring of recovery; and a detailed mapping, by degrees of cardiac arrest and extent of brain injury, of the functional and neuropsychologic patient consequences. The data presented herein offer a compelling argument for the greater involvement of all physicians to learn cardiac arrest treatments and interventions directed to brain recovery within the minutes and first hours after cardiac arrest. For all the patients, families, and physicians treating cardiac arrest, this is great news. 0733-8619/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.ncl.2005.12.003 neurologic.theclinics.com

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FOREWORD

We thank Dr. Geocadin and his colleagues for opening the door to a better way of doing things. Daniel F. Hanley, MD Departments of Neurology Neurosurgery and Anesthesiology–Critical Care Medicine Johns Hopkins University School of Medicine 600 North Wolfe Street–Meyer 8-140 Baltimore, Maryland 21287, USA E-mail address: [email protected]

Neurol Clin 24 (2006) xiii–xvi

Preface

Brain Injury and Cardiac Arrest

Romergryko G. Geocadin, MD Guest Editor

The importance of brain injury after resuscitation from cardiac arrest has been recognized since the days of the pioneering works of Peter Safar in 1958, at the Baltimore City Hospital (currently Johns Hopkins Bayview Medical Center) on airway methods of artificial respiration and Koewenhoven, Jude, and Knickerbocker at the Johns Hopkins Hospital in the early 1960s on the closed cardiac massage with external defibrillation. This gave way to the development of modern cardiopulmonary resuscitation. In their 2000 Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care, the American Heart Association highlighted brain injury by providing that ‘‘The cerebral cortex, the tissue most susceptible to hypoxia, is irreversibly damaged, resulting in death or severe neurological damage. The need to preserve cerebral viability must be stressed in research endeavors and in practical interventions.’’ Advances in cardiopulmonary resuscitation and critical care contributed to the increasing success in patient survival; however, a significant number of survivors live with poor neurologic function. Numerous neuroprotection clinical trials undertaken in the last three decades failed to show functional benefit to survivors until the recent success of therapeutic hypothermia. This therapy shows that brain injury can be ameliorated, leading to improved survival and functional outcome in survivors. Although much of the research in this field has been undertaken by cardiologists, emergency medicine physicians, anesthesiologists, and intensivists, injury to the brain requires more involvement by neurologists. 0733-8619/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.ncl.2005.12.001 neurologic.theclinics.com

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The clinical practice of neurology in this area is also limited, mainly in the care of post–cardiac arrest complications and prognostication of outcome. After cardiac arrest, the neurologist is typically consulted to evaluate unresponsive patients only several days after medical stabilization. The neurologist may be called earlier if the possibility of seizures or stroke is entertained. The key questions are: When should the neurologist get involved? What can the neurologist offer other than prognostication? With the onset of brain ischemia, complex cascades of events amplify the ischemic injury during the first few hours. Early involvement of the neurologist during the very acute and early recovery period after cardiac arrest may greatly enhance multidisciplinary strategies on brain preservation and functional recovery. My experience performing both research and patient care in this area has been very encouraging. I noted that medical, critical care, and emergency medicine specialists know that the neurologist has much to contribute with regard to care for brain injury and research to further improve survival and quality of life. Despite the best efforts of specialists, irreversible brain injuries still occur in survivors that will lead to long-term morbidities. With the early recognition of the potential long-term neurologic problems, the neurologist can play a significant role in improving the quality of life of survivors. This issue of Neurologic Clinics revisits brain injury after resuscitation from cardiac arrest. The goal of this issue is to provide the neurologist with a comprehensive and multidisciplinary review of the current research and clinical practices related to brain injury and cardiac arrest. It is my hope that the recent advances in cardiac arrest resuscitation and acute neurology will transform the traditional role of the neurologist as a diagnostician to a neuroclinician who can work directly with other services to provide acute interventions that will ameliorate acute brain injury. A similar change has been successfully undertaken with the acute neurologic interventions in the areas of acute stroke and neurointensive care. It is also my hope that this issue will spark more interest in neurologic research in the area to further facilitate the transformation. As a comprehensive and multidisciplinary review, this issue is a collection of articles written by leading experts. The first article by Drs. Bhardwaj and Harukuni, renowned researchers in ischemic brain injury, does not limit itself to the mechanism of brain injury but provides therapeutic consideration related to the injury mechanisms. The next article takes the reader to the event immediately around the cardiac arrest. As leaders in the field of emergency medicine, Drs. Ornato and Peberdy provide neurologists with critical insights into resuscitation and neuroprotection out in the field and in the emergency department. From the emergency department, the patient moves to the intensive care area. The article by Dr. Schulman and colleagues on the intensive care of these patients will provide a joint cardiac and neurologic critical care approach to post–cardiac

PREFACE

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arrest patients. After successful resuscitation, consideration for therapeutic hypothermia has to be made for all appropriate patients. Dr. Stephen Bernard, the lead author of one of the landmark clinical studies on therapeutic hypothermia, provides an authoritative review. While therapeutic hypothermia may benefit some patients, many survivors will still have a poor outcome. The following article by Drs. Popp and Bo¨ttiger provides a look into the development of very promising therapies in the area. They have highlighted in their article the clinical trial in Europe, led by Dr. Bo¨ttiger, using thrombolytics to improve functional recovery after cardiac arrest. The succeeding articles provide updates on the traditional and novel applications of diagnostic tools that are available to enhance the care of these patients. The article by Dr. Koenig and colleagues reviews the role of neuroelectrophysiologic tests in prognostication and provides novel approaches and applications of electrophysiologic testing to enhance not only the prognostication but also the early detection of brain injury and monitoring of recovery. The article by Drs. Geraghty and Torbey reviews the serological markers of brain injury and provides novel applications of neuroimaging to enhance the prognostication. As the patient moves out of the intensive care unit and the hospital, longterm neurologic complications become the focus of neurologic care. Movement disorder experts Drs. Venkatesan and Frucht address the clinical problems and the need for further research in the area of movement disorders after cardiac arrest. With the more advanced research on the cognitive and behavioral dysfunction in patients who have undergone cardiac bypass procedures than in survivors of cardiac arrest and the numerous similarities of the two global ischemic conditions, the article by Dr. Selnes and colleagues provides critical insight into the cognitive and behavioral dysfunction after a global ischemic injury. The last two articles deal with special topics in this area. In many disease states, children need special consideration. The article by Dr. Hickey, a pediatric emergency physician, and Dr. Painter, a pediatric neurologist, tackles issues of brain injury after cardiac arrest in children. With death as a common outcome even in resuscitated patients, the article by Drs. Manno and Wijdicks provides approaches to withdrawal of life-sustaining therapies and the declaration of brain death in neurologic patients. Many people contributed to this issue. My gratitude goes to the contributors, whose dedication to research and patient care has greatly moved the field forward. I would like to express my deepest gratitude to Dan Hanley and Nitish Thakor, who showed me that we can help critically ill patients and their seemingly insurmountable clinical problems through research, and to Peter Safar, whose enthusiasm and brilliance encouraged me to proceed in this path. I would also like to thank the Neurologic Clinics Editors, Don Mumford, Bob Gardler, and their staff for their patience and assistance. And most importantly, to my wife Effie

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and our children, Ginno and Sofia, whose love and inspiration made all this possible. Romergryko G. Geocadin, MD Departments of Neurology, Neurosurgery and Anesthesiology-Critical Care Medicine Johns Hopkins University School of Medicine 600 North Wolfe Street, Meyer 8-140 Baltimore, MD 21287 USA E-mail address: [email protected]

Neurol Clin 24 (2006) 1–21

Mechanisms of Brain Injury after Global Cerebral Ischemia Izumi Harukuni, MDa, Anish Bhardwaj, MDb,* a

Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Division of Cardiac Anesthesiology, Tower 711, Johns Hopkins Hospital, 600 N. Wolfe Street, Baltimore, MD 21287, USA b Departments of Neurology and Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Neurosciences Critical Care Division, Meyer 8-140, Johns Hopkins Hospital, 600 N. Wolfe Street, Baltimore, MD 21287, USA

Global cerebral ischemia occurs commonly in patients who have a variety of clinical conditions including cardiac arrest (CA), shock, and asphyxia and in patients undergoing complex cardiac surgery [1–4]. In addition to injury to other organs from systemic hypoperfusion, neurologic sequelae from brain injury are varied and constitute a spectrum that includes coma, seizures, ischemic stroke, delirium, and neurocognitive impairment [5–7]. The commonest postulated mechanism for ischemic brain injury after CA (with subsequent resuscitation) is global cerebral ischemia from systemic hypoperfusion that can occur with or without pre-existing large-vessel occlusive disease. Embolism that arises from the heart, from aortic arch artheromas, or from extracorporeal circulation devices occurs more commonly in the perioperative period following complex cardiac surgery and less commonly during resuscitation following CA [7]. Irrespective of the etiology of cerebral ischemia, cellular and molecular processes trigger a cascade of events that culminate in a ‘‘final common pathway,’’ resulting in ischemic neuronal injury. Identification of these injury mediators and pathways in a variety of experimental animal models of global cerebral ischemia has led to investigation of target-specific cytoprotective strategies that are critical to clinical brain injury outcome. Although the authors have previously published on this subject [8], this article expands on the translational significance of many of the potential neuroprotective strategies that have

This work is supported in part by the US Public Health Service National Institutes of Health grant NS046379. * Corresponding author. E-mail address: [email protected] (A. Bhardwaj). 0733-8619/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.ncl.2005.10.004 neurologic.theclinics.com

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provided important insights into the mechanism or mechanisms of ischemic brain injury and might be of therapeutic benefit in the future. Global versus focal cerebral ischemia Ischemia is defined as diminution of cerebral blood flow (CBF) to a critical threshold that propagates brain damage involving the entire brain or a selective region. Global cerebral ischemia entails diminution in CBF over the entire brain, encountered clinically as sequelae during extracorporeal circulation following CA from ventricular fibrillation or asystole that lasts 5 to 10 minutes. Global ischemia from CA results in a predictable pattern of histologic injury in which specific neuronal populations are affected (selective ischemic necrosis) [9–11] (discussed later). Although reperfusion restores CBF, it can lead to secondary brain injury from influx of neutrophils and to increases in reactive oxygen species (ROS), cerebral edema, and hemorrhage. Elevated levels of ROS may lead to damage of intracellular proteins and DNA by way of oxidation and by activating a number of pathways that lead to cell death. Unlike global cerebral ischemia, focal cerebral ischemia entails reduction in regional CBF in a specific vascular territory and is usually encountered clinically as an ‘‘ischemic stroke’’ due to thromboembolic or artherothrombotic vaso-occlusive disease. Normal CBF ranges from 50 to 75 mL/100 g of brain tissue per minute and can differ between the white and gray brain matter. Ischemic depolarization occurs when CBF decreases to levels of approximately 18 mL/100 g of brain tissue per minute, and neuronal cell death ensues if CBF is less than 10 mL/100 g of brain tissue per minute. In focal ischemia, the ischemic vascular bed comprises an area with severe CBF reduction that consists of an ‘‘ischemic core’’ and a more distal ‘‘ischemic penumbra’’ and includes regions that are marginally perfused and might be served by collateral vascular channels. Histopathologic outcome following focal ischemia largely depends on ischemic severity and duration [8–10]. Increasing durations of depolarizing ischemia are associated with a spectrum of histopathologic correlatesdfrom reversible injury to irreversible cerebral infarction. Experimental models of global cerebral ischemia Several animal models have been developed to simulate complete human global cerebral ischemia and have provided histologic evidence of and insight into mechanisms of brain injury. Rodent models (gerbil, mouse, and rat) provide the advantages of being inexpensive, of rendering consistent reproducibility of injury because they possess consistent cerebral vasculature, and of being homogeneous among strains, with transgenic counterparts allowing targeted mechanistic studies for delineating effects of specific gene deletion on ischemic brain injury. Monitoring of critical physiologic variables (pH, arterial blood pressure, arterial blood gases, core body and cranial

BRAIN INJURY AFTER GLOBAL CEREBRAL ISCHEMIA

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temperature, plasma glucose levels) during the peri-ischemic period, however, is suboptimal. Furthermore, assessment of functional neurologic outcomes with a comprehensive behavioral battery presents a challenge in small animal models. Because 50% of Mongolian gerbils possess an incomplete circle of Willis, bilateral carotid artery occlusion results in forebrain ischemia in these animals. The rat model of global cerebral ischemia includes (1) four-vessel occlusion (4-VO) by electrocoagulation of both vertebral arteries, with transient occlusion of both carotid arteries 24 hours later [12]; or (2) ‘‘two-vessel occlusion’’ by transient occlusion of both carotid arteries and accompanying reduction of arterial blood pressure to a level of 40 to 50 mm Hg by phlebotomy [13,14]. Both techniques yield high-grade ischemia of forebrain structures [15]. Larger animal models (rabbit, canine, feline, swine, nonhuman primates) allow for monitoring of critical physiologic variables during and following the ischemic insult and allow for a more accurate delineation of neurologic deficits following the insult; however, high cost and significant ethical concerns limit their use. The methods of brain injury in these larger-animal models include ventricular fibrillation [16], aortic occlusion [17], brachiocephalic or subclavian arterial occlusion in combination with hypotension, elevated intracranial pressure by neck-cuff insufflation, and intraventricular infusion [18]. In these animal models, specific neuronal populations in the brain, including CA1 pyramidal neurons of the hippocampus, medium-sized neurons of the striatum, and the Purkinje cells of the cerebellum [19], are susceptible to injury. The sensitivity of these neuronal populations is varied and dependent on duration and severity of ischemia, and a typical temporal profile is observed following CA. Neurons in the CA1 zone are the most sensitive to depolarizing ischemia (3–5 minutes), whereas the medium-sized neurons of the striatum are more resistant (15–20 minutes) [20]. Following successful resuscitation and cerebral recirculation, progression of irreversible neuronal injury also differs in these selective neuronal populations (eg, neuronal injury is observed within 3 hours of establishing recirculation in medium-sized neurons of the striatum but delayed up to 48–72 hours in CA1 hippocampal neurons, a phenomenon referred to as ‘‘delayed neuronal death’’) [20]. Neuronal injury mechanisms: apoptosis versus necrosis Over the past decade, research has demonstrated that consequences of cerebral ischemia result in two temporally distinct phases or processes of neuronal cell death, which in turn affect surrounding brain tissue. Each phase has characteristic defining morphologic and molecular features, and the distinction between the two processes is based on morphologic findings on electron microscopy [8,21]. Apoptosis or programmed cell death, a process associated with genomic fragmentation, is characterized by cell shrinkage, chromatin aggregation, and preservation of cell membrane integrity and mitochondria without inflammation and injury to surrounding tissue [21–25].

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Conversely, necrosis, a process that is not ‘‘regulated or programmed,’’ is typically observed as a consequence of severe cerebral ischemia and characterized by disruption of cellular homeostasis from energy failure due to severe mitochondrial injury, which leads to cellular swelling, membrane lysis, inflammation, vascular damage, and edema formation. Although apoptosis and necrosis characteristically represent distinct modes of cellular injury, a large body of literature suggests that these processes represent a spectrum that coexists in a spatial distribution within injured tissue (neurons in the core being necrotics and neurons in the penumbra being apoptotic) and is temporally related to duration and severity of the ischemic insult. The accepted tenet is that the excitotoxic cascade triggered by exposure to excitatory amino acids (EAAs) plays a prominent role in neuronal necrosis. In vitro exposure to glutamate, however, results in apoptosis in neurons that survive the early necrotic phase and have partial recovery of mitochondrial function [26]. Therefore, maintenance of mitochondrial function is possibly the critical factor in determining the degree and progression of neuronal injury propagated by excitotoxicity [25]. A common pathway of stimuli leading to apoptosis has not yet been identified; however, a mitochondrial-dependent intrinsic pathway and a receptor-mediated extrinsic pathway are postulated [27,28]. In the intrinsic pathway, cerebral ischemia results in generation of a permeability transition pore in the inner mitochondrial membrane that leads to disruption of the outer mitochondrial membrane due to release of several proapoptotic factors (caspases, endonucleases, cytochrome c, and other proteases related to interleukin-1b converting enzyme) [21,27,28]. These events ultimately lead to DNA fragmentation. The ‘‘mitochondrialindependent’’ or extrinsic pathway of apoptosis involves several death receptor families such as Fas. Bypassing the inhibitory effects of Bcl2-related proteins, which control proteolytic systems, has also been postulated to play an important role in apoptotic cell death, whereas other family members, such as Bax, augment apoptosis. Another family of protein-cleaving enzymes, caspases, is expressed at significant levels during cerebral ischemia, and caspase inhibitors produce resistance to ischemic damage [29]. Excitotoxic brain injury The concept of excitotoxicity, introduced by Olney in 1969 [30], was based on a set of observations that included neuronal injury with local application of glutamate and other acidic amino acids (aspartate, N-methyl-D-aspartate [NMDA], homocysteine, cysteine). Since this description was published, other excitotoxic mediators have been delineated, including catecholamines (dopamine, norepinephrine), nitric oxide (NO), and related species. Glutamate, the most abundant EAA in the brain, serves a variety of important functions (metabolic, neurotrophic, and neurotransmitter) and is compartmentalized in neurons [19,31]. The healthy adult brain has the ability to clear extracellular glutamate by rapid uptake; however, under conditions in which energy stores


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are depleted, such as in hypoxia-ischemia, glutamate efflux into the extracellular compartment due to cellular depolarization [32], coupled with its impaired uptake, results in increases in intracellular Ca2þ. Interference with cysteine uptake (causing depletion of cellular glutathione stores responsible for protecting against oxidative stress) results in neuronal injury [30,33]. Excitotoxic injury is characterized by its maximal effects on neuronal dendrites and soma, with relative sparing of axons, glia, and ependymal and endothelial cells, possibly due to differences in synaptic input, density, distribution of membrane glutamate receptors, and intrinsic defense mechanisms. Glutamate activates three major families of ionophore-linked receptors (NMDA, aamino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA], and kainate) and metabotropic receptors that activate second messenger systems [34]. Although glutamate release simultaneously stimulates NMDA and AMPA receptors, in vitro studies demonstrate that glutamate toxicity occurs in two distinct phases: (1) excitotoxicity is rapidly triggered by brief intense stimulation of NMDA receptors, which is critically dependent on the presence and influx of extracellular Ca2þ through the NMDA-gated receptor channel complex; and (2) a slowly triggered process by the prolonged stimulation of AMPA/kainate receptors that have limited Ca2þ channels [33]. Metabotropic glutamate receptors modify excitotoxic injury, rather than directly mediate the deleterious process. The cascade of events responsible for glutamate excitotoxicity includes three distinct processes: (1) induction, whereby extracellular glutamate efflux is transduced by receptors on the neuronal membrane to cause intracellular Ca2þ overload, which leads to lethal intracellular derangements; (2) amplification of the derangement, with an increase in intensity and involvement of other neurons; and (3) expression of cell death triggered by cytotoxic cascades [33]. Excess release of Ca2þ and its intracellular influx is thought to be the primary trigger for a variety of complex, deleterious intracellular processes that result from activation of catabolic enzymes such as phospholipases (which lead to cell membrane breakdown, arachidonic acid, and free radical formation) and endonucleases (which lead to fragmentation of genomic DNA and energy failure due to mitochondrial dysfunction) (Fig. 1). Distinct neuronal populations are selectively vulnerable to excitotoxic injury, possibly from differences in excitatory synaptic inputs, density of glutamate receptors, or intrinsic defense mechanisms. Perhaps the most compelling evidence for the role of glutamate excitoxicity following focal ischemia and hypoxic-ischemic brain injury from CA is the neuroprotection observed with antiexcitotoxic strategies including NMDA- or AMPA-receptor antagonists [35]. Acute efflux of dopamine and norepinephrine into the extracellular space following cerebral ischemia [36–39] possibly plays a role in the propagation of brain injury. Indirect evidence of the importance of their role in cerebral ischemia stems from amelioration of histopathologic injury following attenuation of ischemia-induced surges in extracellular dopamine pharmacologically

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Decreased cerebral perfusion Depletion in energy stores

Cerebral Ischemia

Apoptosis

Excitotoxicity

Cell shrinkage Chromatin aggregation Preservation of cell membrane integrity Preservation of mitochondria Lack of inflammation

Inflammation (Programmed Cell Death)

EAAs (Glutamate, Aspartate), Catecholamine

Activation of ionophore-linked channels (NMDA, AMPA)

Cytokine (IL-1, TNF- ) production Chemokines Adhesion molecules (selectins, integrins, ICAM-1) Proteases BBB breakdown

Activation of Metabotropic receptors

Influx of intracellular Ca2+

Protein phosphorylation Proteolysis NO, oxygen free radical production Altered gene expression

Modification

Neuronal Cell Death

Fig. 1. Schematic diagram representing events leading to ischemic brain injury.

with barbiturates, isoflurane, and etomidate [40,41]. Furthermore, several lines of evidence suggest that catecholamine release and metabolism might underlie the selective vulnerability of striatal neurons to an ischemic insult [42,43]. For example, depletion of catecholamine stores by a-methyl-paratyrosine exerts a strong protective effect on ischemic damage to nerve terminals [43], and reduction of striatal dopamine content by lesioning the nigrostriatal tract protects intrinsic striatal neurons from injury following global cerebral ischemia [44]. Although the precise mechanism of neuronal injury by dopamine is unclear, by-products of its metabolism, such as hydrogen peroxide, superoxide ion, and hydrogen radicals, have been implicated in this deleterious process [45]. NO, a free radical gas synthesized from the amino acid L-arginine by the enzyme NO synthase (NOS), is produced by a variety of sources (vascular endothelium, neurons, glia, macrophages, white blood cells) [46,47]. NO has several functions in the brain, including regulation of CBF, neurotransmission, and modification of inflammation [46,47]. At least three isoforms of NOS have been identified: the constitutively expressed neuronal and endothelial isoforms (encoded on chromosome 12 and 7) and the inducible isoform (encoded on chromosome 17) [48,49]. Neuronal NOS–containing neurons are widespread in the brain, including in the cerebral cortex, hippocampus, and striatum [47]. NO plays a dual role in ischemic neuropathol-


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ogydbeneficial, in that it is a potent vasodilator, and cytotoxic, in that it inhibits important enzyme systems such as complexes I and II of the mitochondrial transport chain (Fig. 2). Formation of the oxidant perioxynitrite by combination of NO and superoxide anion is considered to be an important trigger in cytotoxicity. Perioxynitrite generation leads to formation of other ROS, hydroxyl free radicals, and nitrogen dioxide, resulting in nitrosylation of tyrosine residues in proteins. One way by which NO is thought to kill neurons is energy-dependent activation of the DNA repair enzyme poly(ADP-ribose) polymerase, leading to consumption of ATP, nicotinamide, and cell death [50]. In cerebral ischemia, constitutive NO activity (endothelial and neuronal isoforms) markedly increases as a consequence of NMDA, AMPA, and metabotropic glutamate receptor stimulation [51,52] culminating in a rise in intracellular Ca2þ, whereas more sustained levels of NO are expressed by the microglia and other inflammatory cells (Ca2þ-independent inducible isoform) 24 hours following the ischemic event [8,48]. Consequently, administration of NO donors and specific NOS inhibitors has yielded mixed results in experimental models of cerebral ischemia. Such varied results are explained by nonselectivity of NOS inhibitors and timing of such interventions in relation to ischemia. For example, infusion of the NO precursor and substrate L-arginine in the immediate period following experimental focal ischemia attenuates infarct volume by accentuating CBF by way of dilation of pial vessels [48,53]. In line with this evidence, male mutant mice that lack the endothelial isoform of NOS sustain larger ischemic injury than their wild-type counterparts following focal ischemia [54]. Infarct volume and functional outcomes are improved in wild-type mice following selective pharmacologic inhibition of neuronal NOS and in mutant mice that do not express genes for the neuronal or inducible isoforms [48,55]. Because vascular NO might favorably affect outcome and the neuronal isoform might adversely affect outcome, selective pharmacologic Nitric Oxide

Beneficial Role (Endothelial)

Increased CBF Decreased platelet aggregation Decreased platelet adhesion Decreased NMDA current

Deleterious Role (Neuronal and Inducible)

Direct Cytotoxic Effects Binding to iron-sulfur complexes Decreased mitochondrial respiratory enzymes Decreased ribonucleotide reductase Decreased aconitase Nitrosylation of thiols and ADP ribosylation Decreased PARP, leading to DNA damage Indirect Cytotoxic Effects Increased peroxynitrite Increased hydroxyl radical Increased nitrogen dioxide

Fig. 2. Beneficial and deleterious effects of nitric oxide in cerebral ischemia. (Reproduced from Bhardwaj et al. [8] and adapted from Dalkara and Moskowitz [49], with permission.)

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inhibition of the neuronal and inducible isoforms of NOS might provide a viable therapeutic strategy in cerebral ischemia. Role of inflammation Cerebral ischemia leads to inflammatory cell infiltrates from nonspecific immunologic reaction, migration of peripheral leukocytes into the brain, and activation of microglia [56]. Release of inflammatory cytokines (interleukin [IL]-1, tumor necrosis factor a [TNF-a]) by ischemic neurons and glia leads to generation of adhesion molecules (selectins, integrins, intercellular adhesion molecule 1) in the cerebral vasculature, which results in breakdown of the blood-brain barrier (BBB), culminating in edema formation [57,58]. Enhanced secretion of cytokines and proteases such as metalloproteinases causes further disruption of the extracellular matrix and the BBB. Although IL-1 is detrimental to ischemic brain injury, roles for IL-6, a proinflammatory cytokine, and IL-10, an anti-inflammatory cytokine, are less clear. TNF-a appears to have a dual role in the ischemic brain, in that it is involved in ischemic tolerance [59] and plays a role in propagating ischemic brain injury [60,61]. Glycemic control A number of studies in animal models of traumatic brain injury [62], focal cerebral ischemia [63], and global cerebral ischemia [64] demonstrate that glycemic control is a critical factor in terms of outcome. Postulated mechanisms include accentuation of release of EAAs, attenuation of neuroinhibitory neurotransmitters [65], massive deposition of neutrophils [66], and early mitochondrial damage by way of activation of cytochrome c, caspase-9, and caspase-3 cleavage [67]. These mechanistic studies have led to clinical observations that poor glycemic control accentuates brain injury in ischemic stroke [68] and following cardiac surgery [69]. Glycemic control with insulin treatment has been demonstrated to improve neurologic outcome in critically ill patients [70] and in patients who undergo cardiac surgery [69]. Although insulin therapy has been shown to ameliorate damage in animal models of global cerebral ischemia [71], further clinical trials are warranted in the setting of aggressive glycemic control with insulin therapy in patients following CA. Role of temperature Experimental studies using animal models of focal and global cerebral ischemia have provided evidence for the importance of brain temperature on functional and histopathologic outcome [72]. Following cerebral ischemia, intraischemic hyperthermia leads to incomplete normalization of highenergy phosphate metabolites and the conversion of selective neuronal necrosis to infarction, increased microvascular injury, and edema, resulting in increased mortality [72]. Spontaneous elevations in body temperature


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have been reported following experimental global and focal ischemia and are thought to be a consequence of brain injury [73]. Mild (34 C) to moderate (30 C) induced systemic hypothermia markedly attenuates ischemic brain injury following experimental CA [74]. Mechanisms of hypothermia-induced ischemic brain protection may be multifactorial and include mitigation of pre- and postsynaptic excitotoxic processes (attenuation of biosynthesis, release and uptake of EAAs), diminished hydroxyl radical production, protection of lipoprotein membranes, attenuation of intracellular acidosis, and reduction of oxygen demand by the injured brain [2]. Recent clinical trials have demonstrated improved neurologic outcome and decreased mortality in patients subjected to mild-to-moderate therapeutic hypothermia [1,2]. Future clinical trials should incorporate other pharmacologic neuroprotective strategies in combination with hypothermia to further enhance outcomes. Ischemic tolerance and preconditioning The concept of ischemic tolerance, introduced 2 decades ago and based on observations in the myocardium [75], was extended to ischemic brain injury, whereby brief ischemic insults protected the brain from subsequent and more severe ischemia [76]. Further experiments in a variety of animal models of focal and global cerebral ischemia confirmed these observations [77,78]. In addition to sublethal ischemia, other conditions such as hyperthermia [79], hypothermia [80], hypoglycemia [81], and pharmacologic agents (eg, antibiotics, erythropoietin, acetylsalicylic acid, volatile anesthetics) [82–85] have been shown to induce ischemic tolerance. The early phase of ischemic tolerance (within 30 minutes following sublethal insult) is thought to be due to flow-metabolism–mediated events, whereas delayed tolerance (O24 hours) involves new gene induction and protein synthesis [86,87]. Molecules such as adenosine, hypoxia inducible factor 1a, TNF-a, ROS, NO, and other receptorlinked events involving NMDA-receptor activation and downstream effects of intracellular calcium influx have been implicated in ischemic tolerance. Although the precise mechanisms of ischemic tolerance have not been elucidated completely, ischemic preconditioning provides a possible venue and therapeutic strategy in ameliorating brain injury in a few, select high-risk patients susceptible to ischemic brain injury. Experimental pharmacologic neuroprotection and its translational significance A comprehensive review of this topic is beyond the scope of this article; however, the interested reader is referred to a recent monograph by Weigl and colleagues [88]. Several pharmacologic agents have undergone investigation in animal models of global cerebral ischemia to directly or indirectly determine efficacy. Methods used to evaluate postischemic hyperemia or hypoperfusion include recovery of somatosensory-evoked potentials, recovery

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of high-energy phosphates, functional neurologic recovery, and histologic injury [29,88]. The basis for the study of these agents is a logical extension of mechanistic studies in a variety of in vitro and in vivo systems of cerebral ischemia. In addition, results from neuroprotective studies with pharmacologic agents provide important insights into mechanisms because they entail disruption of a specific pathway or receptor blockade in the propagation of ischemic neuronal injury. Although many of these agents are still under investigation, data predominantly from studies using the focal ischemia paradigm underscore the future use of pharmacologic therapies following global cerebral ischemia. N-methyl-D-aspartate–receptor antagonists Pre- and post-treatment with dextrorphan, an NMDA-receptor antagonist, improves histologic injury in the hippocampus and the cortex in a 4-VO rat model and attenuates the reduction in loss of activity of calciumdependent protein kinases (protein kinase C and calcium-dependent protein kinase II) [89]. Although the NMDA-receptor antagonist dizoclipine (MK801) has been shown to provide significant histologic neuroprotection in animal models of global cerebral ischemia [90,91], its clinical use in ischemic stroke has been shown to produce significant undesirable side effects (delirium, psychosis, hallucinations, and so forth) [29]. Calcium channel antagonists Because Ca2þ is the final common pathway in excitotoxic neuronal injury, nimodipine, a blocker of Ca2þ influx, has been studied in the experimental paradigm of global cerebral ischemia. Subcutaneous administration of nimodipine failed to demonstrate any histologic or functional neurologic improvement in the 4-VO rat model of global cerebral ischemia [92,93]; however, in a rabbit model, intravenous treatment with nimodipine reduced time of EEG recovery and attenuated the decrement in extracellular Ca2þ and disruption of the BBB. In this study, arterial blood pressure was maintained at 100 mm Hg following the ischemic insult, thereby offsetting the detrimental hypotensive effects of nimodipine. A prospective, randomized, double-blinded trial with nimodipine in patients who had out-of-hospital ventricular fibrillation failed to demonstrate any improvement in 1-year survival rate; however, it demonstrated some benefit in patients who had delayed resuscitation (O10 minutes) [94]. g-Aminobutyric acid and g-aminobutyric acid agonists The premise of using g-aminobutyric acid (GABA) or its agonists as neuroprotectants is based on their inhibitory properties by way of opening of the Cl channels [88]. Pretreatment with GABA attenuated histologic injury and improved neurobehavior in a gerbil model of global cerebral ischemia


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[95]. Treatment following the insult failed to demonstrate any improvement in these parameters. Chlormethiazole, a GABA agonist with anticonvulsant, hypnotic, and sedative properties, failed to demonstrate any improvement in histologic injury or neurobehavior in a rat model of global cerebral ischemia [96]. Furthermore, local infusion of chlormethiazole by way of microdialysis did not alter ischemia-evoked release of dopamine, serotonin, or their metabolites in the ischemic striatum [96]. Intraperitoneal administration of g-hydroxybutyrate improved histologic injury and neurobehavioral outcomes in a 4-VO rat model of global cerebral ischemia [97]. Tiagabine, a selective inhibitor of GABA reuptake, failed to demonstrate any improvement in histologic outcome in the gerbil model when given as a pretreatment [98]. Anticonvulsants The basis for the use of anticonvulsants in ischemic neuroprotection is their ability to stabilize neurons by way of hyperpolarization of the membrane potential by blocking voltage-gated Naþ channels [88]. Treatment with phenytoin attenuates accumulation of Kþ in cerebrospinal fluid in animals subjected to circulatory arrest. Some studies of phenytoin treatment have demonstrated attenuation of brain edema, increased Naþ/Kþ-ATPase activity, decreased intracellular Naþ concentration, and attenuated accumulation of lactate and free fatty acids [99]. Lamotrigine attenuates ischemiainduced increases in extracellular glutamate levels and improves histologic outcomes in the gerbil and rat models of global cerebral ischemia [100]. Magnesium Magnesium sulfate has multimodal actions. It is an NMDA receptor, a calcium antagonist, and a vasodilator. In a rat model of global cerebral ischemia, pre- and post-treatment with bolus intravenous magnesium sulfate followed by a continuous intravenous infusion attenuated injury to CA1 hippocampal neurons [101]. Other investigators have reported that neuroprotection is demonstrated only when magnesium sulfate is administered in combination with mild hypothermia [102]. Anesthetic agents Barbiturates have long been known to exert neuroprotection by coupled decreases in cerebral metabolic rate of oxygen (CMRO2) with CBF and by inhibiting agonist-induced cerebral vasoconstrictor responses, protein kinase C, ischemia-induced increases in free fatty acids, and EAA release [29]. In experimental global cerebral ischemia, however, results have been disappointing. Treatment with pentobarbital failed to improve survival in a dog model of global cerebral ischemia [103]. Clinical investigation with barbiturates has also proved to be disappointing, with lack of therapeutic benefit in the hypoxic-ischemic brain injury from CA and near-drowning [29]. Inhalational

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anesthetics (halothane, isoflurane) have not been thoroughly investigated in the setting of global cerebral ischemia. The premise for their use is their ability to attenuate cerebral metabolic demand, enhance regional CBF, attenuate ischemia-evoked EAA and catecholamine efflux, and attenuate calcium influxes [29]. Cyclooxygenase inhibitors Nimesulide, a cyclooxygenase-2 inhibitor, attenuated injury to the CA1 region of the hippocampus in a gerbil model when administered orally or intraperitoneally as a pre- or post-treatment (up to 24 hours) [104]. Further experimental studies in other animal models are needed to confirm these findings and bring these agents into the clinical paradigm. Immunosuppressants Tacrolimus (FK506) and cyclosporine are immunophilin and calcineurin inhibitors that attenuate apoptotic cell death. Chronic administration of both agents (for 3 days) before the ischemic insult demonstrated neuroprotection in the CA1 region at 7 days of reperfusion in a rat model of global cerebral ischemia [105]. These agents also attenuated calcineurin activity in the CA1, CA3, and dentate gyrus regions of the hippocampus up to 24 hours following the ischemic insult. Pretreatment with cyclosporin and FK506 inhibits dephosphorylation of the proapoptotic protein Bad. The inability of cyclosporine to cross an intact BBB is a significant therapeutic concern. These agents require more rigorous testing with treatment in the postischemia paradigm across different species and animal models of global cerebral ischemia [88]. Potential future of neuroprotective agents Hormonal sex steroids Evidence is mounting that outcome from cerebral ischemia is quantitatively different in adult male and female animals, reflecting patterns of some forms of human cerebrovascular disease [8,106]. Accordingly, it has become increasingly apparent that biologic sex is an important factor in pathophysiology and outcome following cerebral ischemia [107]. For example, when both sexes are studied, ischemic outcome in transgenic mice can be overtly sex dependent, even when the gene of interest (eg, inducible or neuronal NO) is not linked to sexual development [108–111]. These data suggest that molecular mechanisms of cell injury may not be the same or have the same impact in the male and the female brain. Furthermore, most experimental studies underscore the importance of sex steroids (predominantly estrogen) to outcome from focal ischemia [107,112]; recent studies have reported significant neuroprotection in the global cerebral ischemia paradigm [113].


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Opioid-receptor agonists Experimental research over the last 3 decades has implicated the opioidergic receptors in the brain to play an important pathophysiologic role in cerebral ischemia [114,115]. Opiate receptors in the central nervous system have been divided into three subtypes: mu (m), kappa (k), and delta (d). Although the m- and d-receptor subtypes have been shown to play a role predominantly in antinociception, several experimental studies have demonstrated neuroprotective effects of k–opioid-receptor agonists in models of global [116] and focal ischemia [117,118]. Differential time course and alterations in opioid-receptor binding after focal cerebral ischemia in mice indicate that k–opioid-receptor binding sites are preserved much longer (12–48 hours) than other subtypes [119], suggesting a potentially longer therapeutic window with k–opioid-receptor agonists. In vitro studies suggest that k–opioid-receptor agonists modulate the excitotoxic action of glutamate, possibly by the presynaptic inhibition of its release by decreasing the entry of 45Ca2þ into rat cortical synaptosomes [120,121]. It has been demonstrated that the selective k–opioid-receptor agonist BRL 52,537 attenuates in situ NO production at doses that provide ischemic neuroprotection [122] that is receptor selective [123] but does not attenuate ischemiaevoked dopamine release in the ischemic striatum [124]. Furthermore, BRL 52537 provides significant ischemic neuroprotection when administered for up to 6 hours after the onset of focal cerebral ischemia [125], confirming a long therapeutic opportunity to afford ischemic neuroprotection with these compounds. It has recently been demonstrated that ischemic neuroprotection with BRL 52537 is sex specific; it confers neuroprotection only in male animals [126]. Thus, highly selective k–opioid-receptor agonists might hold promise as neuroprotective agents in the future in the global cerebral ischemia paradigm. Sigma-receptor agonists Over the past 2 decades, nonopioid sigma (s)-receptors have been considered to serve an important physiologic function [127]. A number of ‘‘atypical’’ antipsychotics are potent s-receptor ligandsdatypical, in that they are effective antipsychotic agents but have low propensity to induce extrapyramidal side effects [28]. Naturally occurring s-receptor ligands include progesterone and neuropeptide Y [128]. Purification, molecular cloning, and high levels of expression of s1-receptor binding sites in sterol-producing tissues have been demonstrated [129]. Subtyping of the s-receptor into a s1-receptor and s2-receptor is based on important differences in regional distribution, enantomeric selectivity, molecular weights, and second messengers employed in signaling [130,131]. Until recently, specific s1-receptor ligands or antagonists have been lacking. During evaluation as antipsychotic agents, several drugs known to be s-receptor ligands were demonstrated to alter NMDA-receptor function [132]; however, it now appears that the effect

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might be directly mediated through activity at the s-receptor. The authors have demonstrated that the potent s1-receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) provides robust ischemic neuroprotection in animal models of cerebral is chemia [133–135]. Although the exact in vivo mechanisms of neuroprotection by s1-receptor ligands are not completely elucidated, several antiexcitotoxic mechanisms have been postulated, including inhibition of ischemia-induced presynaptic glutamate release, attenuation of postsynaptic glutamate-evoked Ca2þ influx, modulation of neuronal responses to NMDA-receptor stimulation, inhibition of dopamine neurotransmission, and prevention of cortical-spreading depression [133–135]. Recently, it was demonstrated that PPBP provides ischemic neuroprotection in vivo by way of attenuation of ischemia-evoked NO production [134] but does not alter ischemia-evoked dopamine efflux in the ischemic striatum [135]. Based on these data, s1-receptor ligands hold promise for the future as neuroprotectants in the treatment of cerebral ischemia. In addition to the above agents, a number of others that have been studied in the experimental paradigm of global cerebral ischemia hold promise for the future. These agents include anesthetics (etomidate, ketamine, propofol), sodium channel blockers (mexitine, lidocaine), a-receptor agonists (dexmedetomidine), and xanthine oxidase inhibitors (allopurinol). For a complete review of this subject, the reader is referred to the monograph by Weigl and colleagues [88].

Summary Cerebral ischemia results in a rapid depletion of energy stores that triggers a complex cascade of cellular events such as cellular depolarization and Ca2þ influx, resulting in excitotoxic cell death. The critical determinant of severity of brain injury is the duration and severity of the ischemic insult and early restoration of CBF. Induced therapeutic hypothermia following CA is the only strategy that has demonstrated improvement in outcomes in prospective, randomized clinical trials. Although pharmacologic neuroprotection has been disappointing thus far in a variety of experimental animal models, further research efforts are directed at using some agents that demonstrate marginal or moderate efficacy in combination with hypothermia. Although the signal transduction pathways and intracellular molecular events during cerebral ischemia and reperfusion are complex, potential therapeutic neuroprotective strategies hold promise for the future.

Acknowledgments The authors thank Tzipora Sofare, MA, for her editorial assistance in preparing this manuscript.


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[110] Kofler J, Otsuka T, Zhang Z, et al. Differential effect of PARP-2 deletion on brain injury after focal and global cerebral ischemia. J Cereb Blood Flow Metab 2005 [Epub ahead of print]. [111] McCullough LD, Zeng Z, Blizzard KK, et al. Ischemic nitric oxide and poly(ADP-ribose) polymerase-1 in cerebral ischemia: male toxicity, female protection. J Cereb Blood Flow Metab 2005;25:502–12. [112] Garcia-Segura LM, Azcoitia I, DonCarlos LL. Neuroprotection by estradiol. Prog Neurobiol 2001;63:29–60. [113] Noppens RR, Kofler J, Hurn PD, et al. Dose-dependent neuroprotection by 17betaestradiol after cardiac arrest and cardiopulmonary resuscitation. Crit Care Med 2005; 33:1595–602. [114] Fried RL, Nowak TS. Opioid peptide levels in gerbil brain after transient ischemia: lasting depletion of hippocampal dynorphin. Stroke 1987;18:765–70. [115] Zabramski JM, Spetzler RF, Selman WR, et al. Nalaxone therapy during focal cerebral ischemia evaluation in a primate model. Stroke 1984;15:621–7. [116] Tang AH. Protection from cerebral ischemia by U-50,488E, a specific kappa opioid analgesic agent. Life Sci 1985;37:1475–82. [117] Mackay KB, Kusomoto K, Graham DI, et al. Effect of kappa-1 opioid agonist CI-977 on ischemic brain damage and cerebral blood flow after middle cerebral artery occlusion in the rat. Brain Res 1993;629:10–8. [118] Baskin DS, Widmayer MA, Browning JL, et al. Evaluation of delayed treatment of focal cerebral ischemia with three selective k-opioid agonists in cats. Stroke 1994;25:2047–54. [119] Boutin H, Dauphin F, MacKenzie ET, et al. Differential time-course decreases in nonselective mu-, delta-, and kappa-opioid receptors after focal cerebral ischemia in mice. Stroke 1999;30:1271–7. [120] Bradford HF, Crowder JM, White EJ. Inhibitory actions of opioid compounds on calcium fluxes and neurotransmitter release from mammalian cerebral cortical slices. Br J Pharmac 1986;88:87–93. [121] Xiang J-Z, Adamson P, Brammer MJ, et al. The kappa-opiate agonist U50488H decreases the entry of 45Ca into rat cortical synaptosomes by inhibiting N- but not L-type calcium channels. Neuropharmacol 1990;29:439–44. [122] Goyagi T, Toung TJ, Kirsch JR, et al. Neuroprotective kappa-opioid receptor agonist BRL 52537 attenuates ischemia-evoked nitric oxide production in vivo in rats. Stroke 2003;34: 1533–8. [123] Zhang Z, Chen TY, Kirsch JR, et al. Kappa-opioid receptor selectivity for ischemic neuroprotection with BRL 52537 in rats. Anesth Analg 2003;97:1776–83. [124] Chen TY, Goyagi T, Toung TJ, et al. Prolonged opportunity for ischemic neuroprotection with selective kappa-opioid receptor agonist in rats. Stroke 2004;35:1180–5. [125] Chen CH, Toung TJ, Hurn PD, et al. Ischemic neuroprotection with selective kappa-opioid receptor agonist is gender specific. Stroke 2005;36:1557–61. [126] Zeynalov E, Nemoto M, Hurn PD, et al. Neuoprotective effect of selective kappa receptor agonist is gender specific and linked to reduced neuronal nitric oxide. J Cereb Blood Flow Metab 2005 July 27 [Epub ahead of print]. [127] Vu TH, Weissmann AD, London ED. Pharmacological characteristics and distribution of s- and phencyclidine receptors in the animal kingdom. J Neurochem 1990;54:598–604. [128] Su T-P, London ED, Jaffe JH. Steroid binding at sigma receptors suggests a link between endocrine, nervous, and immune systems. Science 1988;240:219–21. [129] Hanner M, Moebius FF, Flandorfer A, et al. Purification, molecular cloning, and expression of the mammalian sigma1-binding site. Proc Natl Acad Sci U S A 1996;93:8072–7. [130] Su T-P. Delineating biochemical and functional properties of sigma receptors: emerging concepts. Crit Rev Neurobiol 1993;7:187–203. [131] Leitner ML, Hohmann AG, Patrick SL, et al. Regional variation in the ratio of s1 to s2 binding in rat brain. Eur J Pharmacol 1994;259:65–9.


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[132] Contreras PC, Gray NM, Ragan DM, et al. BMY-14802 protects against ischemia-induced neuronal damage in the gerbil. Life Sci 1992;51:1145–9. [133] Harukuni I, Bhardwaj A, Shaivitz AB, et al. Sigma1-receptor ligand 4-phenyl-1-(4-phenylbutyl)-piperidine affords neuroprotection from focal ischemia with prolonged reperfusion. Stroke 2000;31:976–82. [134] Goyagi T, Goto S, Bhardwaj A, et al. Neuroprotective effect of s1-receptor ligand, 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) is linked to reduced neuronal nitric oxide production. Stroke 2001;32:1613–20. [135] Goyagi T, Bhardwaj A, Koehler RC, et al. Potent sigma 1-receptor ligand 4-phenyl-1(4-phenylbutyl) piperidine provides ischemic neuroprotection without altering dopamine accumulation in vivo in rats. Anesth Analg 2003;96:532–8.

Neurol Clin 24 (2006) 23–39

Prehospital and Emergency Department Care to Preserve Neurologic Function During and Following Cardiopulmonary Resuscitation Joseph P. Ornato, MD, Mary Ann Peberdy, MD* Department of Emergency Medicine and Internal Medicine, Virginia Commonwealth University Health System, 1200 East Broad Street, West Hospital, 10th Floor, Room 1042, Richmond, VA 23298, USA

Approximately 400,000 to 460,000 cardiac arrests occur out of the hospital in the United States each year [1]. Despite major advances in the Emergency Medical Service (EMS) system, overall survival from out-of-hospital cardiac arrest (OHCA) remains poor, averaging only 5% to 8% in most communities [2]. Sudden death is the first manifestation of underlying cardiovascular disease in most patients who have OHCA [3]. A ventricular tachyarrhythmia (ventricular tachycardia [VT] or ventricular fibrillation [VF]) has been documented to be the triggering event in up to 80% of cases [4]. The purpose of this article is to describe the prehospital and emergency department (ED) approach to resuscitating patients who have OHCA, with particular emphasis on what can be done during resuscitation to preserve neurologic function. The authors review the critical lifesaving interventions that can be provided by the continuum of emergency cardiac cared from citizen first response to EMS and ED care. The OHCA studies that have focused on improving neurologic outcome are reviewed, and the major, new National Institutes of Health (NIH) effort in this area is described. Layperson first responders Early defibrillation The public health and EMS strategy for decreasing the mortality and neurologic sequelae from OHCA has focused on enhancing emergency * Corresponding author. E-mail address: [email protected] (M.A. Peberdy). 0733-8619/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.ncl.2005.10.003 neurologic.theclinics.com

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resuscitation measures because prevention and accurate identification of at risk individuals is difficult. The traditional approach has been to train the public to recognize cardiac arrest, call 9-1-1, and perform cardiopulmonary resuscitation (CPR) while public-safety personnel (fire or police ‘‘first responders,’’ emergency medical technicians [EMTs], or paramedics) rush to the scene to provide defibrillation and other advanced cardiac life support (ACLS) treatments. This sequence of events is the cornerstone behind the American Heart Association’s chain of survival conceptual model for improving outcome from OHCA (Fig. 1) [5]. The patient’s initial cardiac rhythm is a principal determinant of resuscitation survival and neurologic outcome. For example, in one series of 352 consecutive OHCA patients, 67% of the patients who had VT and 23% of those who initially were in VF survived to hospital discharge [6]. None of the patients who presented with an initial pulseless bradycardia or asystole survived to hospital discharge. One obvious hypothesis is that bradyarrhythmia may be a marker for a prolonged downtime interval or a more severe underlying disease process. Because ventricular tachyarrhythmias represent the most common, potentially treatable mechanism of sudden cardiac arrest in adults, the best community resuscitation programs deliver rapid defibrillation to as many patients as possible because the odds of survival decrease by 7% to 10% for each minute that a patient remains in VF [5]. An increasingly popular community approach to increase the number of out-of-hospital VF patients who receive early defibrillation is public-access defibrillation, so named because the intent is to have laypersons perform early defibrillation with automated external defibrillators (AEDs) while awaiting arrival of EMS personnel. Trained public-safety laypersons (eg, law enforcement officers, firefighter first responders, flight attendants, airport employees, casino security officers) can treat cardiac arrest victims safely and

Early Access

Early CPR

Early Defibrillation

Early ACLS

Fig. 1. The chain of survival. (From Cummins RO, Ornato JP, Thies WH, et al. Improving survival from sudden cardiac arrest: the ‘‘chain of survival’’ concept. A statement for health professionals from the Advanced Cardiac Life Support Subcommittee and the Emergency Cardiac Care Committee, American Heart Association. Circulation 1991;83(5):1832; with permission).

PREHOSPITAL AND ED CARE

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effectively with AEDs in a wide variety of public settings [7–13]. In addition, a randomized clinical trial of public-access defibrillation showed that the number of survivors from OHCA in public places doubled after laypersons were trained to perform CPR and use AEDs compared with being trained to perform only CPR while awaiting arrival of EMS personnel [14]. The only problem is that approximately 80% to 85% of all cardiac arrests occur in the home rather than in a public place [15]. The ongoing NIH-sponsored Home AED Trial is attempting to determine whether the family members of high-risk survivors of anterior wall myocardial infarction can save more lives when an AED is present in the home. Early cardiopulmonary resuscitation It is unfortunate that early defibrillation alone is not the answer. Weisfeldt and Becker [16] formulated a three-phased model of resuscitation from cardiac arrest based on the changing physiologic needs of the patient: electrical, hemodynamic, and metabolic. For the first few minutes after the onset of VF (electrical phase), myocardial cells are rich in ATP. Defibrillation may be all that is needed for successful resuscitation. After 3 to 4 minutes, however, depletion of myocardial ATP prevents the heart from resuming effective contractions following defibrillation. Attempts at defibrillation during this period usually result in asystole or pulseless electrical activity (PEA). A brief period of effective CPR before defibrillation during this second (hemodynamic) phase can boost myocardial ATP levels, increasing the likelihood of restoration of spontaneous circulation (ROSC) following defibrillation. Finally, if spontaneous circulation is not restored until after 8 to 9 minutes, then a cascade of devastating cellular metabolic events frequently leads to irreversible end organ injury (including anoxic brain damage). Cellular reperfusion protection strategies are needed in this third (metabolic) phase. Increasing evidence suggests that a brief (90 seconds to 3 minutes) period of CPR before attempted defibrillation may be beneficial in treating VF patients whose cardiac arrest was not witnessed by firefighters or paramedics. Cobb and colleagues [17] observed that routine provision of approximately 90 seconds of CPR before firefighter AED use was associated with increased survival when fire or EMS response time intervals were 4 minutes or longer compared with using a ‘‘shock first’’ strategy. Wik and coworkers [18] conducted a randomized clinical trial in 200 patients who had out-of-hospital VF in Oslo, Norway, to determine whether survival would be better with immediate defibrillation (n ¼ 96) or CPR first, with 3 minutes of basic CPR by ambulance personnel before defibrillation (n ¼ 104). For patients with fire or EMS response time intervals of longer than 5 minutes, more patients were resuscitated successfully in the CPR-first group (58% versus 38%, P ¼ 0.04). Survival to hospital discharge was also better in the CPR-first group (22% versus 4%, P ¼ 0.006).

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Emergency Medical Service system response EMS systems have three traditional components: emergency medical dispatch, first response, and EMS ambulance response. Emergency medical dispatch Early access to EMS is promoted by a 9-1-1 system currently available to more than 95% of the United States population. Enhanced 9-1-1 systems provide the caller’s location to the dispatcher, which permits rapid dispatch of prehospital personnel to locations even if the caller is not capable of verbalizing or the dispatcher cannot understand the location of the emergency. A major challenge is the widespread proliferation and use of cell phones. Traditional cell phone technology does not provide the location of the caller to an enhanced 9-1-1 center. Instead, such calls are usually answered by the state police, who then attempt to determine the location of the emergency and forward the call to the appropriate 9-1-1 center. Such additional steps often result in substantial delays in the dispatch of emergency units to the scene. Fortunately, new technology exists that allows triangulation of caller location from several cell phone tower locations. This technology is being phased in throughout the country and will soon offer a solution to this vexing problem. In most communities, law enforcement or public-safety officials are responsible for operating 9-1-1 centers because in most locations, 85% of calls are for police assistance, 10% are for EMS, and 5% are for fire-related emergencies. Dispatchers who staff 9-1-1 centers typically have only minimal medical background and training and usually operate by following written cards and protocols that in many cases are designed and updated locally. High-performance centers employ EMTs or paramedics who are specially trained and certified as emergency medical dispatchers. They, too, operate under standardized written protocols, but such protocols are usually developed and upgraded at the national level. Such centers typically have intense quality-assurance programs to ensure that emergency medical dispatchers follow protocols and procedures correctly and consistently, which is particularly true for the prearrival instructions that are given to cardiac arrest bystanders to instruct them on how to perform CPR while awaiting arrival of emergency personnel (‘‘phone CPR’’). Even though CPR performed by layperson bystanders improves the odds of neurologically intact survival from OHCA, only about 25% of bystanders in most United States cities are willing to perform CPR (a notable exception is Seattle, Washington, where 50% of layperson bystanders perform CPR) [19–23]. Unwillingness of laypersons to perform mouthto-mouth ventilation on strangers is a major part of the problem [24,25]. It is fortunate that increasing evidence suggests that chest compressions are much more important than artificial ventilation during the first 5 min after onset of OHCA in adults [23,26–29]. Chest compressions alone cause


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changes in intrathoracic pressure that ventilate the victim adequately for the first 5 to 8 minutes after cardiac arrest. Chest compression–only CPR is being adopted for prearrival resuscitation instruction in many EMS systems. Public-safety first responders To minimize time to treatment, most communities allow volunteer or paid firefighters and other first-aid providers to function as first responders, providing CPR and, increasingly, early defibrillation using AEDs until EMTs and paramedics arrive. Ideally, there should be a sufficient number of trained personnel so that a trained first responder can be at the victim’s side within 5 minutes of the call. Fire department personnel functioning as first responders are the backbone of the public-safety primary response for most United States communities. Most of these personnel are trained as first responders or as basic EMTs. They have the capability to provide lifesaving first aid, CPR, and early defibrillation using AEDs. Some communities train their firefighters to an advanced life support (ALS) level. Another approach has been to supplement the fire department and EMS response with police officers trained and equipped to use AEDs. Such personnel can further enhance survival from OHCA compared with survival achieved by conventional EMS services. White and colleagues [30] studied the outcome of all consecutive adult patients who had nontraumatic cardiac arrest treated in Rochester, Minnesota, from November 1990 through July 1995. In that city, a centralized 9-1-1 center simultaneously dispatched police and an ALS ambulance for suspected cardiac arrest cases. Accurate intervals were obtained by synchronizing all defibrillator clocks with the 9-1-1 dispatch center clock. The personnel who arrived first delivered the initial shock. In patients to whom shocks were delivered initially by police, paramedics provided additional treatment if needed. Main outcome measures were time elapsed before delivery of the first shock, ROSC, and survival to discharge home. Of 84 patients, 31 (37%) were shocked initially by police. Thirteen of the 31 demonstrated ROSC, without need for ALS treatment. All 13 survived to discharge. The other 18 patients required ALS; 5 (27.7%) survived. Among the 53 patients first shocked by paramedics, 15 had ROSC; 14 survived. The other 38 needed ALS treatment; 9 survived. The call-to-shock time interval for all patients was shorter in the police group than in the paramedic group (5.6 versus 6.3 minutes, P ¼ 0.038). For all patients, the call-to-shock time interval was shorter in those who had ROSC than in those who needed ALS (5.4 versus 6.3 minutes, P ¼ 0.011). Survival to discharge was 49% (41 of 84), with 18 of 31 (58%) in the police group and 23 of 53 (43%) in the paramedic group. The callto-shock time interval was shorter for survivors than nonsurvivors (5.8 versus 6.4, P ¼ 0.020). ROSC or discharge survival was not significantly different between police- and paramedic-shocked patients.

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The presence of ROSC after an initial shock and the call-to-shock time intervals were major determinants of survival, whether the first shocks were administered by police or by paramedics. When ROSC occurred after the patient was first shocked, 27 of 28 (96%) patients survived, whereas 14 of 56 (25%) patients who needed additional ALS interventions survived (P ¼ 0.001). This study showed that a high discharge-to-home survival rate could be obtained when early defibrillation was provided by police or paramedics. It is the rapidity of defibrillation that determines outcome, irrespective of who delivers the shock. When initial defibrillation attempts resulted in ROSC, the overwhelming majority of patients survived (96%). Even brief (eg, 1 minute) decreases in the call-to-shock time interval increased the likelihood of ROSC from shocks only, with a consequent decrease in the need for further ALS intervention. Similar results were noted with the use of law enforcement early defibrillation in Miami-Dade County, Florida [10]. Ambulance responders Most cities and larger suburban areas provide EMS ambulance services, with providers from the fire department, a private ambulance company, or volunteers. The most common deployment pattern is a tiered system in which some of the ambulances are staffed and equipped at the basic EMT level, which includes first aid and early defibrillation with AEDs, and other units (transporting or nontransporting) are staffed by paramedics or other intermediate-level EMTs who, in addition to basic care, can start intravenous (IV) drips, intubate, and administer medications. In some systems, the advanced providers can also perform 12-lead ECGs, provide external pacing for symptomatic bradycardia, and other advanced techniques. Some high-performance EMS systems have only ALS-staffed ambulances (all-ALS systems). Advantages of such systems are that they provide a uniform standard of care and, surprisingly, can actually lower costs by eliminating the need to dispatch two units in response to a call in which it is not initially clear to dispatchers whether the patient needs ALS [31]. The potential disadvantage of such models is that they typically have a large number of paramedics, each of whom gets to perform their advanced skills less frequently than the smaller number of paramedics typically found in tiered systems [32]. Rural areas typically provide primarily basic life support ambulance services, usually by volunteers supplemented by a relatively small number of ALS units. In some cases, ALS is provided by paramedics or helicopter personnel who respond to the scene in addition to a basic life support ambulance.

Pharmacologic interventions during resuscitation The most critical pharmacologic intervention during resuscitation involves the use of vasoconstrictors to maximize coronary and cerebral


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perfusion pressure during CPR. Although vasoconstrictors decrease forward cardiac output, oxygenated blood is routed preferentially to the vital organs. Sodium bicarbonate, once a mainstay of pharmacologic therapy during resuscitation, is now believed to be of limited value. Antiarrhythmic medications are used for patients who have recurrent or refractory ventricular tachyarrhythmias and fail to respond to defibrillation alone. Atropine continues to be used for patients who have bradyasystole. Vasoconstrictors Epinephrine, which has a- and b-adrenergic activity, is still considered the vasopressor of choice for use during resuscitation. It improves coronary and cerebral blood flow by increasing peripheral vasoconstriction and preventing arterial collapse. By enhancing coronary perfusion pressure, epinephrine facilitates the resynthesis of high-energy phosphates within myocardial mitochondria and enhances cellular viability and contractile force. The increased myocardial blood flow, however, is at least partially antagonized by the increased myocardial oxygen consumption caused by epinephrine’s b-adrenergic actions [33]. The optimal dose of epinephrine to augment aortic diastolic blood pressure in humans during closed chest compression has been debated. Despite evidence in animal models and anecdotal case series suggesting that higher doses of epinephrine might be needed compared with those that have been administered traditionally, recent prospective, randomized clinical trials have not shown convincing evidence to support the routine use of ‘‘highdose’’ (eg, O1 mg in adults) epinephrine [34,35]. The American Heart Association currently recommendations a 0.5- to 1.0-mg IV epinephrine dose in adults every 3 to 5 minutes during ongoing resuscitation. The use of higher doses of epinephrine after the initial 1-mg dose during resuscitation is not recommended or discouraged. Vasopressin (40 U as a one-time IV dose) is considered an acceptable alternative to epinephrine as the first vasopressor administered to adults in VF. Randomized clinical trials have shown vasopressin to be as effective as epinephrine during resuscitation of adults [36,37] and has the advantage of requiring IV administration only every 10 to 15 minutes. There is even a suggestion that the combination of vasopressin and epinephrine administered in alternating doses may be more beneficial than the use of either drug alone [37,38]. Acid-base management during cardiopulmonary resuscitation The marked fall in cardiac output during closed chest compression critically reduces tissue oxygen delivery. Cells shift to anaerobic metabolism, gradual building up lactic acid as a waste product. During anaerobic metabolism, the carbon dioxide concentration increases rapidly inside cells. Central (mixed) venous blood during closed chest compression is acidotic (pH approximately 7.15) and hypercarbic (PvCO2 approximately 74 mm Hg).

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With hyperventilation, carbon dioxide is removed as blood flows through the lungs. Accordingly, arterial blood is less acidotic. Arterial blood pH during well-performed closed chest compression is usually normal, slightly acidotic, or mildly alkalotic. Arterial blood can be slightly alkalotic, whereas the venous blood is acidotic because pulmonary blood flow is only one fourth to one third of the normal amount during closed chest compression (this phenomenon has been termed the ‘‘venous paradox’’) [39,40]. It is not a paradox, however, but part of normal physiology that occurs when anaerobic metabolism is required (eg, during strenuous exercise), at which time the intramyocardial pH is much closer to the venous pH than the arterial pH. In the past, administration of sodium bicarbonate was recommended during closed chest compression because of the belief that bicarbonate would buffer the hydrogen ions produced during anaerobic metabolism. Sodium bicarbonate, however, contains a high concentration of carbon dioxide (260–280 mm Hg). In plasma, the carbon dioxide is released and diffuses into cells more rapidly than bicarbonate, causing a paradoxic rise in intracellular PCO2 and a fall in intracellular pH. The increases in intracellular PCO2 in heart muscle cells decrease cardiac contractility, cardiac output, and blood pressure. Paradoxic acidosis of cerebrospinal fluid also can occur following the use of sodium bicarbonate [41] and may be responsible for prolonged confusion following a successful resuscitation as the venous acidosis increases. Sodium bicarbonate causes other potentially harmful effects, including hyperosmolality, alkalemia, and sodium overload. At present, no convincing data indicate that treatment with sodium bicarbonate is of benefit during closed chest compression, and it does not improve survival in experimental animals. Sodium bicarbonate should not be administered during a routine cardiac arrest because it provides minimal, if any, benefit and adds significant risk. If used at all, sodium bicarbonate should not be used until proven interventions (such as defibrillation, cardiac compression, and support of ventilation including intubation) and pharmacologic therapies (such as epinephrine and antiarrhythmic agents) have been employed. If used, the initial dose of sodium bicarbonate is 1 mEq/kg. No more than half of the original dose should be administered every 10 minutes thereafter. Alternate buffer agents have not yet been shown to improve survival during cardiac resuscitation. In a recent Scandinavian study, 502 adults who had asystole or VF with failure of the first defibrillation attempt were entered into a prospective, randomized, double-blinded, controlled trial comparing the use of a combination buffer agent (tribonat, containing 250 mL of a sodium bicarbonate-trometamol-phosphate mixture with a buffering capacity of 500 mmol/L) with 250 mL of 0.9% saline placebo [42]. Of the patients receiving buffer, 87 (36%) were admitted to the hospital and 24 (10%) were discharged from the hospital alive; of the patients receiving saline, 92 (36%) were admitted and 35 (14%) were discharged alive (no


31

significant difference between groups). This landmark clinical trial lends further evidence to the belief that buffer therapy does not improve patient outcome from routine cardiac arrest. Management of specific resuscitation scenarios The American Heart Association’s ACLS algorithms provide a ‘‘framework for dealing with the life-threatening cardiopulmonary emergencies in a logical sequence’’ [43,44]. Recurrent or refractory ventricular fibrillation or ventricular tachycardia Electrical countershock is the treatment of choice for VF or pulseless VT. If three initial countershocks at increasing energies (200, 200–300, and 360 J for monophasic defibrillation, using the manufacturer’s recommended energy levels for biphasic defibrillation), intubation, epinephrine, and a fourth countershock fail to terminate the arrhythmia (refractory VF or VT) or if, as in many cases, the arrhythmia rapidly recurs (recurrent VF or VT), then antiarrhythmic drug therapy is recommended. For refractory VF and pulseless VT, an initial lidocaine dose of 1.5 mg/kg is suggested, although the evidence for its benefit is marginal. After ROSC, lidocaine is usually continued as an IV infusion at a rate of 30 to 50 mg/kg/ min (2–4 mg/min). The need for additional bolus doses of lidocaine is usually guided by clinical response or by plasma lidocaine concentrations. More data are available on the use of IV amiodarone to treat patients who have recurrent arrhythmias. Amiodarone is at least as effective as bretylium in terminating refractory or recurrent, life-threatening ventricular tachyarrhythmias but causes fewer side effects. In a randomized, controlled clinical prehospital trial conducted on 504 cardiac arrest patients who had recurrent or refractory ventricular tachyarrhythmias, the administration of a single 300-mg bolus of IV amiodarone at the time of the first IV epinephrine administration resulted in a 26% greater rate of survival to hospital admission compared with standard ACLS therapy [45]. In another recent randomized clinical trial, the use of amiodarone led to substantially higher rates of survival to hospital admission in patients who had shock-resistant OHCA than the administration of lidocaine [46]. Thus, IV amiodarone is quickly becoming the antiarrhythmic drug of choice for use in adults who have recurrent or refractory VF. The principal side effects of IV amiodarone are hypotension and bradycardia, which usually respond readily to therapy (volume infusion and vasopressors, and atropine or electrical pacing, respectively). Bradyasystole Survival is poor regardless of therapy for cardiac arrest patients who present with bradyasystole It is always important to exclude disconnection

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of a lead or monitor electrode before concluding that a ‘‘flat line’’ is the patient’s rhythm because some patients who have such a tracing may have VF (a rhythm more amenable to treatment) masquerading as asystole. Whenever there is any doubt, the monitor lead should quickly be switched to another lead to confirm the diagnosis before treatment. When the diagnosis is still in doubt, the patient should be presumed to have VF and treated accordingly. Other general measures recommended for the treatment of bradyasystole include support of ventilation, properly performed closed chest compression, and frequent doses of epinephrine to maintain arterial perfusion pressure and coronary and cerebral perfusion. Treatment with atropine sulfate may improve outcome in patients who have bradyasystolic cardiac arrest that is due to excessive vagal stimulation, but atropine is less effective when asystole or pulseless idioventricular rhythms are the result of prolonged ischemia or mechanical injury in the myocardium. For patients who have bradyasystolic cardiac arrest, a 1-mg dose of IV atropine is administered and repeated every 3 to 5 minutes if asystole persists. Three milligrams (0.04 mg/kg) of IV atropine is a fully vagolytic dose in most adults patients. The administration of a total vagolytic dose of atropine should be reserved for patients who have bradyasystolic cardiac arrest. Endotracheal atropine produces a rapid onset of action similar to that observed with IV atropine. The recommended adult dose of atropine for endotracheal administration is 1.0 to 2.0 mg diluted in 10 mL of sterile water or normal saline. Pacing (transvenous, transthoracic, or transcutaneous) rarely influences survival in the unwitnessed cardiac arrest patient who has asystole or bradycardia and is initially found without a pulse. Pacing, however, is extremely useful for bradycardic patients who have a pulse and in selected patients in whom a pacemaker can be placed immediately after the development of the conduction disturbance. In such cases, a precordial thump can also stimulate ventricular complexes and a pulse (‘‘fist pacing’’). Pulseless electrical activity PEA is present when there is organized electrical activity on the ECG but no effective circulation, as manifest by a lack of a detectable pulse. There are many underlying potential causes, but the most common denominator may involve myocardial ischemia and dysfunction due to intramyocardial increases in carbon dioxide. Prognosis is generally poor unless a discrete and treatable etiology for PEA can be discerned and corrected. Because of the poor prognosis when a correctable etiology cannot be defined, efforts should be directed toward detecting causes such as hypovolemia, hypoxemia, acidosis, tension pneumothorax, and pericardial tamponade. Normal saline should rapidly be infused IV if there is a suspicion of hypovolemia. Suspected pneumothorax or pericardial tamponade should be confirmed by needle aspiration of the chest or pericardium, respectively (or by


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ECG if available). If confirmed, more definitive surgical management (chest tube or thoracotomy) is usually required. Scrutiny of the neck veins may be helpful in attempting to define an etiology for PEA. Most patients who have cardiac arrest have high, right-sided filling pressures and distended neck veins. When neck veins are not visible in this setting and PEA is present, hypovolemia should be suspected. In the trauma cardiac arrest victim who has obvious or suspected hemorrhage, the presence of prominent neck veins should lead to the suspicion of pericardial tamponade or tension pneumothorax. General measures such as support of ventilation, properly performed closed chest compression, and frequent doses of epinephrine to maintain arterial perfusion pressure and coronary and cerebral perfusion are recommended for treatment of PEA. Bradycardia may be treated with atropine. Although catecholamines are frequently administered, there are no data to suggest a specific benefit (other than improvement in coronary and cerebral blood flow during closed chest compression). Calcium chloride has not been shown to affect clinical survival in controlled trials. If penetrating cardiac trauma is present, then open chest massage can be life saving; otherwise, it is rarely of value.

Emergency department care An increasing number of EDs are staffed with residency-trained, boardcertified emergency physicians. These highly trained and skilled professionals must complete 3 or 4 years of training at a major hospital with a busy ED. Although they spend most of their time training in the ED, they rotate through all major services of the hospital, including anesthesia, cardiology, trauma, and critical care. They are highly skilled and certified in basic cardiac life support, ACLS, pediatric advanced life support, and ALS. The longstanding practice of transporting cardiac arrest patients to EDs with CPR in progress has given way to authorizing paramedics to pronounce patients deceased in the field when standard ACLS interventions are unsuccessful [47,48]. As a result, the most common cardiac arrest patient transported to an ED is one who has been successfully resuscitated in the field. Thus, the principal focus of ED care is on postresuscitation stabilization and management. The most promising intervention at present for postresuscitation care involves the induction and maintenance of mild (32 C–34 C) hypothermia for 12 to 24 hours following successful resuscitation in comatose OHCA patients whose initial rhythm was VF. Two international randomized clinical trials have documented improved survival and neurologic outcome using hypothermia in such patients [49,50]. The International Liaison Committee on Resuscitation has issued an advisory statement supporting the use of induced mild hypothermia in such patients [51].

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Research interventions to improve neurologic outcome Randomized clinical trials on out-of-hospital cardiac arrest Induced mild hypothermia has thus far been the only intervention tested in randomized clinical trials that has been shown to be of limited success in improving neurologic outcome from OHCA [49,50]. In the 1980s, researchers at the University of Pittsburgh conducted a series of randomized clinical trials in an attempt to improve neurologic outcome in patients resuscitated from OHCA. These trials, dubbed the Brain Resuscitation Clinical Trials (BRCT), applied promising pharmacologic interventions as soon as possible after successful resuscitation [52,53]. Each of these interventions appeared to show promise in experimental studies but failed to show benefit in humans. In BRCT-I, 262 comatose survivors of cardiac arrest were randomly assigned to receive standard brain-oriented intensive care or the same standard therapy plus a single IV loading dose of thiopental (30 mg/kg of body weight) [54]. The study was designed to have an 80% probability of detecting a 20% reduction in the incidence of permanent postischemic cerebral dysfunction. Baseline characteristics were similar in the two treatment groups. At the end of 1 year of follow-up, there was no statistically significant difference between treatment groups in the proportion of patients who died (77% of the thiopental group versus 80% of the standard-therapy group), survived with ‘‘good’’ cerebral recovery (20% of the thiopental group versus 15% of the standard-therapy group), or survived with permanent severe neurologic damage (2% of the thiopental group versus 5% of the standard-therapy group). None of these differences was statistically significant. The BRCT-I investigators noted that glucocorticoids were commonly administered to patients who had global brain ischemia, although their efficacy had not been proved. The database of BRCT-I was used for a retrospective review of the effects of glucocorticoid treatment on neurologic outcome after global brain ischemia [55]. The analysis included 262 initially comatose cardiac arrest survivors who made no purposeful response to pain after ROSC. The standard treatment protocol left glucocorticoid therapy to the discretion of the hospital investigator, which resulted in four patient groups receiving no, low, medium, or high doses of glucocorticoids in the first 8 hours after arrest. Neurologic outcome was scored using a modification of the Glasgow Cerebral Performance Category Scale. None of the steroid regimens statistically improved the mean group survival rate or the neurologic recovery rate compared with the no-steroid regimen. BRCT-II tested the value of calcium-entry blockade in preserving neurologic function in OHCA survivors [56,57]. Five hundred twenty patients who had cardiac arrest and remained comatose after ROSC were randomly assigned to receive three doses of lidoflazine (an experimental calcium-entry blocker) or a placebo and were followed for 6 months. Four patients were lost to follow-up. Treated patients received an IV loading dose (1 mg/kg of


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body weight) of lidoflazine and two subsequent doses (0.25 mg/kg) 8 and 16 hours after resuscitation. The investigators were blinded to treatment assignment. There was no statistically significant difference between the lidoflazine group (n ¼ 259) and the placebo group (n ¼ 257) in the proportion of patients who (1) died during the 6-month follow-up (82 versus 83%); (2) survived with good cerebral recovery (15 versus 13%); or (3) survived with severe neurologic deficit (1.2 versus 1.9%). Analysis of the best level of recovery achieved at any time during follow-up also did not show a significant difference between the treatment groups: 24% of those administered lidoflazine and 23% of those administered placebo recovered good cerebral function (normal or only moderately disabled cerebral performance) at some time. Despite these disappointing results, the NIH recently funded a landmark $50 million research project intended to test the most promising resuscitation drugs and devices in a prehospital environment. The Resuscitation Outcomes Consortium involves 10 major United States and Canadian EMS systems that will perform randomized clinical trials research over the next 5 years. Together, the EMS systems in these 10 sites manage over 12,000 OHCA patients per year, giving the consortium the statistical power to conduct definitive clinical trials. The first cardiac arrest project, which will test whether a new inspiratory threshold valve that improves blood flow during resuscitation can improve survival and neurologic outcome, is expected to begin enrolling patients in early 2006. Exception to informed consent Most clinical trials that involve research on emergency patients who cannot give prospective informed consent (including all resuscitation research) were halted during the 1990s in the United States by a regulatory moratorium. The issues and problems surrounding the ban were of concern to federal regulators and many researchers for several years. In May 1993, the US Food and Drug Administration (FDA) prematurely terminated a clinical resuscitation trial involving a comparison of the Ambu CardioPump (Ambu, Denmark) and standard CPR. The FDA believed that the device involved ‘‘significant risk’’ to the subjects and that there were no means for the subjects to give informed consent to participate in the trial [58,59]. The rules and regulations of the FDA or the Department of Health and Human Services (DHHS) did not provide a legal means for Institutional Review Boards to approve emergency medical research in humans when it is impossible to obtain informed consent. On October 25, 1994, the Coalition Conference of Acute Resuscitation and Critical Care Researchers was held in Washington, DC, to discuss informed consent in emergency research. Representatives from more than 20 organizations explored the issues and produced consensus recommendations for resolving some of the difficult issues that surround emergency medical research.

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These recommendations and many other ideas were presented and discussed at the FDA/NIH Public Forum on Informed Consent in Clinical Research Conducted in Emergency Circumstances, held in Bethesda, Maryland, on January 9 and 10, 1995. Soon thereafter, the FDA and DHHS released new rules that allowed limited resumption of resuscitation research in humans using an ‘‘exception to informed consent’’ process. Although initial experience with the rules was problematic, the public-access defibrillation trial demonstrated that this exception to informed consent process could be used successfully in a wide array of clinical practice settings [14]. Summary Considerable progress has been made in providing high-quality prehospital and emergency cardiac care for OHCA victims. The use of early CPR, early defibrillation, early ACLS, and state-of-the-art postresuscitation care offers the best promise for improved community survival and neurologic outcome statistics in the future. The NIH-sponsored Resuscitation Outcomes Consortium represents the largest governmentally sponsored effort of its kind that that will test the value of promising pharmacologic and device interventions on improving survival and neurologic outcome in OHCA patients. References [1] Centers for Disease Control and Prevention (CDC). State-specific mortality from sudden cardiac deathdUnited States, 1999. MMWR Morb Mortal Wkly Rep 2002;51(6):123–6. [2] Nichol G, Laupacis A, Stiell IG, et al. Cost-effectiveness analysis of potential improvements to emergency medical services for victims of out-of-hospital cardiac arrest. Ann Emerg Med 1996;27(6):711–20. [3] Fornes P, Lecomte D, Nicolas G. [Sudden coronary death outside of hospital: a comparative autopsy study of subjects with and without previous cardiovascular diseases]. Arch Mal Coeur Vaiss 1994;87(3):319–24. [4] Bayes de Luna A, Coumel P, Leclercq JF. Ambulatory sudden cardiac death: mechanisms of production of fatal arrhythmia on the basis of data from 157 cases. Am Heart J 1989;117: 151–9. [5] Cummins RO, Ornato JP, Thies WH, et al. Improving survival from sudden cardiac arrest: the ‘‘chain of survival’’ concept. A statement for health professionals from the Advanced Cardiac Life Support Subcommittee and the Emergency Cardiac Care Committee, American Heart Association. Circulation 1991;83(5):1832–47. [6] Weaver WD, Cobb LA, Hallstrom AP, et al. Factors influencing survival after outof-hospital cardiac arrest. J Am Coll Cardiol 1986;7:754. [7] Mosesso VN Jr, Newman MM, Ornato JP, et al. Law Enforcement Agency Defibrillation (LEA-D): proceedings of the National Center for Early Defibrillation Police AED Issues Forum. Prehosp Emerg Care 2002;6(3):273–82. [8] White RD, Hankins DG, Bugliosi TF. Seven years’ experience with early defibrillation by police and paramedics in an emergency medical services system. Resuscitation 1998;39(3): 145–51. [9] Valenzuela TD, Roe DJ, Nichol G, et al. Outcomes of rapid defibrillation by security officers after cardiac arrest in casinos. N Engl J Med 2000;343(17):1206–9.


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[10] Myerburg RJ, Fenster J, Velez M, et al. Impact of community-wide police car deployment of automated external defibrillators on survival from out-of-hospital cardiac arrest. Circulation 2002;106(9):1058–64. [11] O’Rourke MF, Donaldson E, Geddes JS. An airline cardiac arrest program. Circulation 1997;96(9):2849–53. [12] Page RL, Joglar JA, Kowal RC, et al. Use of automated external defibrillators by a US airline. N Engl J Med 2000;343(17):1210–6. [13] Caffrey SL, Willoughby PJ, Pepe PE, et al. Public use of automated external defibrillators. N Engl J Med 2002;347(16):1242–7. [14] Hallstrom AP, Ornato JP, Weisfeldt M, et al. Public-access defibrillation and survival after out-of-hospital cardiac arrest. N Engl J Med 2004;351(7):637–46. [15] Becker L, Eisenberg M, Fahrenbruch C, et al. Public locations of cardiac arrest. Implications for public access defibrillation. Circulation 1998;97(21):2106–9. [16] Weisfeldt ML, Becker LB. Resuscitation after cardiac arrest: a 3-phase time-sensitive model. JAMA 2002;288(23):3035–8. [17] Cobb LA, Fahrenbruch CE, Walsh TR, et al. Influence of cardiopulmonary resuscitation prior to defibrillation in patients with out-of-hospital ventricular fibrillation. JAMA 1999; 281(13):1182–8. [18] Wik L, Hansen TB, Fylling F, et al. Delaying defibrillation to give basic cardiopulmonary resuscitation to patients with out-of-hospital ventricular fibrillation: a randomized trial. JAMA 2003;289(11):1389–95. [19] Cummins RO, Eisenberg MS, Hallstrom AP, et al. Survival of out-of-hospital cardiac arrest with early initiation of cardiopulmonary resuscitation. Am J Emerg Med 1985;3(2): 114–9. [20] Eisenberg MS, Hallstrom AP, Carter WB, et al. Emergency CPR instruction via telephone. Am J Public Health 1985;75(1):47–50. [21] Kellermann AL, Hackman BB, Somes G. Dispatcher-assisted cardiopulmonary resuscitation. Validation of efficacy. Circulation 1989;80(5):1231–9. [22] Valenzuela TD, Spaite DW, Meislin HW, et al. Emergency vehicle intervals versus collapse to CPR and collapse to defibrillation intervals: monitoring emergency medical services system performance in sudden cardiac arrest. Ann Emerg Med 1993;22(11):1678–83. [23] Van Hoeyweghen RJ, Bossaert LL, Mullie A, et al. Quality and efficiency of bystander CPR. Belgian Cerebral Resuscitation Study Group. Resuscitation 1993;26(1):47–52. [24] Ornato JP. Should bystanders perform mouth-to-mouth ventilation during resuscitation? Chest 1994;106(6):1641–2. [25] Ornato JP, Hallagan LF, McMahon SB, et al. Attitudes of BCLS instructors about mouthto-mouth resuscitation during the AIDS epidemic. Ann Emerg Med 1990;19:151–6. [26] Wik L, Kramer-Johansen J, Myklebust H, et al. Quality of cardiopulmonary resuscitation during out-of-hospital cardiac arrest. JAMA 2005;293(3):299–304. [27] Kern KB, Hilwig RW, Berg RA, et al. Importance of continuous chest compressions during cardiopulmonary resuscitation: improved outcome during a simulated single lay-rescuer scenario. Circulation 2002;105(5):645–9. [28] Hallstrom A, Cobb L, Johnson E, et al. Cardiopulmonary resuscitation by chest compression alone or with mouth-to-mouth ventilation. N Engl J Med 2000;342(21):1546–53. [29] Berg RA, Kern KB, Sanders AB, et al. Bystander cardiopulmonary resuscitation. Is ventilation necessary? Circulation 1993;88(4 Pt 1):1907–15. [30] White RD, Asplin BR, Bugliosi TF, et al. High discharge survival rate after out-of-hospital ventricular fibrillation with rapid defibrillation by police and paramedics. Ann Emerg Med 1996;28(5):480–5. [31] Wilson BD, Graton MC, Overton J, et al. Unexpected ALS procedures on non-emergency ambulance calls: the value of a single tier system. Prehosp Disaster Med 1991;6:382. [32] Stout J, Pepe PE, Mosesso VN Jr. All-advanced life support vs tiered-response ambulance systems. Prehosp Emerg Care 2000;4(1):1–6.

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[33] Ditchey RV, Lindenfeld J. Failure of epinephrine to improve the balance between myocardial oxygen supply and demand during closed-chest resuscitation in dogs. Circulation 1988; 78(2):382–9. [34] Brown CG, Martin DR, Pepe PE, et al. A comparison of standard-dose and high-dose epinephrine in cardiac arrest outside the hospital. The Multicenter High-Dose Epinephrine Study Group. N Engl J Med 1992;327(15):1051–5. [35] Stiell IG, Hebert PC, Weitzman BN, et al. A study of high-dose epinephrine in human CPR. N Engl J Med 1992;327:1047–50. [36] Stiell IG, Hebert PC, Wells GA, et al. Vasopressin versus epinephrine for inhospital cardiac arrest: a randomised controlled trial. Lancet 2001;358(9276):105–9. [37] Wenzel V, Krismer AC, Arntz HR, et al. A comparison of vasopressin and epinephrine for out-of-hospital cardiopulmonary resuscitation. N Engl J Med 2004;350(2):105–13. [38] Lurie KG, Voelckel WG, Iskos DN, et al. Combination drug therapy with vasopressin, adrenaline (epinephrine) and nitroglycerin improves vital organ blood flow in a porcine model of ventricular fibrillation. Resuscitation 2002;54(2):187–94. [39] Grundler W, Weil MH, Rackow EC. Arteriovenous carbon dioxide and pH gradients during cardiac arrest. Circulation 1986;74(5):1071–4. [40] Grundler W, Weil MH, Yamaguchi M, et al. The paradox of venous acidosis and arterial alkalosis during CPR. Chest 1984;86:282. [41] Berenyi KJ, Wolk M, Killip T. Cerebrospinal fluid acidosis complicating therapy of experimental cardiopulmonary arrest. Circulation 1975;52:319–24. [42] Dybvik T, Strand T, Steen PA. Buffer therapy during out-of-hospital cardiopulmonary resuscitation. Resuscitation 1995;29(2):89–95. [43] The American Heart Association in collaboration with the International Liaison Committee on Resuscitation. Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Part 6: advanced cardiovascular life support: 7C: a guide to the International ACLS algorithms. Circulation 2000;102(8 Suppl):I142–57. [44] The American Heart Association in collaboration with the International Liaison Committee on Resuscitation. Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Part 6: advanced cardiovascular life support: 7B: understanding the algorithm approach to ACLS. Circulation 2000;102(8 Suppl):I140–1. [45] Kudenchuk P. Amiodarone in out-of-hospital Resuscitation of Refractory Sustained Ventricular Tachyarrhythmias (ARREST) study. American Heart Association Scientific Sessions Late-Breaking Clinical Trials Presentation. 1997. [46] Dorian P, Cass D, Schwartz B, et al. Amiodarone as compared with lidocaine for shockresistant ventricular fibrillation. N Engl J Med 2002;346(12):884–90. [47] Hick JL, Mahoney BD, Lappe M. Factors influencing hospital transport of patients in continuing cardiac arrest. Ann Emerg Med 1998;32(1):19–25. [48] Heckerson EW. Termination of field resuscitation. Emerg Med Serv 1997;26(8):51–7. [49] Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346(8):557–63. [50] The Hypothermia After Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002;346(8):549–56. [51] Nolan JP, Morley PT, Vanden Hoek TL, et al. Therapeutic hypothermia after cardiac arrest: an advisory statement by the Advanced Life Support Task Force of the International Liaison Committee on Resuscitation. Circulation 2003;108(1):118–21. [52] Edgren E, Hedstrand U, Kelsey S, et al. Assessment of neurological prognosis in comatose survivors of cardiac arrest. BRCT I Study Group. Lancet 1994;343(8905):1055–9. [53] Abramson NS, Safar P, Kelsey SF, et al. Clinical trials and cerebral resuscitation research. Ann Emerg Med 1984;13(9 Pt 2):868–72. [54] Brain Resuscitation Clinical Trials Group. Randomized clinical study of thiopental loading in comatose survivors of cardiac arrest. Brain Resuscitation Clinical Trial I Study Group. N Engl J Med 1986;314(7):397–403.


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[55] Jastremski M, Sutton-Tyrrell K, Vaagenes P, et al. Glucocorticoid treatment does not improve neurological recovery following cardiac arrest. Brain Resuscitation Clinical Trial I Study Group. JAMA 1989;262(24):3427–30. [56] Brain Resuscitation Clinical Trials Group. A randomized clinical trial of calcium entry blocker administration to comatose survivors of cardiac arrest. Design, methods, and patient characteristics. The Brain Resuscitation Clinical Trial II Study Group. Control Clin Trials 1991;12(4):525–45. [57] Brain Resuscitation Clinical Trials Group. A randomized clinical study of a calcium-entry blocker (lidoflazine) in the treatment of comatose survivors of cardiac arrest. Brain Resuscitation Clinical Trial II Study Group. N Engl J Med 1991;324(18):1225–31. [58] Lurie KG, Shultz JJ, Callaham ML, et al. Evaluation of active compression-decompression CPR in victims of out-of-hospital cardiac arrest. JAMA 1994;271(18):1405–11. [59] Olson CM. The letter or the spirit: consent for research in CPR. JAMA 1994;271(18):1445–7.

Neurol Clin 24 (2006) 41–59

Intensive Care After Resuscitation from Cardiac Arrest: A Focus on Heart and Brain Injury Steven P. Schulman, MDa,*, Tracey K. Hartmann, LPN, CCRPb, Romergryko G. Geocadin, MDc a

Department of Medicine (Cardiology), Johns Hopkins University School of Medicine, Baltimore, MD, USA b Division of Brain Injury Outcomes, Johns Hopkins Medical Institutions, Baltimore, MD, USA c Departments of Neurology, Neurosurgery and Anesthesiology–Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Although national statistics are not available, community-wide studies suggest only a minority of patients have return of spontaneous circulation (ROSC) after an out-of-hospital cardiac arrest. Of the estimated 350,000 to 450,000 out-of-hospital cardiac arrests, 100,000 patients have an attempted resuscitation. Of these, 40,000 patients have ROSC and are admitted to ICU. Half of these patients survive the hospitalization and another half of this group survive without major neurologic sequelae. Therefore, less than 3% of all patients who have out-of-hospital cardiac arrests have ROSC, survive the hospitalization, and have a reasonable functional recovery [1]. The fact that many patients who have ROSC ultimately die or fail to have favorable neurologic recovery, suggests that processes that occur after hospitalization, especially in an ICU, have an impact on survival and neurologic recovery. This article addresses the acute care, with emphasis on the cardiac and neurologic aspects, that patients who have postcardiac arrest are provided in the cardiac ICU.

Dr. Geocadin is supported in part by National Institutes of Health (NIH) grants R44NS-38016 and RO1-HL-EB 71568 and Ms. Hartmann is supported in part by NIH grant R44-NS-38016. * Corresponding author. Johns Hopkins Hospital, 600 North Wolfe Street, Carnegie 568, Baltimore, MD 21287. E-mail address: [email protected] (S.P. Schulman). 0733-8619/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.ncl.2005.11.002 neurologic.theclinics.com

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The factors that influence survival in a prehospital setting are well known, including whether or not the arrest is witnessed and the rapidity in which resuscitative efforts, including defibrillation, are initiated. (See the article by Ornato and Peberdy elsewhere in this issue for discussion of these factors.) Much less is known about the factors that influence survival and neurologic recovery during the first hours and days of ICU evaluation and management of patients who have sudden cardiac death and who have ROSC. In spite of the fact that there has been recent improved short-term survival from out-of-hospital cardiac arrest to hospital admission, the hospital survival rate with favorable neurologic outcomes has been unchanged during the past several years [2]. The lack of national or worldwide guidelines results in marked variability in the management of patients who have sudden cardiac death and ROSC and who are admitted to an ICU. As anticipated, this variability affects outcome. In a study from Sweden [3], a single emergency medical services unit admitted to two hospitals, with similar prehospital care for sudden cardiac death. In this observational series, 579 patients were admitted alive after cardiac arrest to one hospital and 459 patients were admitted alive after cardiac arrest to a second neighboring hospital during a concurrent time interval. Survival was significantly different between the two hospitals. The hospital with improved survival to discharge after ROSC for out-of-hospital cardiac arrest had a more aggressive approach to patient management, including a higher percentage of patients undergoing coronary angiography, echocardiography, electrophysiologic studies, and stress testing. These data suggest that the course of patients who have ROSC after an out-of-hospital cardiac arrest and are admitted to an ICU is affected by the level of care when hospitalized.

Cardiac arrest: etiology and severity Etiology of cardiac arrest Autopsy studies show that most sudden death survivors have structural heart disease, with atherosclerotic coronary artery disease by far the most common underlying substrate, seen in approximately 80% of sudden death victims [1,4,5]. In addition to atherosclerotic coronary disease, autopsy evidence of plaque rupture in men and plaque erosion in women who have subsequent coronary thrombosis is the underlying pathology in the majority of cases of sudden cardiac death [6]. Given the frequent prevalence of coronary disease, the majority of patients admitted to the ICU should undergo coronary angiography to define the coronary anatomy with possible revascularization at some point during the hospitalization. The American Heart Association and American College of Cardiology recommend coronary angiography in all survivors of sudden cardiac death [7]. The timing of coronary angiography depends on whether or not there is evidence of acute myocardial infarction or hemodynamic instability and the overall neurologic prognosis.

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In patients who do not have evidence of acute ST-segment elevation, myocardial infarction, or cardiogenic shock, delay until a neurologic prognosis is determined seems reasonable. Other underlying pathologic substrates found in cardiac arrest victims are listed in Box 1. These include nonischemic dilated cardiomyopathy; infiltrative cardiomyopathies; primary electrical abnormalities, such as long QT syndrome; presence of drugs that prolong the QT interval; electrolyte abnormalities; and toxins. In addition to cardiac substrates, there are several other causes of sudden death and ventricular arrhythmias. These include pulmonary causes, such as pulmonary embolism, respiratory arrest followed

Box 1. Underlying substrates for out-of-hospital cardiac arrest 1. Coronary artery disease Acute myocardial infarction Chronic ischemic cardiomyopathy Coronary vasospasm or dissection Anamolous coronary artery 2. Nonischemic heart disease Dilated cardiomyopathy Hypertrophic cardiomyopathy Arrythmogenic right ventricular dysplasia Infiltrative cardiomyopathy Myocarditis Valvular heart disease (aortic stenosis) 3. Primary electrical abnormalities Long QT syndrome Brugada syndrome Wolff-Parkinson-White syndrome Idiopathic ventricular tachycardia 4. Drug or toxin induced Cocaine Proarrhythmia from antiarrhythmic medications QT interval–prolonging drugs, such as erythromycin antibiotics and psychotropic medications 5. Electrolytic or metabolic Thyrotoxicosis Poisoning Hypokalema, hypomagnesemia 6. Mechanical Pulmonary embolism Tension pneumothorax Trauma

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by cardiac arrest from pneumonia, and so forth. In addition to mimicking acute myocardial infarction, primary neurologic events, such as subarachnoid hemorrhage, also can cause neurogenic cardiac injury leading to ventricular fibrillation and cardiac arrest (Fig. 1) [8]. Because subsequent therapy depends to a great degree on the cause of the cardiac arrest, such as heparin for a pulmonary embolism, direct percutaneous coronary intervention for ST-segment elevation myocardial infarction, an evaluation to determine the underlying substrate of sudden cardiac death is important in the early management of these patients. Cardiac arrest and brain injury The duration of cardiac arrest as the clinical marker of global ischemia is correlated highly with brain injury [9–12]. The precise duration of cardiac arrest with the cessation of blood flow to the brain represents the primary insult and is one of the most important clinical factors in determining the severity of the brain injury [10,12]. During the Brain Resuscitation Clinical Trials (BRCT), a duration of cardiac arrest of 6 minutes or longer and a resuscitation time to achieve ROSC of 28 minutes or longer indicate poor neurologic recovery. Shorter cardiac arrest times and resuscitation times, indicating lesser injury, are associated with favorable outcomes. A European study reports a similar observation of patients having favorable outcomes with short cardiac arrest times (4.1 minutes) and unfavorable outcomes

Fig. 1. Electrocardiogram of a 50-year-old woman who presented to the emergency room with an out-of-hospital cardiac arrest from ventricular fibrillation. She was resuscitated and the initial postresuscitation electrocardiogram is shown. She went to emergent cardiac catheterization where an intra-aortic balloon pump was placed for cardiogenic shock. Coronary angiography demonstrated normal coronary arteries in spite of the dramatic ST-segment elevation at the time of angiography. Upon return to the coronary care unit, neurologic examination revealed fixed and dilated pupils. An emergent head CT showed a massive subarachnoid hemorrhage.


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with cardiac longer arrest time (8.0 minutes) [11]. In the same study, a resuscitation time leading to achieving ROSC with an average of 17 minutes was more likely to result in a favorable outcome than resuscitation time greater than 34.5 minutes [11].

Clinical evaluation Cardiac and systemic evaluation Postresuscitation cardiac examination should focus on blood pressure, heart rate, and clinical evidence of hypoperfusion, such as cool extremities and oliguria. Lung examination for edema also is important. Clinical cardiogenic shock is evident with blood pressure less than 90 mm Hg, pulmonary edema on examination, and evidence of hypoperfusiondall in the setting of acute myocardial infarction. Finally, detection of heart murmurs, such as aortic stenosis, and a comprehensive neurologic evaluation add important information. The ICU team and neurologist often work as a team in the early assessment of patients. An electrocardiogram not only shows evidence of ischemia but also should be evaluated for prolongation of the QT interval, delta waves in Wolff-Parkinson-White syndrome, right ventricular overload seen with pulmonary embolism, hypertrophy and pseudoinfarction pattern seen in hypertrophic cardiomyopathy, and low voltage pattern with atrial enlargement seen with infiltrative cardiomyopathy. Laboratory tests focusing on the cardiac cause, including standard electrolytes and magnesium, are determined and optimized. A toxicology screen should be sent on many patients, if the diagnosis is not immediately evident. Cocaine use is associated with cardiac arrest and myocardial infarction, the treatment of which differs from the treatment of typical coronary artery disease [13]. After resuscitation, most patients have evidence of cardiac enzyme elevation, including creatine kinase and troponin I or T. The sensitivity and specificity of troponin to diagnose myocardial infarction after successful ROSC in patients who have cardiac arrest are 96% and 80%, respectively [14]. For most patients admitted to an ICU after resuscitation for cardiac arrest, an echocardiogram early in the hospital course often gives useful information, such as overall left ventricular function; a wall motion abnormality consistent with myocardial infarction; valvular abnormalities, such as aortic stenosis; and the presence of a pericardial effusion. This information not only gives the clinician information about the possible cause of the cardiac arrest but also assists in management, particularly if hypotension is present. Other potentially treatable conditions associated with cardiac arrest include acidosis, toxins, cardiac tamponade, moderate to severe hypothermia, hypoxia, poisoning, hyperkalemia, pulmonary embolism, and tension pneumothorax [1]. Routine testing, including examination, electrolytes, blood gas, and chest radiograph, often results in a correct diagnosis.

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Another frequent diagnostic test obtained in the first 24 hours, depending on the clinician’s index of suspicion, is CT imaging of the brain and lungs. Neurologic evaluation Many studies describe functional recovery in relation to the neurologic clinical function of patients resuscitated from cardiac arrest [15–20]. Many of the clinical findings of these studies are incorporated into the bedside practice of prognosticating functional outcome in this patient population. The interventions provided to patients in the studies describe the evolution of neurologic recovery, because the vast majority of these patients were subjected only to normothermic conditions. Therefore, the data derived from a normothermic population can be applied properly only to patients who are normothermic. With the development of effective therapies, such as hypothermia (see the article by Bernard elsewhere in this issue) and other potential therapies still being studied (see the article by Popp and Bo¨ttiger elsewhere in this issue), caution must be used when applying data from previous studies of dissimilar patient populations and interventions. When evaluating neurologic injury in patients resuscitated from cardiac arrest, a complete bedside neurologic evaluation is essential consisting of evaluation of mental status, which needs to address patients’ ability to arouse and engage in a meaningful interaction with the examiner. The cranial nerves have to be assessed appropriately in responsive and in unresponsive patients. Cranial nerve function and sensorimotor and other reflexes may provide critical insight into the extent of injury in unresponsive patients. Although the autonomic system may be affected largely by the cardiac arrest, certain neurologically relevant manifestations of the autonomic system are worth observing, such as the patterns of breathing, temperature, heart rate, and blood pressure. Breathing patterns may indicate injury to specific areas of injury at the level of the brainstem, whereas the occurrence of bradycardia and hypertension may suggest intracranial pressure (ICP) elevation or Cushing’s reflex. As clinical indicators of functional outcome, the neurological examination must be taken in the proper context of the overall clinical picture. Parameters that may confound findings on physical examination as predictors of poor outcome must be taken into consideration, however, including medications, especially sedatives and illicit drugs used before arrest; hypotension; focal cerebral ischemia; seizures; electrolyte abnormalities; hepatic or renal failure; and acidosis. In 1985, a landmark study was undertaken by Levy and colleagues describing the neurologic findings of patients who were comatose after resuscitation after cardiac arrest [16]. A similar study was undertaken in 1994, in the multicenter BRCT, in relation to the assessment of neurologic prognosis in comatose survivors of cardiac arrest [18]. With more studies on this subject, Zandbergen and colleagues [15] provide a systematic review of the prediction of poor outcome in anoxic-ischemic coma.


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In patients who are unresponsive after resuscitation from cardiac arrest, several neurologic findings may show some predictive value for functional outcomes at various times during the recovery period. Pupillary light reflex, brainstem reflexes, and motor response to pain are the best studied and most helpful clinical predictors of outcome [15,16,18]. In 1985, Levy and colleagues reported a 100% positive predictive value for predicting severe or worse outcomes if the pupillary light reflex was absent on the initial examination after resuscitation [16]. Subsequent studies show that that lack of pupillary light reflex immediately after resuscitation has a low specificity and not always is indicative of poor outcome [18–20]. As the absence of the pupillary light reflex in these patients becomes more persistent, especially on or after 3 days, the likelihood of a poor outcome approaches 100% [15]. Brainstem dysfunction as manifested by the absence of two or more brainstem reflexes (pupillary light response, corneal reflex and occulocephalic reflex) for more than 6 hours after arrest also are highly predictive of poor outcome [15]. Lack of oculocephalic reflex after 8 hours is highly predictive of poor outcome and its specificity improves at 24 hours [17]. Motor response to painful stimuli consistently is shown to be a reliable component of the physical examination of unresponsive patients [21,22]. Edgren and colleagues in 1994 [18] reported that lack of any motor response to painful stimuli at 3 days after arrest was the best and only independent predictor of poor outcome that could be identified. Similar findings were reported [16] in patients who were unresponsive at 3 days and had no withdrawal or flexor motor response to pain. Investigators have tested the predictive value of the Glasgow Coma Scale (GCS) and find that a GCS score less than 5 for more than 2 to 3 days and the persistence of a GCS score greater than 8 for more than 1 week also are predictors of poor outcome [18,23]. GCS score reaches greatest specificity at 3 days [15]. Although 3 days is the traditional minimum time of observation in relation to the absence of pupillary light reflex and motor response, a meta-analysis by Booth and colleagues in 2004 reported that the absence of 5 clinical signs (absent corneal reflexes at 24 hours, absent pupillary response at 24 hours, absent withdrawal response to pain at 24 hours, no motor response at 24 hours, and no motor response at 72 hours) is sufficient to predict death or poor outcome as early as 24 hours [24]. The investigators also suggest that although useful signs occur at 24 hours after cardiac arrest, an earlier prognosis should not be made by clinical examination alone [24]. The absence of findings (pupillary light reflex, brainstem reflex, and motor response) may help determine poor functional outcome at 24 or 72 hours. This information is used routinely to aid in the decision of level and duration of care provided to these patients. The observation period is at least 24 hours; therefore, these parameters may have no relevance to neuroprotective therapies that ideally are provided acutely (within 24 hours) in the period of cardiac arrest and resuscitation. Also, no clinical findings are widely validated that provide health care providers with information that indicates the

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likelihood of a favorable outcome in patients. Therefore, there still is a need to undertake research and identify early (within minutes or few hours of injury) neurologic markers of brain injury and recovery. These markers, if identified, may aid in the development of more effective therapies.

Optimizing survival and functional outcome in the ICU Coronary revascularization and reperfusion in survivors of out-of-hospital cardiac arrest Because the pathophysiology of cardiac arrest often involves plaque rupture and thrombosis [6], and because many patients, after resuscitation from cardiac arrest, evolve a myocardial infarction, emergent revascularization may benefit certain patients. This may be beneficial particularly in improving the left ventricular dysfunction that frequently is present after resuscitation. This concept of emergent coronary revascularization was evaluated in a prospective trial where a select group of out-of-hospital sudden death survivors underwent emergent angiography and possible percutaneous coronary intervention [25]. This study was conducted in Paris, France, where physicians staffed the ambulances. Successfully resuscitated patients between 30 and 75 years of age were eligible if there was no obvious noncardiac cause and the patients previously had been well. Of the 1762 cases of suspected outof-hospital sudden cardiac arrest cases responded to by the ambulance study team, only 85 patients were eligible to be transferred for emergent cardiac catheterization. The majority of patients were excluded because of failure to resuscitate and fatal recurrent cardiac arrest while in transport. Of the 84 patients who underwent emergent angiography, 60 patients had significant coronary disease, with coronary artery occlusion found in 40 patients, and were treated with coronary angioplasty. The mean ejection fraction was significantly depressed at 34%. The two independent predictors of coronary artery occlusion on angiography in this select group of patients who had out-of-hospital cardiac arrest were ST-segment elevation on the admission electrocardiogram and chest pain before the arrest. The presence of one of these predictors had positive and negative predictive values for coronary artery occlusion of 0.63 and 0.74, respectively. The presence of chest pain before the arrest and ST-segment elevation on the electrocardiogram had a positive predictive value of 0.87 and negative predictive value of 0.61. Nine of 85 patients who demonstrated an occluded coronary artery on angiography had neither chest pain preceding the arrest nor ST-segment elevation on the admission electrocardiogram. Predictors of survival to hospital discharge included absence of inotropic drug support during transport and successful coronary angioplasty. A longer time from cardiac arrest to resuscitation was associated with worse survival. The poor predictive value of clinical and electrocardiographic data in predicting coronary occlusion on angiography is not surprising, given the frequent lack of history in comatose


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patients and the many other causes of cardiac arrest that may be associated with significant ST changes [8]. One aspect of this study was that of the large number of cardiac arrests screened, only 1 in 20 subjects were taken to cardiac catheterization. This selection bias plus the lack of any data regarding whether or not routine percutaneous coronary intervention improves neurologic outcomes puts into question whether or not coronary angiography and percutaneous coronary intervention should be performed on an emergent basis in all patients surviving out-of-hospital cardiac arrests. As with any indication for an invasive procedure, the risks and benefits need to be individualized before proceeding to angiography. If methodologies progress such that an early and accurate determination that neurologic recovery in particular sudden death survivors is likely, a more aggressive approach to emergent coronary angiography likely will evolve. Patients who have ST-segment elevation on electrocardiogram with hemodynamic compromise, such as cardiogenic shock, should be considered for emergent coronary angiography. A randomized trial in patients who had cardiogenic shock shows that an invasive approach with catheterization and coronary revascularization improves short- and long-term outcomes [26]. Other survivors of cardiac arrest who have ROSC and who should be considered for early angiography with possible coronary revascularization include those who have ST-segment elevation within 12 hours of symptom onset with evidence of or suggestion that neurologic recovery is likely. Some small series and one underpowered randomized study of 35 patients who had out-of-hospital cardiac arrest evaluate whether or not thrombolytic therapy at the time of emergency room arrival improves outcomes [27]. The premise for this provocative therapy rests on the role of thrombus (coronary ischemia and pulmonary embolism) in the etiology of out-ofhospital cardiac arrest. Although these small studies suggest a possible benefit for some patients, a larger randomized placebo controlled trial shows no benefit using the fibrinolytic agent, tissue plasminogen activator [28]. In this study, 233 patients who had an out-of-hospital cardiac arrest and demonstrated 1-minute or greater pulseless electrical activity, despite initiation of standard cardiopulmonary resuscitation, were randomized to placebo or a 100-mg dose of tissue plasminogen activator. The primary endpoint was survival to hospital discharge, which occurred in one patient randomized to fibrinolytic therapy compared with no patients randomized to placebo. These data show the terrible outcomes in patients who have pulseless electrical activity and no benefit for fibrinolytic therapy in this patient group. Associated risk of brain hemorrhage post systemic thrombolysis Thrombolysis, either local or systemic, after resuscitation from cardiac arrest is a concern because of the potential increased risk of intracranial bleeding. Several uncontrolled studies find thrombolysis safe for the brain. A retrospective analysis reports on 68 patients who received systemic

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thrombolytics after resuscitation from cardiac arrest for presumed acute myocardial infarction. Cardiac reperfusion was achieved in 71% of the patients treated. Intracranial hemorrhage was reported in only one patient, whereas four others had bleeding outside the central nervous system [29]. A study of the use of intravenous thrombolytics as therapy for brain injury after cardiac arrest currently is taking place in Europe. (See the article by Popp and Bo¨ttiger elsewhere in this issue for discussion of this therapy.) ICU therapy After resuscitation from cardiac arrest, admitted patients generally are intubated with varying degrees of mechanical ventilatory support and require general supportive measures in the ICU, such as sedation, deep vein thrombosis prophylaxis, and stress gastritis prophylaxis. In the absence of randomized clinical trials and treatment guidelines for many ICU conditions in these patients, this article discusses considerations for management based on existing literature and the authors’ own clinical experience. Hemodynamic instability Many patients, after resuscitation from cardiac arrest, have significant hemodynamic lability. More than half of patients who are resuscitated require vasopressor support during the first 72 hours of their hospitalization [30]. Many of the early deaths in the ICU result from circulatory collapse. The cause of the hypotension often is multifactorial, including left ventricular dysfunction and inappropriate peripheral vasodilatation. The peripheral vasodilatation and left ventricular dysfunction result from the global ischemia and reperfusion that occur after cardiac arrest and resuscitation [31]. During reperfusion from an ischemic episode, as occurs during cardiac arrest, there is a dramatic release of oxygen-free radicals; activation of cytokines, complement, and neutrophils; and activation of endothelial surface adhesion molecules. Cytokine levels rise rapidly after resuscitation from cardiac arrest. In a series of 61 patients who had out-of-hospital cardiac arrest and ROSC, cytokine levels drawn on admission to the hospital were markedly elevated and comparable to the levels seen in patients who have septic shock [31]. In this study, cytokines, such as interleukin 6 (IL-6) and tumor necrosis factor a (TNF-a), correlate with the level of lactic acid on admission. Nonsurvivors and patients requiring vasopressor support had significantly higher levels of cytokines, such as IL-6 and TNF-a [31]. The elevation of cytokines was independent of any evidence of infection. Endothelial adhesion molecules for neutrophils also are up regulated rapidly after total body ischemia and reperfusion that occurs with ROSC after cardiac arrest [31]. Therefore, one mechanism of vasodilatory shock after ROSC in many patients who have out-of-hospital cardiac arrest and are admitted to an ICU is a systemic inflammatory response. This response is associated


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with marked elevation of cytokines, such as IL-6 and TNF-a, which predict mortality. The correlation between lactic acid and cytokine levels suggests that one cause of this systemic inflammatory response is whole-body ischemia and reperfusion that occurs in cardiac arrest survivors. Also contributing to circulatory collapse after ROSC after cardiac arrest is inappropriate nitric oxide expression and elaboration [32]. The expression of inducible nitric oxide synthase (iNOS) that is stimulated by cytokines contributes to the systemic inflammatory response and inappropriate vasodilatation. Observations in patients who have cardiogenic shock complicating an acute myocardial infarction show that systemic vascular resistance often is inappropriately low, whereas overall ejection fraction is not impaired horrendously [33]. After exposure to a variety of cytokines that are produced after ischemia and reperfusion, iNOS is expressed by many cell types. This can lead to toxic levels of nitric oxide and its metabolites, such as peroxynitrite. High levels of nitric oxide and nitric oxide metabolites directly inhibit myocardial function, suppress oxidative metabolism, reduce responsiveness to catecholamines, and induce systemic vasodilatation. Animal models support a role for iNOS and elevated nitric oxide levels contributing to the hemodynamic collapse seen in many patients who have ROSC after cardiac arrest. Inhibition of nitric oxide synthase improves left ventricular function in the ischemia and reperfusion mode [34]. Current human trials with nitric oxide synthase inhibition are ongoing to determine whether or not cardiogenic shock patients benefit from this therapy. Hypotension Transient left ventricular dysfunction, commonly present after ROSC from cardiac arrest, also contributes to the hypotension and vasopressor support often required in this patient population. This left ventricular dysfunction typically lasts 48 to 72 hours, followed by gradual improvement of the cardiac output [30]. The dose of epinephrine required for resuscitation is the primary factor that correlates best with postresuscitation left ventricular transient dysfunction. These data suggest that high levels of catecholamines cause transient left ventricular dysfunction or stunning and contribute to the transient shock often present in this patient population. These data are supported by the transient left ventricular dysfunction or stunning recently demonstrated in patients who have severe emotional stress [35]. Catecholamine concentrations in this population also are elevated, suggesting that endogenous and exogenous catecholamines can cause transient myocardial stunning, with improvement in left ventricular function during the next 48 to 72 hours. In patients who have hypotension, a trial of volume expansion often is beneficial. Although in certain situations, pulmonary artery catheterization gives important information, routine management of hypotension with a pulmonary artery catheter generally is not indicated [36,37]. Randomized

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trials in postsurgical patients, patients who are postmyocardial infarction, and patients who have critical illness show no benefit and possible worse outcome in those randomized to pulmonary artery catheterization compared with conventional therapy [37]. This adverse outcome may result from misinterpretation of the data from the pulmonary artery catheterization or overuse of vasopressor medications that can worsen ischemia and left ventricular function in patients who have depressed cardiac outputs. Selective use instead of routine use of a pulmonary artery catheter should be considered in patients who have ROSC and cardiogenic shock with hypotension, pulmonary edema, and depressed left ventricular function. In patients who do not respond to volume and low-dose vasopressors, placement of a pulmonary artery catheter also should be considered. If vasopressors are required for refractory vasodilatory shock, combination therapy with modest catecholamine infusion plus vasopressin is preferable to high doses of catecholamines. In a study of 46 patients who had vasodilatory shock requiring norepinephrine, patients were randomized to the addition of vasopressin versus continued escalation of norepinephrine doses. The former group had less tachycardia, fewer atrial arrhythmias, improved cardiac output, and better markers of organ perfusion [38]. The impact of hypotension on the progression of neurologic injury may affect functional outcome significantly. Persistent systemic hypotension leading to cerebral hypoperfusion can worsen neurologic outcome and should be avoided. Due to impairment of cerebral autoregulation in patients after cardiac arrest the ideal mean arterial pressure (MAP) range for brain preservation is not known [39]. Good functional neurologic recovery is associated positively with higher spontaneous arterial blood pressure during the first 2 hours after cardiac arrest [40]. Cardiac arrhythmia Many patients admitted to an ICU have had an antiarrhythmic agent initiated either in the field or emergency department. A randomized trial shows that an amiodorone bolus of 300 mg is superior to placebo in shockresistant ventricular fibrillation in patients suffering out-of-hospital cardiac arrest [41]. An amiodorone bolus also is superior to lidocaine in producing ROSC [42] and is the antiarrhythmic agent of choice in shock-resistant ventricular fibrillation. In patients who receive amiodorone therapy for out-ofhospital cardiac arrest with ROSC, there is a lack of randomized trial data concerning length of therapy with an antiarrhythmic agent. Nevertheless, continuing an intravenous infusion for 24 hours seems reasonable. Thereafter, the amiodorone generally can be stopped and not resumed unless recurrent and sustained ventricular arrhythmias become evident. Most sudden death survivors have coronary artery disease, with myocardial infarction present in a large percentage of patients. In addition, an enhanced adrenergic state contributes to ventricular fibrillation. Therefore, beta-


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blockade should be initiated on admission to an ICU, if blood pressure and hemodynamics permit [43]. Beta-blockade is contraindicated in patients who have cardiac arrest and ROSC and who also have hypotension, significant bradyarrhythmias, and severe pulmonary edema. Sepsis and temperature control Sepsis occurs frequently in patients who have cardiac arrest. Two common sources of sepsis are aspiration during arrest and abdominal sepsis. The latter arises from the bowel ischemia as a consequence of ischemia and reperfusion. The majority of patients should have routine cultures performed on admission. In patients who are hypotensive after ROSC, physicians should consider the initiation of broad-spectrum antibiotics that cover lung and bowel flora until further culture data are available and hemodynamics improve. As with sepsis, elevated body temperature occurs often. Increased body temperature after cardiac arrest is associated with worse outcome and brain death [44]. In a study of 40 patients, all 20 patients who had a peak axillary temperature above 39 within the first 72 hours after cardiac arrest became brain dead versus only 3 of 20 patients who had a peak temperature less than 39 C [44]. Considerations related to the cause of temperature elevation may have contributed significantly to the poor outcome, but with recent evidence that hypothermia is beneficial, the prevention of hyperthermia with routine antipyretics and cooling measures are important clinical interventions. In appropriate situations, therapeutic hypothermia can be instituted during the early period after cardiac arrest [45,46]. (See the article by Bernard elsewhere in this issue for discussion of this therapy.) Coagulopathy Frequently contributing to the postarrest syndrome and also mimicking sepsis is a coagulopathy. Many patients, after ROSC, have marked activation of blood coagulation without adequate activation of endogenous fibrinolysis. This can lead to microvascular thrombosis, resulting in further organ dysfunction [47]. The activation of the coagulation system also is related to the large increase in cytokines seen in patients who have ROSC after cardiac arrest. In a study of 67 patients admitted after out-of-hospital cardiac arrest with ROSC, measures of cytokines and coagulation were obtained [47]. Patients had increased IL-6, coagulation activity (elevated levels of thrombinantithrombin complex), reduced anticoagulation (depressed antithrombin, protein C, and protein S), activated fibrinolysis (elevated plasmin-antiplasmin complex), and inhibited fibrinolysis (increased plasminogen activator inhibitor 1 levels). Activation of coagulation and fibrinolysis and reduced anticoagulation at admission were more pronounced in nonsurvivors, in particular patients dying in hospital of refractory shock. These data suggest that nearly all survivors of out-of-hospital cardiac arrest have a systemic

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coagulopathy present on admission to the ICU, such as coagulation activation, diminished anticoagulant factors, or increased fibrinolysis. The coagulopathy likely originates from cytokine up regulation of tissue factor, known to be up regulated after cardiopulmonary resuscitation [48]. These coagulation abnormalities also may contribute to the high early mortality seen in those surviving out-of-hospital cardiac arrest. (See the article by Popp and Bo¨ttiger elsewhere in this issue for discussion of management consideration of this problem.) Antiplatelet and anticoagulation therapies Aspirin should be given on admission to the hospital and continued daily, unless contraindicated or clinical data exist that patients do not have obstructive coronary artery disease [49]. Full-dose anticoagulation with heparin is another consideration for patients after sudden cardiac death with ROSC. In general, patients who have possible or definite acute coronary syndromes from plaque rupture are anticoagulated with heparin for 48 hours after admission to the hospital [50]. This therapy reduces recurrent ischemic events. Initiation of full-dose anticoagulation depends on the clinical suspicion of an acute plaque rupture event resulting in ischemia, ventricular fibrillation, and sudden cardiac death. The bleeding risks of anticoagulation with heparin (chest trauma from cardiopulmonary resuscitation) versus the benefit of full-dose anticoagulation in patients who have acute coronary syndrome need to be considered carefully by clinicians. Heparin needs to be held until the coagulopathy, if present, resolves. Seizures and myoclonus Seizures and myoclonus are common after cardiac arrest, occurring in approximately one third of patients [51]. (See the article by Koenig and colleagues elsewhere in this issue for discussion of these clinical problems.) Clinical or electrographic seizure activity persisting more than 30 to 60 minutes usually, but not invariably, is associated with poor outcome [52–55]. Status epilepticus, the persistence of a seizure activity, often is considered a predictor of poor outcome, as is persistent myoclonus. Caution must be taken, however, in characterizing epileptic and myoclonic activity properly after arrest. Postanoxic myoclonus (Lance-Adams syndrome), previously regarded as a predictor of poor outcome, may improve as neurologic status improves [56]. (See the article by Venkatesan and Frucht elsewhere in this issue for description of this clinical condition.) Postanoxic myoclonus tends to be more common in patients who have respiratory causes of arrest. A state of status myoclonus, however, defined as more than 30 minutes of myoclonic activity associated with burst suppression on electroencephalogram (EEG) [53], which occurs commonly after cardiac arrest, is considered an indicator of extremely poor prognosis, and treatment with antiepileptics tends not to influence short-term or long-term outcomes [53,57]. Status


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myoclonus tends to last only a few days. Differentiation between these two states can be difficult, but it is important to identify the difference. EEG monitoring and repeated evaluation may be helpful. Myoclonic status epilepticus, defined as myoclonic jerks merging with tonic-clonic seizures and lasting more than 30 minutes, is associated with failure to recover consciousness [17], although some investigators question this [58]. Seizures can delay the recovery of consciousness after cardiac arrest, and subclincial status epilepticus can depress the neurologic examination falsely and can be a cause for persisting unresponsiveness. An EEG should be obtained if seizures are suspected. Once seizures are found to occur, they should be treated aggressively to optimize recovery. Reports on the use of prophylactic antiepileptics therapy are limited, however, and not well clarified in the literature. Cerebral edema and intracranial pressure elevation Global cerebral ischemia may lead to brain edema. In one study, up to 47% of patients resuscitated from out-of-hospital arrest showed cerebral edema on head CT at day 3 [59]. In another study, more patients (92%) who had cerebral edema on head CT were noted among those who had primary respiratory arrest [59]. Cerebral edema can quantified objectively by the degree of obliteration gray matter–white matter demarcation by brain CT scan [60]. Torbey and colleagues find that the progressive loss of gray matter–white matter demarcation as a reflection of brain injury is associated with poor outcome [60]. In these reports, brain edema is a marker of brain injury and associated with poor neurologic outcomes. (See the article by Geraghty and Torbey elsewhere in this issue for a detailed discussion of this approach at prognostication.) Several small studies have attempted to define the occurrence of intracranial pressure elevation after resuscitation from cardiac arrest. In a study of ICP monitoring starting as early as 3 hours for a period of 2 to 7 days, ICP persistently remained below 20 mm Hg in five of the six patients. ICP elevation to 57 mm Hg was noted in one patient who had seizure activity. Although the study was limited by sample size, the absence of intracranial pathology or seizures made ICP elevation unlikely [61]. Another study showed that ICP elevation was associated with delayed hyperemia by transcranial Doppler ultrasound after resuscitation from cardiac arrest [62]. Therefore, the use of acute hyperventilation and mannitol therapy may be beneficial at the time of ICP elevation. These therapies are used successfully in other pathologies, but their use in edema related to global ischemia is not well described. Use of steroids does not provide benefit and can lead to adverse outcomes [63]. Hyperglycemia Elevated serum glucose is associated with unfavorable outcome after global ischemia from cardiac arrest [63,64]. Serum glucose elevation is

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believed to be a marker of the severity of injury. In a series of 145 nondiabetic patients evaluated after witnessed ventricular fibrillation cardiac arrest, a strong association between high median blood glucose levels during 24 hours and poor neurologic outcome was found [65]. Elevation of serum glucose after acute neurologic injury may be harmful, therefore treatment of hyperglycemia in patients who have nonlacunar stroke, and global ischemia is advocated [66]. In the absence of controlled human trials showing the benefit of glucose control in patients resuscitated from cardiac arrest, some insights may be taken from the general critical care literature. Although the precise effect of elevated glucose on neurologic injury of patients who have postcardiac arrest remains not well defined, tight glucose control is associated with improved survival and outcome in patients who are critically ill [67]. Until a dedicated controlled clinical trial in the specific area is undertaken, glucose monitoring in the ICU is strongly suggested, and providing tight control may provide benefits to patients who have postcardiac arrest. Age and systemic complications Many victims of cardiac arrest are elderly and have serious underlying comorbidities [9]. A review of noncardiac complications in cardiac arrest survivors notes that the most frequent complications are pneumonia, electrolyte abnormalities, and gastrointestinal hemorrhage in approximately 45%; followed by seizures and elevated liver enzymes in approximately 28%; and septicemia, acute renal failure, and acute respiratory distress syndrome in approximately 5% to 7% of patients [68]. Although advanced age (older than 65) is a risk factor for decreased overall survival after cardiac arrest, age is not an independent risk factor for poor neurologic outcome [12]; therefore, age consideration should be taken into account as plans for therapy are undertaken. Future directions in the ICU Much of the injury resulting in hemodynamic instability, cardiac dysfunction, and brain injury results from ischemia and reperfusion injury. Animal models demonstrate that many therapies given before ischemia and reperfusion improve outcomes. Naturally, pretreatment is impossible in patients after cardiac arrest. Several therapies currently in clinical trial may improve cardiac function in the setting of ischemia and reperfusion [69]. Certainly, therapies already demonstrated to reduce reperfusion injury, such as hypothermia, need to be applied more widely. Future technologies that assess neurologic prognosis more readily and accurately will assist in patient selection for early coronary angiography. Continued research in the identification of high-risk patients for sudden cardiac death may result in better preventative strategies [70].


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Neurol Clin 24 (2006) 61–71

Therapeutic Hypothermia after Cardiac Arrest Stephen Bernard, MD, FACEM, FJFICM Intensive Care Unit, Dandenong Hospital, David Street, Dandenong, Victoria 3175, Australia

Out-of-hospital sudden cardiac arrest (SCA) is common, occurring in approximately 1 in 2000 adults per year [1]. This number is likely to increase in the future because of an ageing population. Also, the number of patients who are initially resuscitated from SCA is expected to increase as a result of early defibrillation programs [2,3]. At present, 30% to 40% of SCA patients who have an initial cardiac rhythm of ventricular fibrillation achieve a successful return of a spontaneous circulation in the field; however, only 1% to 10% of patients survive to hospital discharge [4–6]. There are very few survivors (1%–2%) if the initial cardiac rhythm on arrival of paramedics is asystole [7]. On the other hand, those patients who regain consciousness have a good long-term prognosis [8]. Previously, the management of SCA patients after hospital arrival was largely supportive. Recently, randomized, prospective, controlled trials of induced hypothermia (IH) to 33 C for 12 to 24 hours has been shown to improve outcome significantly in SCA patients when the initial cardiac rhythm is ventricular fibrillation [9,10]. This article reviews the history of the use of IH after SCA, the physiologic effects of IH, and current cooling techniques. A protocol is described for the management of the post-SCA patient that includes the implementation of IH.

The history of hypothermia after cardiac arrest In 1950, Bigelow introduced hypothermia as a means of cerebral protection during cardiac surgery [11]. Subsequently, cooling to mild hypothermic levels was used during the 1950s for a range of neurologic indications, including head injury, stroke, and anoxic injury [12]. The first reported use of IH for neurologic injury after cardiac arrest was in 1958 in four patients [13].

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The following year, the same investigators treated 12 patients who remained comatose after resuscitation from in-hospital cardiac arrest with IH maintained for up to 8 days [14]. In this latter study, there were six survivors (50%), compared with one survivor in seven historical controls. For reasons that are unclear, there were few subsequent reports of the use of IH after cardiac arrest until this therapy was studied in laboratory animals in the early 1990s. Interest in the use of IH after cardiac arrest was revived in 1991, at the time Sterz and colleagues [15] demonstrated in a dog model that IH induced after 15 minutes of cardiac arrest was associated with significant improvements in neurologic outcome. Similar outcomes in other laboratory studies [16,17] renewed interest in the application of this therapy in humans. Several centers then started feasibility and safety studies of the use of IH after resuscitation from SCA. In 1997, the author’s experience in 22 patients post arrest suggested that IH was well tolerated; and side effects were able to be managed adequately in a modern intensive care unit [18]. Other preliminary clinical studies confirmed these findings [19–21]. Between 1997 and 2000, prospective, randomized, controlled clinical trials were conducted in Australia [9] and Europe [10]. In an Australian study, 77 patients were enrolled [9]. There was good outcome (defined as discharge from hospital either to home or to a rehabilitation facility) in 49% of the patients treated with hypothermia (33 C for 12 hours) compared with 26% of patients who were maintained at normal temperature. The adjusted odds ratio for good outcome with IH was 5.25 (95% confidence intervals 1.47–18.76); and there was no significant increase in the incidence of side effects. In the European study, there were 273 patients enrolled, with 136 patients undergoing IH (33 C for 24 hours) and 137 patients maintained at normothermia [10]. At 6 months, 55% of the IH patients had good outcome, compared with 39% of normothermic controls (risk ratio, 1.4; 95% confidence interval, 1.08–1.81). The complication rate did not differ between the two groups. On the basis of these studies, in 2003 the International Liaison Committee on Resuscitation endorsed the use of hypothermia for patients who have neurologic injury after ventricular-fibrillation cardiac arrest [22]. Since that time, clinical studies have largely focused on determining the optimal timing and technique for the induction of hypothermia after cardiac arrest, as well as on the applicability to nonventricular-fibrillation arrest patients. The physiologic effects of hypothermia The use of IH after cardiac arrest requires an understanding of the physiologic effects of IH on each organ system. The following provides an overview that is relevant for the physician during the first 24 hours of patient management after resuscitation from SCA.

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Neurologic system Although the precise effects of hypothermia on the injured brain are uncertain, there is considerable laboratory evidence that continuing neurologic injury occurs in the early post-arrest period (the ‘‘reperfusion injury’’) [23]. The injury is caused by several biochemical cascades that are believed to be very temperature sensitive [24], providing the main scientific rationale for treatment with hypothermia for hours to days after resuscitation. Other proposed mechanisms by which hypothermia may be effective are uncertain, but may include improvements in cerebral oxygen delivery. For example, cerebral edema may occur in the postarrest period, particularly when the cause of the arrest was asphyxia [25]. Hypothermia is known to decrease intracranial pressure [26] and this proposed mechanism may be another way in which hypothermia proves helpful in such patients. Respiratory system Pulmonary complications after SCA resuscitation include aspiration pneumonitis and chest wall injuries from prolonged external cardiac massage. Although nosocomial pneumonia may be seen when IH is used for periods longer than 48 hours [27], there seems to be minimal risk for ventilator-acquired pneumonia when IH is used for periods up to 24 hours. Cardiovascular system The cause of SCA may not be apparent on the basis of history, physical examination, and ECG; and 90% of post-SCA patients do not have ECG criteria suggesting acute coronary syndrome [9]. On the other hand, early coronary angiography in patients who have had SCA may reveal unexpected lesions that are amenable to therapy. In one study, it was found that 48% of patients had an acute coronary artery lesion that was considered responsible for the ventricular arrhythmia [28]. There is also evidence that aggressive interventional cardiac care after SCA resuscitation is associated with improved outcomes [29]. Therefore, in the comatose post-arrest patient who may or may not have ECG criteria for an acute coronary syndrome, consideration should be given to urgent interventional revascularization. Myocardial dysfunction is common after resuscitation from SCA [30], and inotropic drug therapy may be required in many patients for the maintenance of adequate cerebral perfusion pressure. The hemodynamic effects of IH include a decrease in heart rate and an increase in systemic vascular resistance, with stroke volume and mean arterial blood pressure maintained [9]. There does not seem to be an increase in the number of patients who have cardiac arrhythmias during IH therapy [9]. There is some evidence that IH may be beneficial to the post-arrest heart and the brain during the reperfusion period. This benefit was demonstrated in studies of IH (using an intravascular cooling device) during interventional

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cardiology [31]. Also, IH has been used for the treatment of cardiogenic shock that was not responsive to usual therapy [32]. Acid base There is debate on whether blood gases should be corrected for temperature; however, it is only of practical importance when moderate hypothermia (!32 C) is used, for example, in deep hypothermia for cardiac or neurologic surgery. Hypothermia after SCA does not significantly increase metabolic acidosis or lactate levels [9]. Renal/electrolytes An increase in the serum creatinine level is usually seen during the first 24 hours after SCA; however, there is rarely a need for renal replacement therapy [9]. Of more importance, the potassium level decreases during induction of hypothermia [9], and therefore its level needs to be monitored every 1 to 2 hours during the initial period of care. Magnesium and phosphate levels also decrease during IH and may need supplementation [33]. Hematologic Decreased temperature has a small effect on clotting times and platelet counts during prolonged (O48 hours) hypothermia [27]. In any case, many patients who are post SCA will receive antiplatelet and/or anticoagulation therapy as part of therapy for suspected acute coronary syndrome. The clinical trials of IH after cardiac arrest demonstrated that there was no added risk for bleeding in hypothermic patients compared with normothermic controls [9,10] Gastrointestinal Hypothermia increases the blood glucose as a result of decreased insulin release from the pancreas [34]. It is also known that hyperglycemia is associated with worse outcome after (focal) anoxic injury [35]. Because tight control of blood glucose (between 4 and 6mmol/L) has been shown to improve outcome in critically-ill surgical patients [36], it is reasonable (although of unproven benefit) to monitor strictly and treat hyperglycemia after anoxic brain injury using an intravenous (IV) infusion of insulin. However, the exact blood glucose target is uncertain. Cooling techniques Surface cooling Laboratory studies suggest that outcomes are further improved when IH is commenced as early as possible after cardiac arrest [15,37]. Therefore,


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vigorous patient cooling should be undertaken immediately after hospital arrival to decrease core temperature toward 33 C. In practice, however, the rapid induction of hypothermia using surface cooling in adults is problematic. In Australian hypothermia trials [9,18], a neuromuscular blocking drug and extensive surface cooling with icepacks was used; but it provided for relatively slow core cooling (approximately 0.9 C/h) and was considered very inconvenient by attending medical and nursing staff. The European trial of hypothermia after cardiac arrest used a refrigerated air blanket; it was also a very slow technique, with a decrease in core temperature of only 0.3 C/h [10]. Many of the patients in this study also required icepacks after 4 hours if cold-air cooling had not been effective. More effective surface cooling seems possible using cooling blankets, which are specially manufactured to provide adhesion to the skin (Arctic Sun, Medivance, Inc., Colorado, USA). Preliminary data indicate that this device provides accurate temperature control in patients who are febrile [38], and further studies using this technology for IH after cardiac arrest are currently being conducted. Surface cooling using helmet devices does not appear to provide particular significant protection to the brain directly [39] but does decrease core temperature slowly [40]. Core cooling A relatively simple, inexpensive technique for the induction of mild hypothermia using core cooling is the use of large volume, ice cold intravenous fluid (LVICF). In a pilot study of 22 patients, a large-volume (30 mL/kg) ice-cold (4 C) crystalloid fluid (lactated Ringer’s solution) was rapidly infused intravenously, together with a large dose of a long-acting neuromuscular blocker (vecuronium bromide) to prevent shivering [41]. This therapy decreased core temperature by 1.6 C and increased blood pressure, without any patient developing pulmonary edema. The fluid was infused into a peripheral intravenous cannula using a pressure bag to ensure a high flow rate through a standard IV-giving set. The use of LVICF has also been studied by Kim and colleagues [42]. That study determined the effect of infusing 2000 mL of ice-cold saline rapidly into a peripheral vein on temperature and hemodynamics in 17 hospitalized survivors of out-of-hospital cardiac arrest. Cardiac function was assessed by transthoracic echocardiography before and after fluid administration. Infusion of cold saline resulted in a mean temperature drop of 1.4 C at 30 minutes after the initiation of infusion. There was no increase in central venous pressure, pulmonary pressures, or left atrial filling pressures as assessed by echocardiography. Contraindications to LVICF therapy would include the presence of pulmonary edema or patients who have chronic renal failure (on dialysis) who may be unable to excrete a large fluid load.

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Alternative core cooling techniques for the rapid induction of IH are currently under investigation and include intravascular cooling devices [43]. These devices consist of a large catheter inserted into the femoral vein and recirculation of cold saline. A feedback circuit with core temperature input allows automatic temperature control. These devices provide for very rapid temperature decreases [31,43]. Other extracorporeal circulation strategies have been described [44,45], but these techniques would generally be beyond the capabilities of most emergency departments. In addition, they entail expensive machines, require specialized physician training for catheter insertion, and take considerable time to establish. During the cooling phase, patients require sedation to prevent shivering. Because all patients will be ventilated mechanically, muscle relaxants may also be given as required. In a study of awake patients undergoing IH for stroke, an infusion of magnesium facilitated the cooling procedure [46]; however, the relevance of this intervention in the patient who is being ventilated is uncertain. Core temperature measurement In patients who have neurologic injury for which the use of IH is planned, it is essential that core temperature be monitored continuously and accurately. There is a minimal temperature gradient among brain, esophageal, and bladder temperatures [47]; therefore, it is recommended that esophageal or bladder temperature be monitored continuously after arrival at hospital. Tympanic temperature monitoring may be inaccurate when the head is surrounded by icepacks and cold water has entered the external auditory canal. A protocol for cooling after cardiac arrest The following protocol has developed from the experience of clinical trials [9,18,27,41] and comprises an initial evaluation in the emergency department, immediate interventions focusing on cerebral resuscitation, history taking, secondary survey, and definitive cardiac care. The protocol includes early, rapid induction of hypothermia to 33 C immediately after arrival at the hospital. Initial patient evaluation Airway/breathing All patients who have been resuscitated from prolonged SCA will remain comatose and will require endotracheal intubation for airway protection, oxygenation, and ventilation control. Mechanical ventilation with 100% oxygen at a tidal volume of 10 mL/kg and a rate of 8 to 10 breaths per minute are initial ventilator settings that should ensure normocapnea. The


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production of carbon dioxide is decreased by 30% when core temperature is 33 C, therefore the ventilator rate may need to be decreased to only 6 to 8 breaths per minute, guided by end-carbon dioxide readings and arterial blood gas analysis. To facilitate mechanical ventilation and assist in the rapid induction of hypothermia, a large dose of a nondepolarising long-acting muscle relaxant (ie, vecuronium bromide) should be administered immediately after initial neurologic assessment. Concurrently, a chest radiograph should be performed during initial evaluation to exclude right main bronchus intubation and to diagnose aspiration pneumonitis or pulmonary edema. Circulation There is evidence from laboratory studies that mild hypertension after SCA improves neurologic outcome [48,49]. One strategy that both induces mild hypothermia and improves blood pressure is the rapid infusion of LVICF as outlined in the discussion above. If hypotension (mean arterial pressure [MAP] !70 mmHg) persists despite this fluid therapy, then an inotropic drug should be infused. In the author’s studies [9,18,41], epinephrine was used without apparent adverse cardiac effect. If the patient is initially hypertensive, an infusion of propofol G glyceryl trinitrate should be considered. Initial procedures After the initial ‘‘ABC’’ resuscitation measures described in the discussion above, the following procedures and investigations need to be undertaken. A nasogastric tube should be inserted, because bystander-expired air ventilation commonly results in air inflation of the stomach. The insertion of an arterial line facilitates continuous blood pressure monitoring and the drawing of blood for routine laboratory tests. A 12-lead electrocardiogram is required to diagnose acute coronary syndromes. Central venous access may be required for right atrial pressure monitoring or inotropic drug infusion. A femoral venous line may be a safer option than subclavian or internal jugular puncture, especially if thrombolysis is planned [50]. Patient history Information relating to the patient who is in cardiac arrest should be sought from paramedics and family members concurrently with the initial resuscitation measures listed in the discussion above. In particular, the time between collapse and return of spontaneous circulation, initial cardiac rhythm, whether the arrest was witnessed, and whether bystander cardiopulmonary resuscitation was performed are factors that relate to eventual prognosis. Other important historical information includes past medical history, current medication, and known allergies.

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Secondary survey Following the initial evaluation and treatment, there should be a thorough secondary physical examination. In particular, the presence of head injury should be excluded, because SCA patients may fall and strike their heads. In such cases, the neck must be immobilized and computed tomography of the brain and cervical spine undertaken before consideration of thrombolytic therapy. Examination of the chest should focus on the presence of chest trauma as a result of external cardiac massage. This injury may cause bleeding after thrombolysis; however, even if it is present, the incidence of major hemorrhage is low [51]. Maintenance of hypothermia During the induction of IH, the SCA patient will shiver vigorously between 34 C and 35 C, which may be associated with increased oxygen demand and possible myocardial ischemia [52]. The maintenance of this temperature is therefore difficult without pharmacologic paralysis or deep sedation. However, once a core temperature of less than 34 C is reached, adult patients tend to become poikliothermic and not shiver. At temperatures about 33 C, the judicious use of sedation rather than pharmacologic paralysis may maintain core temperature. A benzodiazepine, such as midazolam, given by continuous infusion is commonly used; but propofol infusions should be used very cautiously because of risk for hypotension. If a cooling device is not available, icepacks will need to be applied to the head, neck, and torso of the patient if the core temperature starts to increase (O33.5 C). If core temperature decreases (!32.5 C), icepacks should be removed and paralyzing drugs withheld while a heated-air blanket is applied. The optimal duration of IH after SCA resuscitation is uncertain. The Australian study used 12 hours [9], while the European study used 24 hours [10]. More recently, an animal study of asphyxial cardiac arrest demonstrated clearly that a 24-hour period was associated with improved neurologic recovery compared with 6 hours of IH [53]. Therefore, for most patients who have significant neurologic injury, the use of IH for 24 hours, followed by 12 hours of controlled rewarming seems reasonable. Rewarming from hypothermia Active rewarming of the hypothermic patient requires the use of a heatedair blanket to increase core temperature. During this time, any shivering must be suppressed with sedation. In addition, rewarming may result in peripheral vasodilatation, and (warm) IV fluid therapy may need to be given to maintain MAP. There is some evidence that rapid rewarming may be harmful [54]; therefore, careful monitoring and control of temperature at this time is required.


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Summary The use of IH for 24 hours in patients who remain comatose following resuscitation from out-of-hospital cardiac arrest improves outcomes. However, the induction of hypothermia has several physiologic effects that need to be considered. A protocol for the rapid induction of hypothermia is described. At present, the rapid infusion of a large volume (40 mL/kg) of icecold crystalloid (ie, lactated Ringer’s solution) would appear to be an inexpensive, safe strategy for the induction of hypothermia after cardiac arrest. Hypothermia (33 C) should be maintained for 24 hours, followed by rewarming over 12 hours. Particular attention must be paid to potassium and glucose levels during hypothermia.

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[18] Bernard SA, Jones BM, Horne MK. A clinical trial of induced hypothermia in comatose survivors of prehospital cardiac arrest. Ann Emerg Med 1997;30:146–53. [19] Yanagawa Y, Ishihara S, Norio H, et al. Preliminary clinical outcome study of mild resuscitative hypothermia after out-of-hospital cardiac arrest. Resuscitation 1998;39:61–6. [20] Nagao K, Hayashi N, Kanmatsuse K, et al. Cardiopulmonary cerebral resuscitation using emergency cardiopulmonary bypass, coronary reperfusion therapy, and mild hypothermia in patients with cardiac arrest outside the hospital. J Am Coll Cardiol 2000;36:776–83. [21] Zeiner A, Holzer M, Sterz F, et al. Mild resuscitative hypothermia to improve neurological outcome after cardiac arrest: a clinical feasibility trial. Stroke 2000;31:86–94. [22] Nolan JP, Morley PT, Hoek TL, et al. Therapeutic hypothermia after cardiac arrest: an advisory statement by the Advancement Life Support Task Force of the International Liaison Committee on Resuscitation. Resuscitation 2003;57:231–5. [23] Safar P, Behringer W, Bottinger BW, et al. Cerebral resuscitation potentials for cardiac arrest. Crit Care Med 2002;30:S140–4. [24] Takata K, Takeda Y, Sato T, et al. Effects of hypothermia for a short period on histologic outcome and glutamate concentration during and after cardiac arrest in rats. Crit Care Med 2005;33:1340–5. [25] Morimoto Y, Kemmotsu O, Kitami K, et al. Acute brain swelling after out-of-hospital cardiac arrest: pathogenesis and outcome. Crit Care Med 1993;21:104–10. [26] Clifton GL, Miller ER, Sung CC, et al. Lack of effect of induction of hypothermia after acute brain injury. N Engl J Med 2001;344:556–63. [27] Bernard SA, Jones BM, Buist M. Experience with prolonged induced hypothermia in patients with severe head injury. Crit Care 1999;3:167–72. [28] Spaulding CM, Joly LM, Rosenberg A, et al. Immediate coronary angiography in survivors of out-of-hospital cardiac arrest. N Engl J Med 1997;336:1629–33. [29] Engdahl J, Abrahamsson P, Bang A, et al. Is hospital care of major importance for outcome after out-of-hospital cardiac arrest? Experience acquired from patients with out-of-hospital cardiac arrest resuscitated by the same emergency medical service and admitted to one of two hospitals over a 16-year period in the municipality of Goteborg. Resuscitation 2000;43: 201–11. [30] Laurent I, Monchi M, Chiche JD, et al. Reversible myocardial dysfunction in survivors of out-of-hospital cardiac arrest. J Am Coll Cardiol 2002;40:2110–6. [31] Dixon SR, Whitbourn RJ, Dae MW, et al. Induction of mild systemic hypothermia with endovascular cooling during primary percutaneous coronary intervention for acute myocardial infarction. J Am Coll Cardiol 2002;40:1928–34. [32] Dalrymple-Hay MJ, Deakin CD, Knight H, et al. Induced hypothermia as salvage treatment for refractory cardiac failure following paediatric cardiac surgery. Eur J Cardiothorac Surg 1999;15:515–8. [33] Polderman KH, Peerdeman SM, Girbes ARJ. Hypophosphatemia and hypomagnesemia induced by cooling of patients with severe head injury. J Neurosurg 2001;94:697–705. [34] Curry DL, Curry KP. Hypothermia and insulin secretion. Endocrinology 1970;87:750–3. [35] Baird TA, Parsons MW, Phanh T, et al. Persistent poststroke hyperglycemia is independently associated with infarct expansion and worse clinical outcome. Stroke 2003;34: 2208–14. [36] Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001;345:1359–67. [37] Kuboyama K, Safar P, Radovsky A, et al. Delay in cooling negates the beneficial effect of mild resuscitative cerebral hypothermia after cardiac arrest in dogs: a prospective, randomized study. Crit Care Med 1993;21:1348–58. [38] Mayer S. Surface cooling for fever control in brain-injured patients. Crit Care Med 2005;33: 1891–5. [39] Hachimi-Idrissi S, Corne L, Ebinger G, et al. Mild hypothermia induced by a helmet device: a clinical feasibility study. Resuscitation 2001;51(3):275–81.


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[40] Wang H, Olivero W, Lanzino G, et al. Rapid and selective cerebral hypothermia achieved using a cooling helmet. J Neurosurg 2004;100:272–7. [41] Bernard SA, Buist MD, Monterio O, et al. Induced hypothermia using large volume, ice-cold intravenous fluid in comatose survivors of out-of-hospital cardiac arrest: a preliminary report. Resuscitation 2003;56:9–13. [42] Kim F, Olsufka M, Carlbom D, et al. Pilot study of rapid infusion of 2 L of 4 degrees C normal saline for induction of mild hypothermia in hospitalized, comatose survivors of out-of-hospital cardiac arrest. Circulation 2005;112:715–9. [43] Georgiadis D, Schwarz S, Kollmar R, et al. Endovascular cooling for moderate hypothermia in patients with acute stroke: first results of a novel approach. Stroke 2001;32:2550–3. [44] Piepgras A, Roth H, Schurer L, et al. Rapid active internal core cooling for induction of moderate hypothermia in head injury by use of an extracorporeal heat exchanger. Neurosurgery 1998;42:317–8. [45] Holzer M, Behringer W, Janata A, et al. Extracorporeal venovenous cooling for induction of mild hypothermia in human-sized swine. Crit Care Med 2005;33:1346–50. [46] Zweifler RM, Voorhees ME, Mahmood MA, et al. Magnesium sulfate increases the rate of hypothermia via surface cooling and improves comfort. Stroke 2004;35:2331–4. [47] Henker R, Brown D, Marion M. Comparison of brain temperature with bladder and rectal temperatures in adults with severe head injury. Neurosurgery 1998;42:1071–5. [48] Safar P, Xiao F, Radovsky A, et al. Improved cerebral resuscitation from cardiac arrest in dogs with mild hypothermia plus blood flow promotion. Stroke 1996;27:105–13. [49] Safar P, Kochanek P. Cerebral blood flow promotion after prolonged cardiac arrest. Crit Care Med 2000;28:3104–6. [50] Desmond J, Megahed M. Is the central venous pressure reading equally reliable if the central line is inserted via the femoral vein. Emerg Med J 2003;20:467–9. [51] Scholz KH, Tebbe U, Herrmann C, et al. Frequency of complications of cardiopulmonary resuscitation after thrombolysis during acute myocardial infarction. Am J Cardiol 1992;69: 724–8. [52] Frank SM, Fleisher LA, Breslow MJ, et al. Perioperative maintenance of normothermia reduces the incidence of morbid cardiac events: a randomised clinical trial. JAMA 1997;277: 1127–34. [53] Katz LM, Young A, Frank JE, et al. Neurotensin-induced hypothermia improves neurologic outcome after hypoxic-ischemia. Crit Care Med 2004;32:806–10. [54] Ueda Y, Suehiro E, Wei EP, et al. Uncomplicated rapid posthypothermic rewarming alters cerebrovascular responsiveness. Stroke 2004;35:601–6.

Neurol Clin 24 (2006) 73–87

Cerebral Resuscitation: State of the Art, Experimental Approaches and Clinical Perspectives Erik Popp, MD, Bernd W. Bo¨ttiger, MD, DEAA* Department of Anesthesiology, University of Heidelberg, Im Neuenheimer Feld 110, D-69120, Heidelberg, Germany

Every day, up to 1000 persons in the United States and another 1000 in Europe go into cardiocirculatory arrest with subsequent cardiopulmonary resuscitation (CPR), and only about 2% to12% of them survive. Postarrest brain damage is a key issue. In the western industrialized nations, CPR is attempted in 40 to 90 of 100,000 inhabitants annually, and restoration of spontaneous circulation (ROSC) can be achieved in about 25% to 50% of these patients. The hospital discharge rate, however, is only 2% to 12% (Fig.1) [1]. Therefore, out of up to 300,000 cardiac arrest victims annually in the United States and in Europe, more than 270,000 are not treated successfully, if one uses complete neurologic restoration as the standard. The major reason for postarrest in-hospital mortality and morbidity is persistent brain damage. Brain damage following cardiocirculatory arrest is related to the short period of tolerance to hypoxic stress and specific reperfusion disorders [2,3]. The individual, social, and economic consequences of brain damage following cardiac arrest are immense [4–6]. One of the most important issues in cardiac arrest and resuscitation (‘‘whole body ischemia and reperfusion‘‘) research, therefore, is cerebral resuscitation and the inhibition of postarrest cerebral damage [3,7]. Current research focuses on pathophysiology and problems during reperfusion [7,8]. The mechanisms of brain damage following global cerebral ischemia and cardiac arrest are complex [2,3,7]. Major issues are hypoxia and subsequent necrosis, reperfusion injury with free radical formation and cellular calcium influx, release of excitatory amino acids, neuronal apoptosis, and cerebral

* Corresponding author. E-mail address: [email protected] (B.W. Bo¨ttiger). 0733-8619/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.ncl.2005.10.008 neurologic.theclinics.com

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Fig.1. Survival after out-of-hospital cardiac arrest of cardiac etiology and subsequent cardiopulmonary resuscitation (CPR) in the area of Heidelberg, Germany (36-month period). The great discrepancy between patients who show restoration of spontaneous circulation (ROSC) and the hospital discharge rate is – in major parts – because of postarrest brain damage [1]. (Adapted from Bo¨ttiger BW, Grabner C, Bauer H, et al. Long-term outcome after out-of-hospital cardiac arrest with physician staffed emergency medical services: the Utstein style applied to a midsized urban/suburban area. Heart 1999;82:674–9; with permission.)

microcirculatory reperfusion disorders [2,3,7,9]. Several clinical trials attempted to improve neurologic outcome after cardiac arrest by focusing on brain protection with the therapeutic use of barbiturates and by focusing on reperfusion injury with the use of calcium channel blockers. No positive effects on neurological outcome could be established, however [10,11]. To date, no specific pharmacologic postarrest treatment options are available to improve neurologic outcome following cardiocirculatory arrest in the clinical setting, with cardiocirculatory arrest being the most relevant clinical feature of global cerebral ischemia. The most important therapeutic options to improve neurologic outcome following cardiac arrest currently under study are focusing on (1) selective neuronal vulnerability and delayed neuronal death [8,12,13], (2) on cerebral microcirculatory reperfusion [14–17] and (3) on therapeutic hypothermia, the topic with the most clinical evidence [18–20].

From experimental concepts to clinical strategies Selective neuronal vulnerability and delayed neuronal death Selective neuronal vulnerability and delayed neuronal death contribute to neuronal damage following global cerebral ischemia resulting from cardiac arrest in the clinical and the experimental settings [8]. Short periods of global cerebral ischemia resulting from cardiocirculatory arrest induce neuronal cell damage primarily in so-called ‘‘selectively vulnerable’’ brain areas, such as the hippocampal CA1 sector, the thalamic reticular nucleus, and different layers of the neocortex [8,20]. In a recently developed model of cardiac arrest in rats, strong evidence for neuronal apoptosis in selectively vulnerable areas of the brain was found. Using the TUNEL-technique

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(terminal deoxynucleotidyltransferase [TdT]-mediated d-uracil triphosphate [UTP]-biotin nick end-labeling), a characteristic apoptotic morphology with DNA-laddering and apoptotic bodies was detected in the hippocampal CA1 sector and the thalamic reticular nucleus [8,9,13]. Positive TUNEL staining is an important indicator of apoptotic degeneration. Quantitative analysis of TUNEL-positive neurons per tissue section revealed marked differences with regard to the time course between the hippocampal CA1 sector and the thalamic reticular nucleus. TUNEL staining demonstrated early onset degeneration in the thalamic reticular nucleus at 6 hours; it peaked at 3 days. In contrast, degeneration was delayed in the hippocampal CA1 sector, showing an onset at 3 days and a maximum of TUNEL-positive cells at 7 days [8,9,13]. These data suggest that apoptosis contributes to neuronal cell death after cardiac arrest. Moreover, delayed neuronal degeneration reflects a time window in which potential therapeutic interventions can be established after cardiac arrest [7]. Cascades of death The current concepts of apoptosis suggest that there are several steps between the initial ischemic/hypoxic insult and the final DNA fragmentation leading to cell death (Fig. 2) [21–23]. Within this cell death cascadedconsisting of various signals, modulatory proteins, and degradation enzymesd several molecules and proteins facilitating neuronal survival compete with factors contributing to cell death. Ultimately, the balance between survival factors and death factors determines the fate of the cell. Proteins such as

ischemia / hypoxia survival signals (e.g. BDNF / IGF)

signals

Death

Survival Bcl-2 / Bcl-XL

death signals (e.g. Fas-FasL)

modulators

Bax / Bid / Bad

caspase inhibitors (e.g. z-VAD-FMK, p35)

proteases

Caspase 3, 6, 7

cleavage of target proteins

APOPTOSIS

„apoptotic bodies“ DNA fragmentation

Fig. 2. A simplified scheme of the pathophysiologic concepts of neuronal apoptosis suggests that there are several steps between the initial ischemic/hypoxic insult and the final DNA fragmentation leading to cell death [9,21,23,24]. Within this cell death cascade, consisting of signals, modulators, and degradation enzymes, there are several molecules and proteins that facilitate neuronal survival and compete with factors that contribute to the cell-death cascade. Ultimately, the balance between survival factors and death factors determines the fate of the cell. Proteins such as Bcl-2 and Bcl-XL promote survival, while Bax, Bid, and Bad promote death. The final step of this cascade is initiated with the activation of caspase 3.

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Bcl-2 and Bcl-XL promote survival, whereas Bax and Bad promote death. The final step in this cascade is initiated with the activation of caspase 3. Activation of caspase 3 leads to a cleavage of poly(ADP-ribose)polymerase (PARP), which is an important DNA-repair enzyme [21,23,24]. Combined with the cleavage of other important substrates, activation of caspase 3 is believed to be the final trigger of DNA fragmentation and apoptotic cell death, which can be viewed as a form of endogenous ‘‘cell suicide.’’ This final caspase activation step can be blocked by synthetic caspase inhibitors and different viral antiapoptotic proteins, such as the baculovirus protein p35 and the cowpox virus protein crmA [23]. An important step in confirming that delayed neuronal death after cardiac arrest is based on apoptosis was the demonstration of upregulated caspase 3-like protease activity in different brain regions 24 hours after global cerebral ischemia induced by cardiac arrest [25]. In particular, a significant increase in caspase 3 mRNA and caspase 3-like proteolytic activity in the hippocampus was observed. Preincubation of hippocampal extracts with a specific caspase 3 inhibitor completely blocked protease activity. Thus, one of the final steps in an apoptotic cascade, activation of caspase 3, occurs in the brain after cardiac arrest at the transcriptional and the posttranscriptional level [25]. This finding gives further support to the hypothesis that apoptotic degeneration contributes to neuronal death after cardiocirculatory arrest and suggests that antiapoptotic treatment may play an important role in promoting neuronal survival after cardiac arrest in the future. Inhibiting cerebral apoptosis In an attempt to inhibit neuronal apoptosis, a transgenic rat line was created that expressed the antiapoptotic baculovirus protein p35 in neurons postnatally [26]. Those animals and their nontransgenic littermates underwent a period of 6 minutes of cardiac arrest induced by ventricular fibrillation of the heart. There was a marked difference with regard to the rate of ROSC; and the rate of 7-day survival was significantly higher in p35 transgenic animals [26]. Therefore, antiapoptotic strategies may be indicated to improve outcome following global cerebral ischemia and cardiocirculatory arrest [7,26]. However, additional studies using the intracerebroventricular application of artificial caspase inhibitors, such as the specific synthetic caspase inhibitor z-DEVD-FMK, did not show a significant positive effect on caspase-3 activation, neuronal degeneration, and neurologic outcome following 6 minutes of cardiocirculatory arrest in rats [27]. Recent data from focal cerebral ischemia demonstrate the possibility of inhibiting the apoptotic cascade further upstream with the use of neurotrophins and growth factors. Brain-derived neurotrophic factor (BDNF) is one of the best characterized neurotrophic factors of the nerve growth factor family. BDNF acts on a set of high-affinity receptor kinases (mainly tyrosine kinase B [TrkB]) to promote survival, differentiation, and neurite


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extension in many types of neurons in the mammalian central nervous system [28–32]. In vivo, BDNF rescues motoneurons and substantia nigra dopaminergic cells from traumatic and toxic brain injury [33,34]. Intracerebroventricular BDNF administered after focal cerebral ischemia significantly reduced infarct volume, primarily in the cortex [35,36]. Another mechanism of neuroprotection achieved by growth factors after hypoxic/ischemic events is probably prevention of excitotoxicity [31]. Glutamate-triggered excitotoxicity with subsequent Ca2þ overload of cells is thought to be one of the major causes of cellular death after ischemia [37]. BDNF protects neuronal cells in vitro against glutamate-induced neurotoxicity and the subsequently high intracellular calcium levels [31,32]. By inducing an antioxidant defense system, BDNF suppresses the glutamate-triggered accumulation of peroxide, which contributes to the loss of Ca2þ homeostasis [38]. Also, BDNF induces the activation of the IP3 kinase, phospholipase C, and Ras/MAPKinase (MAPK) pathways via the TrkB receptor, exhibiting further neuroprotective cellular stimulation. Those pathways could also be activated effectively by the insulin-like growths factor 1 (IGF-1) and erythropoietin (EPO) [39]. Those growth factors/neurotrophins have been evaluated in models of cardiac arrest with rats. Neither BDNF, nor IGF-1 nor EPO, however, could demonstrate beneficial effects on cerebral recovery and neuronal survival when administered intracerebroventricularily or intraperintoneally after 6 minutes of cardiac arrest [13,40]. Cerebral microcirculatory reperfusion A major area of experimental resuscitation research has focused on cerebral microcirculatory reperfusion and associated disorders following cardiac arrest, including endothelial cell swelling, increased leukocyte-endothelial interactions, and a disseminated intravascular activation of blood coagulation [7,14–17]. A most relevant cause of cerebral dysfunction after cardiac arrest is reflected by the cerebral ‘‘no reflow’’ phenomenon, which describes the regional microcirculatory reperfusion deficits that occur despite adequate systemic hemodynamics. Some years ago, Fischer and Hossmann [16] treated cats after 15 minutes of cardiac arrest and 4 minutes of CPR with hypertonichyperoncotic solutions during a 30-minute reperfusion period. Such solutions decrease endothelial cell swelling resulting from the high intravascular osmotic pressure that is generated by this kind of intervention. In these studies, early cerebral microcirculatory reperfusion disorders (cerebral ‘‘no reflow’’) were reduced with the administration of these solutions, suggesting that therapeutic interventions that focus on a decrease in endothelial cell swelling have positive effects on cerebral microcirculatory reperfusion after cardiac arrest [16]. As in several other experimental studies, cerebral perfusion pressure immediately at the start of reperfusion is correlated negatively with the extent of cerebral microcirculatory

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reperfusion disordersdthe higher the early reperfusion pressure, the lower the amount of cerebral ‘‘no reflow’’ [14,16,41,42]. Leukocytes in trouble Another important mechanism of reperfusion injury and reperfusion failure in the microcirculation may be leukocyte adherence and leukocyte sticking and, therefore, blocking of microvessels [43,44]. Following 10 minutes of cardiac arrest and 6 hours of reperfusion, an increase in the number of polymorphonuclear leukocytes in the brain suggests that leukocytes may play a role in early cerebral microcirculatory reperfusion failure after cardiac arrest, as they play a role in reperfusion injury in other organs and different models [8]. This finding has been supported by clinical studies demonstrating that cardiocirculatory arrest and successful CPR are associated with a marked increase in the serum levels of polymorphonuclear neutrophil leukocyte (PMN) elastase, complement split products, terminal complement complex (sC5b-9), and soluble intercellular adhesion molecules [45–47]. Coagulation without fibrinolysis The most important pathophysiologic mechanism responsible for cerebral microcirculatory reperfusion disorders seems to be the activation of blood coagulation without adequate activation of endogenous fibrinolysis [48–52]. Intravascular fibrin formation and microthromboses are distributed throughout the entire microcirculation after cardiocirculatory arrest, and interventions that focus on hemostasis may be indicated during reperfusion. In the 1950s, Crowell and coworkers [53] demonstrated beneficial effects of anticoagulatory interventions for the first time in animals. Following 10 minutes of cardiac arrest, only a few dogs survived without heparin pretreatment, while the survival rate was 16% and 67% when doses of heparin, 2 mg/kg and 5 mg/kg of body weight respectively, were given before cardiac arrest [53]. In a later study, Crowell demonstrated beneficial effects of pretreatment with thrombolytic agents before cardiac arrest. In the control group, 14 of 15 animals died after 15 minutes of cardiac arrest [54]. The surviving animal suffered from severe neurologic damage. In contrast, only 2 of 14 animals died if streptokinase had been administered before cardiac arrest. Almost all neurologic deficits after cardiac arrest in this group disappeared within 2 months after stabilization [54]. Lin and coworkers [55] demonstrated that the administration of streptokinase combined with dextran reduces the duration of a flat line electroencephalogram (EEG) and improves cerebral blood flow after cardiac arrest in dogs. Safar and coworkers [56] observed an improvement in neurologic outcome in dogs receiving heparin, dextran, and hypertensive reperfusion as a combined therapeutic approach following 12 minutes of cardiac arrest. Based on clinical experience [57,58], the effect of thrombolysis during CPR on the extent of the cerebral ‘‘no reflow’’ phenomenon was


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investigated in cats [16]. Following 15 minutes of cardiac arrest, animals were allowed to reperfuse spontaneously for 30 minutes. Treated animals received a bolus injection of recombinant tissue-type plasminogen activator (rt-PA), 1 mg/kg of body weight, combined with heparin, 100 U/kg of body weight, during CPR, followed by another 1 mg/kg dose of rt-PA during reperfusion [16]. The administration of rt-PA and heparin led to a significant reduction (8% versus 29%) in the cerebral ‘‘no reflow’’ phenomenon in the entire forebrain. This positive effect was particularly relevant in basal ganglia and brainstem, and bleeding complications did not occur either [16]. Therefore, there is profound experimental evidence suggesting that hemostatic disorders may affect overall outcome, and particularly cerebral outcome, after cardiac arrest. Clinical investigations Based on this promising data, a prospective pilot intervention trial in patients undergoing CPR after out-of-hospital cardiac arrest was performed [59]. Overall, 90 patients were included. Heparin and rt-PA were given in 40 patients. In the rt-PA group, ROSC was achieved in 68%; and 58% of patients were able to be admitted to a cardiac intensive care unit, as compared with 44% and 30% of controls. These differences were significant. At 24 hours after cardiac arrest, 35% of patients who were treated with rt-PA (versus 22% of controls) were still alive, and 15% of rt-PA-treated patients (versus 8% of controls) were discharged from the hospital. There were no bleeding complications related to the CPR procedures. These data were supported by a retrospective case-control study of 108 patients who were treated with rt-PA [60]. A randomized and controlled multicenter clinical trial on thrombolysis during CPR is currently underway. Overall, more than 1000 patients will be enrolled in more than 40 centers. The results of this large-scale, randomized, controlled clinical trial to improve microcirculatory reperfusion following cardiac arrest (Thrombolysis in Cardiac Arrest [TROICA] trial) will be available in 2006 [61–63]. Therapeutic mild hypothermia The use of therapeutic hypothermia following different hypoxic-ischemic insults has played an important role in various concepts of nonspecific protection of cells for a long time [64]. Within several cell and animal experimental models, hypothermia was shown to inhibit a wide range of intracellular death cascades. A large body of evidence suggests that the protective effects of cooling are much greater than can be explained by the reduction in oxygen and glucose metabolism of about 5% to 7% per C alone [65–72]. Mild therapeutic hypothermia has shown to foster neuroprotection via inhibition of apoptosis [66], reduction of free radicals [67,68] and excitatory neurotransmitters [69–71], and stabilization of membranes [72].

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Several case reports of accidental hypothermia and good neurologic outcome even after long periods of ischemia [73] led to clinical attempts to use deep hypothermia (!28 C) in the setting of severe head injury [74] and perioperatively during cardiac surgery and neurosurgery [75–77]. Although the use of deep therapeutic hypothermia after cardiac arrest in the last century did not lead to an improved outcome [78], recent data show positive effects of mild therapeutic hypothermia [18,79–81] after cardiac arrest and other life-threatening events [82]. The data from the European multicenter trial (‘‘hypothermia after cardiac arrest,’’ HACA trial [19]), as well as those from Australia [18], clearly demonstrate a decrease in mortality (Fig. 3) and a better neurologic outcome for patients who are cooled to 32 C to 34 C for 12 or 24 hours. The European trial included 275 patients with witnessed cardiac arrest and ventricular fibrillation and who were comatose at hospital admission. One hundred thirty-eight of them were cooled to a bladder temperature of 32 C to 34 C for 24 hours (Fig. 4), whereas 137 remained normothermic. The hypothermia group showed a good neurologic outcome (able to live independently and work at least part-time; 55% versus 39%) significantly more often with a number needed to treat (NNT) of 6 (relative risk 1.40; 95% confidence interval 1.08 to 1.81) and higher 6 months survival rate (59% versus. 49%; relative risk 0.74; 95% confidence interval 0.58-0.95; NNT ¼ 7). Even when the duration of hypothermia is shortened to 12 hours (target temperature 33 C), as done in the Australian study [18], survival rate with good neurologic outcome is improved (hypothermia 49% versus normothermia 26%; n ¼ 43 versus 34). In 2003, such findings led to the implementation of mild therapeutic hypothermia (32 C–34 C) in the International Liaison Committee on Resuscitation (ILCOR) recommendations and

Fig. 3. Kaplan-Meier blot of the cumulative survival in the normothermia and hypothermia groups of the European trial on hypothermia after cardiac arrest [19]. (From The Hypothermia After Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002;346:549–56; with permission.)


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Fig. 4. Bladder temperature in the normothermia and hypothermia groups of the European trial on hypothermia after cardiac arrest [19]. The T bars indicate the 75th percentile in the normothermia group and the 25th percentile in the hypothermia group. (From The Hypothermia After Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002;346:549–56; with permission.)

guidelines for the treatment of unconscious patients after prehospital cardiac arrest [20]: On the basis of the published evidence to date, the ILCOR ALS Task Force has made the following recommendations: Unconscious adult patients with spontaneous circulation after out-ofhospital cardiac arrest should be cooled to 32-34.8 C for 12-/24 h when the initial rhythm was VF. Such cooling may also be beneficial for other rhythms or in-hospital cardiac arrest.

Therefore, therapeutic hypothermia should be implemented in clinical practice. It is now the first clinically relevant therapeutic approach to improve cerebral and overall outcome after cardiac arrest. Glucose control Hyperglycemia is a common problem in the postarrest period [83,84]. Experimental and clinical data demonstrate that postischemic blood glucose concentration plays an important role in modulating ischemic cerebral infarction and selective neuronal death [85]. Data from several experimental animal studies suggest the use of insulin infusion to overcome those devastating effects of high levels of glucose after ischemic brain damage [86,87]. Recently a large study of critically ill patients admitted to surgical ICUs demonstrated a significant mortality benefit when glucose levels were set to a range between 80 and 110 mg/dL using insulin infusion [88]. Up to now there is no prospective, controlled human trial after cardiac arrest to

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support this practice directly. The biologic plausibility of the benefit from controlling hyperglycemia with insulin infusion is strong, however; and therefore there is a ‘low grade’ recommendation to adjust blood glucose levels to between 90 and 145 mg/dL [89]. Future perspectives More experimental approaches are focusing on the use of a hibernating state after cardiac arrest. Various animals use hibernation during times of extreme environmental conditions like low temperature or food and water deprivation. Hibernation in mammals is characterized by a physiologic state with significant reduction in body-core temperature and metabolic rate [90] resulting from a reduced set-point of thermoregulation. Those physiologic changes provide strong resistance to cerebral ischemia [91]. Reducing bodycore temperature by way of modulation of the set-point, as done within hibernation, might be a superior concept to forced hypothermia because of the avoidance of the homeostatic mechanisms counteracting reductions in body temperature. Physiologic stress accompanied by a myriad of responses like shivering and increased catecholamine and cortisol levels during forced hypothermia might decrease cooling speed and efficacy of the hypothermic treatment [92]. Therefore the evaluation of controlled hypothermia- or hibernation-inducing drugs in future studies seems mandatory. Several substances have been tested for their efficiency in inducing regulated hypothermia/hibernation. The hibernation-induction trigger, an 88 kd peptide found in the serum of hibernating ground squirrels, can increase the survival time in a multiorgan preparation model with dogs [93]. Within the same model, it was shown that a delta opiode receptor agonist like D-Ala2, D-Leu5-enkephalin (DADLE) extends hypothermic preservation time of the lung [94]. A modified neurotensin 77 given intravenously is able to induce hibernation for several hours in rats [95] and improves neurologic outcome after hypoxic-ischemia [96]. Recently an article in Science demonstrated that H2S induces a suspended–animation-like state in mice by way of inhibiting oxidative phosphorylation [97]. Taken together, there are several at least theoretical possibilities for inducing regulated hypothermia by way of modulation of the thermoregulatory set-point. Clinical practice Neuronal injury following global cerebral ischemia continues to be a central problem of patients in the postresuscitation phase. Particular attention must be paid to measures that serve to preserve neurologic function. Besides all measures focusing on rapid restoration of spontaneous circulation, such as the use of defibrillators to treat ventricular fibrillation and the choice of a suitable vasopressor, several postarrest treatment options have been explored in recent years. Probably the most effective treatment after cardiac arrest, as shown by large randomized trials, is the use of therapeutic mild


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hypothermia. Current guidelines of ILCOR recommend the use of therapeutic mild hypothermia for all unconscious patients after cardiac arrest. To date, there is no specific neuroprotective treatment available. However, good practice of critical care, such as the control of blood glucose, blood pressure, and oxygenation, should be provided. Promising animal experimental data concerning the use of thrombolytic agents during cardiopulmonary resuscitation has led to a large European multicenter trial (TROICA trial) that will provide its data in 2006.

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[61] Bo¨ttiger BW, Spo¨hr F. The risk of thrombolysis in association with cardiopulmonary resuscitation: no reason to withhold this causal and effective therapy. J Intern Med 2003;253: 99–101. [62] Spo¨hr F, Bo¨ttiger BW. Safety of thrombolysis during cardiopulmonary resuscitation. Drug Saf 2003;26:367–79. [63] Spo¨hr F, Bo¨ttiger BW. Thrombolytic therapy during or after cardiopulmonary resuscitation. Efficacy and safety of a new therapeutic approach. Minerva Anestesiol 2003;69:357–64. [64] Williams GR Jr, Spencer FC. The clinical use of hypothermia following cardiac arrest. Ann Surg 1958;148:462–8. [65] Rosomoff HL, Holaday DA. Cerebral blood flow and cerebral oxygen consumption during hypothermia. Am J Physiol 1954;179:85–8. [66] Xu L, Yenari MA, Steinberg GK, et al. Mild hypothermia reduces apoptosis of mouse neurons in vitro early in the cascade. J Cereb Blood Flow Metab 2002;22:21–8. [67] Hashimoto T, Yonetani M, Nakamura H. Selective brain hypothermia protects against hypoxic-ischemic injury in newborn rats by reducing hydroxyl radical production. Kobe J Med Sci 2003;49:83–91. [68] Kil HY, Zhang J, Piantadosi CA. Brain temperature alters hydroxyl radical production during cerebral ischemia/reperfusion in rats. J Cereb Blood Flow Metab 1996;16:100–6. [69] Takata K, Takeda Y, Sato T, et al. Effects of hypothermia for a short period on histologic outcome and extracellular glutamate concentration during and after cardiac arrest in rats. Crit Care Med 2005;33:1340–5. [70] Busto R, Globus M, Dietrich W, et al. Effect of mild hypothermia on ischemia-induced release of neurotransmitters and free fatty acids in rat brain. Stroke 1989;20:904–10. [71] Hachimi-Idrissi S, Van Hemelrijck A, Michotte A, et al. Postischemic mild hypothermia reduces neurotransmitter release and astroglial cell proliferation during reperfusion after asphyxial cardiac arrest in rats. Brain Res 2004;1019:217–25. [72] Fischer S, Renz D, Wiesnet M, et al. Hypothermia abolishes hypoxia-induced hyperpermeability in brain microvessel endothelial cells. Brain Res Mol Brain Res 1999;74:135–44. [73] Husby P, Andersen KS, Owen-Falkenberg A, et al. Accidental hypothermia with cardiac arrest: complete recovery after prolonged resuscitation and rewarming by extracorporeal circulation. Intensive Care Med 1990;16:69–72. [74] Fay T. Observation on generalized refrigeration in cases of severe cerebral trauma. Res Publ Assoc Res Nerv Ment Dis 1945;4:611–9. [75] Bigelow WG, Callaghan JC, Hopps JA. General hypothermia for experimental intracardiac surgery; the use of electrophrenic respirations, an artificial pacemaker for cardiac standstill, and radio-frequency rewarming in general hypothermia. Trans Meet Am Surg Assoc Am Surg Assoc 1950;68:211–9. [76] Botterell EH, Lougheed WM, Morley TP, et al. Hypothermia in the surgical treatment of ruptured intracranial aneurysms. J Neurosurg 1958;15:4–18. [77] Botterell EH, Lougheed WM, Scott JW, et al. Hypothermia, and interruption of carotid, or carotid and vertebral circulation, in the surgical management of intracranial aneurysms. J Neurosurg 1956;13:1–42. [78] Weinrauch V, Safar P, Tisherman S, et al. Beneficial effect of mild hypothermia and detrimental effect of deep hypothermia after cardiac arrest in dogs. Stroke 1992;23:1454–62. [79] Bernard SA, Jones BM, Horne MK. Clinical trial of induced hypothermia in comatose survivors of out-of-hospital cardiac arrest. Ann Emerg Med 1997;30:146–53. [80] Eisenburger P, Sterz F, Holzer M, et al. Therapeutic hypothermia after cardiac arrest. Curr Opin Crit Care 2001;7:184–8. [81] Leonov Y, Sterz F, Safar P, et al. Mild cerebral hypothermia during and after cardiac arrest improves neurologic outcome in dogs. J Cereb Blood Flow Metab 1990;10:57–70. [82] Dixon SR, Whitbourn RJ, Dae MW, et al. Induction of mild systemic hypothermia with endovascular cooling during primary percutaneous coronary intervention for acute myocardial infarction. J Am Coll Cardiol 2002;40:1928–34.


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[83] Longstreth WT Jr, Inui TS. High blood glucose level on hospital admission and poor neurological recovery after cardiac arrest. Ann Neurol 1984;15:59–63. [84] Longstreth WT Jr, Diehr P, Cobb LA, et al. Neurologic outcome and blood glucose levels during out-of-hospital cardiopulmonary resuscitation. Neurology 1986;36:1186–91. [85] Mullner M, Sterz F, Binder M, et al. Blood glucose concentration after cardiopulmonary resuscitation influences functional neurological recovery in human cardiac arrest survivors. J Cereb Blood Flow Metab 1997;17:430–6. [86] Voll CL, Auer RN. The effect of postischemic blood glucose levels on ischemic brain damage in the rat. Ann Neurol 1988;24:638–46. [87] Voll CL, Whishaw IQ, Auer RN. Postischemic insulin reduces spatial learning deficit following transient forebrain ischemia in rats. Stroke 1989;20:646–51. [88] van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patient. N Engl J Med 2001;345:1359–67. [89] Bell DD, Brindley PG, Forrest D, et al. Management following resuscitation from cardiac arrest: recommendations from the 2003 Rocky Mountain Critical Care Conference. Can J Anaesth 2005;52:309–22. [90] Frerichs KU, Dienel GA, Cruz NF, et al. Rates of glucose utilization in brain of active and hibernating ground squirrels. Am J Physiol 1995;268:R445–53. [91] Frerichs KU, Hallenbeck JM. Hibernation in ground squirrels induces state- and speciesspecific tolerance to hypoxia and aglycemia: an in vitro study in hippocampal slices. J Cereb Blood Flow Metab 1998;18:168–75. [92] Gordon CJ. The therapeutic potential of regulated hypothermia. Emerg Med J 2001;18: 81–9. [93] Chien S, Oeltgen PR, Diana JN, et al. Two-day preservation of major organs with autoperfusion multiorgan preparation and hibernation induction trigger. A preliminary report. J Thorac Cardiovasc Surg 1991;102:224–34. [94] Wu G, Zhang F, Salley RK, et al. delta Opioid extends hypothermic preservation time of the lung. J Thorac Cardiovasc Surg 1996;111:259–67. [95] Tyler BM, Douglas CL, Fauq A, et al. In vitro binding and CNS effects of novel neurotensin agonists that cross the blood-brain barrier. Neuropharmacology 1999;38:1027–34. [96] Katz LM, Young A, Frank JE, et al. Neurotensin-induced hypothermia improves neurologic outcome after hypoxic-ischemia. Crit Care Med 2004;32:806–10. [97] Blackstone E, Morrison M, Roth MB. H2S induces a suspended animation-like state in mice. Science 2005;308:518.

Neurol Clin 24 (2006) 89–106

Clinical Neurophysiologic Monitoring and Brain Injury from Cardiac Arrest Matthew A. Koenig, MDa,*, Peter W. Kaplan, MBBSb, Nitish V. Thakor, PhDc a

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA b Department of Neurology, Johns Hopkins Bayview Medical Center, Baltimore, MD, USA c Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA

With the introduction of closed chest compressions and the advent of modern cardiopulmonary resuscitation (CPR) techniques in the 1960s, physicians gained a simple means of restoring circulation after cardiac arrest. Although basic CPR techniques and postresuscitation intensive care management have improved during the past 4 decades, outcomes after cardiac arrest have remained static. Only approximately 50% of CPR attempts restore spontaneous circulation successfully [1]. Of these survivors, 80% remain unconscious in the immediate postresuscitative period and only 10% to 20% ever have meaningful neurologic recovery [1,2]. Much effort has been devoted to early prognostication while patients remain in coma after successful CPR. Given the ethical, familial, and economic burden of continuing intensive care management of patients unlikely to achieve meaningful neurologic recovery, there exists a profound need for accurate methods of early injury stratification. Investigational tools used in early prognostication include cerebrospinal fluid markers of brain injury, electrophysiologic monitoring early and late in the recovery period, functional and anatomic imaging techniques, microdialysis of markers implicated in secondary brain injury, and calculation of brain oxygen extraction. This review focuses on the use of electrophysiologic tools, electroencephalography (EEG) and somatosensory evoked potentials (SSEP), in monitoring brain function after resuscitation from cardiac arrest. * Corresponding author. Johns Hopkins Hospital, Department of Neurology, 600 North Wolfe Street, Baltimore, MD 21287. E-mail address: [email protected] (M.A. Koenig). 0733-8619/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.ncl.2005.11.003 neurologic.theclinics.com

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EEG has been used since the 1960s to prognosticate in patients who are comatose after cardiac arrest. Many injury stratification schemes have been devised and several malignant patterns identified, the best validated of which are reviewed. The limitation of EEG for prognostication is that although some patterns seem specific for poor outcomes, the prognostic accuracy of EEG is poor unless those patterns are present. SSEP has been studied more recently and seems to offer higher specificity for determining bad outcomes but probably is less accurate than EEG in determining which patients are destined to have good recovery. EEG and evoked potentials have remained popular for evaluation of patients in coma after cardiac arrest because they are noninvasive, widely available, inexpensive to perform and interpret, familiar to referring physicians, and validated for this purpose. The traditional role of neurologists in the care of cardiac arrest survivors is to prognosticate based on a combination of neurologic signs and electrophysiologic tests that can be performed hours to days after resuscitation. With some exceptions, neurologists rarely are involved during the resuscitative effort or immediate postarrest care. From an investigational standpoint, the period immediately after resuscitation involves dynamic changes in regional brain perfusion, secondary neuronal injury, and electrophysiologic recovery. Rather than focusing on the usefulness of electrophysiologic monitoring for prognostication, investigational techniques are explored for using EEG and evoked potentials in real-time monitoring of coma arousal after cardiac arrest, early injury stratification, defining a time window for potential neuroprotective strategies, and monitoring response to therapeutic efforts. In addition, this article reviews advances of quantitative EEG and SSEP techniques in tracking injury and recovery in several animal models of cardiac arrest. Electroencephalography Over the years, many grading scales have been proposed to predict survival and neurologic outcomes in comatose survivors of cardiac arrest, but the most popular scale was published by Hockaday and colleagues in 1965 [3]. This scale divided the EEG into five distinct grades based on the dominant frequency and presence of specific unfavorable patterns (Table 1). The EEG grades subsequently have been demonstrated to correlate with prognosis, especially when unfavorable EEG patternsdincluding electrocerebral silence (ECS) and burst suppressiondare present more than 24 hours after cardiac arrest. Prior [4] reports EEG findings from 96 comatose survivors of cardiac arrest. All 25 patients who had sustained ECS and 25 of 26 patients who had burst suppression remained in coma indefinitely or died. Of the 45 patients who had benign EEG tracings, most recovered initially to some extent, but 31 subsequently succumbed to underlying systemic diseases. Møller and coworkers [5] report EEG findings from 185 patients who had cardiac arrest after myocardial infarction. In this population, 70% of patients who had grade I or II EEG (n ¼ 115) survived to discharge with no neurologic

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Table 1 Classification of electroencephalogram findings Grade I Grade I Grade III Grade IV

Grade V

Dominant, normal alpha activity Dominant, normal alpha activity with theta-delta activities Dominant theta-delta activity with still detectable normal alpha activities Theta-delta activity without alpha activities Delta activity, low voltage, possibly with short isoelectric intervals Dominant, monomorphic, nonreactive alpha activity (alpha coma) Periodic generalized phenomena (spikes, sharp waves, slow waves) with very low-voltage background activity Very flat to isoelectric EEG (less than 10–20 mV)

From Scollo-Lavizzari, G, Bassetti C. Prognostic value of EEG in post-anoxic coma after cardiac arrest. Eur Neurol 1987;26:161–70.

deficit or minor impairment, whereas only 3% (n ¼ 70) who had grades III to V EEG survived. In the high-grade survivors, serial EEG testing demonstrates a shift from high-grade to low-grade patterns over subsequent days. These findings emphasize that EEG patterns are dynamic after cardiac arrest, and application of the standard grading scale early after resuscitation seems to have lower validity. Different iterations of the coma grading scale have been applied in many studies of prognosis after cardiac arrest. Scollo-Lavizzari and Bassetti [6] reviewed the literature on prognosis of comatose survivors of cardiac arrest by EEG recorded at least 6 hours after resuscitation. Reviewing the records of 408 patients, they found meaningful neurologic recovery in 78% of grade I, 0% of grades IV and V, and intermediate recovery in grades II and III (Table 2). The lack of a uniform patient population renders comparison between studies difficult. In particular, the level of arousal at the time of EEG, duration of coma, and interval between resuscitation and EEG recording all change the prognostic value. Edgren and colleagues [2] report EEG tracings in 32 patients recorded 24 hours after cardiac arrest. Patients in this series had at least 10 minutes of coma after cardiac arrest, but many were not in coma at the time the EEG was recorded. In this population, a good outcome was achieved in 7 of 8 patients who had grade I EEG, 5 of 13 who had Table 2 Prognosis with the five electroencephalogram grades given (408 cases from the literature) Electroencephalogram category

Recovery (%)

Survival with permanent neurologic damage (%)

Death (%)

Grade Grade Grade Grade Grade

79 51 26 0 0

10 13 7 2 0

11 36 67 98 100

I II III IV V

From Scollo-Lavizzari, G, Bassetti C. Prognostic value of EEG in post-anoxic coma after cardiac arrest. Eur Neurol 1987;26:161–70.

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grade II, and none of 8 who had higher-grade findings at 24 hours. Alternatively, Bassetti and coworkers [7] report on 60 patients who were in coma for more than 6 hours after resuscitation from cardiac arrest. In this study, all 20 patients who had grade IV or V EEG either died or remained in coma indefinitely and only 4 of 10 patients who had favorable EEG (grade I or II) had a good neurologic recovery. In another series [8] of 64 patients in coma for greater than 24 hours after cardiac arrest, there was no correlation between EEG grade and duration of survival. In this population, only 2 of 8 patients who had grade I EEG patterns survived, both with mental impairment. The discrepancies between these results emphasize the degree to which the prognostic grading scale is changed by the population studied. The duration of coma is an independent risk factor for poor outcome, so normal or mildly abnormal EEG findings are an unreliable predictor of good outcome in prolonged coma. In addition, high-grade EEG findings have low sensitivity, identifying only half of patients who are comatose who die or remain in a vegetative state. Binnie and colleagues [9] drew early attention to the concept that regardless of the dominant EEG frequency, the failure of EEG tracings to react to external stimuli portends a poor prognosis for meaningful recovery. Analyzing the EEG characteristics beyond dominant frequency may improve the diagnostic accuracy of low-grade EEG patterns. Synek [10,11] emphasizes the importance of reactivity and amplitude of the EEG pattern and the presence or absence of epileptiform activity beyond the dominant frequency. He reports that the diagnostic accuracy of the EEG grading scale improves to 98.4% when the scale is altered to include reactivity, epileptiform activity, and amplitude at each of the first three grades [10]. Although numbers were small in each group, survival occurred in 2 of 2 patients who had reactive grade III EEG, 3 of 4 patients who had unreactive grade III, 2 of 4 patients who had grade III EEG and epileptiform activity, and none of 3 patients who had low-amplitude grade III EEG [11]. Generalized electrical suppression Some patterns of EEG activity seem to portend an extremely poor prognosis in comatose survivors of cardiac arrest, especially when reported more than 24 hours after resuscitation. Several reports emphasize the prognostic gravity of ECS, burst suppression, and generalized alpha or theta activity unreactive to external stimulation (alpha and theta coma) [12]. There are no generally accepted criteria for ECS, although some investigators attempt to provide voltage criteria. Young [13] reports survival in 1 patient who had incomplete EEG suppressiondvoltage between 10 and 20 mVdafter 24 hours but none who had voltage lower than 10 mV. There are no reports in the adult or pediatric literature of survival with true ECS that was recorded more than 24 hours after resuscitation. In normothermic patients who are free of toxic ingestion or pharmacologic sedation, the presence of ECS


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more than 24 hours after cardiac arrest is the only undisputed indication of no chance of meaningful neurologic recovery. Generalized burst suppression Generalized burst suppression after cardiac arrest usually, but not invariably, is associated with no prognosis for meaningful neurologic recovery [13]. The term, burst suppression, indicates bursts of electrical activity of variable duration separated by periods of generalized suppression lasting at least 1 second [14]. The bursts may range from high-amplitude delta activity or polyspike and slow wave complexes with epileptiform characteristics [14]. The physiology of burst suppression remains to be elucidated fully, but the generally accepted theory relates burst suppression to functional dissociation of the cortex from the intrinsic pacemaker firing of neurons in the reticular thalamus [15,16]. As such, persistent burst suppression seems to be a marker for severe injury to the thalamus, cerebral cortex, and interconnecting relay circuits. Burst suppression may occur alone or in combination with underlying low-voltage unreactive alpha or theta activity [17,18]. Burst suppression is associated with a universally fatal outcome or persistent vegetative state (PVS) in multiple series [19,20]. There are scattered reports of survival and good neurologic recovery in patients who are comatose with burst suppression after cardiac arrest [21,22], especially when the EEG is performed early after resuscitation and epileptiform activity is absent. Spontaneous movement is seen variably in association with bursts and can range from simple mouth movements to violent, generalized myoclonic jerks of the extremities. The presence or absence of movement during bursts does not seem to alter the prognostic implications of this EEG pattern, however [23]. Like ECS, it is important to ensure that patients have not been exposed to anesthetic agents or toxic medication overdose before placing undue prognostic importance on burst suppression. Alpha and theta coma Reactivity of the EEG carries greater prognostic importance than the dominant frequency alone. Patients who have the normal posteriorly dominant pattern of alpha activity that is suppressed by eye opening and enhanced by eye closure or noxious stimulation have a good prognosis for meaningful recovery in the appropriate clinical context. This pattern is in stark contrast to comatose cardiac arrest survivors who have generalized or frontally dominant alpha patterns with constant, unwavering frequency and amplitude that is unresponsive to stimulation. Also known as alpha comador theta coma when extending into the fast theta banddthis EEG pattern may be seen in 10% to 15% of cases of postanoxic coma [5,24]. The physiology of alpha coma and its distinction from physiologic alpha remain to be elucidated. It probably is regarded best, however, as a transitional pattern that evolves into a more prognostically definitive pattern in 90% of

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patients within 6 days [25]. On serial EEG, those patients who die without regaining consciousness evolve into burst suppression and survivors regain electrographic reactivity to external stimuli [12,26]. Chokroverty [27] reports survival of 2 of 12 patients who had alpha coma patterns after cardiac arrest. In both cases, the EEG was recorded early after resuscitation and serial testing revealed evolution to more benign patterns. In a large series of patients who underwent continuous EEG recording immediately after CPR, however, alpha coma patterns were detected early after resuscitation in 31 patients, 25 of whom eventually regained consciousness and 9 of whom progressed to full recovery [28]. Overall, however, alpha and theta coma are associated with an 88% chance of death or PVS according to a metaanalysis of the world literature [12]. Electroencephalogram patterns evolve after resuscitation The proximity of the first EEG recording to the time of resuscitation after cardiac arrest has a major impact on the distribution and prognostic importance of electrical patterns (Figs. 1 and 2). Several investigators report EEG findings in patients during cardiac arrest and resuscitation. Losasso and coworkers [29] report a case of asystole lasting 2 minutes in a patient undergoing continuous EEG monitoring during carotid endarterectomy. Within 10 seconds of asystole, there was generalized suppression on the EEG,

Fig. 1. Burst-suppression EEG pattern after cardiac arrest demonstrating periodic generalized bursts of sharply contoured electrical activity separated by periods of EEG suppression.


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Fig. 2. Alpha coma EEG pattern after cardiac arrest demonstrating unwavering generalized alpha frequency electrical activity unresponsive to stimulation and lacking the normal posterior predominance.

leading immediately to ECS. Low-voltage, high-frequency activity began to return within 15 to 20 seconds of external chest compressions with gradual re-emergence of baseline EEG rhythm. Another patient had EEG monitoring during a 27-second episode of asystole [30]. In this case, the EEG returned immediately to baseline after return of spontaneous circulation (ROSC). Case reports using bispectral index [31] and compressed spectral array monitoring of EEG [32] during intraoperative cardiac arrest yield similar findings. Clute and Levy [33], in an unusual study design, monitored EEG changes in humans undergoing automated internal cardioverting defibrillator (AICD) placement. During AICD testing, patients routinely underwent brief induction of ventricular fibrillation resulting in a controlled period of cardiac arrest. In this study, the mean time of onset of EEG change from baseline was 10.2 seconds (range 3.3–21.1 seconds) after induction of ventricular fibrillation. The majority of patients demonstrated slowing and attenuation or sudden loss of activity above the delta range. EEG activity returned to baseline immediately after cardioversion. Several series are published of serial EEG recordings or continuous monitoring of patients within hours of resuscitation from cardiac arrest. Pampiglione [34] reports the frequent occurrence of burst suppression within hours of cardiac arrest in a series of children. A study of EEG recorded within 3 hours of birth asphyxia in full term infants, however, reports survival

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with good neurologic outcomes in 3 infants whose initial EEG had burst suppression [35]. In these cases, the EEG evolved from burst suppression to continuous activity within 3 hours. All of these infants, however, had been treated with phenobarbital before the EEG recording. In a series of 42 cases of cardiac arrest survivors who underwent EEG within the first 12 hours after resuscitation, Cloche and coworkers [22] report the EEG pattern changed within the first 48 hours, including five cases in which ECS evolved into a reactive pattern after several hours. Regardless of changes in the EEG pattern, however, they found that patients who had an initial EEG demonstrating ECS or burst suppression had a uniformly fatal outcome. Similar results were reported in a series of 371 patients studied soon after resuscitation [36], although exact times were not provided. A more definitive description of the evolution of human EEG in the hours after resuscitation comes from an important series of publications from Jørgensen and colleagues. A neurologist was present during the resuscitative effort and monitored EEG and neurologic examination findings continuously during and after ROSC. In a series of 37 patients who regained consciousness after resuscitation from cardiac arrest, all patients displayed ECS immediately upon re-establishment of circulation [37]. During this period, decerebrate posturing and return of cranial nerve reflexes often occurred. The first electrical activity resumed 10 minutes to 8 hours thereafter. In most cases, the EEG initially showed burst suppression before fusion to a continuous rhythm. Decorticate posturing and myoclonus sometimes occurred during this phase of recovery. Burst suppression lasted as long as 16 hours before fusion in 1 patient. In the minority of cases, continuous electrical activity occurred without a preceding period of burst suppression. In all cases, the frequency and amplitude of continuous activity increased with time. Re-emergence of continuous activity was correlated poorly with arousal, however, and predominant alpha activity often was reported before awakening [37]. In a second series of 88 patients who did not regain consciousness after CPR, 71 patients regained electrocortical activity at some point after resuscitation [38]. Of these patients, only 12 regained continuous electrical activity, whereas the remainder continued in burst suppression indefinitely. The time of initial electrical activity was significantly later in these patients, ranging from 15 minutes to 124 hours after resuscitation. In the small number of patients who regained continuous EEG activity, the interim to EEG fusion also was longer (range 4 to 127 hours) compared with patients who emerged ultimately from coma. In a third series of 231 patients who underwent EEG monitoring immediately after CPR, those who had immediate return of EEG activity after resuscitation made a full recovery more often than those who had initial ECS [28]. The duration of burst suppression before return of continuous EEG activity also correlated with prognosis for coma emergence. In these series, the longest interval after resuscitation for a patient who subsequently regained consciousness to remain with ECS was 3.3 hours and 10.5 hours for burst suppression [36].


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Real time measures of brain electrophysiology during cardiac arrest and the immediate period after resuscitation, however, are studied best with animal models. Models of cardiac arrest have been developed and validated using rats, monkeys, dogs, and cats during the past few decades. Improving technology in signal processing and quantitative EEG during the past few years has led to new tools to track recovery after cardiac arrest and to define the window of time for possible neuroprotective intervention. EEG recordings during experimental cardiac arrest closely mirror the findings reported by Jørgensen and colleagues in humans immediately after resuscitation. In dogs, ECS occurs within 10 to 30 seconds of cardiac arrest [39]. Several hours of burst-suppression EEG also are reported in dogs after resuscitation [39–42]. The burst-suppression pattern evolved over 2 to 3 hours, with shortening of the duration of suppression and increasing frequency, duration, and complexity of burst periods until activity fused to a continuous pattern [41]. In the dog model, the rate of EEG recovery correlated with degree and rate of recovery, as determined by pathologic evidence of ischemic neurons and neurologic examination deficit scales [42]. Prognosis for neurologic recovery was correlated directly with the latency of initial EEG activity, continuous activity, and the duration of burst suppression [42–44]. Similar EEG recovery patterns also are reported in monkey [45] and neonatal piglet models of cardiac arrest [46]. A rat model of electrophysiologic monitoring after cardiac arrest has been developed more recently. This model is validated by demonstration of histologic evidence of ischemic cell death in the expected brain structures after cardiac arrest [47,48]. In this model, ECS is achieved within seconds of cardiac arrest, followed by continued silence for a variable period after ROSC [49]. As in other models, a period of burst suppression precedes return of continuous EEG activity [50,51]. As in the dog model, the duration of burst-suppression activity before return of continuous EEG is correlated with outcomes, using pathologic evidence and neurologic deficit scales to quantify injury [51]. Those rats destined for poor outcomes at 48 hours demonstrated longer intervals of suppression and less frequent bursts at each time point during the recovery period, compared with animals with good outcomes [51,52]. The interval to return of continuous EEG activity also correlated with clinical signs of arousal, whereby rats who achieved EEG fusion earlier also demonstrated earlier purposeful hind limb movements [52]. The interval to return of continuous EEG also can be used to track secondary injury. Those rats subjected to hyperglycemia after cardiac arrest, which is known to exacerbate ischemic injury, remained in burst suppression longer than normoglycemic controls [50]. Quantitative electroencphalogram To increase the objectivity and sensitivity of EEG analysis for markers of recovery, several quantitative EEG techniques have been applied to the rat

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model of cardiac arrest. Using cepstral distance, a frequency-based measure of difference between baseline EEG and various time points during recovery, graded injury can be quantified accurately after cardiac arrest [52,53]. Rats subjected to graded injury by 1-, 3-, 5-, and 7-minute cardiac arrest duration can be distinguished using cepstral distance measures to quantify the time to EEG recovery. These quantitative EEG measures also correlate with clinical and pathology extent of injury [53,54]. Power spectral analysis of EEG also has been undertaken in dogs [55]. In this model, dogs treated with neuroprotective free radical scavengers had earlier restitution of EEG power in the high frequency range compared with untreated controls after resuscitation from cardiac arrest [55]. More recently, quantitative EEG measurement of entropy shows promise in prognosticating degree of injury and monitoring therapeutic responses to neuroprotective therapies [56,57]. Entropy, a mathematic measure of randomness or predictability of EEG patterns, may be an ideal technique for monitoring injury because all of the pathologic patterns after cardiac arrestdseizure activity, burst suppression, alpha coma, and ECSdhave low entropy compared with continuous EEG patterns seen in animals with good potential for recovery [57–59]. Recent data from the authors’ work show that treatment with mild hypothermiadwhich has demonstrated neuroprotective effects in rats after ischemic brain injurydcauses a more rapid increase in EEG entropy compared with that in controls [60]. The potential to use quantitative EEG measures to quantify injury, track recovery, test neuroprotective strategies, provide early prognostic information, and define the therapeutic time window currently is being explored in humans and animals. Somatosensory evoked potentials Short-latency median nerve SSEP studies also can provide a prognosis in comatose survivors of cardiac arrest. This electrophysiologic test examines for continuity of the sensory pathways triggered by an electrical stimulus applied to the median nerve sensory distribution. Response to the sensory stimulus then is monitored through the peripheral nerve, nerve root, spinal cord, subcortical brain structures, and primary sensory cortex. The negative slope of the scalp-evoked potential (P15-N20) is generated by the thalamocortical radiation, whereas the following positive wave (N20-P25) reflects cortex [61]. Damage to subcortical structures, therefore, is reflected in slowing of central conduction with reduction of the N20 amplitude, whereas absence or distortion of the N20 peak represents cortical injury [61]. Bilateral loss of cortical N20 peaks, in the absence of known pre-existing cortical injury, is interpreted as widespread cortical injury after cardiac arrest. Several series demonstrate death or PVS in 100% of comatose cardiac arrest survivors who had bilaterally absent N20 peaks hours to days after resuscitation [7,61–64]. A recent meta-analysis [65] of reliable indicators of prognosis after cardiac arrest finds that only absent cortical SSEP responses, pupillary


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light reflexes on day 3, and motor response to pain on day 3 had 100% specificity for poor outcomes. The prognostic importance of reduced N20 amplitudes and prolonged central conduction times are less clear. In one series, 8 of 9 patients who had 50% to 75% decrement in N20 amplitude remained in PVS at 8 weeks [61]. In a different series, delayed or low amplitude N20 potentials were associated with poor outcome in 11 of 12 patients [7]. In another series, however, N20 amplitude and central conduction times were similar in patients who had good outcomes compared with those who died or remained comatose [66]. SSEP has excellent specificity for poor outcome after cardiac arrest when N20 peaks are absent, but the presence of normal N20 peaks has poor accuracy for predicting good outcomes. In an early series of patients who were in coma after cardiac arrest, all 6 patients who had normal N20 potentials ultimately aroused from coma and had good neurologic recovery [61]. In subsequent studies, however, normal SSEP responses are an unreliable predictor of good outcome [7,67]. Only 50% of patients who had normal N20 potentials ultimately regained consciousness in one series [7] and 25% in another [68]. To improve the ability of SSEP to predict more accurately good outcomes in comatose cardiac arrest survivors, Madl and coworkers evaluated long-latency N70 peaks in 66 patients [69]. In this series, N70 latency was less than 118 milliseconds in all patients who had good recovery and was absent or greater than 118 milliseconds in patients who had poor outcome [69]. In a larger series of 305 comatose cardiac arrest survivors, N70 peaks were present in 98% of those who ultimately made a good neurologic recovery [70]. Long latency responses are believed to reflect complex corticocortical pathways, important for intellectual functions. Somatosensory evoked potentials patterns after resuscitation Like EEG, recovery of SSEP also follows a predictable time course (Fig. 3). For this reason, assessment of SSEP early after resuscitation may lead to a falsely pessimistic interpretation. In a study of serial SSEP testing of comatose cardiac arrest survivors beginning 4 hours after resuscitation, there was significant improvement in SSEP responses in 76% of patients during a 24-hour period [71]. In particular, 2 patients who initially had absent N20 responses regained them within 12 hours after ROSC. The specificity for poor outcome with absent N20 responses increased from 0.43 at 4 hours to 1.0 at 24 hours [71]. The N20 peak latency declined significantly during the first 24 hours in the majority of patients. The detection of N70 peaks also increased from 7 of 25 patients at 4 hours to 14 of 25 patients at 24 hours, although the N70 latency tended to improve during the same time frame [71]. Only 3 of 7 patients who had eventual good outcomes had an N70 latency less than the 130 milliseconds at 4 hours, whereas all 7 were below this threshold at 24 hours [71]. At the same time, 3 patients who ultimately had poor outcomes also regained an N70 latency less than

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Fig. 3. Median nerve SSEP after cardiac arrest demonstrating absence of the cortical N20 peak (arrow).

130 milliseconds after 24 hours, suggesting the specificity of this finding for good outcomes decreases as the sensitivity rises. These findings contradict the results of a similar study in 30 patients who underwent SSEP 30 to 150 minutes after resuscitation from cardiac arrest [72]. In this series, no patients who had absent N20 responses on the first examination regained those responses with subsequent SSEP testing [72]. More recent studies have tried to further differentiate surviving patients who will be slightly or moderately disabled from those who would be


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severely disabled or in PVS. Gue´rit and colleagues studied event-related potentials produced by a passive auditory oddball paradigm in 103 patients as a function of GCS [73]. In a subset of 83 patients examined within 4 days, a biphasic negative-positive evoked potential (EP) complex was identified to have high specificity but low sensitivity for bad outcomes. This complex has a high sensitivity but low specificity for bad outcomes. The cortex is particularly sensitive to anoxia, whereas the brainstem is relatively resistant, explaining why the negative predictive value of late cortical EP likely is better than that of early subcortical EP. These assumptions are confirmed with studies using long- and short-latency auditory EP [74–76]. Because of these limitations, Gue´rit and colleagues adopted a three-modality approach dependent on two indices: the index of global cortical functioning, graded from I to IV based on visual evoked potentials and SSEP components after N20; and the index of brainstem conduction, calculated from brainstem auditory evoked potentials (BAEP) and SSEP components before and including N20 [76]. These investigators demonstrate that only the index of global cortical functioning was helpful prognostically in anoxic coma. Grades I, II, III, and IV were observed between the first and the third day of anoxic coma in 60%, 40%, 15%, and 0% of patients, respectively, who had good outcomes [76]. More detailed examination of the loss of evoked responses during cardiac arrest and the sequence of restitution of potentials after ROSC can be gleaned from animal models. In a cat model of SSEP during cardiac arrest, cortical responses were lost within 12 to 15 seconds of ischemia [77]. The shorter latency potentials then were lost sequentially during the ensuing 2 to 6 minutes. After resuscitation, shorter latency potentials recovered more rapidly and cortical evoked potentials regained 75% of their baseline amplitude within 6 hours [77]. In a dog model, all central components of the SSEP waveform were lost shortly after cardiac arrest [55]. The short latency components of the SSEP waveform, reflecting activation of the dorsal columns, thalamocortical relay structures, and cortical N20 potentials, recovered within 1 hour after resuscitation. The long latency N70 potentials recovered only in animals treated with neuroprotective medications but not in control animals after cardiac arrest. In simultaneously recorded BAEP in dogs, the amplitude began to decrease within 5 to 6 minutes after cardiac arrest [55]. Waves II through V, representing projections from the auditory nucleus through the inferior colliculus, flattened at 7 to 8 minutes. Wave I, representing potentials from the auditory nerve, flattened at 9 to 10 minutes after cardiac arrest. After ROSC, the BAEP gradually normalized in a caudorostral progression during the first hour, after which all latencies were normal [55]. This BAEP data is similar to a case report in a human subject resuscitated from cardiac arrest while undergoing BAEP testing [78]. This patient lost all BAEP responses within minutes of cardiac arrest. Waves I and II returned within 5 minutes of ROSC. Waves III through V also returned after 5 minutes but continued to have prolonged latencies out to 50 minutes from ROSC [78]. Taken

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together with the time course of EEG restitution, these data reflect the progressive loss of electrical activity in a rostrocaudal pattern during cardiac arrest and the caudorostral restitution of electrical activity after resuscitation. Those regions most resistant to electrical dysfunction after cardiac arrest are the first to return after resuscitation. With microelectrode placement into the ventroposterolateral (VPL) nucleus of the thalamus simultaneous to SSEP examination of the primary sensory cortex, the restitution of structures integral to generation of SSEP waveforms can be studied directly. In a rat model of graded injury from cardiac arrest, animals were subjected to 3, 5, and 7 minutes of arrest [54]. At the onset of asphyxia, thalamic firing was characterized by an increasingly asynchronous pattern followed by loss of firing during a 15-second span [79]. The rhythmic spindle oscillations of the VPL neurons were replaced by increased tonic firing during the first 45 seconds of asphyxia, followed by VPL silence within 1 minute [79]. In all three arrest times, restitution of the N20 potentials recovered to 60% of baseline at 2 hours after resuscitation. The VPL response occurred simultaneous with the recovery of N20 potentials in the short arrest times but was delayed relative to cortical responses in the 7-minute model [54,79]. These data demonstrate thalamocortical dissociation after cardiac arrest, during the period in which the EEG demonstrates burst suppression [54,79]. Summary Electrophysiologic testing continues to play an important role in injury stratification and prognostication in patients who are comatose after cardiac arrest. As discussed previously, however, the adage about treating whole patients, not just the numbers, is relevant in this situation. EEG and SSEP can offer high specificity for discerning poor prognosis as long as they are applied to appropriate patient populations. As discussed previously, EEG and SSEP patterns change during the first hours to days after cardiac arrest and negative prognostic information should not be based solely on studies performed during the first 24 hours. Both electrophysiologic techniques also are susceptible to artifacts that may worsen the electrical patterns artificially and suggest a falsely poor prognosis. EEG is suppressed by anesthetic agents and hypothermia, both of which may produce ECS and burst suppression. Patients who experience respiratory arrest from a toxic ingestion of narcotics or barbiturates, in particular, may present with high-grade EEG patterns initially. Many patients also receive anesthetic medications at the time of tracheal intubation, which may linger beyond their normal half-life in patients who have hepatic or renal insufficiency or concurrent use of interacting medications. SSEP is much less susceptible to sedative anesthetic agents, but hypothermia is demonstrated to prolong evoked potential latencies [60]. As therapeutic hypothermia becomes more common after cardiac arrest, the effect of temperature on electrophysiologic testing needs to be taken into account. The publications discussed


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previously also emphasize the need to adjust the prognostic value of electrophysiologic tests to the pretest probability of meaningful neurologic recovery in individual patients. Clearly, grade I EEG patterns and normal N20 potentials indicate a much better prognosis in patients who have a short duration of cardiac arrest, short duration of coma after resuscitation, and when the studies are performed within the first few days. In patients who remain in coma days after resuscitation and lack appropriate brainstem reflexes, however, even the most normal appearing electrophysiologic patterns do little to change the overall prognosis. Aside from prognostication, electrophysiologic testing holds great promise in defining the basic anatomy and physiology of coma emergence after cardiac arrest. In addition, quantitative EEG and automated evoked potentials have the potential to render these tools less subjective and arcane and more applicable for monitoring patients in the period during and immediately after resuscitation. Quantitative EEG also has great potential as a tool to define the time window for neuroprotective intervention and the means to track the response to such therapies in real time.

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Neurol Clin 24 (2006) 107–121

Neuroimaging and Serologic Markers of Neurologic Injury after Cardiac Arrest Madeleine C. Geraghty, MDa, Michel T. Torbey, MD, MPH, FAHAb,* a

Department of Neurology, University of Wisconsin Hospital and Clinics, 600 Highland Avenue, Madison, WI 53792, USA b Departments of Neurology and Neurosurgery, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI 53226, USA

For as long as patients have been comatose after cardiac arrest (CA), physicians have been searching for a reliable way to predict their outcomes. Although nearly half of all CA patients are resuscitated successfully, only 10% to 20% of these patients make a good functional recovery [1–3]. Most patients either die or survive with severe disability, often after a prolonged stay in the ICU. The lengthy stays in ICUs have a significant associated cost burden. A 1991 study determined that a hospital stay for a comatose survivor of CA cost up to $95,000 [4]. Multiple scales based on physical and neurologic examinations were developed to assist in identifying patients who have no hope of recovery; but in the era of intensive care management, these scales are often compromised by use of sedation and paralytic agents in ventilated patients and, at times, by fluctuations of the neurologic examination. Models based on electrophysiologic function are not only operator-dependent but also often confounded by the electrical ‘‘noise’’ present in the background of most ICUs. Many hospitals do not have easily available electroencephalography or evoked-potential capabilities for assessment of postanoxic patients. Not all facilities have MRI available within the hospital. Therefore, valid bedside tests with readily available tools for the early prediction of poor outcome following postanoxic coma are necessary. A quantitative prognostic model of outcome that can be applied early on to a patient who has been sedated following CA has become almost a Holy Grail for many intensive care practitioners, not only to assist

* Corresponding author. E-mail address: [email protected] (M.T. Torbey). 0733-8619/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.ncl.2005.10.006 neurologic.theclinics.com

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the grieving families in making difficult decisions, but also to ensure efficient use of precious limited resources. The ideal prognostic test is readily available, easily reproducible, and associated with a high degree of specificity for poor outcome. The goal is not to define which patients may recover, but which patients have no likelihood of meaningful neurologic recovery at all to justify early withdrawal of support. It is acceptable to identify only a subset of the patients who will not recover neurologically to avoid giving a falsely pessimistic prediction. One must be careful when prognosticating to clarify that it is purely prognosis of neurologic recovery; these patients remain critically ill and may die from nonneurologic causes even if their neurologic outcome seems good. Despite the many studies evaluating a wide range of prognostic variables following anoxic insult, it has been difficult to compare the variables directly. Studies have been limited by different causes of cardiopulmonary arrest, different outcomes scales, different time frames for prognostication, and small numbers of patients. This article presents an objective assessment of serum and radiologic markers of recovery following CA and a proposed algorithm for prognostication in CA patients. Serologic markers The most convenient markers of recovery are those that (1) can be obtained easily at the bedside and (2) measure enzymes in the bloodstream or the cerebrospinal fluid (CSF). There have been contradictory reports about the development of elevated intracranial pressure following CA [5,6], suggesting that lumbar puncture in the setting of post-anoxic coma may increase the risk for herniation. None of these studies reported herniation as a direct result of lumbar puncture. Nonetheless, elevated intracranial pressure remains at least a theoretic concern; and the search continues for prognostic peripheral markers in the bloodstream. Table 1 summarizes the performance of various biochemical markers in predicting poor outcome. In these studies, poor outcome is variably defined as death, poor functional recovery, or both. If the predictive indices were not provided in the articles, the authors calculated them de novo from the data specific for global anoxia caused by CA, if the data were available for analysis. Glucose Glucose is the main source of energy for the brain. Several investigators reported a significant association between elevated blood glucose following cardiac resuscitation and poor neurologic recovery [3,7–9,10]. The Longstreth Awakening Scale [3] went so far as to include admission blood glucose levels as one of the four main variables in the model, where blood glucose levels less than 300 mg/dL predicted awakening. It is unclear if postanoxic hyperglycemia is causative or simply correlative with poor outcomes, because the relationship between glucose levels and duration of resuscitation

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Table 1 Predictive indices of biomarkers by timeframe Marker NSE Serum

CSF S-100 Serum CSF CK-BB CSF

Cutoff values (ng/mL)

Time

Specificity (%)

Sensitivity (%)

PPV (%)

NPV (%)

13.3–20.0 8.8–25.0 16.4–100.0 24.0 50.0

24 h 24–48 h 72 h 24 h 48 h

89–100 100 100 100 83

51–59 59–76 70–100 74 89

86–100 100 100 100 96

65–70 10–80 72–100 89 63

24 h 48 h 48 h

80–96 70–100 60

55–100 79–100 93

71–95 75–100 93

63–100 89–100 63

24 h

50–98

40–52

66–93

25–77

0.2–0.7 0.2 6.0 17.0

Abbreviations: CK-BB, brain-type isoenzyme of creatine kinase; CSF, cerebrospinal fluid; NPV, negative predictive value; NSE, neuron specific enolase; PPV, positive predictive value; S-100, an astroglial protein established as a marker for cerebral injury.

is inconsistent across studies. If causative, the hypothesis is that hyperglycemia during cerebral ischemia drives anaerobic glycolysis and thus leads to increased lactate production and an increase in intracellular acidosis. In 1997, Mullner and colleagues [11] evaluated the role of postischemic blood glucose levels in a carefully defined subset of 145 patients in whom ventricular fibrillatory arrest had been witnessed. They excluded patients who had diabetes and those who received either insulin or glucose within the first 24 hours. They found that in CA survivors, high blood glucose levels over the first 24 hours after return of spontaneous circulation were independently associated with unfavorable functional neurologic recovery (146 G 39 mg/dL compared with 184 G 88 mg/dL). It is unfortunate, but because of overlap between the values for the groups, no ‘‘cutoff’’ point was established by this study; and emphasis was placed instead on the trend toward poorer outcomes with higher glucose levels. If attempting to use glucose as a prognostic indicator, the practitioner must take into account multiple variables, such as the presence of preexisting diabetes mellitus, the use of glucose or insulin during the periarrest period, and the total dosage of epinephrine used during the resuscitation [7]. There does not appear to be support for using glucose as a primary variable in predicting outcome following CA. However, the admission glucose and median glucose over the first 24 hours can be used as an adjunctive measurement supporting the gestalt of the individual patient’s prognosis. Lactate The oxygen deficiency inherent in anoxic injury leads to anaerobic glycolysis and therefore to lactate overproduction. At the same time, the profound

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ischemic state may impair liver function, leading to reduced lactate elimination [12]. These factors suggest that lactate levels may be a useful marker for severe anoxic injury [13]. Measurements of serum lactate levels on admission have not been particularly accurate at predicting prognosis in postanoxic patients, requiring excessively high levels to achieve 100% specificity for poor neurologic outcome [14,11]. Serial lactate measurements fared slightly better, with levels higher than 2 mmol/L after 48 hours correlating well with mortality or severe neurologic disability. This elevation, although statistically significant, was low in absolute numbers; and the specificity was less than ideal at 86%. A series of five patients in anoxic coma following CA suggested that perhaps it is not the absolute elevation of lactate that predicts poor outcome, but the failure of the lactate levels to decline [15]. One concern with using serum lactate that has not been addressed by the prior studies is controlling for the use of lactated intravenous fluid during the resuscitation. Elevated lactate levels in the CSF have been reported to provide more accurate information regarding the extent of brain damage caused by CA. A small case series of seven postanoxic patients revealed a mean CSF lactate of 2.5 G 0.5 mmol/L over the first 28 hours in patients who regained consciousness versus 3.8 G 0.9 mmol/L in patients who remained comatose and died. No cutoff value was determined [16]. Much like the use of glucose, serum and CSF levels of lactate can be used as supporting data; but neither should be used as the primary method of prognostication in an individual patient. S-100 S-100, an astroglial protein, has been established as a marker for cerebral injury. It may also be released from cardiac tissues [17] and from tumors, such as glioma, schwannoma, neuroblastoma, and melanoma [18–20]. Increased levels of serum S-100 have been correlated with cerebral injury [21–23]. Global cerebral circulatory arrest causes diffuse brain edema and selective neuronal death in vulnerable areas of the brain, and extended anoxia time leads to infarctions in cortical and subcortical regions [24,25]. The initial elevation of S-100 may represent blood–brain barrier breakdown in conjunction with astroglial damage and early brain edema. Rosen and colleagues [26] found that comatose CA patients who had serum S-100 levels persistently greater than 0.2 mcg/L over 48 hours died within 14 days of CA. They controlled for the possible release of cardiac S-100 by comparing levels to those of patients who experienced myocardial infarction but did not undergo resuscitation. Martens and colleagues [27] achieved the same results with a post hoc cutoff value of 0.7 mcg/L over 48 hours; and they found that this cutoff value was useful for prediction at 24 hours as well, although the specificity was not as good compared the 48-hour S-100 levels. The cutoff value of 0.7 mcg/L has been supported recently by Hachimi-Idrissi and colleagues [28] with good specificity, even using the admission levels of S-100 protein.


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Creatine kinase brain-type isoenzyme The brain-type isoenzyme of creatine kinase (CK-BB) is primarily located in neurons and astrocytes, and it comprises 95% of the total creatine kinase activity of the brain [29]. Normal serum contains little, if any, CK-BB. Levels of CK-BB have been noted to be elevated following global cerebral ischemic injury [30]. There have been several difficulties noted in the use of serum CK-BB as a prognostic indicator. Many patients suffering CA will also develop myocardial infarctions with resultant release of the CK-MB isoenzyme into the serum. Many of the available assays have some cross-reactivity between the MB and BB isoenzymes, making a serum test less accurate. In addition, the CK-BB fraction peaks rapidly in the serum and is rapidly inactivated, with individual variation as to the speed of inactivation [31]. Neither the optimal time for testing nor the need for serial testing have yet been determined. Roine and colleagues [32] compared the levels of CK-BB in the serum and in the CFS of survivors of out-of-hospital ventricular fibrillatory arrest at approximately 24 hours postinjury. Although they found that patients who remained comatose had higher levels of CK-BB in the serum than did patients who regained consciousness, there was significant overlap between the values; and no cutoff value was established. CFS levels of CK-BB at 24 hours were a better predictor of outcome. Using a cutoff value of 17 ng/mL, established post hoc, the CSF CK-BB measurement had a specificity of 98% and a sensitivity of 52%. A smaller study by Clemmensen and colleagues [33] was not able to support using CSF CK-BB because of poor specificity (54%), but this study was underpowered to detect large differences. They did, however, notice that patients who had low levels of CK-BB in their CSF were more likely to make a good neurologic recovery. The serum CK-BB and the CSF CK-BB levels did not correlate well with each other. These results have been duplicated, with CSF levels of CK-BB measured between 28 and 76 hours following injury being useful. Again, serum CK-BB was not found to have prognostic value [16,34,35]. As with previous biomarker studies, it seems that elevated CK-BB levels in the CSF at 24 hours postinjury might be useful as adjunctive prognostic indicators for poor neurologic outcome but would not be recommended as the primary evidence on which to base a decision to withdraw care. A prospective predictive study with preestablished cutoff values would be required to elucidate further the usefulness of CSF CK-BB isoenzymes following CA. Neuron-specific enolase Neuron-specific enolase (NSE) is a glycolytic enzyme present almost exclusively in neurons and neuroendocrine cells. Of all the biochemical markers available for prognosis following CA, NSE seems to be the most substantiated. NSE levels in serum and CSF have been investigated several

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times for possible use in estimating neuronal injury and predicting the clinical outcome of patients who have anoxic encephalopathy. In 1989, Roine and colleagues [32] published the first trial investigating the levels of NSE in serum and CSF of survivors of out-of-hospital ventricular fibrillatory arrest at approximately 24 hours postinjury. Using a cutoff value of 24 ng/mLdestablished post hocdthe CSF NSE measurement had a specificity of 100% and a sensitivity of 74% for predicting death. Multiple studies have followed evaluating the prognostic value of serum NSE, CSF NSE, and serial NSE measurements [27,35–41]. Several trials thus far have noted an association between decreasing serum NSE levels and good neurologic outcome [39,41,42], so perhaps the rate of decrease may be used to prognosticate in addition to the absolute level of NSE. Although one study [43] failed to show a correlation between serum NSE and neurologic outcome, the remaining studies have shown generally good predictive power using serial serum NSE measurements over the first 72 hours. One of the provisos with the use of NSE levels is that platelets and red blood cells contain small amounts of this enzyme, so hemolysis can increase the total level of NSE [44]. Accordingly, CSF samples from traumatic lumbar puncture and hemolysed blood samples should not be used for prognosis. Serum NSE is easier to collect than CSF and allows for serial sampling. The coincidental occurrences of other conditions known to elevate NSE levels, such as neuroblastoma and small-cell lung cancer, are rare enough not to interfere with prognostication. However, stroke can and does occur in the setting of CA and elevates the serum and CSF levels of NSE [45,46]. It is not known whether the elevation of NSE secondary to stroke should be included or excluded from the mortality prediction. Ultimately, a cutoff value should be set prospectively and followed to determine specificity, sensitivity, and positive predictive value before the use of NSE as a primary prognostic indicator. Radiologic markers Gray matter (GM), with emphasis on the hippocampus, caudate/putamen, thalamus, large cell layers of the neocortex, and Purkinje cells of the cerebellar cortex, has long been considered to be selectively vulnerable to hypoxic injury. This susceptibility does not imply that white matter (WM) is invulnerable to hypoxia, and the different reactions of the two tissue types to hypoxic injury hold potential in the quest for reliable objective measurements for prognosis following CA. White matter injury, a delayed leukoencephalopathy, has been described weeks to months following global anoxic injury [47,48]. CT and conventional MRI imaging in the acute period following diffuse cerebral anoxia is often read as normal or with subtle findings only. The imaging findings of diffuse anoxia include diffuse cerebral edema, obscuration of gray–white matter borders, so-called ‘‘watershed’’ infarctions, and selective neuronal necrosis affecting the deep gray nuclei and


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of the cortical layers III, IV, and V [25,49–51]. The advent of diffusionweighted (DWI) MRI enhanced the ability to detect these early changes of cerebral anoxia. MRI Although earlier studies focused primarily on GM injury following cerebral ischemia, DWI opened the door for evaluating WM injury also. Arbelaez and colleagues [52] evaluated DWI findings in ten patients who had global cerebral anoxia. Only 6 of 10 patients had primary CA. Using low-b value (B ¼ 30 s/mm2) and high-b value (B ¼ 1100 s/mm2) diffusion imaging, investigators were able to find abnormal signal in the cerebellum, basal ganglia, and cortex in less than 24 hours and WM changes in the late subacute period of 14 to 20 days following injury. All of the patients demonstrating DWI changes had a poor neurologic outcome (death or vegetative state). This study demonstrated that, although GM has traditionally been considered as more vulnerable to hypoxic injury, WM is also susceptible to injury earlier than previously postulated [47] and that DWI holds potential for prognostication. Chalela and colleagues [53] presented a case series in which MRIs with T2-weighted imaging and DWI were obtained on seven comatose patients between one and six days following severe anoxic injury. Only two of the seven patients had primary CA. Restricted diffusion was prominent throughout the WM in the periventricular region, corpus callosum, and internal capsule. These findings were corroborated with decreased apparent diffusion coefficient mapping. GM damage was demonstrated more readily on T2-weighted imaging than by DWI. This study demonstrated that myelinopathy can occur early following anoxic injury and holds potential for evaluation as a prognostic indicator. Similarly, Wijdicks and colleagues [54] evaluated the MRI features in ten comatose male survivors of CA. All ten of the patients had intact brainstem reflexes on physical examination. Five patients had electroencephalography, none of which demonstrated alpha-coma or burst-suppression patterns. Six patients received median somatosensory evoked potentials, which were either normal (four patients) or indeterminate (two patients). The outcomes of these patients ran the gamut from good neurologic function to death. MR imaging was obtained between 1 and 15 days following the anoxic insult. Eight of the patients showed diffuse GM signal abnormalities on fluid-attenuated inversion recovery (FLAIR) sequences and DWI. Signal abnormalities were specifically noted in cerebral and cerebellar cortices, caudate nuclei, putamen, globus pallidi, and thalami. Eight of the ten patients had diffuse abnormalities in these regions on FLAIR and DWI, and these patients either died or recovered to a vegetative state. The two patients who made good recoveries had minimal (no cortical involvement) or no abnormalities seen on MRI. Although the numbers are small, this study

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supported earlier findings that early MRI changes may be reliable predictors of poor outcome. Fig. 1 demonstrates some of the MRI features of global cerebral anoxia. This 55-year-old man presented in CA with a duration of more than 20 minutes. He was comatose, sedated, and intubated following the arrest with a Glasgow Coma Scale score of 3. DWI and corresponding apparent diffusion coefficient map show diffuse laminar restriction of diffusion. These findings are subtle but definite using low b-value diffusion. The advantage of the increased sensitivity of MRI is offset by patient instability, need for monitoring, and cost. Many hospitals have limited MR resources; and the MR scanner may not be located within the hospital building, necessitating a ‘‘road trip’’ for a critically ill patient. Transportation requires monitoring by critical-care-trained staff and often also may require an anesthesiologist. Many critically ill patients are not stable enough to be moved, and there is some evidence that the mere act of moving some of these patients may be subtly detrimental [54–56]. The logistical difficulties inherent in obtaining an MRI on a critically ill patient currently limit the application of this technology in obtaining outcomes data. Magnetic resonance spectroscopy Magnetic resonance spectroscopy (MRS) was developed in 1988. Early studies of cerebral ischemia demonstrated an increase in the lactate spectrum as a consequence of anaerobic glycolysis, cellular necrosis, and hypoperfusion, with accompanying disturbances of lactate removal [57]. Berek and colleagues [24] evaluated the use of MRS to detect elevated cerebral

Fig. 1. (A) The axial diffusion-weighted image (low b-value, b ¼ 30 s/mm2) shows diffusely restricted diffusion in a laminar fashion along the cortex, most prominent along the bilateral parieto–occipital cortices (large arrows). More subtle regions of restricted diffusion are noted at the right insular cortex and bilateral frontal cortices (small arrows). (B) The apparent diffusion coefficient map shows subtle focal areas of decreased signal in locations corresponding to the restricted diffusion image on the left.


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lactate resonances as a prognostic indicator in 30 patients who had suffered out-of-hospital CA. The presence of a lactate peak on MRS correlated with death or severe disability at one month. Patients who lacked a lactate peak either had good neurologic recovery or else died from extracranial causes, typically cardiac. Further quantification beyond presence or absence of a lactate peak was not attempted. Positron emission tomography Positron emission and single-photon emission tomography may be useful in the acute phase of postanoxic injury, but these tests are not widely available and are difficult to obtain in patients who are critically ill [58]. One study has shown a nearly 50% reduction in cerebral glucose metabolism following CA, but was unable to identify any specific patterns of metabolic change that would be useful for prognostication of outcome [59,60]. Computerized tomography The most commonly ordered and most widely available imaging modality for comatose CA patients is the CT scan. A normal CT scan of the brain shows a clear difference between the WM with its high lipid content and the GM with its high water content [61]. Following severe global anoxia, there is a loss of distinction between the GM and WM in the brain as seen on head CT [62]. This difference is not reliably noted on visual assessment. However, measuring the Hounsfield unit (HU) density may allow a reliable quantifiable comparison between GM and WM. HUs are measurements of x-ray attenuation used in CT scanning where each pixel is assigned a value on a scale on which air is 1000 HU, water is 0 HU, and bone is þ1000 HU [63]. Torbey and colleagues [64] compared the HU density of GM of the caudate nucleus and the HU of the WM of the posterior limb of the internal capsule (Fig. 2). On noncontrast CT scans performed within 48 hours of CA, the GM/WM ratios were significantly lower than those of control patients. This loss of differentiation was due more to a loss of GM density than to an increase in WM density. Using a receiver operating characteristic curve analysis, a GM/WM ratio of less than 1.18 was 100% predictive of death, whereas the survival rate was 46% among patients who had a GM/WM ratio of greater than or equal to 1.18. Of note, the noncontrast CT scans were obtained primarily between 24 and 48 hours. It is unclear if CT scans obtained in less than 24 hours might miss some abnormal findings.

Summary The current serum or radiologic markers have their pros and cons. Clearly, what is needed to prognosticate accurately following CA is a multimodal

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Fig. 2. Hounsfield unit density of a 10 mm2 region of (1) caudate nucleus and Hounsfield unit density of a 10 mm2 region of the posterior limb of the (2) internal capsule. The measurements should be taken from the same axial head CT slice at the basal ganglia level, defined as the level in which the caudate nucleus, internal capsule, third ventricles, and sylvian fissures are all visualized.

scale or algorithm that incorporates multiple parameters, specifically serum markers, radiologic markers, and the neurologic examination. Zingler and colleagues [65] found that combining NSE and S-100 could markedly increase the sensitivity of prediction from 75% to 87.5% on day 3 without sacrificing specificity. Continuing the multimodal approach, the Brain Arrest Neurologic Outcome Scale (BrANOS) was developed in 2004 as a way of encompassing clinical and radiologic markers of brain injury into a predictive model in the setting of global anoxic injury following CA. The scoring system is outlined in Table 2. In 32 patients who had a witnessed CA, survivors had a significantly lower BrANOS score (8 G 2 points) compared with nonsurvivors (13 G 1 points). The scale predicted death within 2 weeks with 100% positive predictive value (PPV) and 100% specificity for a score greater

Table 2 Brain arrest neurologic outcome scale (BrANOS) Scoring system Duration of arrest (DAR) 0–5 min 6–15 min O15 min Best reverse Glasgow Coma Scale score (GCS) (15-GCS) in 24 h Hounsfield unit ratio (HUR) !1.18 R1.18 Total

Points 1 2 3 0–12 1 0 1–16


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than or equal to 14. Using a perhaps more realistic measurement of outcome, the scale also predicted the combined outcome of death and severe disability (Glasgow Outcome Score ¼ 3) with 100% PPV and specificity for a score greater than or equal to 10 [66]. This scale provides another method to predict outcome quantitatively, although it will need to be validated prospectively before general application. The authors further recommend a prospective evaluation of a ‘‘cardiac arrest prognosis protocol,’’ which would include serial measurements of serum NSE and serum S-100 protein over 72 hours in addition to incorporating imaging between 24 and 48 hours. The authors believe that the specificity and sensitivity of serum NSE are highest over a 72-hour period. Although the S-100 protein levels may have already peaked by day 3, testing over 72 hours allows capture of any late-peaking levels. Although the other biomarkers, such as lactate, glucose, and CSF CK-BB, also allow for some prognostication, they either lack ease of use or enough specificity to make reliable markers at this time. For such a prospective evaluation, the authors recommend the protocol represented in Table 3. Until these parameters have been evaluated prospectively, the treating physician may also wish to rely on the ‘‘standard’’ clinical and electrophysiologic parameters.

Future directions The ability to determine a reliable prognosis in CA survivors continues to improve as more advanced methods of data collection are developed. Fiberoptic jugular venous oximetry is a newer technique for assessing global cerebral oxygen use. Monitoring the jugular venous oxygen saturation provides an early diagnosis of global ischemia by venous desaturation [67]. The catheter can be placed rapidly at the bedside, and there may be potential to detect ultra-early cerebral anoxic injury even before changes can be detected on imaging or with serum markers. Table 3 Cardiac arrest prognosis protocol Tests/Scores to obtain

Poor prognostic indicators

Admission Glasgow Coma Scale score Serial NSE levels on days 0–3 Serial S-100 levels on days 0–3 Admission glucose level Head CT at 24–48 h BrANOS score Head MRI at 72 h

GCS ! 8 Peak value O 35 ng/mL Peak value O 0.2 ng/mL Initial value O 300 mg/dL GM/WM ratio ! 1.18 R10 Restricted diffusion in the cerebral and cerebellar cortices, caudate nuclei, putamen, globus pallidi, and/or thalami.

Abbreviations: BrANOS, Brain Arrest Neurologic Outcome Scale; GM, gray matter; GCS, Glasgow Coma Scale; NSE, neuron-specific enolase; S-100, an astroglial protein established as a marker for cerebral injury; WM, white matter.

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The recent development of cerebral microdialysis catheters may be able to collectdalbeit in an invasive fashiondfar more detailed quantitative information on neurochemical markers of cerebral metabolism in the immediate postresuscitation period [55,68]. Animal studies of microdialysis monitoring in the setting of induced hypothermic circulatory arrest have demonstrated high cerebral lactate/glucose ratios are predictive of postoperative death [69]. The reevaluation of glucose and lactate as biochemical markers for prognosis in the setting of cerebral microdialysis will be most interesting in the upcoming years. Used in conjunction with jugular bulb oxygen monitoring in the early phase following global anoxic injury, these techniques may be able to guide therapy (increasing cerebral oxygen delivery) as well as predict outcomes. Portable CT scanners are now available, and their cost is roughly half that of a ‘‘fixed’’ helical CT scanner [70]. The patient is scanned without stripping an ICU of skilled caregivers to accompany a patient during transport. Patients who are considered too unstable from either a neurologic or cardiologic standpoint will benefit as these portable modules become more widely used and as more ICUs install dedicated CT scanners directly within the units. As these techniques are being evaluated more closely and as imaging modalities increase in sensitivity and portability, physicians will continue to assist families by providing some guidance as to which patients have no chance of meaningful recovery. In carefully applied settings, serum NSE levels, S-100 protein levels, and multimodal scales such as BrANOS may help in the making of these decisions.

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Movement Disorders after Resuscitation from Cardiac Arrest Arun Venkatesan, MD, PhDa,*, Steven Frucht, MDb a

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA b Neurological Institute, Columbia University College of Physicians and Surgeons, New York, NY, USA

Those who survive cardiac arrest often experience significant neurologic impairment. A rare, but often debilitating, consequence of cardiac arrest is the development of movement disorders. A wide range of movement disorders, with many different causes, is observed after cardiac arrest. Cardiac arrest survivors may develop movement disorders from metabolic disturbances resulting from hypoxic-ischemic damage to the liver or kidney, from medications administered to treat other complications of cardiac arrest, or from cardioembolic ischemic stroke as a result of impaired myocardium or cardiac valves. This review focuses on movement disorders caused by cerebral hypoxia after cardiac arrest. Many different movement disorders are described after hypoxic-ischemic brain injury, including parkinsonism, dystonia, chorea, tics, athetosis, tremor, and myoclonus [1–5]. Of these movement disorders, the one reported and investigated most extensively is posthypoxic myoclonus (PHM). Hence, this article describes the clinical spectrum, pathophysiology, and treatment of PHM before briefly discussing other posthypoxic movement disorders.

Posthypoxic myoclonus Myoclonus refers to sudden, shock-like, involuntary movements that can manifest in various patterns. Myoclonus may be focal, where a few adjacent muscles are involved; multifocal, where many muscles jerk asynchronously; or generalized, where most of the muscles of the body are involved in * Corresponding author. Department of Neurology, Johns Hopkins Hospital Pathology, 509 600 North Wolfe Street, Baltimore, MD 21287. E-mail address: [email protected] (A. Venkatesan). 0733-8619/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.ncl.2005.11.001 neurologic.theclinics.com

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synchronized fashion. Additionally, myoclonic movements may be spontaneous or they may be activated by either movement or sensory stimulation. Finally, myoclonus may be comprised of ‘‘positive’’ movements, in which a burst of electromyographic activity is associated with the movement, or negative movements, in which a brief pause of tonic muscular activity leads to a jerk [6,7]. The causes of myoclonus are many. In 1963, however, Lance and Adams described four patients who developed severe myoclonus after surviving cardiac arrest [8]. These patients initially developed a generalized myoclonus accompanied by dysmetria, dysarthria, and ataxia. Over time, the myoclonus persisted but its character changed to a predominantly action myoclonus involving the limbs. Lance and Adams hypothesized that this particular constellation of symptoms observed after cardiac arrest was the result of cerebral hypoxia [8]. Since this initial description, more than 40 years ago, more than 100 patients who have had PHM have been reported in the medical literature [9–11], many of whom suffered hypoxia from cardiac arrest. Concordant with the initial descriptions by Lance and Adams, it is recognized that there are two types of PHM: acute PHM, which occurs soon after a hypoxic insult and is characterized by generalized myoclonus; and chronic PHM (Lance-Adams syndrome), which begins after a period of delay and is manifested predominantly by action myoclonus. Acute posthypoxic myoclonus Acute PHM occurs soon after a hypoxic episode and is characterized by severe, generalized myoclonic jerks in patients who are deeply comatose [7]. The jerks begin typically within the first 24 hours after hypoxia and often are characterized by violent flexion movements. When they persist for more than 30 minutes or occur for most of the first postresuscitation day, some term the abnormal movements, myoclonic status epilepticus (MSE), despite the lack of definitive evidence that these movements represent epileptic activity. Posthypoxic MSE occurs in approximately 30% to 40% of comatose adult survivors of cardiopulmonary resuscitation and is difficult to control and associated with a poor prognosis. In the largest published series of posthypoxic MSE, Wijdicks and colleagues find that all 40 patients had intermittent generalized myoclonus involving both face and limb muscles. Stimuli, such as touch, tracheal suctioning, and loud handclaps, triggered myoclonic jerks in most of the patients. None of the 40 patients who had acute posthypoxic MSE awakened, improved in motor response, or survived [12]. In another review of 18 patients who had posthypoxic MSE, 14 patients died within 2 weeks and the two patients who survived were left with profound disability [13]. A meta-analysis of patients who had posthypoxic MSE paints a similarly grim picture: of 134 pooled cases, 119 (88.8%) died, 11 (8.2%) remained in a persistent vegetative state, and 4 (3.0%) survived. Of the four patients who survived, two were described as having a good outcome [13].

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Clues to the pathophysiology of acute PHM arise from electrophysiologic and histopathologic studies. The electroencephalograms (EEGs) in these patients are variable, but often display bursts of generalized spikes and polyspikes or a burst suppression pattern, believed to be consistent with severe neuronal injury. On autopsy, patients who have acute posthypoxic MSE have evidence of neuronal ischemia and cell death in the cerebral cortex, deep gray nuclei (ie, basal ganglia and thalamus), hippocampus, and cerebellum [13]. Cortical damage is more severe in patients who have MSE than in those who do not have myoclonus, however [14]. Because the severity of cortical damage implies that the cortex may not be capable of generating any activity, including myoclonic activity, it is postulated that acute PHM arises from a brainstem generator [7]. Treatment of myoclonic jerks in acute PHM is difficult and of questionable usefulness, particularly in the setting of posthypoxic MSE. Multiple medications often are used, the most common of which are phenytoin, valproate, and benzodiazepines. In one study of 18 patients who had posthypoxic MSE, 13 patients required intravenous anesthesetic agents, including propofol and midazolam [13]. Despite aggressive treatment of the myoclonic jerks, poor prognosis resulting from the severity of underlying brain injury is the rule rather than the exception. Chronic posthypoxic myoclonusdLance-Adams syndrome Chronic PHM, also known as Lance-Adams syndrome, typically occurs within a few days to a few weeks after hypoxic injury. In a series of 14 patients who had chronic PHM, all but one were noted to have the onset of myoclonus while still in coma [9]. The myoclonus has several characteristic features. Patients have an action myoclonus involving predominantly the limbs. Myoclonic jerks commonly appear immediately on attempting to move or position a limb and occasionally spread to other portions of the body. The jerks generally disappear with relaxation of the limb. The precision of the motor task seems to be proportional to the severity of myoclonus, making everyday tasks, such as bringing a cup to the mouth or grasping a small object, extremely difficult [8,10,11]. In addition, the myoclonus of chronic PHM has several other distinctive characteristics. In their series of 14 patients, Werhahn and colleagues report that 11 had stimulussensitive myoclonus [9]. Negative myoclonic jerks also contribute significantly to morbidity in patients who have chronic PHM. Postural lapses resulting from negative myoclonus predispose patients to frequent falls and often result in patients being confined to wheelchairs [10]. Chronic PHM is a syndrome with diverse clinical, electrophysiologic, and neurochemical abnormalities [7,10], and the pathophysiology of this condition is poorly understood. An example of the diversity of the disorder lies in the nature of the myoclonus itself. The myoclonus in chronic PHM may have a cortical or subcortical origin. Clinical clues suggestive of a cortical

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origin include myoclonus that is distally predominant, highly action induced, and stimulus sensitive. A cortical origin for myoclonus also is supported by electrophysiologic measures, such as enlarged somatosensory evoked potentials and the gold standard, back-averaged EEG. Using such measures, it seems that cortical myoclonus is much more common in chronic PHM than subcortical myoclonus, the latter of which tends to cause violent jerks of the proximal limbs and trunk [10]. Patients who have chronic PHM, however, may suffer from cortical myoclonus, subcortical myoclonus, or a combination of the two, and there are no prognostic factors that can predict which subtype of myoclonus a patient will develop. The neurochemical and anatomic bases of chronic PHM remain unclear. Several lines of evidence suggest that specific neurotransmitter abnormalities are involved in the pathogenesis of chronic PHM. Isolated reports demonstrate that low levels of 5-hydroxyindole amino acid (5-HIAA), a serotonin metabolite, are present in the cerebrospinal fluid of patients who have PHM [15]. Some patients who have chronic PHM improve with administration of the serotonin precursor, 5-hydroxytryptophan (5-HTP) [16]. Further support for a role of the serotonergic system in chronic PHM comes from animal models. Several groups demonstrate that, in rat models of PHM, myoclonus improves with 5-HTP treatment and severity of myoclonus correlates inversely with levels of striatal serotonin and cortical 5-HIAA. In addition, direct modulation of serotonin receptors affects PHM, as demonstrated in animal models in which the administration of agonists and certain antagonists of serotonin receptors can ameliorate PHM [17–20]. Another clue that serotonin signaling may be involved in the pathophysiology of PHM lies in the finding that the majority of patients in the largest published series on PHM are female. A recent study examines the role of estrogen in PHM and finds that estrogen treatment of female rats that were ovariectomized resulted in a significant increase in intensity and duration of PHM [21]. It is hypothesized that estrogen, through its regulation of serotonergic activity, may influence the clinical course of PHM. Thus, it seems that although serotonergic modulation affects PHM, the relative contributions of serotonin metabolism and of specific serotonin receptors to the overall mechanisms of PHM remain unclear. A recent report that describes marked exacerbation of chronic PHM in a patient administered trimethoprim-sulfamethoxazole (TMP-SMX) may implicate phenylalanine, a neurotransmitter precursor, in the pathogenesis of PHM. A patient who had high-grade non-Hodgkin’s lymphoma and chronic PHM whose myoclonus was well treated with oral piracetam developed marked worsening of myoclonus on exposure to high-dose intravenous TMP-SMX. A reduction of the dosage of TMP-SMX resulted in a dramatic and rapid improvement of the myoclonic jerks [22]. The investigators believed it unlikely that alterations of renal or hepatic metabolism, or pharmacokinetic or pharmacodynamic interactions between TMP-SMX and piracetam, accounted for the worsening of myoclonus; rather, they hypothesized that


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TMP-SMX may have resulted in increased myoclonus by its well-described action of impairing phenylalanine metabolism and, thereby, elevating phenylalanine levels. Elevated phenylalanine levels, in turn, are linked to several neurologic conditions. Unfortunately, neither serum nor cerebrospinal fluid phenylalanine levels were obtained to support this hypothesis. Recently, radiologic tools have been used in an attempt to understand the anatomic and pathophysiologic basis of PHM. Seven patients who had chronic PHM and EEG back averaging that demonstrated cortical myoclonus underwent fluorodeoxyglucose–positron emission tomographic scanning. Comparedwith control subjects, patients who had PHM exhibited significant increases in glucose metabolism in several brain regions, including the ventrolateral thalamus [23]. Such findings may be compatible with the rat PHM model, in which the ventrolateral thalamic nucleus is implicated indirectly in the pathogenesis of PHM; Purkinje cell death occurs selectively in the paravermal and vermal areas, which project mainly to the dorsolateral protuberance of the fastigial nucleus and, in turn, to the ventrolateral thalamic nucleus [24]. Thus, there may be a link between the Purkinje cell death seen in PHM rats and the increased metabolic uptake observed by PET scanning in the ventrolateral thalamic nucleus of humans who have PHM. The treatment of chronic PHM can pose a challenge for several reasons. As previously alluded to, chronic PHM is a syndrome with diverse clinical presentations likely stemming from varied pathophysiologies. In addition, the effect of many drugs reported in the literature is given in qualitative fashion, providing only an approximation of an agent’s efficacy. Also, the small number of patients who develop this syndrome obviates the possibility of largescale clinical trials to evaluate the efficacy of antimyoclonic agents. Despite these difficulties, a recent review of the literature, which includes more than 100 cases of PHM, supports several important conclusions. Clonazepam, valproate, and piracetam demonstrate significant efficacy in approximately 50% of patients in whom these agents were instituted. Therefore, the authors consider these to be first-line agents in the treatment of chronic PHM. A role for 5-HTP also is supported by the authors’ recent literature review. 5-HTP resulted in marked or full improvement in 40% of patients in whom the effect was reported; however, concomitant treatment with carbidopa often is necessary to prevent the severe nausea that accompanies administration of this drug. Several other drugs, including baclofen, diazepam, ethanol, and methysergide, also are reported as efficacious in a limited number of patients. An analysis of these 122 cases reveals that there are several drugs that were reported to be not significantly efficacious in any case of chronic PHM; these include phenytoin, primidone, phenobarbitol, and tetrabenazine [10]. Several newer agents also are reported to have efficacy in the treatment of chronic PHM. Levetiracetam, chemically related to piracetam, has been studied by several groups of investigators. Krauss and colleagues note that one of two patients who had chronic PHM experienced substantial improvement in myoclonus, whereas the other experienced some improvement

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with doses of 500 to 750 mg twice daily [25]. Another study of the effects of levetiracetam on myoclonus of different causes notes that rapid and sustained symptomatic improvement occurred only in a single patient who had chronic PHM [26]. The authors also have studied the efficacy of levetiracetam in PHM. They conducted an open-label, dose-escalation trial of this medication in seven patients who had chronic myoclonus (including three who had posthypoxic myoclonus) and showed that the mean Unified Myoclonus Rating Scale scores trended downward in every section after administration of levetiracetam, with significant decreases in the sections addressing patient self-assessment and physician assessment of global disability [27]. Several reports describe patients who have PHM experiencing improvement of myoclonus with administration of alcohol [28,29]. Based on a previous report that a patient who had alcohol-responsive myoclonus-dystonia had significant improvement when treated with g-hydroxybutyric acid (GHB) [30], the authors recently studied the efficacy of GHB in one patient who had alcohol-responsive chronic PHM. Using an open-label, dose-finding, blinded-rater approach, they found that oral GHB was markedly effective in ameliorating severe alcohol-sensitive PHM in this single patient [31]. Regardless of treatment, the majority of patients who have chronic PHM improve over time. Myoclonus, ataxia, and speech all tend to improve over several years, and disability scores reflective of the ability to ambulate, communicate, and take care of themselves also improve [8,9]. In one series of 14 patients who had chronic PHM, only four patients did not have an improvement in global disability score at a mean follow-up of 3.7 years [9]. Although many patients do experience significant improvement in symptoms, some who have chronic PHM remain significantly disabled despite medical therapy. Currently, there are no well-accepted surgical options for such patients. The authors hypothesize, however, that, given the ventral thalamic hypermetabolism observed on PET scan in these patients and the fact that thalamotomy and thalamic stimulation are applied successfully to single patients who have intractable myoclonus, stereotactic targeting of the ventrolateral thalamus using deep brain stimulation may be appropriate in some patients who have severe, medication-refractory chronic PHM [23]. Other posthypoxic movement disorders A variety of other movement disorders are observed after cerebral hypoxia, including parkinsonism, dystonia, chorea, athetosis, and tremor [1–5]. Although PHM may result from injury to the cerebellum or thalamus, many of these other movement disorders are caused by damage of the basal ganglia. Dystonia is one of the more common movement disorders to occur after cerebral hypoxia and may develop in combination with an akinetic-rigid (parkinsonian) syndrome. This article discusses the clinical spectrum of posthypoxic dystonic and akinetic-rigid syndromes and focuses on the pathophysiology of basal ganglia dysfunction in these conditions.


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Dystonic and akinetic-rigid syndromes, alone or in combination, represent a sizeable proportion of the posthypoxic movement disorders described in the literature. Many of these cases are reported in patients surviving cardiac arrest. These syndromes may occur acutely, either at the time the hypoxic insult occurs or shortly thereafter, or more commonly in delayed fashion, months to years after the initial hypoxic insult [32]. The posthypoxic akinetic-rigid syndrome usually is a symmetric condition characterized by various combinations of bradykinesia, micrographia, axial and appendicular rigidity, resting or postural tremor, and marked postural instability [3,33]. Posthypoxic dystonia can affect the limbs and face and often is asymmetric at onset with progression to a symmetric, generalized dystonia. In a review of 12 patients who previously were normal and who suffered hypoxic ischemic insults of various causes, including cardiac arrest, Marsden and colleagues note that six of the patients developed a pure dystonic syndrome, two developed a pure akinetic-rigid syndrome, and four initially developed an akinetic-rigid syndrome followed later by a dystonic syndrome [34]. The akinetic-rigid syndrome developed typically within 3 months of the hypoxic event; after a rapid evolution, the majority of patients remained clinically stable for many subsequent years. In contrast, the pure dystonic syndrome developed, on average, 10 months after the hypoxic event, and progressed gradually over several years. The majority of patients had visible lesions in the basal ganglia on brain CT or MR imaging. Treatment of akinetic-rigid symptoms with levodopa or dopamine agonists and administration of high-dose anticholinergic drugs for dystonic symptoms conferred little benefit to these patients. Why do some patients who have basal ganglia lesions after cerebral hypoxia develop an akinetic-rigid syndrome, whereas others develop a predominantly dystonic syndrome? Marsden and colleagues note that the mean age of the akinetic-rigid group at the time of anoxia was 41 years, whereas that of the pure dystonic group was 13.5 years. Indeed, all six patients who developed a pure dystonic syndrome were ages 21 years or less. This observation led to the hypothesis that an age-dependent difference in the clinical manifestations of hypoxia exists, with younger people more prone to dystonia and older individuals more prone to an akinetic-rigid state [33]. Such age-dependent differences also are observed in conditions, such as Parkinson’s disease, in which early-onset patients are predisposed to dystonia. A mechanistic understanding of these observations, however, remains elusive. The location of brain injury within the basal ganglia seems to be another factor that governs whether or not patients develop dystonia versus an akinetic-rigid state after cerebral hypoxia. Hawker and Lang, in their case series of three patients who had suffered cerebral hypoxia, note that the two patients who had primarily dystonic syndromes had lesions of the putamina on head CT, whereas the patients who had an akinetic-rigid syndrome had marked bilateral lesions of the globus pallidus. Similar clinicoanatomic associations are found in a wide variety of insults to the basal ganglia,

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including trauma, neurodegenerative diseases, and encephalitides [4]. This has led to the proposal that in the setting of hypoxia, lesions of the globus pallidus are responsible for the akinetic-rigid syndrome, whereas lesions of the putamen account for dystonia [2]. Further support for this hypothesis is provided by Marsden and colleagues, who find that dystonia is associated with putaminal injury in 10 of 14 cases and an akinetic-rigid syndrome is associated with globus pallidus lesions in 11 of 14 cases. This association is not absolute, however, as several examples of dystonia associated with pallidal lesions and parkinsonism associated with putaminal lesions are noted [33]. Two other questions arise with respect to the pathophysiology of hypoxiainduced basal ganglia lesions. First, why are the basal ganglia so vulnerable to hypoxic insults? Two main hypotheses are put forth to explain this selective vulnerability. The ‘‘vascular hypothesis’’ states that selective hypoperfusion results from the vascular supply of the basal ganglia and, in particular, the globus pallidus, underlies its susceptibility to hypoxic injury. The second theory is the ‘‘metabolic hypothesis,’’ which postulates that factors intrinsic to the striatum, such as intrinsically high oxidative metabolism or high density of excitatory amino acid receptors, results in hypoxic damage [2,34]. Further studies are needed to determine whether or not vascular, metabolic, or other factors underlie the susceptibility of the basal ganglia to hypoxic injury. The second main question that arises is, how can a single exposure to cerebral hypoxia lead to the delayed onset and progression of symptoms years later? Several mechanisms, including aberrant sprouting, synaptic reorganization, ephaptic transmission, and inflammatory changes, are suggested as possible mechanisms of delayed symptomatology. Parallels with other neurodegenerative diseases, in which excitotoxicity is followed by mitochondrial dysfunction, oxidative stress, and eventual neuronal apoptosis, also are speculated to play a role [34,35]. Regardless of the mechanism, it seems that damage to the basal ganglia with preservation of the pyramidal system is a pathologic correlate of delayed posthypoxic dystonia or akinetic-rigid syndromes [36]. Summary It is difficult to predict precisely the final neurologic outcome from cardiac arrest and accompanying cerebral hypoxia. Although rare, several movement disorders may arise as a consequence of hypoxic injury, including myoclonus, dystonia, akinetic-rigid syndromes, tremor, and chorea. Dysfunction of various portions of the central nervous system, including the basal ganglia, thalamus, midbrain, and cerebellum, is implicated in the pathogenesis of these posthypoxic movement disorders. The development of animal models of posthypoxic movement disorders and of newer imaging techniques applied to human patients who have movement disorders after hypoxic episodes has improved understanding of the pathophysiology of posthypoxic movement disorders and has suggested newer treatments.


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Many outstanding questions remain, however. What factors promote susceptibility to the development of posthypoxic movement disorders? Why do patients who have similar clinical hypoxic insults develop markedly dissimilar movement disorders? Why are the basal ganglia especially vulnerable to cerebral hypoxia? Why do some movement disorders occur in delayed fashion and progress for years after the hypoxic insult? Is the pathogenesis of progressive posthypoxic movement disorders related to that of neurodegenerative diseases? What are the most effective medications for the various posthypoxic movement disorders? Is there a role for deep brain stimulation in the treatment of posthypoxic movement disorders? We anticipate that current and future research in the area of posthypoxic movement disorders will reveal answers to some of these important questions.

References [1] Fahn S. Posthypoxic action myoclonus: literature review update. Adv Neurol 1986;43: 157–69. [2] Hawker K, Lang AE. Hypoxic-ischemic damage of the basal ganglia. Case reports and a review of the literature. Mov Disord 1990;5:219–24. [3] Feve AP, Fenelon G, Wallays C, et al. Axial motor disturbances after hypoxic lesions of the globus pallidus. Mov Disord 1993;8:321–6. [4] Bhatia KP, Marsden CD. The behavioral and motor consequences of focal lesions of the basal ganglia in man. Brain 1994;117:859–76. [5] Govaerts A, Zandijcke MV, Dehaene I, et al. Posthypoxic midbrain tremor. Mov Disord 1998;13:359–61. [6] Fahn S, Marsden CD, Woert MHV. Definition and classification of myoclonus. Adv Neurol 1986;43:1–5. [7] Hallett M. Physiology of human posthypoxic myoclonus. Mov Disord 2000;15(Suppl 1): 8–13. [8] Lance JW, Adams RD. The syndrome of intention or action myoclonus as a sequel to hypoxic encephalopathy. Brain 1963;86:111–36. [9] Werhahn KJ, Brown P, Thompson PD, et al. The clinical features and prognosis of chronic posthypoxic myoclonus. Mov Disord 1997;12:216–20. [10] Frucht S, Fahn S. The clinical spectrum of posthypoxic myoclonus. Mov Disord 2000; 15(Suppl 1):2–7. [11] Frucht SJ. The clinical challenge of posthypoxic myoclonus. Adv Neurol 2002;89:85–8. [12] Wijdicks EFM, Prisi JE, Sharbrough FW. Prognostic value of myoclonus status in comatose survivors of cardiac arrest. Ann Neurol 1994;35:239–43. [13] Hui ACF, Cheng C, Lam A, et al. Prognosis following postanoxic myoclonus status epilepticus. Eur Neurol 2005;54:10–3. [14] Young GB, Gilbert JJ, Zochodne DW. The significance of myoclonic status epilepticus in postanoxic coma. Neurology 1990;40:1843–8. [15] Fahn S. Posthypoxic action myoclonus: review of the literature and report of two new cases with response to valproate and estrogen. Adv Neurol 1979;26:49–82. [16] Woert MHV, Rosenbaum D. L-5-hydroxytryptophan therapy in myoclonus. Adv Neurol 1979;26:107–15. [17] Truong DD, Matsumoto RR, Schwartz PH, et al. Novel rat cardiac arrest model of posthypoxic moclonus. Mov Disord 1994;9:201–6. [18] Matsumoto RR, Aziz N, Truong DD. Association between brain indole levels and severity of posthypoxic myoclonus in rats. Pharmacol Biochem Behav 1995;50:553–8.

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[19] Goetz CG, Vu TQ, Carvey PM, et al. Posthypoxic myoclonus in the rat: natural history, stability, and serotonergic influences. Mov Disord 2000;15(Suppl 1):39–46. [20] Truong DD, Kirby M, Kanthasamy A, et al. Posthypoxic myoclonus animal models. Adv Neurol 2002;89:295–306. [21] Kompoliti K, Goetz CG, Vu TQ, et al. Estrogen supplementation in the posthypoxic myoclonus rat model. Clin Neuropharm 2001;24:58–61. [22] Jundt F, Lempert T, Dorken B, et al. Trimethoprim-sulfamethoxazole exacerbates posthypoxic action myoclonus in a patient with suspicion of Pneumocystis jiroveci infection. Infection 2004;32:176–8. [23] Frucht SJ, Trost M, Ma Y, et al. The metabolic topography of posthypoxic myoclonus. Neurology 2004;62:1879–81. [24] Welsh JP, Yeun G, Placantonakis DG, et al. Why do Purkinje cells die so easily after global brain ischemia? Aldolase C, EAAT4, and the cerebellar contribution to posthypoxic myoclonus. Adv Neurol 2002;89:331–59. [25] Krauss GL, Bergin A, Kramer RE, et al. Suppression of posthypoxic and postencephalitic myoclonus with levetiracetam. Neurology 2001;56:411–2. [26] Lim LL, Ahmed A. Limited efficacy of levetiracetam on myoclonus of different etiologies. Park Rel Dis 2005;11:135–7. [27] Frucht SJ, Louis ED, Chuang C, et al. A pilot tolerability and efficacy study of levetiracetam in patients with chronic myoclonus. Neurology 2001;57:1112–4. [28] Genton P, Guerrini R. Effect of alcohol on action myoclonus in Lance-Adams syndrome and progressive myoclonic epilepsy. Mov Disord 1992;7:92. [29] Jain S, Jain M. Action myoclonus (Lance-Adam syndrome) secondary to strangulation with dramatic response to alcohol. Mov Disord 1992;6:183. [30] Priori A, Bertolasi L, Pesenti A, et al. Gammahydroxybutyric acid for alcohol-sensitive myoclonus with dystonia. Neurology 2000;54:1706. [31] Frucht SJ, Bordelon Y, Houghton WH. Marked amelioration of alcohol-responsive posthypoxic myoclonus by gamma-hydroxybutyric acid (Xyrem). Mov Disord 2005;20:745–51. [32] Burke RE, Fahn S, Gold AP. ‘‘Delayed-onset dystonia in patients with ‘‘static’’ encephalopathy. J Neurol Neurosurg Psychiatry 1980;43:789–97. [33] Bhatt MH, Obeso JA, Marsden CD. Time course of postanoxic akinetic-rigid and dystonic syndromes. Neurology 1993;43:314–7. [34] Kuoppamaki M, Bhatia K, Quinn N. Progressive delayed-onset dystonia after cerebral anoxic insult in adults. Mov Disord 2002;17:1345–9. [35] Scott BL, Jankovic J. Delayed-onset progressive movement disorders after static brain lesions. Neurology 1996;46:68–74. [36] Boylan KB, Chin JH, DeArmond SJ. Progressive dystonia following resuscitation from cardiac arrest. Neurology 1990;40:1458–61.

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Cognitive and Neurobehavioral Dysfunction after Cardiac Bypass Procedures Ola A. Selnes, PhDa,*, Guy M. McKhann, MDa,b, Louis M. Borowicz, Jr, MSb, Maura A. Grega, RN, MSNc a Department of Neurology, Division of Cognitive Neuroscience, Johns Hopkins University School of Medicine, Reed Hall East–2, 1620 McElderry Street, Baltimore, MD 21287, USA b Zanvyl Krieger Mind/Brain Institute, The Johns Hopkins University, 3400 N. Charles Street, 338 Krieger Hall, Baltimore, MD 21218, USA c Department of Surgery, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Blalock 618, Baltimore, MD 21287, USA

Since the introduction of cardiopulmonary bypass nearly 5 decades ago, there has been a significant reduction in the morbidity and mortality associated with open heart surgery. Nonetheless, adverse neurologic outcomes after cardiac surgery continue to remain a significant concern. The spectrum of these outcomes ranges from coma and debilitating stroke to encephalopathy, delirium, and cognitive impairment. Recent studies suggest that the incidence of these adverse outcomes may be closely related to the status of the patient’s brain before surgery. Patients who have had transient ischemic attacks or stroke or who have a history of risk factors for cerebrovascular disease appear to be at greater risk for postoperative neurologic complications. This article focuses on the short- and long-term cognitive changes after coronary artery bypass grafting (CABG).

This research was supported by grant 35610 from the National Institutes of Health National Institute of Neurological Disorders and Stroke, the Dana Foundation, and the Johns Hopkins Medical Institutions GCRC grant RR 00052. * Corresponding author. E-mail address: [email protected] (O.A. Selnes). 0733-8619/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.ncl.2005.10.001 neurologic.theclinics.com

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Short-term cognitive changes Numerous studies have examined the incidence of cognitive decline after bypass surgery, but several questions regarding the specificity, epidemiology, and pathophysiology of these changes remain unanswered. Estimates of cognitive change after CABG have been highly variable because of differences in study exclusion criteria, choice of time points for measuring follow-up, and statistical criteria used for defining decline. Although early studies focused almost exclusively on the role of surgery-related factors, recent studies have attempted to take into account patient-related variables as well. The patients undergoing CABG today not only are older but they also have a greater prevalence of comorbid diseases, particularly those that are known risk factors for cerebrovascular disease. Methodologic issues The incidence of short-term cognitive changes varies according to the interval between surgery and follow-up testing. Neurocognitive test performance at the time of hospital discharge after CABG may be subject to potential confounders relating to the pharmacologic effects of anesthetic drugs or other clinical issues [1]. Therefore, some investigators have chosen to defer follow-up testing until 3 to 4 weeks after surgery. Although this strategy may yield follow-up data that are less contaminated by nonspecific surgical factors, extending the follow-up time may also mask transient changes in cognition. Not only may recognition of such cognitive outcomes be important for understanding the pathophysiology of early post-CABG cognitive changes but some researchers have suggested that early, transient postoperative cognitive changes may also be predictive of late cognitive decline up to 5 years after surgery [2]. A second factor of critical importance for accurately estimating the incidence of postoperative cognitive decline after CABG is the inclusion of a control group. Some studies have controlled for the effect of age on cognitive performance [3], whereas others have chosen control patients who have been diagnosed with coronary artery disease [4] or have chosen hospitalized inpatients undergoing noncardiac procedures [5]. Because of the importance of controls for interpreting cognitive changes after CABG, this review emphasizes studies that included a control group. Controlled studies In a recent study of acute postoperative cognitive outcomes from Germany, 67 CABG patients were examined before surgery and at days 3, 6, and 9 after surgery [6]. The study group was relatively healthy, in that patients who had a history of previous stroke, carotid stenosis, or general medical disorders and those who had low baseline cognitive test scores were excluded. Hospitalized patients who had peripheral neuropathy served as

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control subjects. Although there was a significant decline in neuropsychologic test performance at days 3 and 6, return to baseline levels of performance or above was observed by day 9. Thus, in a relatively low-risk group of CABG patients, postoperative cognitive decline appeared to be mild and reversible within a period of less than 2 weeks. In a study comparing the neuropsychologic test performance of 57 CABG patients with 55 control subjects from a senior citizen wellness program, 37 of the CABG patients completed follow-up testing 3 to 4 weeks after surgery. Patients who had previous CABG and those who had a history of visual impairments were excluded. The CABG patients had significantly lower baseline performance than the control subjects for some tests. Although the neuropsychologic test performance of the CABG group did not decline for any of the neuropsychologic tests at follow-up, the CABG group showed a reduced practice effect compared with the control subjects. Thus, in this relatively unselected group of CABG patients, lower than expected cognitive performance was observed preoperatively, but no significant decline was observed compared with healthy control subjects at 3 to 4 weeks after surgery [3]. In a recent study, the authors [4] evaluated 140 CABG patients and 92 demographically similar control subjects who had diagnosed coronary artery disease but no surgery. Both groups improved from baseline to 12 weeks, and apart from an unexpected greater improvement in verbal memory among the CABG patients, there were no statistically significant differences between the two groups. Together with the findings from other studies of earlier postoperative outcomes, this study demonstrates that cognitive decline after CABG is transient and reversible and that most patients return to their baseline cognitive performance between 3 to 12 weeks after surgery. There is little consensus regarding which specific cognitive functions are most vulnerable during the immediate postoperative period. Some studies have reported early decline in several cognitive domains including memory, psychomotor speed, executive functions, and visuoconstructional abilities, suggesting that multiple brain regions may be involved [7]. From the perspective of the patient and family members, the most frequent complaint involves changes in concentration and memory [8]. Because subjective cognitive complaints do not always correlate well with objective neuropsychologic test performance, some investigators have dismissed such subjective complaints as being secondary to depression. There is some evidence from noncardiac populations, however, that subjective memory complaints may reflect changes in memory that may not be captured by standardized tests of new verbal memory and delayed recall [9]. Pathophysiology of early cognitive changes No single factor that can account for the early postoperative cognitive changes has yet been identified. The focus of most investigations has been

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on neural injury secondary to surgery-related factors, including microemboli, hypoperfusion, and the systemic inflammatory response. It has proved surprisingly difficult, however, to find direct evidence that any of these variables, individually or in combination with other risk factors, can account for the short-term cognitive changes. Microemboli Patients who have atherosclerosis, especially of the carotid arteries and aortic arch, are known to be at increased risk for cerebral microemboli during the surgery [10]. Several studies using transcranial Doppler have demonstrated that showers of emboli are common during cardiac surgery [11], particularly during cannulation and clamping/unclamping of the aorta. These emboli vary in size and composition. Some studies have reported that most of these emboli appear to be gaseous rather than solid [12]; however, the clinical significance of the emboli remains to be determined. Some earlier studies demonstrated a modest association between embolic counts and short-term cognitive outcomes [13,14], but others have not found any statistically significant correlations [15–17]. It is unclear whether these discrepant findings are due to technical aspects such as problems distinguishing between solid versus gaseous emboli or to other factors. It is possible that the cognitive manifestations of microemboli may depend as much on patient- related risk factors (such as the degree of preexisting cerebrovascular disease) as on the number and size of the embolic load [18]. Patients who do not have significant pre-existing cerebrovascular disease may have a higher tolerance for embolic injury than those who have such disease. Consistent with this, the predictors of cognitive decline in a large multicenter Department of Veterans Affairs study included cerebrovascular disease, peripheral vascular disease, and a history of chronic disabling neurologic illness [19]. It is also expected that the cognitive implications of embolic injury depend on which parts of the brain are most heavily exposed. Special staining techniques have demonstrated numerous capillary and arteriolar dilitations in the brains of patients who die shortly after their surgery, but the regional distribution of these emboli has not been described. Most of these presumed embolic changes disappear over time and are not seen in patients who come to autopsy a week or longer after the surgery [20]. Other studies have reported low numbers of emboli in the brains of patients who die shortly after CABG, but cerebral microbleeds are relatively common [21]. Atrial fibrillation Atrial fibrillation is a common complication after CABG surgery and may be associated with hemodynamic changes, increased risk for adverse neurologic outcomes, and prolonged hospitalization. The only variable


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that has been consistently associated with the development of postoperative atrial fibrillation is older age [22]. Approximately one third of patients undergoing cardiac surgery with cardiopulmonary bypass have new-onset postoperative atrial fibrillation [23,24]. Those who have recurrent episodes of atrial fibrillation are at increased risk of stroke [25] and neurocognitive decline [26]. Hypoperfusion Longstanding hypertension and aging are associated with morphologic changes of the brain vascular supply that may predispose the elderly to the effects of hypoperfusion. Certain regions of the brain, including the hippocampus, periventricular white matter areas, and watershed areas, may be more susceptible to the effects of hypoperfusion. Abildstrom and colleagues [27] found that candidates for CABG had lower global cerebral blood flow preoperatively than controls, but there was no correlation between neuropsychologic test performance and postoperative global or regional blood flow. Caplan and Hennerici [28] proposed that emboli and hypoperfusion may play a synergistic role (ie, decreased flow during the surgery may result in reduced washout of embolic materials from the brain) and that the watershed areas are particularly susceptible to this combination. Anesthesia A significant percentage of elderly patients undergoing major noncardiac surgery with general anesthesia also suffer short- or long-term cognitive dysfunction. Although increasing age appears to be the principal risk factor, postoperative cognitive decline has also been reported in younger patients. In a study of patients in the 40- to 60-year age range, 19% were found to have cognitive decline 7 days after surgery with general anesthesia, which is comparable to the incidence reported for patients 60 years or older [29]. Studies comparing regional and general anesthesia have not found any difference in the incidence of cognitive decline 3 months after surgery, thus questioning a direct causal relationship between general anesthesia and postoperative cognitive dysfunction [30]. Regardless of the specific etiology of postoperative cognitive impairment after general anesthesia, there is evidence of some degree of short-term cognitive decline even after major noncardiac surgery with general anesthesia. Depression Mild to moderate depression is common after CABG, but one of the best predictors of postoperative depression is being depressed preoperatively, thus suggesting that postoperative depression is not caused by CABG. Anecdotally, short-term cognitive decline after CABG was often attributed to depression, and some cross-sectional investigations in noncardiac populations

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have reported an association between depression and performance on neuropsychologic tests [31]. In prospective studies, however, there is no evidence that new-onset depression after CABG correlates with short- or long-term changes in cognitive performance [32]. Genetic factors The possibility of a link between genetic factors and risk of cognitive decline after CABG was suggested by a study that found a greater likelihood of decline in patients who had the apolipoprotein (apo) E epsilon4 allele [33]. Subsequent studies, however, have not been able to replicate these findings [34]. Steed and colleagues [35] evaluated 111 CABG patients preoperatively and at 4 to 7 weeks postoperatively and reported no relationship between change in neuropsychologic test performance and apo E allele status. In a study of longer-term cognitive outcomes after CABG, no significant association was found between apo E status and cognitive decline at 5 years [36].

Long-term changes Although most studies have focused on short-term cognitive decline after CABG, a study from Duke University raised the possibility of late or delayed cognitive decline after CABG. Newman and colleagues [2] studied 261 patients before surgery and followed them prospectively before discharge and at 6 weeks, 6 months, and 5 years after CABG surgery. The incidence of decline at the time of discharge was 53%, dropping to 24% at 6 months. At 5 years, 66% of the patients were available for follow-up testing, and an unexpected 42% of these patients performed below their baseline performance on a global measure of cognition. Predictors of late cognitive decline included older age, fewer years of education, higher baseline score, and cognitive decline at the time of discharge. Selnes and colleagues [34] evaluated 172 patients before and after CABG and followed them prospectively for up to 5 years. Similar to the findings from the Duke study, a statistically significant decline in performance was observed for most cognitive domains between 1 and 5 years. Comparing baseline to performance at 5 years, decline was observed for only two cognitive domains (psychomotor speed and visuoconstruction). In a more recent study, Stygall and coworkers [36] obtained 5-year neuropsychologic follow-up on 107 of 171 CABG patients who were evaluated before surgery. Relative to baseline performance, they found decline in the overall neuropsychologic change z-score score at 6 days, followed by improvement at 8 weeks and decline at 5 years. As in previous studies of late cognitive decline, the greatest change was observed for measures of motor and psychomotor speed. Surprisingly, no decline was observed for most measures of verbal learning and memory. The number of emboli during the surgery, the degree of decline at the time of discharge, and the degree of


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recovery between discharge and follow-up testing at 6 to 8 weeks were among the predictors of late decline. The investigators suggested that the number of emboli during surgery might be a surrogate marker for severity of cerebrovascular disease and that patients who have more severe pre-existing cerebrovascular disease might be more likely to have late decline. Some studies, however, have not found evidence of late cognitive decline after CABG. In a small study from Germany, 52 patients were followed up to 5 years after CABG [5]. None of these patients had what was considered clinically significant cognitive decline and only a small subset had mild decline. The investigators suggested that better control of hypertension, hypercholesterolemia, and other risk factors for cerebrovascular disease during the 5-year follow-up period was a possible explanation for the lack of late decline in their study. If these findings are replicated in larger cohorts, it would suggest that late cognitive decline after CABG could be avoided by improved postoperative control of risk factors that accelerate progression of underlying cerebrovascular disease [37]. Only two long-term follow-up studies published to date have included a control group. Hlatky and colleagues [38] obtained cross-sectional neuropsychologic test performance data for patients who had been randomized to standard coronary artery bypass (N ¼ 125) or angioplasty (N ¼ 64) 5 years earlier. In an intention-to-treat analysis, there were no significant differences in the 5-year cognitive test scores for these two groups. Although this study did not evaluate cognitive changes prospectively, the findings nonetheless confirm that 5 years after the procedure, the cognitive performance of patients who had coronary artery bypass surgery did not differ from that of patients who had angioplasty. In a study of twins, the postoperative cognitive performance of 232 CABG patients, stratified across three age categories, was compared with that of their twins who did not undergo CABG. Surprisingly, CABG patients who had their surgery at a relatively young age (between age 63 and 70 years) had better cognitive performance 1 to 2 years postoperatively than the co-twin who did not have surgery. No significant differences in cognitive performance were found for the twin pairs in the older age groups [39]. In summary, there is evidence from several studies that late cognitive decline occurs between baseline and 5 years after surgery. The degree of decline relative to baseline performance appears to be relatively minor and is observed mainly in the domains of motor or psychomotor speed, with no significant decline in memory performance. The pattern of these late cognitive changes is similar to what is seen in patients who have mild subcortical vascular disease. Etiology of late cognitive changes Of the prospective studies that found evidence of late cognitive decline after CABG, none included a control group. It remains unclear, therefore,

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whether the late cognitive changes are causally related to cardiopulmonary bypass with general anesthesia 5 years earlier, normal aging, development of Alzheimer’s disease during the follow-up period, or other causes. The selection of an appropriate control group for patients undergoing CABG has been controversial. Patients undergoing CABG today are known to have a high prevalence of hypertension, diabetes, and other risk factors for cerebrovascular disease. Because these factors by themselves are associated with mild cognitive decline over time, the control group should include subjects who have a similar profile of risk factors for cerebrovascular disease. Duration or severity of these risk factors cannot easily be measured, however, and how these risk factors translate into eventual vascular disease of the brain remains unknown. Cerebrovascular disease risk factors There is accumulating evidence from several epidemiologic studies demonstrating that a history of one or more risk factors for cerebrovascular disease may be associated with accelerated cognitive decline even without cardiac surgery [40–43]. In a study of community-dwelling individuals, Knopman and colleagues [44] reported that participants who had a history of diabetes or hypertension at baseline had greater cognitive decline over a 4- to 6-year follow-up period than participants who did not have such risk factors. Other studies have found that diabetes alone may be associated with cognitive decline over time. Fontbonne and colleagues [45] reported that subjects who had diabetes had lower cognitive test scores at 4-year follow-up testing than subjects who had normal glucose levels. There is evidence that longer duration of diabetes is associated with worse cognitive performance [46], and data suggest that individuals who have diabetes and hypertension have greater cognitive decline in late life [47]. Finally, there is evidence that treatment of these risk factors for vascular disease may prevent any late cognitive consequences [46,48]. These findings are consistent with the findings from the 5-year CABG follow-up study by Mullges and colleagues [5]. These investigators hypothesized that better control of risk factors for vascular disease during the 5 years after surgery may have accounted for the lack of late decline seen in their study. In summary, there is now considerable evidence from epidemiologic studies demonstrating an association between the duration and degree of vascular disease and the risk of cognitive decline during the later years of life, even in community-dwelling elderly individuals who have not undergone CABG. Pre-existing MRI abnormalities Some studies have found that nearly one third of otherwise asymptomatic individuals have silent brain infarcts on MRI. Several studies have concluded that older age and hypertension are significant risk factors for having such


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MRI abnormalities [49]. The presence of such lesions may be associated with progressive cognitive decline or late dementia [49,50]. The neuropsychologic profile of patients who have subcortical silent infarcts depends on the overall volume and location of the lesions, but there may be additional hemodynamic factors that contribute to the clinical expression of such lesions [51]. Several studies have reported that motor and psychomotor speed are typically slowed in patients who have silent subcortical infarcts [49,52]. Given the high prevalence of silent infarcts in community-dwelling individuals, one would expect such MRI findings to be even more common among candidates for CABG. Because of the relatively short time between admission and surgery, however, preoperative brain imaging has been difficult to obtain. In a study from Japan, preoperative MRI scans were performed in 421 candidates for CABG [53]. Of these patients, 30% were found to have single, small brain infarctions and 20% had multiple infarctions. Thus, an unexpected half of this group had evidence of silent brain abnormalities before surgery. Patients who had single or multiple infarctions had lower baseline cognitive performance and were more likely to have decline in cognitive test performance postoperatively. A more recent study confirmed a high frequency of cerebrovascular disease in candidates for CABG. Nakamura and colleagues [54] obtained preoperative MRI scans in 91 patients and found that 33 had small infarctions, 38 had multiple small infarctions, and 8 had infarctions greater than 15 mm. Thus, silent ischemic cerebral disease is commonly seen preoperatively in patients undergoing CABG and is associated with an increased risk of postoperative cognitive decline in the short-term. Whether pre-existing silent MRI abnormalities are also predictive of late cognitive changes has not yet been examined.

Off-pump coronary artery bypass graft The recent development of techniques for performing CABG surgery without the use of cardiopulmonary bypass has generated considerable optimism that such techniques might lead to a reduction of adverse neurologic and cognitive outcomes. Direct comparison with outcomes in CABG populations has been difficult because most off-pump CABG studies included relatively healthy, low-risk patients [55]. Although the incidence of postoperative atrial fibrillation may be lower after off-pump CABG, it nonetheless remains a common postoperative complication [22]. Several studies have demonstrated that the use of off-pump surgery is associated with a reduction in the number of emboli to the brain [56,57], but clear-cut benefits in terms of neurocognitive outcomes are less obvious. In the only large-scale prospective randomized study to date, there was no significant difference in the incidence of decline between patients having conventional on-pump versus off-pump surgery at 3 or 12 months [58]. Prospective long-term follow-up studies of cognition in

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off-pump patients have not yet been reported; therefore, it is not known whether the degree of late decline in these patients differs from that observed in CABG patients. Summary From a cognitive standpoint, CABG as currently practiced appears to be safe for the great majority of patients, but transient changes involving memory, executive functions, and motor speed may still occur in a subset of patients during the first few days to weeks after CABG. The etiology most likely is multifactorial and includes a synergistic effect of microemboli, hypoperfusion, and other variables associated with major surgery. Older age and degree of pre-existing cerebrovascular disease have been identified as important risk factors. The short-term cognitive changes appear to be reversible by 3 months after surgery for most patients. Late cognitive decline after CABG, occurring between 1 and 5 years after the surgery, has been well documented, but controlled studies demonstrating that this decline is specifically attributable to the use of cardiopulmonary bypass itself rather than to progression of underlying cerebrovascular disease or other age-related changes are pending. Acknowledgments The authors thank the staff and participants in this study and are particularly grateful for the ongoing collaboration with Dr. W. Baumgartner and other participating cardiac surgeons and cardiologists. References [1] Johnson RG. Abnormal neuropsychometrics early after coronary artery bypass grafting. Crit Care Med 2000;28(6):2142–3. [2] Newman MF, Kirchner JL, Phillips-Bute B, et al. Longitudinal assessment of neurocognitive function after coronary artery bypass surgery. N Engl J Med 2001;344:395–402. [3] Keith JR, Puente AE, Malcolmson KL, et al. Assessing postoperative cognitive change after cardiopulmonary bypass surgery. Neuropsychology 2002;16(3):411–21. [4] Selnes OA, Grega MA, Borowicz LM Jr, et al. Cognitive changes with coronary artery disease: a prospective study of coronary artery bypass graft patients and nonsurgical controls. Ann Thorac Surg 2003;75(5):1377–84. [5] Mullges W, Babin-Ebell J, Reents W, et al. Cognitive performance after coronary artery bypass grafting: a follow-up study. Neurology 2002;59:741–3. [6] Mullges W, Berg D, Schmidtke A, et al. Early natural course of transient encephalopathy after coronary artery bypass grafting. Crit Care Med 2000;28(6):1808–11. [7] Selnes OA, Goldsborough MA, Borowicz LM, et al. Determinants of cognitive change after coronary artery bypass surgery: a multifactorial problem. Ann Thorac Surg 1999;67: 1669–76. [8] Bergh C, Backstrom M, Jonsson H, et al. In the eye of both patient and spouse: memory is poor 1 to 2 years after coronary bypass and angioplasty. Ann Thorac Surg 2002;74(3): 689–93.


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[9] Bassel C, Rourke SB, Halman MH, et al. Working memory performance predicts subjective cognitive complaints in HIV infection. Neuropsychology 2002;16(3):400–10. [10] Goto T, Baba T, Matsuyama K, et al. Aortic atherosclerosis and postoperative neurological dysfunction in elderly coronary surgical patients. Ann Thorac Surg 2003;75(6):1912–8. [11] Mullges W, Franke D, Reents W, et al. Brain microembolic counts during extracorporeal circulation depend on aortic cannula position. Ultrasound Med Biol 2001;27(7):933–6. [12] Abu-Omar Y, Balacumaraswami L, Pigott DW, et al. Solid and gaseous cerebral microembolization during off-pump, on-pump, and open cardiac surgery procedures. J Thorac Cardiovasc Surg 2004;127(6):1759–65. [13] Clark RE, Brillman J, Davis DA, et al. Microemboli during coronary artery bypass grafting. Genesis and effect on outcome. J Thorac Cardiovasc Surg 1995;109:249–57 [discussion: 257–8]. [14] Fearn SJ, Pole R, Wesnes K, et al. Cerebral injury during cardiopulmonary bypass: emboli impair memory. J Thorac Cardiovasc Surg 2001;121(6):1150–60. [15] Braekken SK, Reinvang I, Russell D, et al. Association between intraoperative cerebral microembolic signals and postoperative neuropsychological deficit: comparison between patients with cardiac valve replacement and patients with coronary artery bypass grafting. J Neurol Neurosurg Psychiatry 1998;65(4):573–6. [16] Neville MJ, Butterworth J, James RL, et al. Similar neurobehavioral outcome after valve or coronary artery operations despite differing carotid embolic counts. J Thorac Cardiovasc Surg 2001;121(1):125–36. [17] Browndyke JN, Moser DJ, Cohen RA, et al. Acute neuropsychological functioning following cardiosurgical interventions associated with the production of intraoperative cerebral microemboli. Clin Neuropsychol 2002;16(4):463–71. [18] Andrell P, Jensen C, Norrsell H, et al. White matter disease in magnetic resonance imaging predicts cerebral complications after coronary artery bypass grafting. Ann Thorac Surg 2005;79(1):74–9. [19] Ho PM, Arciniegas DB, Grigsby J, et al. Predictors of cognitive decline following coronary artery bypass graft surgery. Ann Thorac Surg 2004;77(2):597–603. [20] Brown WR, Moody DM, Challa VR. Cerebral fat embolism from cardiopulmonary bypass. J Neuropathol Exp Neurol 1999;58(2):109–19. [21] Emmrich P, Hahn J, Ogunlade V, et al. Neuropathological findings after cardiac surgeryd retrospective study over 6 years. Z Kardiol 2003;92(11):925–37. [22] Zangrillo A, Landoni G, Sparicio D, et al. Predictors of atrial fibrillation after off-pump coronary artery bypass graft surgery. J Cardiothorac Vasc Anesth 2004;18(6):704–8. [23] Mathew JP, Fontes ML, Tudor IC, et al. A multicenter risk index for atrial fibrillation after cardiac surgery. JAMA 2004;291(14):1720–9. [24] Crystal E, Connolly SJ. Atrial fibrillation: guiding lessons from epidemiology. Cardiol Clin 2004;22(1):1–8. [25] Lahtinen J, Biancari F, Salmela E, et al. Postoperative atrial fibrillation is a major cause of stroke after on-pump coronary artery bypass surgery. Ann Thorac Surg 2004;77(4):1241–4. [26] Stanley TO, Mackensen GB, Grocott HP, et al. The impact of postoperative atrial fibrillation on neurocognitive outcome after coronary artery bypass graft surgery. Anesth Analg 2002;94(2):290–5. [27] Abildstrom H, Hogh P, Sperling B, et al. Cerebral blood flow and cognitive dysfunction after coronary surgery. Ann Thorac Surg 2002;73(4):1174–8. [28] Caplan LR, Hennerici M. Impaired clearance of emboli (washout) is an important link between hypoperfusion, embolism, and ischemic stroke. Arch Neurol 1998;55(11):1475–82. [29] Johnson T, Monk T, Rasmussen LS, et al. Postoperative cognitive dysfunction in middleaged patients. Anesthesiology 2002;96(6):1351–7. [30] Rasmussen LS, Johnson T, Kuipers HM, et al. Does anaesthesia cause postoperative cognitive dysfunction? A randomised study of regional versus general anaesthesia in 438 elderly patients. Acta Anaesthesiol Scand 2003;47(3):260–6.

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Neurol Clin 24 (2006) 147–158

Brain Injury from Cardiac Arrest in Children Robert W. Hickey, MDa,*, Michael J. Painter, MDb a

Division of Pediatric Emergency Medicine, Department of Pediatrics, University of Pittsburgh, Children’s Hospital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, PA 15213, USA b Division of Child Neurology, Department of Pediatrics, University of Pittsburgh, Children’s Hospital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, PA 15213, USA

Many of the features of postischemic brain injury in children are similar to injury in adults; thus, much of this issue of the Neurologic Clinics of North America applies to children and adults. There are two important differences, however, that merit a separate section focused on pediatric injury. First, the mechanism of cardiac arrest in children differs, with respiratory causes far outnumbering cardiac causes (Tables 1 and 2). Second, the developing brain has different vulnerability and potential for repair compared with the mature brain. This article reviews these differences and the available clinical data relevant to pediatric brain injury following cardiac arrest.

Asphyxial cardiac arrest The most common cause of nontraumatic cardiopulmonary arrest in children is airway compromise [1–3]. Although ventricular fibrillation (VF) or ventricular tachycardia (VT) occurs less commonly in children than in adults, it is not rare: approximately 5% to 15% of children with prehospital arrest have VF/VT [4–6]. Asphyxia can be clinically defined as airway obstruction or inadequate ventilation leading to hypoxemia and hypercarbia. Examples include drowning, choking, and coma accompanied by loss of airway patency. The typical progression of untreated asphyxia is hypertension and increased

This work was supported by the National Institutes of Health grant NIH KO8 HD40848 to Robert W. Hickey. * Corresponding author. E-mail address: [email protected] (R.W. Hickey). 0733-8619/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.ncl.2005.10.002 neurologic.theclinics.com

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Table 1 Etiology of out-of-hospital cardiac arrest in children Cause of arrest

n (%)

Sudden infant death syndrome Trauma Respiratory Submersion Cardiac Central nervous system Burn Poisoning Other Unknown

136 118 96 73 48 35 6 6 63 20

(23) (20) (16) (12) (8) (6) (1) (1) (10) (3)

Data from Young KD, Gausche-Hill M, McClung CD, et al. A prospective, populationbased study of the epidemiology and outcome of out-of-hospital pediatric cardiopulmonary arrest. Pediatrics 2004;114(1):157–64.

work of breathing (where possible), followed by bradycardia, hypotension, pulseless electrical activity, and eventually, asystole. Although both VF and asphyxial cardiac arrest result in global brain ischemia, the pattern of ischemia differs (Table 3). VF causes an abrupt cessation of cardiac output, whereas asphyxia causes an initial hypertension, followed by a gradual decrease in flow until pulseless electrical activity and, finally, asystole occur. Paradoxically, although low cerebral blood flow is better than no flow, a ‘‘trickle’’ of flow can be worse than no flow. This phenomenon was demonstrated in a study by Bottiger and colleagues [7] that showed worse postresuscitation cerebral reperfusion in rats that had 12-minute untreated VF plus 5-minute VF treated with cardiopulmonary resuscitation compared with rats subjected to 17-minute untreated VF. Theories for the damaging effect of trickle flow include (1) the continued delivery of substrate during conditions of anaerobic metabolism, causing worse tissue acidosis; and (2) the continued delivery of platelets and coagulation factors, causing worse microvascular plugging that would Table 2 Characteristics of children with in-hospital cardiac arrest Patient characteristic

n (%)

Cardiac arrest No CPR (terminal phase of chronic disease) CPR performed Chronic disease in subset with CPR Respiratory failure in subset with CPR Circulatory shock in subset with CPR

176 47 129 92 79 37

(100) (27) (73) (71) (61) (29)

Abbreviation: CPR, cardiopulmonary resusciation. Data from Reis AG, Nadkarni V, Perondi MB, et al. A prospective investigation into the epidemiology of in-hospital pediatric cardiopulmonary resuscitation using the international Utstein reporting style. Pediatrics 2002;109(2):200–9.

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Table 3 Comparison of injury from ventricular fibrillation versus asphyxial cardiac arrest Injury

Ventricular fibrillation

Asphyxial cardiac arrest

Postresuscitation cardiac injury Postresuscitation cerebral injury Cerebral blood flow

Relatively more Relatively less Sudden complete ischemia No Relatively less Yes

Relatively less Relatively more Trickle flow prior to complete ischemia Yes Relatively more Yes

Yes

Yes

Scattered microinfarcts Injury to basal ganglia Selective vulnerability of CA1 hippocampus Selective vulnerability of cerebellar Purkinje’s cells

Comparisons are extrapolated from animal experiments.

impair reperfusion during resuscitation. Asphyxia, but not VF/VT, has an interval of trickle cerebral blood flow accompanied by profound hypoxemia. The histology of cerebral injury following asphyxia differs from that seen in VF. Safar and colleagues [8,9] showed that brain damage from asphyxial cardiac arrest in dogs is worse than the damage found after equivalent periods of circulatory arrest from VF. In addition, asphyxiated brains had scattered microinfarcts and hemorrhage not seen in VF animals. Thus, laboratory experiments demonstrate that the severity and pattern of cerebral injury following asphyxial cardiac arrest differs from VF arrest. Clinical evidence of a difference in injury patterns is suggested by a report from Morimoto and colleagues [10] that described increased prevalence of brain edema (diagnosed by head CT) in adults remaining comatose following respiratory-induced cardiac arrest compared with cardiac arrhythmia– induced cardiac arrest. Do the differences between asphyxial brain injury and ‘‘cardiac-mediated’’ brain injury have clinical relevance? They do to the extent that asphyxial injuries are more severe. Both injuries, however, demonstrate selective vulnerability and delayed neuronal death. Specifically, both mechanisms cause cell death that is ‘‘delayed’’ and is first seen on histology at 24 to 72 hours following reperfusion. The most prominent of these ‘‘selectively vulnerable’’ regions are the hippocampus and reticular thalamus. Thus, although an asphyxial injury may be more severe than a cardiac-mediated injury for an equivalent period of ischemia, asphyxial injuries should respond similarly to neuroprotective therapies. The developing brain Brain maturation entails a complex coordination of neuronal proliferation, migration, synaptic overgrowth, pruning, and myelination. Although proliferation and migration are complete in humans at birth, the remaining processes continue into early adulthood, with completion of the myelination

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of long association pathways occurring in the third decade of life. Accordingly, the brain’s vulnerability to injury is not constant across different age ranges [11]. For example, rodents are extraordinarily resistant to ischemic injury when first born and then go through a period of increased sensitivity to injury, followed by intermediate sensitivity that lasts into adulthood [12–15]. The period of increased vulnerability correlates with maturation of receptors for excitatory neurotransmitters and maximal synaptogenesis. Laboratory data also show that immature neurons and oligodendrocytes have a lower threshold for initiating programmed cell death (apoptosis) compared with mature cells [16–19]. These developmental events that determine susceptibility to brain injury in laboratory models also occur during normal human development [20]. Synaptogenesis in human striatal cortex accelerates between age 2 and 4 months, creating a condition of exuberant connectivity that is subsequently pruned by 40% between age 8 months and 11 years [21]. A second wave of synaptic formation and pruning, primarily in the frontal cortex, has now been identified in adolescence [22]. In addition, 31P magnetic resonance spectroscopy shows that the metabolic rate for local cerebral regions is 190% to 226% of adult levels between age 3 and 8 years, and there is a peak in the phosphomonoester spectrum that is indicative of active myelination just before age 2 years [23]. Functional development Coincident to maturation seen at the tissue and cellular layer, the functional capabilities of the brain also mature over time. The acquisitions of gross motor, fine motor, and cognitive skills during youth are well-recognized phenomena. Beyond early youth, brain growth continues into the twenties and is associated with maturation of executive functions. Perhaps not surprisingly, functional imaging studies show that risk-taking during adolescence is associated with an immature pattern of cerebral activity compared with adult activity. Some skills can only be acquired during specific periods of development (‘‘use it or lose it’’). For example, temporary monocular occlusion in children at the time when visual cortical pathways are being established can result in permanent cortical blindness in the occluded eye. Likewise, patching the ‘‘good eye’’ in patients with strabismus improves vision in the ‘‘weak eye’’ only when patching is initiated at a young age. A more prosaic example is the ability of young children to speak a second language without accent. There is also an age-dependent capacity for repair [24]. A dramatic example of plasticity is the recovery that can occur in young children, but not adults, undergoing hemispherectomy for intractable seizures [25,26]. Children who have had hemispherectomy are more capable than adults of reallocating functions from the removed hemisphere to the remaining hemisphere. Similarly, language deficits are less common in children suffering injury to the dominant hemisphere before age 8 years.


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The impact of global brain ischemia on functional outcome during ‘‘developmentally sensitive’’ periods of skill acquisition and the role of plasticity in recovery from global ischemia has not been systematically studied. One challenge is that injury obtained in young patients may not become apparent until the functional correlates are required for normal behavior and are testable. For example, children who have learning disabilities are often not diagnosed until the requisite learning skills become necessary for school performance. A greater understanding of the dynamic between injury and development has considerable potential benefit for children who have ischemic brain injury. Clinical experience Young and Seidel [27] recently summarized the results from 44 studies reporting on 3094 pediatric patients with cardiopulmonary arrest. The data showed an overall survival rate from cardiopulmonary arrest of 13%, with in-hospital arrest rates being higher than out-of-hospital arrest rates (24% versus 9%). Most of the reviewed studies reported good neurologic outcome in approximately 60% of survivors; however, comparison between studies is difficult because of the differences in inclusion criteria and the definition of ‘‘good’’ neurologic outcome. Neurologic outcome assessments that target motor function and rudimentary life-skill tasks suggest that most patients have full recovery or severe disability [28–35]. Patients who have poor outcome have generally suffered a severe, acute asphyxial event. Among children with good neurologic outcome, assessments that measure IQ or psychocognitive function often reveal impaired performance [36– 40]. Robertson and colleagues [39] recently published data on a cohort of 53 children younger than age 3 years admitted to an ICU who had traumatic brain injury (n ¼ 26) or hypoxic ischemic (HI) brain injury (n ¼ 27) and an initial Glasgow Coma Scale of 8 or less. Of the 23 children identified as having ‘‘good recovery’’ based on the Glasgow Outcome Scale, 15 (65%) had below-average scores on the Mental Developmental Index or Performance Developmental Index. These indices, however, have imperfect correlation with later cognitive assessments and it is possible that additional recovery may occur or that deficits may remain ‘‘dormant’’ until uncovered by increasingly complex cognitive demands associated with maturation. Additional studies are desirable to better define long-term psychocognitive outcome. Specific patterns of functional deficits have been described; notably, memory deficits in adults who have global brain injury [41,42] and cerebral palsy in neonatal asphyxia [43,44]. Similarly, the neurodevelopmental outcomes of premature infants have been well characterized in a meta-analysis of 227 studies by Bhutta and colleages [45]. The infrastructure that directs high-risk neonatal ICU graduates into comprehensive assessment/treatment programs, however, does not exist for older children who have HI injury

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and, thus, the functional outcome of children who have HI injury is less well characterized. Prognosis Recently, Mandel and colleagues [46] reported on clinical and electrophysiologic predictors of outcome in 42 pediatric patients who remained comatose or had impaired consciousness at 24 hours following an HI injury. Twelve patients had an eventual good outcome, 4 had mild to moderate disability, 7 had severe disability or survival in a persistent vegetative state, and 19 ultimately died (9 with brain death, 2 after failed repeated resuscitation attempts, 8 after withdrawal of therapy). The positive predictive value for poor outcome (severe disability, persistent vegetative state, or death; n ¼ 26) was 91% for duration of initial cardiopulmonary resuscitation exceeding 10 minutes and 100% for (1) Glasgow Coma Scale scores less than 5, (2) absence of spontaneous respirations, or (3) absence of pupillary reflex at 24 hours. The positive predictive value for poor outcome was 100% for discontinuous electroencephalographic activity, epileptiform electroencephalographic activity, or bilateral absent N20 latency on sensory evoked potential. This study is in agreement with other studies that have found neurologic examination and electrophysiology studies to be good predictors of outcome [47]. The main limitations of many of these studies are the small sample sizes and the post hoc derivation of decision rules. Imaging Neuroimaging techniques have identified specific patterns of cerebral injury in adults and newborns with ischemic injury. Data from human neonates and experimental primate models of neonatal asphyxia reveal that imaging abnormalities correlate with the nature and duration of the insult and the maturational stage of the brain at time of injury [48]. The immature brain of premature neonates is more vulnerable to white matter injury, whereas the brain of term neonates is more vulnerable to gray matter injury [49]. Acute, total asphyxia tends to result in greater injury to the brainstem and thalamus, whereas prolonged, partial asphyxia results in greater injury to the cortex and subcortical regions [50]. Even so, full-term infants who have prolonged, partial ischemia have a different pattern of injury compared with premature infants who have prolonged, partial ischemia. Thus, there are different patterns of HI brain injury relative to gestational age in newborns. What is not known is whether there are different patterns of injury relative to age in children outside of the newborn period suffering ischemia. MRI can be used to measure regional volume (morphometrics) and thus characterize brain injury/recovery during follow-up of HI injury. A series of 17 adults surviving cardiac arrest studied by MRI at 6 months following resuscitation reported reduced hippocampal volume and a global reduction in


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brain volume [51]. The reduction in hippocampal volume is consistent with the specific cognitive memory impairments commonly documented in adults following cardiac arrest [52]. The reduction in global brain volume is consistent with the more widespread deficits in memory, visuospatial, and executive functions that have also been documented. Similarly, follow-up MRI for former low birth weight preterm infants demonstrates smaller regional cortical volumes [53] and selective loss of hippocampal volume [54] compared with control subjects. The volume losses in these former preterm infants is correlated with memory performance and full-scale, verbal, and performance IQ scores. Again, information on the predictive value and long-term changes seen in MRI imaging of older children who have HI is limited [55]. Kreis and colleagues [56] used proton spectroscopy to study 16 children suffering near-drowning from age 7 months to 6 years. Loss of N-acetylaspartate from gray matter preceded the loss observed in white matter and was more severe. There was a delayed second peak of lactate, similar to the delayed secondary energy failure documented in neonatal HI. A spectroscopic index was derived that predicted neurologic outcome in this small series with greater accuracy than published clinical criteria. A contemporary variation of diffusion-weighted MRI (diffusion tensor imaging; DTI) analyzes vector forces of diffusion patterns. Diffusion patterns are highly dependent on development and orientation of axonal fibers and oligodendroglia; thus, DTI is a sensitive tool for detecting white matter development (myelination) and injury. DTI scans obtained from premature infants who have white matter injury demonstrate disorganized vector forces consistent with disrupted white matter tract development [57]. Furthermore, white matter injury has been shown to correlate with diminished volume in the associated gray matter. DTI studies on older children who have HI injury have not been reported; however, DTI and MRI studies of normal children at different ages confirm that myelination continues through the second decade of life in an age-dependent, region-specific fashion [58–62]. Thus, it is likely that patterns of white matter injury vary by age. If so, DTI may be useful for identifying white matter injury and directing rehabilitative therapy to the associated cortical (and functional) brain regions. Treatment Following resuscitation from cardiac arrest, there is a period of increased sensitivity of the brain to secondary injury. A review by Kochanek and colleagues [63] provided the known precipitants of secondary injury, which include hypotension, hypoxia, hyperglycemia, and hyperthermia. Early postresuscitative care should focus on avoiding these causes of secondary injury (Box 1). Detailed discussion of intensive care therapy is beyond the scope of this article. Instead, discussion is limited to hyperventilation and hypothermia (hyperventilation because it is a pervasive problem and hypothermia because it is the most promising neuroprotective strategy).

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Box 1. Postresuscitation treatment priorities

Avoid hypotension Maintain normoxia (avoid hypoxia and prolonged hyperoxia) Maintain euglycemia (avoid hyperglycemia and hypoglycemia) Avoid hyperventilation Avoid hyperthermia Avoid rewarming Consider induced hypothermia

One preventable cause of secondary injury is iatrogenic hyperventilation. Hyperventilation has been shown to cause vasoconstriction and significantly decreased cerebral blood flow in children following traumatic brain injury [64] and in adults recovering from cardiac arrest [65]. Hyperventilation can also decrease cerebral blood flow by increasing intrathoracic pressure, causing a decrease in cardiac output and cerebral venous return. In addition, respiratory alkalosis shifts the oxygen hemoglobin dissociation curve to the left, reducing oxygen delivery to tissue. These alterations are particularly dangerous early after resuscitation when there is prolonged, multifocal decreased cerebral blood flow [66]. Avoidance of hyperventilation is challengingd caregivers under stressful circumstances unintentionally but predictably hyperventilate patients [67,68]. Tobias and colleagues [69] published a study on pediatric patients transported from the ICU to the radiology suite by nurses and respiratory therapists blinded to end tidal CO2 values: 23% of readings were less than 20 torr. Increased use of quantitative continuous CO2 monitors throughout the health care system would decrease the potential for harm secondary to inadvertent hyperventilation. Measurement and control of temperature following cardiac arrest is an important part of patient management. After arrest, children commonly have an initial period of spontaneous hypothermia followed by a delayed (approximately 24 hours) development of fever [69a]. These temperature changes are relevant because hypothermia is neuroprotective, whereas hyperthermia can exacerbate brain injury. Accordingly, routine warming of patients during initial hypothermia is no longer recommended. Rewarming can negate the neuroprotective effects of hypothermia and may cause an ‘‘overshoot’’ of temperature that contributes to subsequent fever. Intentional induction or maintenance of hypothermia (therapeutic hypothermia) has recently been shown to be beneficial in adults recovering from cardiac arrest and in newborns recovering from birth asphyxia [70–73]. Although the studies in adults excluded asphyxia (enrollment was limited to patients who had VF/VT), there are significant animal data to support the use of hypothermia in asphyxial arrest [74]. Thus, consideration should be given to actively cooling children who remain comatose following resuscitation


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from cardiac arrest. In addition, temperature should be monitored closely and fever should be treated aggressively. Knowledge gaps and future directions There is an accumulating literature on neurologic outcome in adults resuscitated from cardiac arrest and newborns recovering from perinatal asphyxia. In contrast, there is very little information on children resuscitated from cardiac arrest. Animal models showing age-dependent susceptibility to injury and clinical data showing age-dependent windows for learning and plasticity suggest that extrapolating from neonatal or adult experience will be imperfect. Thus, there is a critical need for studies targeting the pediatric age range between these populations. Important areas of inquiry include Age-dependent susceptibilities for injury and repair Contemporary imaging strategies targeting white matter development, morphometric measurements, and functional imaging Clinical or laboratory markers for severity of the initial event Role of antiapoptotic neuroprotective strategies in children Induced hypothermia Rehabilitation strategies (eg, enriched environment, forced use) that target age-dependent injury/repair susceptibilities Because of the infrequent occurrence of pediatric cardiac arrest and the number of confounding variables, advances in understanding will likely require multicenter and interdisciplinary collaborations. Although studies of brain injury in children across a range of developmental stages will be challenging, they will also be unique opportunities to increase our understanding of brain development, learning, and plasticity. References [1] Kuisma M, Suominen P, Korpela R. Paediatric out-of-hospital cardiac arrestsdepidemiology and outcome. Resuscitation 1995;30(2):141–50. [2] Sirbaugh PE, Pepe PE, Shook JE, et al. A prospective, population-based study of the demographics, epidemiology, management, and outcome of out-of-hospital pediatric cardiopulmonary arrest. Ann Emerg Med 1999;33(2):174–84. [3] Young KD, Gausche-Hill M, McClung CD, et al. A prospective, population-based study of the epidemiology and outcome of out-of-hospital pediatric cardiopulmonary arrest. Pediatrics 2004;114(1):157–64. [4] Hickey RW, Cohen DM, Strausbaugh S, et al. Pediatric patients requiring CPR in the prehospital setting. Ann Emerg Med 1995;25:495–501. [5] Appleton GO, Cummins RO, Larson MP, et al. CPR and the single rescuer: at what age should you ‘‘call first’’ rather than ‘‘call fast?’’. Ann Emerg Med 1995;25(4):492–4. [6] Mogayzel C, Quan L, Graves JR, et al. Out-of-hospital ventricular fibrillation in children and adolescents: causes and outcomes. Ann Emerg Med 1995;25(4):484–91. [7] Bottiger BW, Krumnikl JJ, Gass P, et al. The cerebral ‘no-reflow’ phenomenon after cardiac arrest in ratsdinfluence of low-flow reperfusion. Resuscitation 1997;34(1):79–87.

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[8] Vaagenes P, Safar P, Diven W, et al. Brain enzyme levels in CSF after cardiac arrest and resuscitation in dogs: markers of damage and predictors of outcome. J Cereb Blood Flow Metab 1988;8(2):262–75. [9] Vaagenes P, Safar P, Moossy J, et al. Asphyxiation versus ventricular fibrillation cardiac arrest in dogs. Differences in cerebral resuscitation effectsda preliminary study. Resuscitation 1997;35(1):41–52. [10] Morimoto Y, Kemmotsu O, Kitami K, et al. Acute brain swelling after out-of-hospital cardiac arrest: pathogenesis and outcome. Crit Care Med 1993;21:104–10. [11] Rice D, Barone S Jr. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect 2000;108(Suppl 3): 511–33. [12] Ikonomidou C, Mosinger JL, Salles KS, et al. Sensitivity of the developing rat brain to hypobaric/ischemic damage parallels sensitivity to N-methyl-aspartate neurotoxicity. J Neurosci 1989;9(8):2809–18. [13] Yager JY, Shuaib A, Thornhill J. The effect of age on susceptibility to brain damage in a model of global hemispheric hypoxia-ischemia. Brain Res Dev Brain Res 1996;93(1–2): 143–54. [14] Grafe MR. Developmental changes in the sensitivity of the neonatal rat brain to hypoxic/ ischemic injury. Brain Res 1994;653(1–2):161–6. [15] Towfighi J, Mauger D, Vannucci RC, et al. Influence of age on the cerebral lesions in an immature rat model of cerebral hypoxia-ischemia: a light microscopic study. Brain Res Dev Brain Res 1997;100(2):149–60. [16] McDonald JW, Behrens MI, Chung C, et al. Susceptibility to apoptosis is enhanced in immature cortical neurons. Brain Res 1997;759(2):228–32. [17] Bittigau P, Sifringer M, Pohl D, et al. Apoptotic neurodegeneration following trauma is markedly enhanced in the immature brain. Ann Neurol 1999;45(6):724–35. [18] Hu BR, Liu CL, Ouyang Y, et al. Involvement of caspase-3 in cell death after hypoxiaischemia declines during brain maturation. J Cereb Blood Flow Metab 2000;20(9):1294–300. [19] Ness JK, Romanko MJ, Rothstein RP, et al. Perinatal hypoxia-ischemia induces apoptotic and excitotoxic death of periventricular white matter oligodendrocyte progenitors. Dev Neurosci 2001;23(3):203–8. [20] Greenamyre T, Penney JB, Young AB, et al. Evidence for transient perinatal glutamatergic innervation of globus pallidus. J Neurosci 1987;7(4):1022–30. [21] Huttenlocher PR, de Courten C. The development of synapses in striate cortex of man. Hum Neurobiol 1987;6(1):1–9. [22] Giedd JN, Blumenthal J, Jeffries NO, et al. Brain development during childhood and adolescence: a longitudinal MRI study. Nat Neurosci 1999;2(10):861–3. [23] Hanaoka S, Takashima S, Morooka K. Study of the maturation of the child’s brain using 31P-MRS. Pediatr Neurol 1998;18(4):305–10. [24] Stiles J. Neural plasticity and cognitive development. Dev Neuropsychol 2000;18(2):237–72. [25] Bittar RG, Rosenfeld JV, Klug GL, et al. Resective surgery in infants and young children with intractable epilepsy. J Clin Neurosci 2002;9(2):142–6. [26] Vining EP, Freeman JM, Pillas DJ, et al. Why would you remove half a brain? The outcome of 58 children after hemispherectomydthe Johns Hopkins experience: 1968 to 1996. Pediatrics 1997;100(2 Pt 1):163–71. [27] Young KD, Seidel JS. Pediatric cardiopulmonary resuscitation: a collective review. Ann Emerg Med 1999;33(2):195–205. [28] Dean JM, Kaufman ND. Prognostic indicators in pediatric near-drowning: the Glasgow coma scale. Crit Care Med 1981;9(7):536–9. [29] O’Rourke PP. Out-of-hospital cardiac arrest in pediatric patients. Crit Care Med 1984;12: 283. [30] O’Rourke PP. Outcome of children who are apneic and pulseless in the emergency room. Crit Care Med 1986;14:466–8.


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[31] Davies CR, Carrigan T, Wright JA. Neurologic outcome following pediatric resuscitation. Neuroscience 1987;19:205–10. [32] Quan L, Wentz KR, Gore EJ, et al. Outcome and predictors of outcome in pediatric submersion victims receiving prehospital care in King County, Washington. Pediatrics 1990;86(4): 586–93. [33] Kriel RL, Krach LE, Luxenberg MG, et al. Outcome of severe anoxic/ischemic brain injury in children. Pediatri Neurol 1994;10:207–12. [34] Torres A Jr, Pickert CB, Firestone J, et al. Long-term functional outcome of inpatient pediatric cardiopulmonary resuscitation. Pediatr Emerg Care 1997;13(6):369–73. [35] Spack L, Gedeit R, Splaingard M, et al. Failure of aggressive therapy to alter outcome in pediatric near-drowning. Pediatr Emerg Care 1997;13(2):98–102. [36] Pearn J. Neurological and psychometric studies in children surviving freshwater immersion accidents. Lancet 1977;1:7–9. [37] Bell TS, Ellenberg L, McComb JG. Neuropsychological outcome after severe pediatric neardrowning. Neurosurgery 1985;17:604–8. [38] Morris RD, Krawiecki NS, Wright JA. Neuropsychological, academic, and adaptive functioning in children who survive in-hospital cardiac arrest and resuscitation. J Learn Disabil 1993;26:46–51. [39] Robertson CMT, Joffe AR, Moore AJ, et al. Neurodevelopmental outcome of young pediatric intensive care survivors of serious brain injury. Pediatr Crit Care Med 2002;3(4): 345–50. [40] Clark RSB. Out of the frying pan and into the fire: neurodevelopmental outcome in pediatric intensive care unit survivors of serious brain injury. Pediatr Crit Care Med 2002;3(4):384–5. [41] Longstreth WT, Dikmen SS. Outcomes after cardiac arrest. Ann Emerg Med 1993;22:64–9. [42] Grubb NR, O’Carroll R, Cobbe SM, et al. Chronic memory impairment after cardiac arrest outside hospital. BMJ 1996;313:143–6. [43] Maneru C, Junque C, Botet F, et al. Neuropsychological long-term sequelae of perinatal asphyxia. Brain Inj 2001;15(12):1029–39. [44] Dixon G, Badawi N, Kurinczuk JJ, et al. Early developmental outcomes after newborn encephalopathy. Pediatrics 2002;109(1):26–33. [45] Bhutta AT, Cleves MA, Casey PH, et al. Cognitive and behavioral outcomes of school-aged children who were born preterm: a meta-analysis. JAMA 2002;288(6):728–37. [46] Mandel R, Martinot A, Delepoulle F, et al. Prediction of outcome after hypoxic-ischemic encephalopathy: a prospective clinical and electrophysiologic study. J Pediatr 2002;141(1): 45–50. [47] Jacinto SJ, Gieron-Korthals M, Ferreira JA. Predicting outcome in hypoxic-ischemic brain injury. Pediatr Clin North Am 2001;48(3):647–60. [48] Painter MJ. Animal models of perinatal asphyxia: contributions, contradictions, clinical relevance. Semin Pediatr Neurol 1995;2(1):37–56. [49] Johnston MV, Trescher WH, Taylor GA. Hypoxic and ischemic central nervous system disorders in infants and children. Adv Pediatr 1995;42:1–45. [50] Barkovich AJ. MR and CT evaluation of profound neonatal and infantile asphyxia. Am J Neuroradiol 1992;13(13):973–5. [51] Grubb NR, Fox KA, Smith K, et al. Memory impairment in out-of-hospital cardiac arrest survivors is associated with global reduction in brain volume, not focal hippocampal injury. Stroke 2000;31(7):1509–14. [52] Ng T, Graham DI, Adams JH, et al. Changes in the hippocampus and the cerebellum resulting from hypoxic insults: frequency and distribution. Acta Neuropathol (Berl) 1989;78: 438–43. [53] Peterson BS, Vohr B, Staib LH, et al. Regional brain volume abnormalities and long-term cognitive outcome in preterm infants. JAMA 2000;284(15):1939–47. [54] Isaacs EB, Lucas A, Chong WK, et al. Hippocampal volume and everyday memory in children of very low birth weight. Pediatr Res 2000;47(6):713–20.

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[55] Sie LT, van der Knaap MS, Oosting J, et al. MR patterns of hypoxic-ischemic brain damage after prenatal, perinatal or postnatal asphyxia. Neuropediatrics 2000;31(3):128–36. [56] Kreis R, Arcinue E, Ernst T, et al. Hypoxic encephalopathy after near-drowning studied by quantitative 1H-magnetic resonance spectroscopy. J Clin Invest 1996;97:1142–54. [57] Huppi PS, Murphy B, Maier SE, et al. Microstructural brain development after perinatal cerebral white matter injury assessed by diffusion tensor magnetic resonance imaging. Pediatrics 2001;107(3):455–60. [58] Klingberg T, Vaidya CJ, Gabrieli JD, et al. Myelination and organization of the frontal white matter in children: a diffusion tensor MRI study. Neuroreport 1999;10(13):2817–21. [59] Paus T, Collins DL, Evans AC, et al. Maturation of white matter in the human brain: a review of magnetic resonance studies. Brain Res Bull 2001;54(3):255–66. [60] Mukherjee P, Miller JH, Shimony JS, et al. Normal brain maturation during childhood: developmental trends characterized with diffusion-tensor MR imaging. Radiology 2001; 221(2):349–58. [61] Boujraf S, Luypaert R, Shabana W, et al. Study of pediatric brain development using magnetic resonance imaging of anisotropic diffusion. Magn Reson Imaging 2002;20(4):327–36. [62] Schmithorst VJ, Wilke M, Dardzinski BJ, et al. Correlation of white matter diffusivity and anisotropy with age during childhood and adolescence: a cross-sectional diffusion-tensor MR imaging study. Radiology 2002;222(1):212–8. [63] Kochanek PM, Clark RS, Ruppel RA, et al. Cerebral resuscitation after traumatic brain injury and cardiopulmonary arrest in infants and children in the new millennium. Pediatr Clin North Am 2001;48(3):661–81. [64] Skippen P, Seear M, Poskitt K, et al. Effect of hyperventilation on regional cerebral blood flow in head-injured children. Crit Care Med 1997;25(8):1402–9. [65] Buunk G, van der Hoeven JG, Meinders AE. Cerebrovascular reactivity in comatose patients resuscitated from a cardiac arrest. Stroke 1997;28(8):1569–73. [66] Vaagenes P, Ginsberg M, Ebmeyer U, et al. Cerebral resuscitation from cardiac arrest: pathophysiologic mechanisms. Crit Care Med 1996;24:S57–68. [67] Aufderheide TP, Sigurdsson G, Pirrallo RG, et al. Hyperventilation-induced hypotension during cardiopulmonary resuscitation. Circulation 2004;109(16):1960–5. [68] Aufderheide TP, Lurie KG. Death by hyperventilation: a common and life-threatening problem during cardiopulmonary resuscitation. Crit Care Med 2004;32(Suppl 9):S345–51. [69] Tobias JD, Lynch A, Garrett J. Alterations of end-tidal carbon dioxide during the intrahospital transport of children. Pediatr Emerg Care 1996;12(4):249–51. [69a] Hickey RW, Kochanek PM, Ferimer H, et al. Hypothermia and hyperthermia in children after resuscitation from cardiac arrest. Pediatrics 2000;106(1Pt 1):118–22. [70] Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346(8):557–63. [71] Hypothermia After Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002;346(8):549–56. [72] Nolan JP, Morley PT, Hoek TL, et al. Therapeutic hypothermia after cardiac arrest. An advisory statement by the Advancement Life support Task Force of the International Liaison Committee on Resuscitation. Resuscitation 2003;57(3):231–5. [73] Gluckman PD, Wyatt JS, Azzopardi D, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 2005; 365(9460):663–70. [74] Hickey RW, Callaway CW. Asphyxia. In: Tisherman SA, Sterz F, editors. Therapeutic hypothermia. New York: Springer; 2005. p. 119–34.

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The Declaration of Death and the Withdrawal of Care in the Neurologic Patient Edward M. Manno, MD*, Eelco F.M. Wijdicks, MD Division of Critical Care Neurology, Department of Neurology W8B, Mayo Clinic College of Medicine, 200 First Street Southwest, Rochester, MN 55905, USA

Advances in critical care medicine and neurology have led to an increase in survival of critically ill patients who previously would have succumbed to their illnesses. Whereas some may progress to lose all brain function, many will survive with severe neurologic impairment. Under these circumstances, many patients or families may choose to withdraw medical care. Physicians and staff caring for these patients are often presented with various complex medical, moral, and ethical issues. This article discusses some of the issues involved in the transitional period around the time of withdrawal of care or the declaration of death by neurologic criteria.

Ethical and legal issues involved in the withdrawal of care Considerable confusion and misconceptions exist about withdrawal of care in a patient who is neurologically impaired. In a recent survey, many neurologists believed that they needed legal counsel to withdraw therapy in the patient who is neurologically compromised and that withdrawal of care in these instances was tantamount to killing the patient [1]. This survey highlighted the limitations of many physicians’ knowledge and experience in dealing with end-of-life issues. Physician misunderstanding may lead to overaggressive treatment of patients beyond their wishes [2]. Some patient and family surveys have suggested that patients who are dying often receive unwanted procedures and interventions [2–4]. * Corresponding author. E-mail address: [email protected] (E.M. Manno). 0733-8619/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.ncl.2005.10.005 neurologic.theclinics.com

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A patient’s right to informed consent and right to refuse treatment have been basic tenets of modern western medicine [5]. The right to informed consent is based on the ethical concept of self-autonomy and the legal concept of self-determination [5]. Valid informed consent requires that the treating physician provides adequate information about the risks and benefits of all therapeutic options. The patient also must be competent to make medical decisions and must not be coerced [5]. Competence is often the key feature that needs to be evaluated in the patient who is neurologically impaired to ensure that a request for withdrawal of care is valid. Usually, competence can be evaluated adequately as part of the neurologic examination. Care must be taken not only to evaluate orientation and reasoning, but also to look for signs of depression or adjustment disorder that may influence a patient’s decision. In some circumstances, psychiatric input is needed to assess competence. In its strictest sense, competence is a legal determination that can be made only in a court of law. In rare instances, such as family disputes, court evaluation may be required to determine competence [5]. When a patient is unable to participate in medical decisions, a surrogate is assigned. The surrogate is typically a family member or members acting jointly. Most hospitals have an order as to who can make decisions for the patient. The sequence can vary according to different hospital or local jurisdictions. In general, the typical stratification of surrogate decisionmakers starts with the appointed legal guardian and runs in descending order to spouse, adult children, parents, siblings, and then more distant relatives. The role of surrogate decision-making has been clearly delineated. The surrogate should make decisions according to the patient’s previously stated wishes. If these wishes are not known, then the surrogate makes decisions based on the patient’s cultural and belief systems. This concept is best expressed as the surrogate attempting to reproduce the decision the patient would make if he or she were able to participate in the discussion concerning continued care. If this aspect is also unknown, then the surrogate should make decisions based on a patient’s perceived best interest [5,6]. There is no ethical or legal difference between withdrawal of therapy and refusal of treatment; therefore, there is no difference between stopping a treatment that has been initiated and never starting the treatment. There is also ethical and legal consensus that artificial hydration and nutrition are forms of medical therapy that can be refused by a patient or surrogate [5]. Withdrawal of care: the decision Whereas much has been written about the legal and ethical aspects of the withdrawal of care, little has been written about how the process should actually occur. In particular, the withdrawal of care in the patient who is neurologically devastated raises specific issues that may not occur with other patients.

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The first issue in the process of withdrawing care from a patient who is neurologically devastated is to clarify the diagnosis and prognosis ‘‘since all subsequent decision making must start from this’’ [7]. Questions that are often encountered include: ‘‘What are the chances of recovery?’’ ‘‘What tests need to be performed?’’ ‘‘Has anyone ever improved?’’ ‘‘Could your diagnosis or prognosis be wrong?’’ The answers to these questions are not often clear-cut. Retrospective evaluations of patients who have global cerebral anoxic injury have provided some guidelines in assessing patient outcome [8–11]. The most consistent predictors of prognosis after intracerebral hemorrhage include the size of the initial hemorrhage, the amount of intraventricular blood, and the initial clinical presentation of the patient [12]. Prognosis after subarachnoid hemorrhage is based largely on the amount of blood and initial presentation of the patient [13]. Multiple studies have evaluated prognosis after ischemic stroke [14–16]. The outcome after head trauma may be hard to predict initially, particularly in the patient who is young. In addition, the action of withdrawal of care may actually influence prognostic models, leading to a self-fulfilled prophecy [17]. Thus the ability to predict early in the course of a neurologic disease may be limited. In general, prognosis often becomes clear with extended and repeated observations and examinations. Ancillary testing may serve several roles. Neuroimaging is often required for making an accurate diagnosis. It can also be helpful to show to families the significance of the neurologic injury. Electroencephalography (EEG) can detect subclinical seizure activity. EEG evaluation after global anoxic injury may have limited prognostic use; however, specific EEG coma patterns may portend a poor outcome [9]. A lack of a cortical signal during somatosensoryevoked potentials seems to have the most significance for predicting poor outcome after anoxic injury [10]. Family discussion and decision about continued medical support are often addressed at the time the prognosis for a functional recovery seems unlikely. These discussions need to be accurate, honest, and direct about the prognosis and chance of recovery. They commonly occur at critical decision points along the continuum of care for the patient. It may be at the time a tracheostomy or feeding tube needs to be placed. Several important issues need to be explored at this time if these have not been previously discussed. Is there an advanced directive or any written instructions to provide some guidelines about potential withdrawal of support? Did the patient express any feelings, wishes, or desires about end-of-life care? Who and how will decisions be made about continued care? In family disagreements, social services may be able to provide some support. In rare instances, the legal department may need to evaluate and address some of the above questions. It is important to elucidate the physicians’ and families’ understanding of what represents a functional neurologic recovery and what condition would be acceptable to the patient. What types of abilities would the patient need to regain in order for the family to view its loved one’s recovery as

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functional? Does that mean a certain level of consciousness or physical capability, or an ability to interact with family briskly and genuinely? Is a long-term care facility acceptable to the family or consistent with the patient’s previously expressed wishes? The physician must also be cognizant of his or her own prejudices, because it has been implied in several studies that physicians may apply their personal biases when entertaining decisions about withdrawal of care [18–20]. Physicians need to be sensitive to various cultural, family, and individual preferences about end-of-life care because some families may have limited ability to understand an oftentimes confusing and complicated process. Withdrawal of care: the process At the time death seems imminent or if a patient is so severely impaired that there is little chance of recovery, many families may elect not to continue with medical care. When a surrogate or family decides to withdraw treatment from a patient, the plan of care for the patient proceeds from a tactical approach designed to identify and treat a specific illness to a strategic plan with a newly defined goal [2]. The new goal and strategic plan need to be defined clearly. The goal of medical care after the decision for withdrawal of support is to provide palliative care. The family discussion needs to describe exactly what is to be done. Issues that need to be clarified include what, when, and how specific interventions will be discontinued. The process may occur in a stepwise fashion or move directly to comfort measures only. The discussion and the plan of care need to be documented in the medical record. When advanced directives are not available, phrases such as ‘‘these plans are consistent with the patient’s previously expressed wishes or desires’’ provides documentation for the family or legal guardian that the decisions made represented substituted judgment based on the patient’s value system. Further discussions with the family, plans for withdrawal, and sedation should be carefully noted. Once the plan for withdrawal of care has been developed, it is the job of the treating physician and team to implement the plan. Physicians will have to consider the timing of and which life support measures will be discontinued [18]. Many families or physicians may have reservations about specific therapies that can or cannot be withdrawn. In practice, all measures can be withdrawn, including vasopressors, drugs, mechanical ventilation, and nutritional support [18]. Most physicians, however, withdraw care in a stepwise fashion [21], often based on cost or medical or ethical misconceptions [22]. The purpose of withdrawal of support is to maximize comfort for the patient. To that end, if a stepwise withdrawal meets this purpose, it may be best to proceed in that manner. For instance, if a patient depends on vasopressors for blood pressure support, withdrawal of these medications may lead predictably and expeditiously to death without the need to withdraw


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mechanical ventilation. Similarly, some physicians have recommended a terminal weaning protocol for mechanical ventilation rather than proceeding directly to extubation [23]. In many cases, however, a stepwise withdrawal of care may not lead predictably to death. In these situations, a slow withdrawal of treatments may actually prolong the dying process and potentially increase suffering. The patient who is neurologically devastated differs in many respects from other terminally ill patients. In most cases, medical decision will need to be made by legal guardians or families. Many patients who have neurologic injury will be intubated for concerns over airway protection and not because of a primary pulmonary process [24]. Graduated withdrawal of ventilatory rates or oxygen levels may not be necessary because pulmonary function may be normal in these individuals. The need for sedation and analgesia for the patient who is neurologically devastated is unknown; however, cerebral blood flow patterns in patients in a vegetative state resemble patterns of patients under anesthesia, suggesting that patients with diffuse neocortic damage do not perceive pain [25,26]. Grimacing and many facial expressions are mediated at a brainstem level; and although they may not denote pain for the patient, it may be distressing for the family to observe. Routine blood draws, medications, and monitoring should be discontinued once the decision has been made to withdraw care. The room should be free of distractions and noisy alarms. If the goal of palliative care is terminal extubation, then plans must be made to assure the patient has adequate airway management postextubation. Usually, careful head positioning accompanied with nasal or oral airways are sufficient to maintain airway patency. If the patient seems to be in pain or is agitated, sedation and analgesia should be given. Typically, morphine, in 5 mg intravenous infusions, may be given initially. A morphine or fentanyl drip is preferred to intermittent intravenous bolus administration to allow for better titration for effect. Morphine administration should be titrated to ensure comfort for the patient. Nurses or physicians may be reluctant to increase medication infusions because of concerns of inducing active euthanasia through respiratory depression. The concern is probably overstated because actual respiratory depression, even with large doses of morphine, is rare [18]. In addition, physicians and nurses are covered medically and legally under the principle of double effect, which ensures that staff is not liable for the untoward secondary effects of a medication if the primary reason a medication is given is to initiate another effect [2,5,18]. In this situation, the reason the medication is given is to provide comfort. Some of this anxiety can be alleviated by writing orders to titrate a medication to a specific effect (ie, a respiratory rate or level of sedation). The use of neuromuscular blockers should be avoided or discontinued if withdrawal is considered because it may not only directly hasten a patient’s death but also may mask any signs of distress that a patient may have [5].

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Predicting the timing of death in a neurologic patient after withdrawal of care can be problematic. In some instances, such as patients who are worsening acutely or patients who have severe brainstem damage, death can be expected in a short time. Other patients may tolerate extubation without incident. Death under these circumstances may not be imminent. It is important to prepare families for a potential variety of scenarios. Explaining to families what they may expect to see may relieve some anxiety. Also, if there is some uncertainty over the timing of death, arrangements should be made to move the patient from an ICU setting to a private or hospice room to allow for a more peaceful environment. Care and counseling of the family should continue as part of care for the patient. Clergy and other support staff should be actively engaged during this period. Most delayed criticisms from families occur during this time, if this period is not carefully and sensitively managed [27,28]. For many, it is important to be present at the time of cardiopulmonary arrest, and some families may request to be present at the time of extubation if death is deemed to be imminent. Families should be counseled about possible terminal limb or body movements that can occur. It is prudent to ask that all present be sitting to avoid any possible vasovagal syncope that could occur to family members during this period of psychosocial stress. Neurologic criteria for the declaration of death Many patients will succumb to their neurologic injuries and subsequently be declared dead by neurologic criteria. Modern critical care techniques have led to the development of a population of patients who have lost all neurologic function but continue to have their respirations supported and sustain a heartbeat. A redefinition of death resulted, initially by the Harvard Ad Hoc committee criteria defining irreversible coma, which were later adapted by the Uniform Determination of Death Act in 1981. This act defined death as either the irreversible cessation of whole brain function or the irreversible loss of circulatory and respiratory function [29–31]. In the United States and in most other countries, the concept of declaring death through neurologic criteria uses the idea of ‘whole brain death.’ In whole brain death, death is declared when there is demonstrated loss of cortical and brainstem reflexes. In Britain, only the loss of brainstem function is required. The concept of ‘whole brain death’ has survived decades of moral, ethical, and legal inspection [32]; however, the implementation of the criteria established to determine brain death has come under scrutiny [33–36]. The American Academy of Neurology [37] established a set of practice parameters for the determination of brain death in 1995; it has been reviewed previously by Wijdicks [38]. In general, the diagnosis of death by neurologic criteria requires the clinical or radiographic evidence for catastrophic and irreversible brain injury, the exclusion of confounding factors, and a neurologic assessment to evaluate cortical and cranial nerve function [36].


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Potential pitfalls in the declaration of death by neurologic criteria There are several potential problems in the process of declaring death by neurologic criteria. The identification of a neurologically devastating injury on neuroimaging provides assurance that a confounding diagnosis is unlikely to account for the neurologic findings. In particular, locked-in syndrome and Guillain-Barre´ syndrome need to be ruled out as possible diagnoses [38]. Severe electrolyte, acid-base, and endocrine disturbances need to be evaluated, although the exact level at which these disturbances would preclude neurologic testing has not been clarified. Drug intoxication needs to be excluded before neurologic testing. Barbiturate levels should be subtherapeutic. Wijdicks has suggested a period of observation for at least four times the elimination half-life of a known intoxicant and a period of observation of 48 hours for an unknown or nonquantifiable substance [38]. The patient may become unstable hemodynamically at the time the last few brain stem reflexes are lost. Most patients can be treated successfully with intravenous fluids and vasopressors. Diabetes insipidus can occur quickly and with dramatic hemodynamic effect. The authors prefer intravenous vasopressin over intranasal or subcutaneous administration because of its more rapid and predictable absorption. The neurologic examination of the patient who is deceased must be performed and carefully documented. Two common pitfalls are to examine patients who are hypothermic or hypotensive. The American Academy Practice Parameters recommend a core temperature of greater than 32 C and a systolic blood pressure of greater than 90 mm/Hg for the clinical declaration of death. Apnea testing requires a temperature of 36.5 C [37,38]. Examination of each cranial nerve may have some potential for error. The patient’s head should be elevated 30 , and tympanic membranes should be identifiable and intact before testing cold caloric responses. Atropine or mydriatics can confound pupillary responses and should be excluded. Bronchial suctioning rather than endotracheal tube movement should be used to assess for a cough reflex [38]. Painful stimuli to the extremities should be significant because this examination must not be misinterpreted. The apnea test is an evaluation of a brainstem reflex. Apnea is the most tolerant reflex to hypoxia, and the absence of breathing is the most associated with death by the public. Special care needs to be taken when performing an apnea test. Apnea tests are not benign and can be associated with injury or cardiopulmonary death if not performed properly [39]. Preoxygenation and normalization of the partial pressure of carbon dioxide (pCO2) is important before starting the test. The examiner must be aware of any reflexive-type movements, which can mimic respiration. The examination should be discontinued if there is significant hypotension or hypoxia during the testing. Vasopressors may be used to support a patient’s blood pressure as needed during the test. If the patient is unable to tolerate or complete the examination, a confirmatory test is required.

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Confirmatory tests are recommended when some portion of the neurologic history or assessment is not known or cannot be performed. There are several tests that are commonly used, including cerebral angiography, EEG, transcranial Doppler ultrasonography, or technetium-99m hexamethylpropyleneamineoxime brain scans. Each test has specific guidelines and limitations to its use [37]. It is unfortunate, but guidelines for the declaration of brain death have only been variably applied. There remains considerable inconsistency in the determination of death by neurologic criteria nationally and internationally [36,40]. Guidelines for the neurologic declaration of death are often determined by individual hospitals [33]. It is important that a physician be familiar with the guidelines at each hospital where he or she practices. The declaration of death and organ donation Once a patient has failed the set of established neurologic criteria, he or she is declared dead. All paperwork or legal documents that need to be completed should list the time of death as the time of death by neurologic criteria and not the time of circulatory or cardiopulmonary arrest. Discussions with families at this time need to be caring but unambiguous and direct in stating that the patient has died. In rare instances, families may not accept this fact or may continue to grieve. Usually, with patience and time, most conflicts can be resolved. The physician is under no moral or legal obligation to continue medical support for a cadaver. In general, family requests to spend time with the body before withdrawal of the ventilator can be accommodated. The acceptance of death by neurologic criteria is accepted by every major religion, with the exceptions of gypsies and selected orthodox Jewish sects [41]. In New York and New Jersey, state laws do not allow the declaration of death by neurologic criteria if the family or individual previously objected to the concept of brain death based on religious beliefs [42,43]. Under these circumstances, the physician is required to continue medical support. The request for organ donation after the declaration of death by neurologic criteria is often a difficult and delicate situation. The structure, environment, and sequence of how organ donation is approached have significant impact on the rates of organ donation [44–46]. In 1998, the centers for Medicare and Medicaid services required that hospitals notify their local organ procurement organization about patients whose death appeared imminent. The federal conditions of participation mandated that any request for donation be performed by a person trained specifically in these matters. This mandate does not exclude physicians or staff, but it does require them to undergo training [47]. Consent for organ donation is highest when the discussion of brain death is separated from the discussion about organ donation, when the request is made by a trained individual, and when the ICU staff and organ


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procurement organizations coordinate their efforts [46,47]. In the authors’ practice, the ICU physicians declare and discuss death with the family. They allow time for questions, grieving, and consolation. They leave the discussion of organ donation to the organ procurement organization but inform patients that someone will inquire about this issue. This ‘‘decoupling’’ of conversations has led to an improvement in the ability to obtain consent for organ donation. Summary Intensive care technologies have led to an increase in patients who are neurologically devastated and deceased. The practical, moral, and ethical situations encountered can be varied and challenging to manage. Decisions and discussions surrounding withdrawal of care, death by neurologic criteria, and organ donation require significant knowledge of the prognosis, ancillary testing, and definitions of these processes. Experience and skill are often required on the part of physicians and staff to guide families through these most difficult of circumstances. References [1] Carver AC, Vickrey BG, Bernat JL, et al. End-of-life care: a survey of US neurologists’ attitudes, behavior, and knowledge. Neurology 1999;53(2):284–93. [2] Brody H, Campbell ML, Faber-Langendoen K, et al. Withdrawing intensive life-sustaining treatmentdrecommendations for compassionate clinical management. N Engl J Med 1997; 336(9):652–7. [3] Solomon MZ, O’Donnell L, Jennings B, et al. Decisions near the end of life: professional views on life-sustaining treatments. Am J Public Health 1993;83(1):14–23. [4] Anonymous. A controlled trial to improve care for seriously ill hospitalized patients. The study to understand prognoses and preferences for outcomes and risks of treatments (SUPPORT). The SUPPORT Principal Investigators. JAMA 1995;274(20):1591–8. [5] Bernat JL. Ethical and legal issues in palliative care. Neurol Clin 2001;19(4):969–87. [6] Bernat JL, Goldstein ML, Viste KM Jr. The neurologist and the dying patient. Neurology 1996;46(3):598–9. [7] Anonymous. Persistent vegetative state: report of the American Neurological Association Committee on Ethical Affairs. ANA Committee on Ethical Affairs. Ann Neurol 1993; 33(4):386–90. [8] Attia J, Cook DJ. Prognosis in anoxic and traumatic coma. Crit Care Clin 1998;14(3): 497–511. [9] Chen R, Bolton CF, Young B. Prediction of outcome in patients with anoxic coma: a clinical and electrophysiologic study. Crit Care Med 1996;24(4):672–8. [10] Zandbergen EG, de Haan RJ, Stoutenbeek CP, et al. Systematic review of early prediction of poor outcome in anoxic-ischaemic coma. Lancet 1998;352(9143):1808–12. [11] Levy DE, Caronna JJ, Singer BH, et al. Predicting outcome from hypoxic-ischemic coma. JAMA 1985;253(10):1420–6. [12] Manno EM, Atkinson JL, Fulgham JR, et al. Emerging medical and surgical management strategies in the evaluation and treatment of intracerebral hemorrhage. Mayo Clin Proc 2005;80(3):420–33. [13] Manno EM. Subarachnoid hemorrhage. Neurol Clin 2004;22(2):347–66.

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[14] Wijdicks EF, Rabinstein AA. Absolutely no hope? Some ambiguity of futility of care in devastating acute stroke. Crit Care Med 2004;32(11):2332–42. [15] Gujjar AR, Deibert E, Manno EM, et al. Mechanical ventilation for ischemic stroke and intracerebral hemorrhage: indications, timing, and outcome. Neurology 1998;51(2):447–51. [16] Toni D, Fiorelli M, Bastianello S, et al. Acute ischemic strokes improving during the first 48 hours of onset: predictability, outcome, and possible mechanisms. A comparison with early deteriorating strokes. Stroke 1997;28(1):10–4. [17] Becker KJ, Baxter AB, Cohen WA, et al. Withdrawal of support in intracerebral hemorrhage may lead to self-fulfilling prophecies. Neurology 2001;56(6):766–72. [18] Rubenfeld GD. Principles and practice of withdrawing life-sustaining treatments. Crit Care Clin 2004;20(3):435–51. [19] Wachter RM, Luce JM, Hearst N, et al. Decisions about resuscitation: inequities among patients with different diseases but similar prognoses. Ann Intern Med 1989;111(6):525–32. [20] Hanson LC, Danis M, Garrett JM, et al. Who decides? Physicians’ willingness to use lifesustaining treatment. Arch Intern Med 1996;156(7):785–9. [21] Faber-Langendoen K. A multi-institutional study of care given to patients dying in hospitals. Ethical and practice implications. Arch Intern Med 1996;156(18):2130–6. [22] Asch DA, Christakis NA. Why do physicians prefer to withdraw some forms of life support over others? Intrinsic attributes of life-sustaining treatments are associated with physicians’ preferences. Med Care 1996;34(2):103–11. [23] Gianakos D. Terminal weaning. Chest 1995;108(5):1405–6. [24] Coplin WM, Pierson DJ, Cooley KD, et al. Implications of extubation delay in brain-injured patients meeting standard weaning criteria. Am J Respir Crit Care Med 2000;161(5):1530–6. [25] Anonymous. Medical aspects of the persistent vegetative state (1). The Multi-Society Task Force on PVS. N Engl J Med 1994;330(21):1499–508. [26] Levy DE, Sidtis JJ, Rottenberg DA, et al. Differences in cerebral blood flow and glucose utilization in vegetative versus locked-in patients. Ann Neurol 1987;22(6):673–82. [27] Abbott KH, Sago JG, Breen CM, et al. Families looking back: one year after discussion of withdrawal or withholding of life-sustaining support. Crit Care Med 2001;29(1):197–201. [28] Mayer SA, Kossoff SB. Withdrawal of life support in the neurological intensive care unit. Neurology 1999;52(8):1602–9. [29] Anonymous. A definition of irreversible coma. Report of the Ad Hoc Committee of the Harvard Medical School to Examine the Definition of Brain Death. JAMA 1968;205(6):337–40. [30] Van Norman GA. Another matter of life and death: what every anesthesiologist should know about the ethical, legal, and policy implications of the non-heart-beating cadaver organ donor. Anesthesiology 2003;98(3):763–73. [31] Manno EM. Donation in the neurologically devastated patient: non-heart-beating donor. NeuroCritical Care, in press. [32] Bernat JL. A defense of the whole-brain concept of death. Hastings Cent Rep 1998;28(2): 14–23. [33] Powner DJ, Hernandez M, Rives TE. Variability among hospital policies for determining brain death in adults. Crit Care Med 2004;32(6):1284–8. [34] Shaner DM, Orr RD, Drought T, et al. Really, most SINCERELY dead: policy and procedure in the diagnosis of death by neurologic criteria. Neurology 2004;62(10):1683–6. [35] Shemie SD. Variability of brain death practices. Crit Care Med 2004;32(12):2564–5. [36] Oropello JM. Determination of brain death: theme, variations, and preventable errors. Crit Care Med 2004;32(6):1417–8. [37] Anonymous. Practice parameters for determining brain death in adults (summary statement). The Quality Standards Subcommittee of the American Academy of Neurology. Neurology 1995;45(5):1012–4. [38] Wijdicks EF. The diagnosis of brain death. N Engl J Med 2001;344(16):1215–21. [39] Saposnik G, Rizzo G, Vega A, et al. Problems associated with the apnea test in the diagnosis of brain death. Neurol India 2004;52(3):342–5.


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[40] Wijdicks EF. Brain death worldwide: accepted fact but no global consensus in diagnostic criteria. Neurology 2002;58(1):20–5. [41] Gallagher C, Wijdicks EFM. Religious and cultural aspects of brain death. In: Wijdicks EFM, editor. Brain Death. Philadelphia: Lippincott Williams & Wilkens; 2001. p. 135–50. [42] Bernat JL. Philosophical and ethical aspects of brain death. In: Wijdicks EFM, editor. Brain Death. Philadelphia: Lippincott Williams & Wilkens; 2001. p. 171–87. [43] Olick RS. Brain death, religious freedom, and public policy: New Jersey’s landmark legislative initiative. Kennedy Inst Ethics J 1991;1(4):275–92. [44] Williams MA, Lipsett PA, Rushton CH, et al. The physician’s role in discussing organ donation with families. Crit Care Med 2003;31(5):1568–73. [45] DeJong W, Franz HG, Wolfe SM, et al. Requesting organ donation: an interview study of donor and nondonor families. Am J Crit Care 1998;7(1):13–23. [46] Gortmaker SL, Beasley CL, Sheehy E, et al. Improving the request process to increase family consent for organ donation. J Transpl Coord 1998;8(4):210–7. [47] Anonymous. Medicare and Medicaid programs; hospital conditions of participation; identification of potential organ, tissue, and eye donors and transplant hospitals’ provision of transplant-related data–HCFA. Final rule. Fed Regist 1998;63(119):33856–75.

2006, Vol.24, Issues 1, Brain Injury and Cardiac Arrest

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