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Pharmacology of Sedative-Analgesic Agents: Dexmedetomidine, Remifentanil, Ketamine,Volatile Anesthetic s , and the Role of Peripheral Mu Antagonists Oliver Panzer, MD, Vivek Moitra, Moitra, MD, Robert N. Sladen, MRCP(UK), FRCP(C), FCCM*
KEYWORDS
Sedation Analgesia Dexmedetomidine Ketamine Volatile anesthetics
Remifentanil
DEXMEDETOMIDINE
Introduction
Dexmedetomidine is a highly selective alpha-2 agonist that provides anxiolysis a cooperative cooperative sedation without without respiratory respiratory depression. It decreases decreases central central nervo system (CNS) sympathetic outflow in a dose-dependent manner and has analge effects best described as opioid-sparing. There is increasing evidence that dexmed Sign up to vote on this title tomidine has organ protective effects against ischemicUseful and hypoxic injury, includ Not useful cardiop cardioprot rotect ection ion,, neurop neuroprot rotect ection ion,, and renopro renoprotec tectio tion. n. After After its approv approval al by Food and Drug Administration (FDA) in 1999, it has become well established in t
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Receptor Pharmacology Sheet Music
Dexmedetomid Dexmedetomidine ine is the dextro enantiomer enantiomer of medetomidine medetomidine,, the methylated tive of etomidine. Its specificity for the alpha-2 receptor is seven times that o dine, dine, with with an alph alphaa-2/ 2/al alpha pha-1 -1 bindi binding ng affi affini nity ty ratio ratio of 1620 1620:1 :1,, and and its its ef dose-dependently reversed by administration of a selective alpha-2 antagoni as atipamezole. 1 Specific Specific alpha-2 recepto receptorr subtypes mediate mediate the varied varied pharmacodyn pharmacodynamic amic ef dexm dexmed edet etom omidi idine ne.. For For exam example ple,, agon agonis ism m at the the alph alphaa-2A 2A rece recepto ptorr app promote sedation, hypnosis, analgesia, sympatholysis, neuroprotection, 2 and tion of insulin secretion. 3 Agonism at the alpha-2B receptor suppresses shiveri trally,4 promote promotes s analge analgesia sia at spinal spinal cord cord sites, sites, and induce induces s vasoco vasoconst nst peripheral arteries. The alpha-2C receptor is associated with modulation of co sensory processing, mood- and stimulant-induced locomotor activity, and reg of epin epinep ephr hrin ine e outf outflo low w from from the the adren adrenal al me medu dulla lla.. 5,6 Inhibition Inhibition of norepi release appears to be equally affected by all three alpha-2 receptor subtypes Dexmede Dexmedetom tomidin idine e also also binds binds to imidazo imidazoline line recept receptors ors,, which which recogn recognize ize the line or oxaziline structure of alpha-2 agonist agents. This activity may explain s the non-al non-alpha pha-2 -2 recept receptor– or–rel relate ated d effect effects s of this this drug class. class. Imidazo Imidazolin line e subtypes have also been identified. Imidazoline-1 receptors modulate blood p regulation regulation and have anti-arrhyth anti-arrhythmic mic effects. effects. 7 They They are found found in the ventro ventrolat latera era and are linked to G-proteins. Imidazoline-2 receptors have been implicated in protection in a cerebral ischemia model in animals and in generation of me They are typically located on the mitochondrial outer membrane and are not Gcoupled, but may exert their effects by decreasing tissue norepinephrine levels Pharmacokinetics
After intravenous (IV) injection, dexmedetomidine has an onset of action after a imately imately 15 minute minutes. s. Peak Peak concen concentra tratio tions ns are usuall usually y achiev achieved ed within within 1 ho continuous IV infusion. Analysis by a 2-compartment model demonstrates ra bution away from the CNS, with an alpha half-life (t 1 / 2 a ) of 6 minutes and a t elimination half-life (t1 / 2 b ) of between 2.0 and 2.5 hours. The drug is highly p bound, with a 6% free fraction, and has a relatively large steady state volume o butio bution n (Vdss, 1.33 1.33 L/kg) /kg).. Exce Except pt for for a larg large er V dss, phar pharma maco coki kine neti tics cs do not not ap substantially altered in mechanically ventilated patients sedated with dexmed dine in an intensive care unit (ICU). 9 Sign up to vote on this title Total plasma clearance of the dexmedetomidine is age thus Not useful Useful independent, rates of infusion infusio n can be used in children and adults to effect a steady state concentr concentration. ation.10 Plasm Plasma a prote protein in bindi binding ng of dexm dexmed edet etom omidi idine ne is also also
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Pharmacology of Sedative-Analgesic Age
sedated for longer than normal controls, suggesting an enhanced pharmacodynam effect, effect, pres presum umabl ably y beca becaus use e of the the prese presenc nce e of va vary rying ing degr degree ees s of urem uremic ic ence encepha pha 14 athy. Thus, dosages should be decreased in the presence of either hepatic or ren disease. Dexmedetomidine decreases cardiac output in a dose-dependent mann but the impact of this on clearance does not appear to be clinically relevant. 15 Dosing and Administration
Phase Phase 1 studies studies demonst demonstrat rated ed that that IV doses doses of dexmed dexmedeto etomidi midine ne induced induced do dependent decreases in systolic and diastolic blood pressure and in heart rate a substa substantia ntiall decrea decreases ses in plasma plasma norepi norepinep nephri hrine ne levels levels.. Howeve However, r, at high-bo high-bolus lus doses (50–75 mg), a transient initial hypertensive response may be seen, presuma becaus because e of act activa ivatio tion n of periphe peripheral ral vascul vascular ar alphaalpha-2 2 recept receptors ors before before the cen 16 sympatholytic effect on the vasomotor center. There do not appear to be any ref or drug-induced alterations in plasma renin activity, atrial natriuretic peptide or ar nine nine va vaso sopr pres essi sin n (AVP). (AVP).17 Dexmed Dexmedeto etomidi midine ne also also produc produces es dose-d dose-depe epend nd decreases in vigilance and increases in sedation that correlate well with electroe cephalogram (EEG)-based spectral entropy monitoring. 18 Initial Initial studie studies s that that target targeted ed plasma plasma dexmed dexmedeto etomid midine ine levels levels reveal revealed ed des pharmacodynamic effects between 0.5 and 1.2 ng/mL. Subsequent clinical stud designed to achieve these effects used a loading dose of 1 mg/kg during a period 10 minutes, followed by a continuous IV infusion rate of 0.2 to 0.7 mg/kg/hr, the dos regimen originally approved by the FDA in 1999. Studies examining very high dexmedetomidine plasma levels (up to 8.0 ng/m demonstrate that the alpha-2C peripheral vasoconstrictor effects become predom nant, nant, with increa increasin sing g system systemic ic vascul vascular ar resista resistance nce and decrea decreasin sing g cardiac cardiac ind asso as soci ciat ated ed with with ma mark rked ed ca cate tech chol olam amin ine e suppr suppres essi sion on and and deep deepen ening ing se sedat dat However, even at these very high plasma levels, there was no clinically significa respiratory depression.19 Indeed, when administered as the sole agent, dexmede midine appears to be remarkably safe. Case reports of large accidental overdos of dexmedetomi dexmedetomidine dine (192 mg loading dose, 2–30 mg/kg/hr) describe overs ove rsedation edation 20 the only notable sign, with resolution within an hour of discontinuation. Moreov dexmedetomidine has been used safely as the sole agent at high rates of infusi (5–15 mg/kg/hr) to an a nesthetize patients with tracheal stenosis while preserving spo taneous ventilation. 21 In October 2008, the FDA approved an increased dose of de medetomidine (up to 1.5 mg/kg/hr) for surgical procedures. In cont contra rast st,, ther there e is a risk risk for for exce excess ssiv ive e brad bradyc ycar ardi dia aSign and and even sion nus s arre ar rest st when when upev to en votesinu this title medeto medetomidi midine ne is adminis administer tered ed in combina combinatio tion n with sympath sympatholy olytic tic choline usefulor choline Useful Not agents (eg, beta-blockers, fentanyl, neostigmine), especially if there is concomita vagal stimulation (eg, sternal separation, laparoscopic insufflation, colonoscopy).
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comparison with GABAnergic agents such as midazolam or propofol. Arousa main ma inta tain ined ed at deep deep leve levels ls of se seda datio tion, n, with with good good corr correl elat atio ion n betwe between en the the leve leve tion tion (Rich (Richmo mond nd agit agitat atio ionn-se seda datio tion n sc scal ale) e) and and the the bispe bispect ctra rall (BIS) (BIS) EEG aroused, aroused, sub jects perform well on tests of vigilance, such as the critical flicker frequency.29 To achieve the same result, infusions of midazolam or propofol m discontinued. This results in so-called ‘‘cooperative sedation,’’ in that patien cooperate with ICU nursing, radiologic, and even airway procedures and und soph sophis istic ticat ated ed neur neurol olog ogic ic test testin ing g durin during g cran cranio ioto tomi mies es for for tumo tumorr diss dissec ec stereotactic implantations. 30,31 In addition, given the demonstrated benefit wake-up trials on outcomes in ICU patients, 32,33 there appears to be particula in a drug such as dexmedetomidine that facilitates the arousal and rapid orient a se seda date ted d patie patient nt and and then then allo allows ws the the patie patient nt to retu return rn to a se seda date ted d st afterward. Seda Sedatio tion n induc induced ed by dexm dexmed edet etom omidi idine ne has has the the resp respira irato tory ry patte pattern rn 34 changes changes commensura commensurate te with natural natural sleep. Dexmedetomid Dexmedetomidine ine induces induces activating endogenous non–rapid eye movement sleep–promoting pathways. ulation of alpha-2A receptors in the nucleus ceruleus inhibits noradrenergic n and disinhibits gamma-aminobutyric acid (GABAnergic) neurons in the ventr preoptic nucleus (VLPO). In contrast, GABAnergic agents, such as propofol or diazepines, directly enhance the inhibitory effects of the GABAnergic system VLPO. VLPO. Norepin Norepineph ephrine rine releas release e from from the locus locus cerule ceruleus us remain remains s unaffe unaffecte cte leading to less restful sleep. Functional MRI studies show that unlike GABA agents, dexmedetomidine preserves a cerebral blood flow pattern akin to sleep.36 The amnestic effects of dexmedetomidine are far less than the benzodiaz which provide profound anterograde amnesia that may contribute to confused on emergence. In contrast, amnesia is achieved with dex medetomidine only plasma levels ( R1.9 ng/mL), without without retrograde retrograde amnesia. 19
Analgesia Dexmedetomidine appears to exert analgesic effects at the spinal cord leve supraspinal sites. However, there has been considerable debate as to whe analgesic effects are primary or simply opioid-sparing. Early studies suggest part of its analgesic benefit might be mediated by attenuation of the affective-m tional component of pain. 37 Nonetheless, in comparison with hypnotic agents s sign propo propofo fol, l, or post postop oper erat ativ ive e opio opioids ids used used alon alone, e,up dexm de xmed edet etom omidi ne sign Sign to vote on this titleidine 38,39 decreases opioid requirement. Useful Not useful Dexmede Dexmedetom tomidin idine e may also also provide provide antino antinocic cicepti eption on throug through h nonspin nonspinal al nisms—intranisms—intra-articu articular lar administratio administration n during knee surgery surgery improves improves postop
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Pharmacology of Sedative-Analgesic Age
initial stimulation stimulation of peripheral peripheral alpha-2B vascular receptors, receptors, followed followed by central central 19 patholysis and a decline in blood pressure.
Respiratory effects Unlike opioids, dexmedetomidine is able to achieve its sedative, hypnotic, and an gesic gesic effect effects s without without causin causing g any clinica clinically lly releva relevant nt respira respirator tory y depres depressio sion, n, when when dose dosed d to plas plasma ma leve levels ls up to 15 time times s thos those e norm normal ally ly ac achi hiev eved ed duri during ng ther therap ap Comp Compar ared ed with with remi remife fent ntan anil, il, hype hyperc rcapn apnic ic arou arousa sall is prese preserv rved ed,, and and the the ap 34 threshold is actually decreased. Administration of dexmedetomidine during se flurane or desflurane anesthesia with spontaneous ventilation has no effect on en tidal carbon dioxide. 42 Arterial saturation is better preserved with dexmedetomid than propofol in children undergoing MRI procedures. 43 A similar similar improve improvemen men 44 oxygenation was observed in extubated patients in an ICU. In contrast to infusions of opioids, benzodiazepines, or propofol, dexmedetomid can safely be infuse infused d throug through h trache tracheal al extuba extubation tion and beyond beyond.. It has been successfully successfully to facilitate facilitate tracheal extubation extubation in patients patients who had previously previously failed 45,46 tubatio tubation n becaus because e of excess excessive ive agitat agitation ion and and with with simi simila larr benef benefit it in ag 47 patien patients ts requirin requiring g noninv noninvasi asive ve ventila ventilatio tion. n. Dexmed Dexmedeto etomid midine ine is effect effective ive in achiev achiev excellent sedation without respiratory depression during fiberoptic intubation or oth difficu difficult lt airway airway proced procedure ures. s.21,48–50 Intu Intubat batin ing g cond conditi ition ons s are are furth further er enha enha because because dexmedetomi dexmedetomidine dine decreases decreases saliva production and airway secretions. secretions. Despi Despite te the the lack lack of respi respira rato tory ry depre depress ssio ion, n, dexm dexmed edet etom omid idine ine was was orig orig approved by the FDA for use in ‘‘initially intubated, mechanically ventilated patient that is, it had to be started on ventilated patients but could be continued through a beyond beyond tracheal tracheal extubation. extubation. In October October 2008, dexmedetomidine dexmedetomidine was FDA-approv FDA-approv for procedural procedural sedation in nonintubate nonintubated d patients. patients.
Metabolic effects Dexmedetomidine and other alpha-2 agonists suppress shivering, possibly by th activit act ivity y at alphaalpha-2B 2B recept receptors ors in the hypoth hypothala alamic mic thermo thermoreg regula ulator tory y center center of brain.4 LowLow-dos dose e dexm dexmede edeto tomi midin dine e has has an additi additive ve effe effect ct with with me mepe perid ridin in 51 lowering the shivering threshold, when these drugs are combined. Dexmedeto dine dine ma may y be bene benefi fici cial al in decr decrea easi sing ng patie patient nt disco discomf mfor ortt from from post postop oper erat ativ ive e shive shiverin rin and controlling shivering that may delay therapeutic hypothermia for acute stroke CNS injury injury.. Howeve However, r, bradyca bradycardia rdia has been been noted noted when when dexmed dexmedeto etomidi midine ne 53 added to remifentanil during therapeutic hypothermia in children. Sign up to vote on this title
Organ protective effects Useful Not useful The ability of alpha-2 agonists to decrease tachycardia and hypertension sugge that that they they ma may y play play a role role in ca cardi rdiop opro rote tect ctio ion n by enha enhanc ncin ing g my myoc ocar ardia diall ox
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Panzer et al
sufficiently sufficiently high cardiac risk, and the dexmedetomidine dexmedetomidine infusion should be co for at least 48 to 72 hours postoperatively. 57 There is considerably more experimental evidence that dexmedetomidine h roprotective effects by several mechanisms. These incl ude sympatholysis, pr tioning, tioning, and attenuation attenuation of ischemia-re ischemia-reperfus perfusion ion injury. injury.58 There is also eviden dexmedetomidine decreases cerebral blood flow, 59,60 but its ratio with with cerebra bolic rate (ie, flow-metabolism coupling) appears to be preserved. 61 Alpha-2 adrenergic agonists, such as clonidine, have an established rol treatment of central hyperadrenergic states induced by withdrawal of drugs, in cocaine, cocaine, alcohol, or opioids. opioids. Numerous Numerous case reports reports of successfu successfull treatment treatment o 62–69 drawal drawal using using dexmed dexmedeto etomidi midine ne have have been been publish published, ed, but but to date date,, no ra trials have been performed. The effects of dexmedetomidine on renal function are complex. Alpha-2 a exert a diuretic effect by inhibiting the antidiuretic action of AVP at the col duct, most likely through alpha-2A receptors, resulting in decreased expres aquapo aquaporin rin-2 -2 recepto receptors rs and decrea decreased sed salt salt and water water reabso reabsorpt rption ion.. 70,71 enhance osmolal clearance through non–AVP-dependent pathways, possibly ated by the alpha-2B receptor. 72 There is experimental evidence that dexmedetomidine attenuates murine rad trast nephropathy by preserving cortical blood flow. 73 This mechanism is sup by the observ observati ation on that that dexmed dexmedeto etomidi midine ne decrea decreases ses the renal renal cortic cortical al rel norepinephrine. 74 There is also evidence that dexmedetomidine attenuates ischemia-re ischemia-reperfus perfusion ion injury. injury. 75 Howeve However, r, prospe prospectiv ctive e human human studie studies s est a benefit are not yet available. REMIFENTANIL
Remifentanil is an ultra–short-acting opioid that acts as a mu-receptor agon 250 times more potent than morphine. In 1996, the FDA approved remifen an anal analge gesi sic c agen agentt for for the the indu induct ctio ion n and and ma main inte tena nanc nce e of anes anesth thes esia ia.. In 2002 2002,, pean Medicines Agency approved its use for analgesia in mechanically ven adult patients in intensive care for up to 3 days. 76 Although remifentanil is us studied extensively in the operating room, its popularity in the critical care a growing.77 The pharma pharmacok cokine inetic tic profile profile of remife remifenta ntanil nil is unique unique in its class. class. Des set a ‘‘forgi ‘forgivin ving g opioid,’ opioid,’’’ remife remifenta ntanil nil is charac character terize ized dSign byup a rapid ra pid on onset ons ettitle and offset off to vote this 78 sion of remifentanil has an onset of action of 1 minute rapidly useful achieves Useful and Not stat state e plasm plasma a leve levels ls.. Its ac acti tion on diss dissipa ipate tes s with within in 3 to 10 minu minute tes s afte afterr disco discont ntin in an infusion. Remifentanil has a t 1 / b of approximately 10 to 20 minutes and
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Pharmacology of Sedative-Analgesic Age
hand, inadvertent or sudden discontinuation of remifentanil may result in rapid retu of the underlying pain. Thus, a longer-acting opioid should be administered befo stopping the remifentanil infusion if it is anticipated that analgesic requirements ongoing. Similar to other opioids, remifentanil can cause bradycardia, hypotension, respi tory depression, nausea, and skeletal muscle rigidity. Bolus injections of remifenta are not recommended because they ma y cause thoracic muscle rigidity with diffic mask or pressure-controlled ventilation. 76 Several cases of acute withdrawal syndrome have been reported after cessation remifentanil infusions in the ICU. Tachycardia, hypertension, sweating, mydriasis, a myoclonus myoclonus have occurred occurred within 10 minutes minutes of discontinuat discontinuation ion of remifentanil remifentanil-bas -bas sedation. Symptoms persisted after administration of morphine and clonidine a were resolved only after remifentanil was reinitiated. 87 Gradual tapering of the infus from 24 to 48 hours may decrease the incidence of a withdrawal syndrome. 87,88 The rapid offset of the analgesic effect of remifentanil has generated considera interest in its use to shorten mechanical ventilator times in the ICU. A regimen us remifentanil infusion (0.1–0.15 mg/kg/min) with midazolam, added as needed, sho ened the duration of prolonged mechanical ventilation by more than 2 days compar with a midazolam infusion with the addition of fentanyl or morphine. 85 In a randomiz contro controlle lled d trial, trial, the duratio duration n of mechan mechanica icall ventila ventilatio tion, n, extuba extubatio tion n times, times, and interval after extubation to ICU discharge were significantly shorter with remifenta infusion (0.15 mg/kg/min) compared with morphine infusion. 89 When remifentanil-m azolam was compared with sufentanil-midazolam for a median duration of 6 days mechanical ventilation, mean weaning time was 22 hours compared with 96 hou even though the sufentanil dose was down-titrated before extubation. 90 In contrast, there was no difference in time to tracheal extubation when combin infusions of remifentanil (0.15 mg/kg/min) and propofol were compared with fenta and propofo propofoll after after shortshort-ter term m ventila ventilatio tion n (12–72 (12–72 hours) hours).. Moreov Moreover, er, patien patients ts received remifentanil complained of more pain during and after tracheal extubation In a subsequent study by the same group, mechanical ventilation time after card surgery was decreased, and ICU discharge was ea earlier rlier with a remifentanil-propo 92 regimen than with a fentanyl-midazolam regimen. These two studies suggest t the the dura durati tion on of ve vent ntila ilatio tion n was was more more infl influe uenc nced ed by the the dura durati tion on of ac actio tion n of hypnotic agent (midazolam vs propofol) than the opioid (fentanyl vs remifentanil). Remifentanil has been evaluated in the neurointensive care setting. Because of short half-life, remifentanil may facilitate frequent awakening toonevaluate Sign up to vote this title neurolog and respiratory respiratory parameters. parameters.76,93 In a study of patients withtraumatic Not useful brain inj Useful who were mechanically ventilated, intracranial pressure (ICP) and cerebral perfus pressure pressure were maintained maintained with remifentanil remifentanil.. 94 However, in patients with severe tra
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become unresponsive to nociceptive stimuli, but may keep their eyes open and tain tain their their refle reflexe xes. s. Bloo Blood d press pressur ure e is ma main inta tain ined ed,, and and spon sponta tane neou ous s breat breathi hing ng geal reflexes are preserved. Ketamine crosses the blood-brain barrier rapid reaches maximal effect in 1 minute. The duration of a single dose of ketamine kg IV) is 10 to 15 minutes. Effective plasma levels of ketamine can be achieved intra intramu musc scula ular, r, subli subling ngua ual, l, or rect rectal al rout routes es,, ma maki king ng it a usef useful ul agen agentt in pedia pediatr tric ic In comparison to etomidate, etomidate, propofol, and midazolam, midazolam, ketamin ketami ne appears to a cardiac stimulant through sympathetic-mediated mechanisms. 98 At clinical c trations, ketamine has a positive inotropic action and induces vasoconstrictio probably probably by inhibit inhibiting ing endoth endotheli elial al nitric nitric oxide oxide produc productio tion, n,101 which which preserv preserves es 102 nami namic c stab stabil ilit ity y ev even en in se sept ptic ic shoc shock. k. In anim animal al stud studie ies, s, keta ketami mine ne a my myoc ocar ardia diall depre depress ssan antt at ve very ry high high plasm plasma a conc concen entr trat atio ions ns,, parti particu cula larly rly in a amine-depleted state, but this manifestation appears extremely rare in clinica cine. cine. Althoug Although h vasoco vasoconst nstrict riction ion and inotro inotropy py are prefer preferable able in certain certain situ ketamine increases myocardial oxygen demand, limiting its use in patients with coronary ischemia. Its sympathomimetic activity is attenuated by concomitant istration istration of benzodiazepi benzodiazepines. nes.103 Keta Ketamin mine e has bronch bronchodi odilato latorr act activi ivity ty and 104,105 helpful in the setting of status asthmaticus and bronchospasm, althou benefit may be counteracted by its propensity to increase oral secretions. Keta Ke tami mine ne has has antii antiinf nfla lamm mmat ator ory y proper properti ties es.. It decr decrea ease ses s the the form format atio io cytokine cytokine precursor, precursor, nuclear nuclear factor kappa-light-cha kappa-light-chain-en in-enhance hancerr of activated activated (NF-kB), and thereby decreases interleukin-, cytokine-, and endotoxin-induced necrosis factor alpha production. 101,106–109 Keta Ke tami mine ne is stil stilll used used in clin clinic ical al anes anesth thes esia ia,, but but its its popu popula lari rity ty is limi limite ted d beca beca undesirable undesirable side-effect side-effect profile of hallucinatio hallucinations ns (during dissociative dissociative anesthesia anesthesia gence delirium and unpleasant recall, increased oral secretions, lacrimation, cardia cardia,, and the potent potential ial for exacer exacerbat bating ing myocar myocardia diall ischem ischemia. ia. Clinici Clinici avoided ketamine in patients at risk for elevated ICP, which may occur in p who are sponta spontaneo neousl usly y ventila ventilatin ting. g. This This observ observati ation on contra contrasts sts with stu show that ketamine does not increase increase cerebral blood flow or ICP if normal 110,111 dioxide levels are maintained. In combinati combination on with benzodiazepines, ke 112–114 prevents increases and decreases in ICP. Hemodynamic variables ap be preserved in brain or spinal cord injured ICU patients. 115 These results s that that the the dept depth h of se seda datio tion n is more more impor importa tant nt than than the the choi choice ce of se sedat dativ iv management of elevated ICP. Concerns for the psychotropic effects of ketamine have restricted Sign up to vote on this title its use as a tive-analgesic in the ICU. However, there is evidence that low-dose Not useful (60–120 Useful ketamine ketamine infusions in combination combination with opioids may not be associated associated with un effects and may improve outcomes in the critically ill. There are several expla
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Pharmacology of Sedative-Analgesic Age
which can cause central sensitization and lead to allodynia (a painful response to innocuous stimulus), hyperalgesia (an exaggerated exaggerated response to a painful stimulu and eventually chronic pain syndromes. 126–128 Opioids themselves can induce hyp alge algesi sia. a. Ke Keta tamin mine e anta antago goni nize zes s the the NMDA NMDA rece recept ptor or to block block thes these e resp respon onse ses, s, redu redu windup windup pain pain and centra centrall hypere hyperexci xcitab tabii lity lity.. Several everal studie studies s report report that that ketam ketam 129,130 decreases decreases opioid-induce opioid-induced d hyperalgesia hyperalgesia.. Potentially, keta etamin mine e can dec 97 opioid requirements, tolerance, and prevent chronic pain. In summary, ketam preven prevents ts opioid-i opioid-indu nduced ced hypera hyperalge lgesia sia,, decrea decreases ses inflamm inflammatio ation, n, and amelio amelio bronchoconstriction.130–133 For these reasons, ketamine has regained its popula as a ‘‘battlefield anesthetic’’ in the Iraq war for the treatment of acute and chro pain and burns. 97,134 There are few reports of adverse long-term psychological sequelae after ketami Its administration has actually been associated with a decreased incidence of po trau trauma matic tic stre stress ss disor disorde derr (PTSD (PTSD)) in soldi soldier ers s in the the Iraq Iraq war. war.134,135 Ther There e is evidence that a single dose of IV ketamine rapidly improves symptoms in patien with treatment-resistant depression. 136 Because PTSD and depression can occu patients who are critically ill, randomized controlled trials to investigate ketamine a novel therapeutic agent would appear to be warranted.
VOLATILE VOLATILE ANESTHETIC ANESTHETIC AGENTS
Volatile Volatile anesthetics anesthetics such as isoflurane, isoflurane, sevoflurane, sevoflurane, and desflurane desflurane are in daily use the operating room in the delivery of general anesthesia. A major advantage of the halogenated ethers is their quick onset, quick offset, and ease of titration in renderi the patient unconscious, immobile, and amnestic. Although volatile anesthetics a generally generally associated with stable hemodynamics hemodynamics with little variation, dose-depen vasodilatation, cardiac depression, and arrhythmias can occur. 137–139 Isoflurane, s oflurane, and desflurane provide cardioprotection through pharmacologic precon tion tionin ing; g; trop tropon onin in leve levels ls and and leng length th of ICU ICU stay stay are are decr decrea ease sed. d. 140–142 Vola anesthetics are also bronchodilators and can be prescribed as therapeutic agen for the treatment of bronchospasm and status asthmaticus. 143–146 Administering Administering sedation sedation through through the the lung is a dependable dependable route for for delivery delivery and el ination. Characterized by a steep dose-response curve, inhalation anesthesia offe a more consistent onset time with less variability compared with traditional IV sed tion.147 Because newer volatile anesthetics (eg, isoflurane, sevoflurane, Sign up to vote on this title desflura are primarily primarily elimin eliminate ated d by the lungs, lungs, there there is very ver y little litt le accumu acc lation ion in pat Useful Not useful umulat with renal and hepatic hepa tic dysfunction, dysfunction, and shorter and more predictable emergen 138,148–150 times are observed. Potential concerns for the accu mulation mulation of inorga
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Several clinical trials have compared volatile anesthetics to IV sedation in care. care. Prelimin Preliminary ary studie studies s evalua evaluatin ting g isoflur isoflurane ane in the ICU found found that that it wa effective, and associ sociat ated ed with with shor shorte terr em emer erge genc nce e time times s than than mida mida 148–150,154 propofol. Compared Compared with propofol, propofol, sevoflurane sevoflurane sedation was ass with shorte shorterr extubation times and length of hospital stay in patients after c surgery.151 Similar observations have been made when desflurane was com with propofol after after surgery, and patients appeared to have better cognitive f after emergence. 138 Long-term (6-month) follow-up of patients found a trend fewer hallucinations and delusions if they had received isoflurane versus mid sedation in the ICU. 155 Given these benefits, a number of major restrictions remain that govern the delivery of volatile anesthesia in the ICU—cost, environmental pollution, and th thesiologist’s expertise. 156 The need for a cumbersome circuit to deliver the anesthetic and the uneconomical anesthetic consumption in an open ICU ve circ circui uitt have have limit limited ed thei theirr effe effect ctiv iven enes ess. s. NonNon-re rebr brea eath thin ing g ICU ve vent ntila ilato tors rs requ require ire enging system to avoid environmental pollution. Several published studies hav a new and fairly simple device, the ‘‘Anesthetic Conserving Device’’ (AnaConD ¨ sby, ¨ sby, Sweden) that allows infusion of liquid volatile ane son RCI, Uppslands Va through the breathing circuit of a standard ICU ventilator. By incorporating a va chamber with a charcoal reflection filter it creates a semi-closed rebreathing that retains 90% of the inhaled anesthetic. Modifications are still required to e safety. Changes in ventilator settings affect the delivery of the anesthetic, a possible that the volatile anesthetic syringe could inadvertently be connecte IV infusion line, but there is little escape of the anesthetic into the atmosphere PERIPHERAL OPIOID RECEPTOR RECEPTOR ANTAG ANTAGONISTS ONISTS
Opioids remain the primary class of analgesic drugs in the ICU and may be infu many days in critically ill patients. patients. Undesired Undesired side effects effects are legion, legion, and in add naus nausea ea,, vomi vomitin ting, g, prur pruritu itus, s, and and urin urinar ary y rete retent ntio ion, n, they they incl includ ude e dela delaye ye emptying, suppression of bowel motility, constipation, and ileus. Methylnalt and alvimopan are members of a new class of drugs—peripherally acting mu receptor antagonists (PAMORAs). In contrast to naloxone, these medications cross the blood-brain barrier to antagonize the central effects of opioids. In they they antago antagoniz nize e the periphe peripheral ral side effect effects s of opioid opioids—n s—nota otably bly constip constipati ati met ileus—while preserving analgesia. The FDA hasSign approved up to vote subcutaneous on this title trexone for the relief of opioid-induced constipation and oral to fa Not alvimopan useful Useful the return of gut dysfunction after anastomotic bowel surgery. The PAMORAs PAMORAs have have the potentia potentiall to marked markedly ly benefi benefitt the manageme manageme
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of thes these e fact factor ors s and and ma may y help help curt curtai aill syst system emic ic inva invasi sion on in pati patien ents ts rece rece 160 opioids. REFERENCES
1. Scheinin Scheinin H, Aantaa R, Anttila M, et al. Reversal of the sedative and sympathol sympathol effects effects of dexmedetomidin dexmedetomidine e with a specific specific alpha2-adren alpha2-adrenocepto oceptorr antagonist antagonist pamezole: a pharmacodynamic and kinetic study in healthy volunteers. Ane thesiology 1998;89:574–84. 2. Ma D, Hossai Hossain n M, Rajaku Rajakumar marasw aswamy amy N, et al. Dexmed Dexmedeto etomid midine ine produc neuroprotective effect via the alpha 2A-adrenoceptor subtype. Eur J Pharma 2004;502:87–97. 3. Fagerholm Fagerholm V, Scheinin Scheinin M, Haaparanta Haaparanta M. Alpha2A-adre Alpha2A-adrenocep noceptor tor antago increases insulin secretion and synergistically augments the insulinotropic eff of glibenclamide in mice. Br J Pharmacol 2008;154:1287–96. 4. Takada K, Clark DJ, Davies MF, MF, et al. Meperidine exerts agonist agonist activity activity at alpha(2B)-adrenoceptor subtype. Anesthesiology 2002;96:1420–6. 5. Fagerholm Fagerholm V, V, Rokka J, Nyman L, et al. Autoradiograp Autoradiographic hic characterizati characterization on of pha(2C)-adrenoceptors in the human striatum. Synapse 2008;62:508–15. 6. Moura E, Afonso J, Hein L, et al. Alpha2-adrenoce Alpha2-adrenoceptor ptor subtypes subtypes involved in regulation of catecholamine release from the adrenal medulla of mice. Br J Ph macol 2006;149:1049–58. 7. Khan ZP, ZP, Ferguson Ferguson CN, Jones RM. Alpha-2 and imidazoline imidazoline receptor receptor agoni Their pharmacology and therapeutic role. Anaesthesia 1999;54:146–65. 8. Takamat akamatsu su I, Iwase Iwase A, Ozaki Ozaki M, et al. Dexmed Dexmedeto etomidi midine ne reduc reduces es long-t long-t potentiation in mouse hippocampus. Anesthesiology 2008;108:94–102. 9. Venn RM, Karol MD, Grounds Grounds RM. Pharmacokine Pharmacokinetics tics of dexmedetomidine dexmedetomidine in sion sions s for for se seda datio tion n of post postop oper erat ative ive patie patient nts s requ requir irin ing g inten intensi sive ve ca care ret. t. Anaesth 2002;88:669–75. 10. Vilo S, Rautiainen Rautiainen P, P, Kaisti K, et al. Pharmacokinetics Pharmacokinetics of intravenous intravenous dexmede midine in children under 11 yr of age. Br J Anaesth 2008;100:697–700. 11. Petroz Petroz GC, Sikich N, James M, et al. A phase I, two-center two-center study of the pharm cokinetics cokinetics and pharmacodyn pharmacodynamics amics of dexmedetomidi dexmedetomidine ne in children. children. Anesth ology 2006;105:1098–110. 12. Kivisto KT, KT, Kallio A, Neuvonen PJ. Pharmacokinetic Pharmacokinetics s and pharmacodyna pharmacodynamics mics transdermal dexmedetomidine. Eur J Clin Pharmacol Sign up to1994;46:345–9. vote on this title 13. Anttila M, Penttila J, Helminen A, et al. Bioavailability Bioavaila dexmedetomidine dexmedetom idine a Useful of Not useful bility extravascular doses in healthy subjects. Br J Clin Pharmacol 2003;56:691–3 14. De Wolf AM, Fragen RJ, Avram MJ, et al. The pharmacokineti pharmacokinetics cs of dexmede
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19. Ebert TJ, Hall JE, Barney JA, et al. The effects of increasing increasing plasma con tions of dexmedetomidine in humans. Anesthesiology 2000;93:382–94. 20. Jorden VS, Pousman Pousman RM, Sanford Sanford MM, et al. Dexmedetomidine Dexmedetomidine overdo perioperative perioperative setting. setting. Ann Pharmacother Pharmacother 2004;38:80 2004;38:803–7. 3–7. 21. Ramsay MA, Luterman DL. Dexmedetomidin Dexmedetomidine e as a total intravenous intravenous ane agent. Anesthesiology 2004;101:787–90. 22. Jalowi Jalowieck eckii P, Rudner Rudner R, Gon Goncia ciarz rz M, et al. Sole use of dexmed dexmedeto etomid mid limited utility for conscious sedation during outpatient colonoscopy. Ane ology 2005;103:269–73. 23.. Munt 23 Muntaz azar ar M, Ku Kuma marr FC. FC. Card Cardia iac c arre arrest st,, a prev preven enta table ble ye yett a poss possib ible le risk risk detomidine: fact or fiction? Anesthesiology 2004;101:1478–9 [author reply 24. Shah AN, Koneru J, Nicoara Nicoara A, et al. Dexmedetomidin Dexmedetomidine e related cardiac cardiac a a patient with permanent pacemaker; a cautionary tale. Pacing Clin Elec siol 2007;30:1158–60. 25. Riker Riker RR, Shehab Shehabii Y, Bokesc Bokesch h PM, et al. Dexmedeto Dexmedetomidi midine ne vs mida sedation of critically ill patients: a randomized trial. JAMA 2009;301:489 26. Venn Venn M, Newman J, Grounds M. A phase II study to evaluate evaluate the efficac medetomidine for sedation in the medical intensive care unit. Intensiv Med 2003;29:201–7. 27. Reid K, Hayashi Y, Y, Guo TZ, et al. Chronic administration of an alpha 2 adr agonist desensitizes rats to the anesthetic effects of dexmedetomidine. P col Biochem Behav 1994;47:171–5. 28. Turkmen A, Altan A, Turgut Turgut N, et al. The correlation between the Richmon tion-sedation scale and bispectral index during dexmedetomidine sedat J Anaesthesiol 2006;23:300–4. 29. Aantaa R. Assessment Assessment of the sedative effects effects of dexmedetomidine, dexmedetomidine, an a adreno adrenocep ceptor tor agonis agonist, t, with ana analys lysis is of saccad saccadic ic eye moveme movements nts.. Pha Toxicol 1991;68:394–8. 30. Bekker Bekker A, Sturaitis Sturaitis MK. Dexmedetomi Dexmedetomidine dine for neurological neurological surgery. surgery. gery 2005;57(1 Suppl):1–10 [discussion: 1–10]. 31. Elias WJ, Durieux ME, Huss D, et al. Dexmedetomidin Dexmedetomidine e and arousal arousal affe thalamic thalamic neurons. neurons. Mov Disord 2008;23:13 2008;23:1317–20 17–20.. 32. Girard Girard TD, Kress Kress JP, JP, Fuc Fuchs hs BD, et al. Efficac Efficacy y and safety safety of a paired paired s and ventilator weaning protocol for mechanically ventilated patients in in care (Awakening and Breathing Controlled trial): a randomised controll Lancet 2008;371:126–34. Sign up to vote on this title 33. Kress Kress JP, JP, O’Conn O’Connor or MF, MF, Pohlma Pohlman n AS, etal. Sedatio Seda tion n of critica critically lly ill Useful Not useful during mechanical ventilation. A comparison of propofol and midazola J Respir Crit Care Med 1996;153:1012–8.
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38. Arain Arain SR, Ebert Ebert TJ. The efficacy efficacy,, side effects, effects, and recove recovery ry cha charac racter terist istics ics dexm dexmed edet etom omidi idine ne ve vers rsus us prop propof ofol ol when when us used ed for for intr intrao aope pera rati tive ve se seda da Anesth Analg 2002;95:461–6, table of contents. 39.. Arai 39 Arain n SR, Ru Rueh ehlo low w RM, RM, Uhric Uhrich h TD, TD, et al. al. Th The e effi effica cacy cy of dexm dexmed edet etom om versus versus morphin morphine e for postop postopera erative tive ana analge lgesia sia after after major major inpatien inpatientt sur Anesth Analg 2004;98:153–8, table of contents. 40. Al-Metwa Al-Metwalli lli RR, Mowafi Mowafi HA, Ismail Ismail SA, et al. Effect Effect of intra-a intra-artic rticula ularr dexmed dexmedeto etomid mid on postope postoperat rative ive ana analge lgesia sia after after arthros arthroscopi copic c knee knee surgery surgery.. Br J Ana Anaesth esth 200 2008;1 8;1 395–9. 41. Yoshitomi oshitomi T, T, Kohjitani Kohjitani A, Maeda S, et al. Dexmedetomid Dexmedetomidine ine enhances the lo anesth ane sthetic etic action action of lidocai lidocaine ne via an alphaalpha-2A 2A adreno adrenocep ceptor tor.. Ane Anesth sth An 2008;107:96–101. 42. Deutsch E, Tobias Tobias JD. Hemodynamic and respiratory changes changes following dexm detomidine administration during general anesthesia: sevoflurane vs desflura Paediatr Anaesth 2007;17:438–44. 43. Korogl Koroglu u A, Teksan eksan H, Sagir Sagir O, et al. A compar compariso ison n of the sedative sedative,, hem namic, namic, and respira respiratory tory effect effects s of dexmed dexmedeto etomidi midine ne and propofo propofoll in chi undergoing magnetic resonance imaging. Anesth Analg 2006;103:63–7, ta of contents. 44. Venn RM, Hell Hell J, Ground Grounds s RM. Respirato Respiratory ry effects effects of dexmede dexmedetom tomidin idine e in surgical patient requiring intensive care. Crit Care 2000;4:302–8. 45. Arpino PA, PA, Kalafatas Kalafatas K, Thompson Thompson BT. BT. Feasibility Feasibility of dexmedetomid dexmedetomidine ine in tating extubation in the intensive care unit. J Clin Pharm Ther 2008;33:25–30 46. Siobal MS, Kallet RH, Kivett VA, VA, et al. Use of dexmedetomid dexmedetomidine ine to facilitate tubati tubation on in surgic surgical al intensi intensiveve-car care-u e-unit nit patien patients ts who failed failed previou previous s wea attempts following prolonged mechanical ventilation: a pilot study. Respir C 2006;51:492–6. 47.. Akad 47 Akada a S, Tak akeda eda S, Yos oshi hida da Y, et al. al. Th The e effi effica cacy cy of dexm dexmed edet etom omidi idi patients with noninvasive ventilation: a preliminary study. Anesth Analg 20 107:167–70. 48.. Be 48 Berg rges ese e SD, Kh Khab abiri iri B, Ro Robe berts rts WD, WD, et al. al. Dexm Dexmed edet etom omidi idine ne for for co cons nsci ciou ous s se tion in difficult awake fiberoptic intubation cases. J Clin Anesth 2007;19:141–4 49. Grant SA, Breslin DS, MacLeod MacLeod DB, et al. Dexmedetomidine Dexmedetomidine infusion infusion for se tion during fiberoptic intubation: a report of three cases. J Clin Anesth 20 16:124–6. batio 50.. Stam 50 Stamen enko kovi vic c DM, DM, Hass Hassid id M. Dexm Dexmed edet etom omidi idine ne upfor fotor vote fiber fibon erop optic intubat io Sign thistic title intu a patient with severe mental retardation and atlantoaxial instability. Not useful Acta Ana Useful thesiol Scand 2006;50:1314–5. 51. Doufas Doufas AG, Lin CM, Suleman Suleman MI, et al. Dexmedetomid Dexmedetomidine ine and meperidine meperidine ad
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56. Wijeysundera Wijeysundera DN, Naik JS, Beattie WS. Alpha-2 adrenergic adrenergic agonists agonists to perioperative cardiovascular complications: a meta-analysis. Am J Med 114:742–52. 57. Biccard Biccard BM, Goga S, de Beurs J. Dexmedetomidin Dexmedetomidine e and cardiac cardiac protec non-cardia non-cardiac c surgery: surgery: a meta-analysi meta-analysis s of randomised randomised controlled controlled trials. thesia 2008;63:4–14. 58. Dahmani Dahmani S, Rouelle Rouelle D, Gressens Gressens P, P, et al. Effects of dexmedetomidine dexmedetomidine on campal campal focal focal adhesi adhesion on kinase kinase tyrosi tyrosine ne phosph phosphory orylati lation on in physio physiolog log ischemic conditions. Anesthesiology 2005;103:969–77. 59. Prielipp Prielipp RC, Wall Wall MH, Tobin JR, et al. Dexmed Dexmedeto etomidi midinene-ind induce uced d sed volunt volunteer eers s decrea decreases ses region regional al and global global cerebr cerebral al blood blood flow. flow. Ane 2002;95:1052–9, table of contents. 60. Zornow Zornow MH, Maze Maze M, Dyck Dyck JB, et al. Dexmed Dexmedeto etomidi midine ne decrea decreases ses c blood flow velocity in humans. J Cereb Blood Flow Metab 1993;13:350– 61. Drummond Drummond JC, Dao AV AV, Roth DM, et al. Effect of dexmedetomidine dexmedetomidine on c blood flow velocity, cerebral metabolic rate, and carbon dioxide resp normal humans. Anesthesiology 2008;108:225–32. 62. Maccio Macciolili GA. Dexmed Dexmedeto etomidi midine ne to facilit facilitate ate drug drug withdra withdrawal wal.. Ane Anesth sth 2003;98:575–7. 63. Multz AS. Prolonged dexmedetomidin dexmedetomidine e infusion as an adjunct adjunct in treat tion-induced withdrawal. Anesth Analg 2003;96:1054–5, table of conten 64. Baddigam K, Russo P, P, Russo J, et al. Dexmedetomidin Dexmedetomidine e in the treatme drawal drawal syndro syndromes mes in cardio cardiotho thorac racic ic surgery surgery patient patients. s. J Intensi Intensive ve Ca 2005;20:118–23. 65. Ken Kentt CD, Kau Kaufma fman n BS, Lowy Lowy J. Dexmede Dexmedetom tomidin idine e facilit facilitate ates s the withdr ventilatory support in palliative care. Anesthesiology 2005;103:439–41. 66. Farag Farag E, Chahla Chahlavi vi A, Argalio Argalious us M, et al. Using dexmedeto dexmedetomidi midine ne to patient patients s with coc cocain aine e and opioid opioid withdraw withdrawal, al, who are underg undergoin oing g angioplasty for cerebral vasospasm. Anesth Analg 2006;103:1618–20. 67. Rovasalo Rovasalo A, Tohmo Tohmo H, Aantaa R, et al. Dexmedetomidin Dexmedetomidine e as an adjuva treatment of alcohol withdrawal delirium: a case report. Gen Hosp Psy 2006;28:362–3. 68. Stemp LI, Karras GE Jr. Jr. Dexmedetomid Dexmedetomidine ine facilitates withdrawal withdrawal of ven support. Anesthesiology 2006;104:890 [author reply 890]. 69.. Darr 69 Darrou oujj J, Puri Puri N, Princ Prince e E, et al. al. Dexm Dexmede edeto tomid midin ine e infu infusio sion n as ad therap therapy y to benzod benzodiaz iazepin epines es for acu acute te alcoho alcSign oholup l withdra with drawal AnnPharm Pharm to vote onwal. this .title 2008;42:1703–5. Useful Not useful 70. Junaid Junaid A, Cui L, Penner SB, et al. Regulation Regulation of aquaporin-2 expression expression alpha(2)-adrenoceptor agonist clonidine in the rat. J Pharmacol Exp The
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75. Kocoglu Kocoglu H, Ozturk H, Yilmaz F, F, et al. Effect of dexmedetomidine dexmedetomidine on ischemia perfusion injury in rat kidney: a histopathologic study. Ren Fail 2009;31:70–4 76. Wilhel Wilhelm m W, Kreue Kreuerr S. The place for short-a short-acti cting ng opioids opioids:: specia speciall emphas emphas remifentanil. Crit Care 2008;12(Suppl 3):S5 [abstract]. 77. Martin J, Franck Franck M, Sigel S, et al. Changes in sedation sedation management management in Germ intensive care units between 2002 and 2006: a national follow-up survey. C Care Care 200 2007;1 7;11:R 1:R124 124.. Availa Available ble at: http://ccforum.com/content/11/6/R124. cessed June 15, 2009. 78. Egan Egan TD, Lemmens Lemmens HJ, Fiset Fiset P, P, et al. The pharmaco pharmacokin kineti etics cs of the new sh acting opioid remifentanil (GI87084B) in healthy adult male volunteers. Anesth siology 1993;79:881–92. 79. Rosow Rosow C. Remife Remifenta ntanil nil:: a unique unique opioid opioid ana analges lgesic. ic. Ane Anesth sthesi esiolo ology gy 199 875–6. 80. Kapila A, Glass PS, Jacobs JR, et al. Measured Measured context-sens context-sensitive itive half-tim remifentanil and alfentanil. Anesthesiology 1995;83:968–75. 81. Westm Westmore orelan land d CL, Hoke Hoke JF JF,, Sebel Sebel PS, et al. Pharmac Pharmacoki okinet netics ics of remife remife (GI87084B) and its major metabolite (GI90291) in patients undergoing elect inpatient surgery. Anesthesiology 1993;79:893–903. 82. Pitsiu M, Wilmer A, Bodenham A, et al. Pharmacokinet Pharmacokinetics ics of remifentanil remifentanil and major metabolite, remifentanil acid, in ICU patients with renal impairment. B Anaesth 2004;92:493–503. 83. Dershwitz Dershwitz M, Rosow CE. The pharmacokin pharmacokinetics etics and pharmacodynamic pharmacodynamics s of mifentanil in volunteers with severe hepatic or renal dysfunction. J Clin Ane 1996;8:88S–90S. 84. Dumont Dumont L, Picard V, V, Marti RA, et al. Use of remifentanil remifentanil in a patient patient with chro hepatic failure. Br J Anaesth 1998;81:265–7. 85.. Bree 85 Breen n D, Ka Kara rabin binis is A, Malbr Malbrai ain n M, et al. al. Decr Decrea ease sed d dura duratio tion n of mech mechan an ventilation ventilation when comparing comparing analgesia-ba analgesia-based sed sedation sedation using remifentan remifentanilil stan standa dard rd hy hypn pnot otic ic-ba -base sed d se seda datio tion n for for up to 10 days days in inte intens nsiv ive e ca care re patients: a randomised trial [ISRCTN47583497]. Crit Care 2005;9:R200–10. 86. Evane TN, Park GR. Remifentanil Remifentanil in the critically critically ill. Anaesthesia Anaesthesia 1997;52:80 1997;52:80 87. Delvaux Delvaux B, Ryckwaert Ryckwaert Y, Y, Van Boven M, et al. Remifentanil Remifentanil in the intensive intensive c unit: tolerance and acute withdrawal syndrome after prolonged sedation. An thesiology 2005;102:1281–2. 88. Jacobi Jacobi J, Fraser Fraser GL, Coursin DB, et al. Clinical Clinical practice guidelines guidelines for the s tained use of sedatives and analgesics in the Sign critically ill on adult. Crit Care M up to vote this title 2002;30:119–41. Useful Not useful 89. Dahaba AA, Grabner T, T, Rehak PH, et al. Remifentanil versus morphine analge and sedati sedation on for mechan mechanica ically lly ventila ventilated ted critica critically lly ill patient patients: s: a random random
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93. Karabin Karabinis is A, Mandra Mandragos gos K, Stergio Stergiopou poulos los S, et al. Safety Safety and efficacy efficacy gesi gesiaa-ba base sed d se seda datio tion n with with remif remifen enta tani nill ve vers rsus us stand standar ard d hy hypno pno regim regimen ens s in inte intens nsiv ive e ca care re un unit it patie patient nts s with with brain brain inju injurie ries: s: a rando rando controlled controlled trial [ISRCTN503083 [ISRCTN50308308]. 08]. Crit Care 2004;8:R268 2004;8:R268–80. –80. 94. Engelhard Engelhard K, Reeker W, W, Kochs E, et al. Effect of remifentan remifentanilil on intracrani sure and cerebral blood flow velocity in patients with head trauma. Acta thesiol Scand 2004;48:396–9. 95. Leo Leone ne M, Albanes Albanese e J, Vivian Viviand d X, et al. The effect effects s of remife remifenta ntanil nil on cheal che al suctio suctionin ning-in g-induc duced ed increa increases ses in intrac intracran ranial ial pressu pressure re in hea patients. Anesth Analg 2004;99:1193–8, table of contents. 96. Domino Domino EF, EF, Chodof Chodofff P, Corsse Corssen n G. Pharmac Pharmacolo ologic gic effect effects s of Ci-581, Ci-581, dissociative anesthetic, in man. Clin Pharmacol Ther 1965;6:279–91. 97.. Malc 97 Malcho how w RJ, RJ, Black Black IH. Th The e ev evol olut utio ion n of pain pain mana managem gemen entt in the the cr trauma patient: emerging concepts from the global war on terrorism. C Med 2008;36:S346–57. 98. Gelissen Gelissen HP, HP, Epema AH, Henning RH, et al. Inotropic effects effects of propof pental, midazolam, etomidate, and ketamine on isolated human atrial m Anesthesiology 1996;84:397–403. 99. Saegusa Saegusa K, Furukawa Furukawa Y, Y, Ogiwara Y, Y, et al. Pharmacologic Pharmacologic analysis of ke induced cardiac actions in isolated, blood-perfused canine atria. J Card Pharmacol 1986;8:414–9. 100. Reich DL, Silvay G. Ketamine: Ketamine: an update on the first twenty-five twenty-five years of experience. Can J Anaesth 1989;36:186–97. 101. Chen RM, Chen TL, Lin YL, et al. Ketamine Ketamine reduces nitric nitric oxide biosyn human human umbilic umbilical al vein vein endoth endotheli elial al cells cells by down-r down-regu egulati lating ng endoth endoth oxid ox ide e synt syntha hase se ex expr pres essi sion on an and d intr intrac acel ellu lula larr ca calc lciu ium m level levels. s. Crit Crit Ca 2005;33:1044–9. 102. Yli-Hankala Yli-Hankala A, Kirvela M, Randell T, T, et al. Ketamine Ketamine anaesthesia anaesthesia in a pati septic shock. Acta Anaesthesiol Scand 1992;36:483–5. 103. Doenicke Doenicke A, Angster R, Mayer M, et al. [The action of S-( 1)-ketamine )-ketamine on catecholamine and cortisol. A comparison with ketamine racemate]. Ana sist 1992;41:597–603 [in German]. 104. Park GR, Manara AR, Mendel L, et al. Ketamine infusion. infusion. Its use as a se inotrope and bronchodilator in a critically ill patient. Anaesthesia 1987;42 105. Sarma VJ. Use of ketamine ketamine in acute severe asthma. asthma. Acta Anaesthesi 1992;36:106–7. Sign up to vote on this title 106. Mazar J, Rogachev Rogachev B, Shaked Shaked G, et al. Involvement Involveme adeno useful sine in the Useful nt ofNotadenosine flammatory flammatory action of ketamine. ketamine. Anesthesiolo Anesthesiology gy 2005;102:1 2005;102:1174–8 174–81. 1. 107. Gurfinke Gurfinkell R, Czeiger Czeiger D, Douvdev Douvdevani ani A, et al. Ketamine Ketamine improves improves surviv
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113.. Strebel 113 Strebel S, Kau Kaufma fmann nn M, Maitre Maitre L, et al. Effects Effects of ketami ketamine ne on cerebra cerebrall blo flow velocity in humans. Influence of pretreatment with midazolam or esmo Anaesthesia 1995;50:223–8. 114. Albanese Albanese J, Arnaud S, Rey M, et al. Ketamine decrease decreases s intracranial intracranial press and electroencephalographic activity in traumatic brain injury patients dur propofol sedation. Anesthesiology 1997;87:1328–34. 115. Hijazi Y, Y, Bodonian C, Bolon M, et al. Pharmacokinetic Pharmacokinetics s and haemodynami haemodynami ketamine in intensive care patients with brain or spinal cord injury. Br J Anae 2003;90:155–60. 116.. Himmel 116 Himmelseh seher er S, Durieu Durieux x ME. Ketami Ketamine ne for periope perioperati rative ve pain pain manage manage Anesthesiology 2005;102:211–20. 117.. Bowdle 117 Bowdle TA, TA, Radant Radant AD, Cowley Cowley DS, et al. Psychedeli Psychedelic c effect effects s of ketami ketami healthy volunteers: relationship to steady-state plasma concentrations. Anesth siology 1998;88:82–8. 118. Hartvig P, P, Valtysson Valtysson J, Lindner KJ, et al. Central nervous nervous system effects of su dissociative doses of (S)-ketamine are related to plasma and brain concent tions measured with positron emission tomography in healthy volunteers. C Pharmacol Ther 1995;58:165–73. 119.. Tuc 119 ucke kerr AP, AP, KimYI, Kim YI, Nades Nadeson on R, et al. al. Inve Invest stiga igatio tion n of thepot the poten entia tiatio tion n of thean the anal al effec effects ts of fenta fentany nyll by ke keta tamin mine e in hu huma mans ns:: a double double-b -blin linde ded, d, rando randomis mised ed,, pla controlled, crossover study of experimental pain[ISRCTN83088383]. BMC An thes thesiol iol 20 2005 05;5 ;5:2. :2. Avail Availab able le at: at: http://www.biomedcentral.com/1471-2253/5 Accessed Accessed June 15, 2009. 120.. Badrin 120 Badrinath ath S, Avramov Avramov MN, Shadric Shadrick k M, et al. The use of a ketami ketaminene-pro pro combination during monitored anesthesia care. Anesth Analg 2000;90:858– 121. Friedberg Friedberg BL. Propofol-ke Propofol-ketamine tamine technique: technique: dissociative dissociative anesthesia anesthesia for off surgery (a 5-year review of 1264 cases). Aesthetic Plast Surg 1999;23:70–5 122. Morse Z, Sano K, Kanri T. T. Effects of a midazolam-ke midazolam-ketamine tamine admixture admixture in hum volunteers. volunteers. Anesth Prog 2004;51:76 2004;51:76–9. –9. 123.. Guillo 123 Guillou u N, Tanguy anguy M, Seguin Seguin P, et al. The effects effects of small-d small-dose ose ketamine ketamine morph morphin ine e co cons nsum umpti ption on in su surg rgic ical al inte intens nsiv ive e ca care re un unit it patie patient nts s afte afterr ma abdominal surgery. Anesth Analg 2003;97:843–7. 124. 12 4. La Laht htin inen en P, Ko Kokk kkii H, Haka Hakala la T, et al. al. S(1)-ketamine as an analgesic adju reduce reduces s opioid opioid con consum sumptio ption n after after cardiac cardiac surgery surgery.. Ane Anesth sth Ana Analg lg 200 1295–301, table of contents. 125. Zielmann Zielmann S, Grote R. [The effects of long-termSign sedation intestina intestinal lfunct up to voteon on this title Anaesthesis Anaesthesistt 1995;44(Supp 1995;44(Suppll 3):S549–58 3):S549–58 [in German]. German Useful]. Not useful 126. Li J, Simone DA, Larson AA. Windup leads to characteristics characteristics of central sens sen zation. Pain 1999;79:75–82.
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132. De Kock M, Lavand’homme Lavand’homme P, P, Waterloos Waterloos H. ‘Balanced ‘Balanced analgesia’ in the perative period: is there a place for ketamine? Pain 2001;92:373–80. 133.. Lois 133 Lois F, De Koc Kock k M. Someth Something ing new about ketami ketamine ne for pediatr pediatric ic ane Curr Opin Anaesthesio Anaesthesioll 2008;21:34 2008;21:340–4. 0–4. 134. McGhee McGhee LL, Maani CV, CV, Garza TH, et al. The correlation correlation between between ketam posttraumatic stress disorder in burned service members. J Trauma 2 S195–8 S195–8 [discussion [discussion:: S7–8]. 135.. Hersac 135 Hersack k RA. Ketamine Ketamine’’s psycho psychologi logical cal effects effects do not con contrai traindic ndicate ate based on a patient’s occupation. Aviat Space Environ Med 1994;65:104 136. Zarate CA Jr, Jr, Singh JB, Carlson PJ, et al. A randomized randomized trial of an N-m aspartate aspartate antagonist antagonist in treatmenttreatment-resist resistant ant major depression. depression. Arch Gen atry 2006;63:856–64. 137. De Hert SG. Volatile Volatile anesthetics anesthetics and cardiac function. function. Semin Cardiothor Anesth 2006;10:33–42. 138. Meiser A, Sirtl C, Bellgardt M, et al. Desflurane Desflurane compared compared with propofol propofol f operative sedation in the intensive care unit. Br J Anaesth 2003;90:273– 139. Campagna Campagna JA, Miller KW, KW, Forman SA. Mechanisms Mechanisms of actions of inhale thetics. N Engl J Med 2003;348:2110–24. 140. De Hert SG, Cromheecke Cromheecke S, ten Broecke Broecke PW, PW, et al. Effects of propofol, ane, and sevoflurane on recovery of myocardial function after coronary s in elderly high-risk patients. Anesthesiology 2003;99:314–23. 141.. De Hert SG, ten Broecke 141 Broecke PW, PW, Mertens Mertens E, et al. Sevoflur Sevoflurane ane but not p preser preserves ves myocar myocardial dial functi function on in corona coronary ry surgery surgery patient patients. s. Ane Anesth sth 2002;97:42–9. 142. Belhomme Belhomme D, Peynet Peynet J, Louzy M, et al. Evidence for preconditionin preconditioning g by ane in coronary artery bypass graft surgery. Circulation 1999;100:II340– 143. Bierman MI, Brown M, Muren O, et al. Prolonged Prolonged isoflurane isoflurane anesthesia anesthesia in asthmaticus. Crit Care Med 1986;14:832–3. 144.. Johnst 144 Johnston on RG, Nosewo Noseworthy rthy TW, TW, Friese Friesen n EG, et al. Isoflu Isofluran rane e therap therapy y asthmaticus in children and adults. Chest 1990;97:698–701. 145. Maltais F, F, Sovilj M, Goldberg P, P, et al. Respiratory Respiratory mechanics in status as cus. Effects of inhalational anesthesia. Chest 1994;106:1401–6. 146. 14 6. Revell Revell S, Green Greenha halgh lgh D, Absal Absalom om SR, et al. al. Isof Isoflu lura rane ne in the the tre asthma. Anaesthesia 1988;43:477–9. 147. Kong KL, Bion JF. JF. Sedating Sedating patients patients undergoing mechanical mechanical ventilati intensive care unit–winds of change? Br J Sign Anaesth 2003;90:267–9. up to vote on this title 148. Millane TA, TA, Bennett ED, Grounds RM. Isoflurane Isoflu rane and propofol long-term Useful Not usefulfor long-term tion in the intensive care unit. A crossover study. Anaesthesia 1992;47:7 149. Kong KL, Willatts SM, Prys-Roberts Prys-Roberts C. Isoflurane compared compared with midazo
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154. Sackey PV, PV, Martling CR, Granath Gr anath F, F, et al. Prolonged isoflurane sedation of int sive care unit patients with the anesthetic conserving device. Crit Care M 2004;32:2241–6. 155.. Sackey 155 Sackey PV, PV, Martlin Martling g CR, Carlsw Carlsward ard C, et al. Short- and long-t long-term erm follow follow-up -up intensive intensive care unit patients after sedation sedation with isoflurane isoflurane and midazolam–a midazolam–a p study. Crit Care Med 2008;36:801–6. 156.. Maccio 156 Macciolili GA, Cohen NH. Gen Genera erall ane anesth sthesi esia a in the intensiv intensive e care care unit? unit? ready for ‘‘prime time’’? Crit Care Med 2005;33:687–8. 157. Berton J, Sargentini Sargentini C, Nguyen JL, et al. AnaConDa reflection reflection filter: filter: bench a patient evaluation of safety and volatile anesthetic conservation. Anesth Ana 2007;104:130–4. 158. 15 8. Murph Murphy y DB, Sutto Sutton n JA, JA, Presc Prescot ottt LF LF,, et al. al. Opioid Opioid-in -indu duce ced d delay delay in ga emptying: a peripheral mechanism in humans. Anesthesiology 1997;87:765– 159.. Yuan 159 Yuan CS, Foss JF JF,, O’Conno O’Connorr M, et al. Effects Effects of low-do low-dose se morphin morphine e on gas emptying in healthy volunteers. J Clin Pharmacol 1998;38:1017–20. 160. Moss J, Rosow CE. Development Development of peripheral peripheral opioid antagonists’ antagonists’ new insig into opioid effects. Mayo Clin Proc 2008;83:1116–30. 161. Ho WZ, Guo CJ, Yuan CS, et al. Methylnaltr Methylnaltrexone exone antagonize antagonizes s opioid-media enhancement of HIV infection of human blood mononuclear phagocytes. J Ph macol Exp Ther 2003;307:1158–62.
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