Cerebral protection


Published on

Published in: Health & Medicine, Business
  • Be the first to comment

  • Be the first to like this

No Downloads
Total views
On SlideShare
From Embeds
Number of Embeds
Embeds 0
No embeds

No notes for slide

Cerebral protection

  1. 1. British Journal of Anaesthesia 99 (1): 10–17 (2007) doi:10.1093/bja/aem140 Cerebral protection S. Fukuda1 and D. S. Warner1 –3* 1 Department of Anesthesiology, 2Department of Neurobiology and 3Department of Surgery, Duke University Medical Center, Box 3094, Durham, NC 27710, USA *Corresponding author: Department of Anesthesiology, Duke University Medical Center, Box 3094, Durham, NC 27710, USA. E-mail: david.warner@duke.edu Ischaemic/hypoxic insults to the brain during surgery and anaesthesia can result in long-term disability or death. Advances in resuscitation science encourage progress in clinical manage- ment of these problems. However, current practice remains largely founded on extrapolation from animal studies and limited clinical investigation. A major step was made with demon- Downloaded from http://bja.oxfordjournals.org/ at McGill University Libraries on March 8, 2012 stration that rapid induction of mild sustained hypothermia in comatose survivors of out- of-hospital ventricular fibrillation cardiac arrest reduces death and neurological morbidity with negligible adverse events. This provides the first irrefutable evidence that outcome can be favourably altered in humans with widely applicable neuroprotection protocols. How far hypothermic protection can be extended to global ischaemia of other aetiologies remains to be determined. All available evidence suggests an adverse response to hyperthermia in ischae- mic or post-ischaemic brain. Management of other physiological values can have dramatic effects in experimental injury models and this is largely supported by available clinical data. Hyperoxaemia may be beneficial in transient focal ischaemia but deleterious in global ischae- mia. Hyperglycaemia causes exacerbation of most forms of cerebral ischaemia and this can be abated by restoration of normoglycaemia. Studies indicate little, if any, role for hyperventilation. There is little evidence in humans that pharmacological intervention is advantageous. Anaesthetics consistently and meaningfully improve outcome from experimental cerebral ischaemia, but only if present during the ischaemic insult. Emerging experimental data portend clinical breakthroughs in neuroprotection. In the interim, organized large-scale clinical trials could serve to better define limitations and efficacy of already available methods of interven- tion, aimed primarily at regulation of physiological homeostasis. Br J Anaesth 2007; 99: 10–17 Keywords: brain, ischaemia; complications, cerebral ischaemia; recovery, neurologicalCerebral ischaemia/hypoxia can occur in a variety of peri- However, it has become increasingly clear that anoperative circumstances. Outcomes from such events range ischaemic/hypoxic insult does not simply constitute energyfrom sub-clinical neurocognitive deficits to catastrophic failure with consequent interruption of ongoing metabolicneurological morbidity or death. Although certain surgical events. Indeed this does occur. In addition, though, ischae-procedures present greater risk for ischaemic/hypoxic mia and hypoxia stimulate active responses in the brain,brain injury, most insults are not presaged but instead arise which persist long after substrate delivery has beenas unintended complications of either the surgical pro- restored. These responses include activation of transcrip-cedure or the anaesthetic. tion factors which up-regulate expression of genes contri- It has been the investigative interest of surgeons and buting to apoptosis and inflammation, inhibition of proteinanaesthesiologists to reduce perioperative brain injury synthesis, sustained oxidative stress, and neurogenesis.for more than 60 yr.12 Classically, such intervention has Although some of these responses may have a teleologicalbeen categorized as either neuroprotection or neuro- advantage [e.g. elimination of dead or dysfunctionalresuscitation. Neuroprotection was defined as treatment tissue or increased tolerance to a subsequent insult ( pre-initiated before onset of ischaemia, intended to modify conditioning)], most responses aggravate damage causedintra-ischaemic cellular and vascular biological responses by the primary insult. Consequently, the concept that neu-to deprivation of energy supply so as to increase tolerance roprotection can be extended well into the reperfusionof tissue to ischaemia resulting in improved outcome. phase seems appropriate, albeit with different targets otherNeuroresuscitation, in contrast, implied treatment begun than preservation of energy stores. This possibility may, inafter the ischaemic insult had occurred with the intent of part, explain the efficacy of various experimental post-optimizing reperfusion. ischaemic interventions, which have manifested either as# The Board of Management and Trustees of the British Journal of Anaesthesia 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
  2. 2. Cerebral protectionTable 1 Evidence-based status of plausible interventions to reduce perioperative ischaemic brain injury. þþ, Repeated physiologically controlled studies inanimals/randomized, prospective, adequately powered clinical trials; þ, consistent suggestion by case series/retrospective or prospective small sample size trials,or data extrapolated from other paradigms; 2/þ, inconsistent findings in clinical trials; may be dependent on characteristics of insult; 2, well-defined absence ofbenefit; 22, absence of evidence in physiologically controlled studies in animals/randomized, prospective, adequately powered clinical trials; 222, evidenceof potential harm; *, out-of-hospital ventricular fibrillation cardiac arrestIntervention Pre-ischaemic Post-ischaemic Pre-ischaemic Post-ischaemic Sustained Sustained efficacy in efficacy in efficacy in efficacy in protection in protection experimental experimental humans humans experimental in humans animals animals animalsModerate þþ þþ 2/þ þþ* þþ þþhypothermiaMild 222 222 22 22 222 22hyperthermiaHyperventilation 22 22 22 22 22 22Normoglycaemia þþ 22 þ þ þþ 22Hyperbaric þþ 22 22 2/þ 22 22oxygenBarbiturates þþ 2 þ 2 22 22 Downloaded from http://bja.oxfordjournals.org/ at McGill University Libraries on March 8, 2012Propofol þþ þ 2 22 22 2Etomidate 222 22 22 22 22 22Nitrous oxide 2 22 22 22 22 22Isoflurane þþ 22 22 22 þþ 22Sevoflurane 22 22 22 þþ 22Desflurane þþ 22 22 22 22 22Lidocaine þþ 22 þ 22 22 22Ketamine þþ 22 22 22 22 22Glucocorticoids 222 22 22 22 22 22clinically available therapies (e.g. mild hypothermia) or contrast, in less severe insults, suppression of activity byinstead as promising candidates for future clinical use tar- the anaesthetic before onset of ischaemia should delaygeting events, such as oxidative stress, apoptosis, and decay of ATP concentrations and thus also delay loss ofneurogenesis. ionic gradients and calcium influx. The above logic is presented as a taste of where we are Many studies have supported this logic. Indeed, duringgoing with investigations aimed at ameliorating long-term abrupt onset of hypoxaemia, barbiturates and isofluraneimprovement from an ischaemic/hypoxic insult that may slow deterioration of ATP concentrations.43 48 Furthermore,occur in the perioperative period. However, the rest of this post-ischaemic treatment with either barbiturates or volatilearticle will focus on the opportunities and limitations of anaesthetics has no effect on outcome.1 59 Surprisingly,currently available interventions (Table 1). irrefutable data supporting efficacy of pre-treatment with anaesthetics have proved difficult to acquire. Early work testing intra-ischaemic anaesthetic efficacyAnaesthetics was confounded by poor physiological control of exper- imental subjects. It was recognized later in the evolution ofBarbiturates anaesthetic efficacy studies that factors such as bloodIt has been postulated for more than 50 yr that anaesthetics glucose, brain temperature, and perfusion pressure wereincrease the tolerance of brain to an ischaemic insult.28 The important determinants of ischaemic outcome and thatlogic is simple. Most drugs selected to be anaesthetics sup- anaesthetics independently modulated these factors. Inpress neurotransmission. This suppression reduces energy addition, early studies typically compared one anaestheticrequirement, and reduction in energy requirement should against another. The assumption was that the ‘control’allow tissue better to preserve energy balance during a tran- anaesthetic was not protective and thus failure to improvesient interruption of substrate delivery. Since adenosine tri- outcome by the ‘test’ anaesthetic indicated lack of a pro-phosphate (ATP) synthesis recovers rapidly after restoration tective state. However, little work was done to confirm thatof substrate delivery, anaesthetics would be expected to be the ‘control’ anaesthetic was not protective. Subsequentprotective if present during ischaemia but not if given after studies, which became feasible as experimental modelsrestoration of substrate delivery. It would also follow that evolved, often found considerable protection from theefficacy of an anaesthetic is dependent upon the severity of ‘control’ anaesthetic when compared with an awake state.the ischaemic insult. If the insult were sufficiently severe to Thus, the field remained confused for more than acause loss of all electrical activity, there would be no decade and insufficient data were generated to warrantactivity for anaesthetics to suppress and thus no mechanism human trials of anaesthetic efficacy when employed intra-for such drugs to increase tolerance to ischaemia. In operatively. Even then, the early results were mixed. One 11
  3. 3. Fukuda and Warnerstudy found efficacy from thiopental when given in is required for a surgical procedure, inclusion of volatilecardiac surgical patients, whereas another did not.50 67 anaesthetics can be considered. Isoflurane and sevofluraneHowever, only short-term outcomes were assessed, which carry the largest data set to this decision. Desflurane alsoprevented assessment of the full evolution of the ischae- offers promise,33 38 but has been insufficiently studied tomic injury. Furthermore, surgical procedures and cardio- determine whether it should be equally considered in thispulmonary bypass conditions were markedly different class of potential neuroprotective compounds.between the two trials. Numerous other explanations havebeen offered, but perhaps the overall potency of barbitu-rates as neuroprotective agents is weak in the face of Other anaestheticssevere ischaemic insults.65 Other anaesthetics possess properties that suggest potential One problem with barbiturates is their prolonged dur- for intra-ischaemic neuroprotection. These include propo-ation of action. It was believed that optimal protection fol, etomidate, and lidocaine. Study of these drugs has notwould be present only when massive doses were adminis- been as extensive as for either barbiturates or volatiletered to abolish electroencephalographic (EEG) activity, anaesthetics. The principle feature of propofol and etomi-thereby eliciting maximal suppression of cerebral meta- date is suppression of CMR by inhibition of synaptic Downloaded from http://bja.oxfordjournals.org/ at McGill University Libraries on March 8, 2012bolic rate (CMR) before onset of the insult. Some activity.19 35 Propofol may also have free radical scaven-practitioners still adhere to this principle when using bar- ging and anti-inflammatory properties.57 Propofol appearsbiturates to protect the brain but such large doses can unique among anaesthetics in the laboratory settingmarkedly delay anaesthesia emergence, which has limited because it offers efficacy with post-ischaemic therapytheir clinical application. Although it is unlikely that these onset, although such treatment provides only transient pro-massive doses are necessary to obtain maximal efficacy,65 tection.9 Propofol appears to offer efficacy similar to bar-recognition that volatile anaesthetics can also produce biturates but a dose-dependent study of its efficacy has notEEG isoelectricity at doses which still allow rapid anaes- been completed, leaving little guidance for potential clini-thesia emergence was greeted with optimism because such cal use. Furthermore, propofol infused to induce EEGcompounds could be more widely applied in clinical burst suppression failed to improve outcome in cardiacsettings. valve surgery patients.56 Etomidate, although initially her- alded as a substitute for barbiturates,8 has never met rigor- ous evaluation for neuroprotective properties. In fact,Volatile anaesthetics some work has indicated that etomidate may paradoxicallyThe efficacy of volatile anaesthetics as neuroprotective exacerbate ischaemic injury by inhibiting nitric oxideagents has undergone more than 30 yr of scrutiny and still synthase, thereby intensifying the ischaemic insult.21 As ano human outcome trials have been conducted to guide result of this and other studies, the use of etomidate forclinical practice. We know the following facts from the neuroprotection has fallen out of favour in clinicallaboratory. Volatile anaesthetics provide major improve- settings.ment in ischaemic outcome. The dose required to obtain Lidocaine also suppresses CMR, but this effect is onlythis protection is within a clinically relevant range, with meaningful at doses beyond those typically employed inhigher doses potentially worsening outcome.46 Volatile clinical environments. Numerous laboratory studies haveanaesthetics protect against both focal (e.g. obstruction of found efficacy for lidocaine, with perhaps its principleflow distal to the circle of Willis) and global (e.g. com- mechanism of action relating to inhibition of apoptosis.39plete cessation of blood flow to the brain or forebrain) The efficacy of lidocaine appears dependent on dose, withischaemia. However, the improvement in outcome is tran- doses in the range used to manage cardiac dysrhythmiassient in global ischaemia,23 whereas it is persistent in having greatest efficacy.61 There have been no long-termfocal ischaemia.58 Sevoflurane has also been shown to outcome studies of lidocaine efficacy in experimentalprovide long-term protection in one experimental model.51 stroke. One small human trial found benefit from low-doseThe mechanism by which volatile anaesthetics protect is, lidocaine infusion during cardiac surgery on long-termin part, attributable to suppression of energy require- neuropsychological impairment.44 Lidocaine should bements.47 Both inhibition of excitatory neurotransmission further evaluated for neuroprotective properties since itsand potentiation of inhibitory receptors are likely to be use is supported by a litany of laboratory successes suchinvolved.15 22 30 It is also likely that volatile anaesthetics as short-duration of action and ease of use. However,have other important effects that include regulation of because it has not been evaluated in a large-scale clinicalintracellular calcium responses during ischaemia,29 and trial, efficacy in clinical environments remains speculative.activation of TREK-1 two-pore-domain Kþ channels.25 Ketamine offers potent inhibition of glutamatergic Although a great deal has been learned from the labora- neurotransmission at the N-methyl-D-aspartate (NMDA)tory, in the absence of human outcome data, it cannot be receptor. There is a long history of NMDA receptor antag-stated that volatile anaesthetics improve outcome from onists as potential neuroprotective agents but, overall, suchperioperative ischaemic insults. However, if an anaesthetic compounds offer little or no protection against global 12
  4. 4. Cerebral protectioninsults. Protection against focal insults is substantial, but the duration of circulatory arrest approaches the limits ofonly if the drug is given before ischaemia onset. Because deep hypothermic neuroprotection.ketamine is clinically available, it is tempting to argue that The story might have ended there had it not been forit should be considered when a focal ischaemic insult is several laboratory studies that ignored the CMR hypoth-anticipated. To date, however, there are no human data esis. Those studies re-visited the possibility that mildsupporting this practice. Little is also known about dose – hypothermia could protect the brain against ischaemiaresponse properties, even in animals. Thus, it is difficult to insults.14 40 To most people’s surprise, reduction in brainrecommend ketamine for the purposes of neuroprotection temperature by only a few degree Celsius provided majorin the clinical environment at this time. protection. These findings stimulated numerous clinical trials in both adults and newborns, which have since pro- vided a scientific basis defining the opportunities and limitations of using off-bypass hypothermia to providePhysiological management meaningful neuroprotection. The first reported work related to traumatic brain injuryTemperature (TBI). Three pilot studies provided suggestive evidence Downloaded from http://bja.oxfordjournals.org/ at McGill University Libraries on March 8, 2012Hypothermia has been proposed to offer therapeutic that mild hypothermia improved either brain physiology orbenefit for more than 60 yr.24 Early investigators examined outcome. However, those studies employed small sampleits effects in both neurosurgery and cardiac surgery sizes and more definitive evidence was needed. Thus, apatients. In the same era, it was also considered to offer large-scale prospective human trial was conducted, butbenefit in survivors of cardiac arrest and hypoxic insults.10 disappointing results were obtained.18 Cooling TBI It remains unclear why hypothermia fell out of favour patients within the first several hours after injury failed toin subsequent decades. One factor may have been its improve outcome. The design and conduct of this trialapparent lack of efficacy, which reduced enthusiasm for have been vigorously debated but what is clear is thatthe logistical issues necessary routinely to cool and induced hypothermia is not a panacea for TBI. If it isre-warm a large patient population. Another factor may proven effective in later trials, it will probably be shownhave been the influence of mechanistic studies conducted to have efficacy only in certain patient populations andin the laboratory.42 That work examined effects of only when conducted with specific protocols. Such workhypothermia on brain energy metabolism and found is ongoing.hypothermia to reduce CMR in a temperature-dependent If the TBI study had been performed in isolation,fashion, which became the presumed mechanism of perhaps off-bypass hypothermia would have been aban-action. The most impressive effects on CMR were at very doned in the clinic again. However, other studies werelow temperatures, and those temperatures required use of already underway, two of which markedly altered thecardiopulmonary bypass. The effects of mild (32 – 358C) mood of the investigative community. Both studies werehypothermia on CMR were negligible. In contrast, barbitu- reported simultaneously and used similar experimentalrates can reduce CMR by 50– 60% without the use of car- designs wherein comatose survivors of out-of-hospitaldiopulmonary bypass and were therefore viewed as having cardiac arrest were randomized to normothermia or milda greater potential benefit. Perhaps for those reasons, the hypothermia, which involved rapid surface cooling asuse of perioperative hypothermia persisted only in the soon as spontaneous circulation was restored.2 11 Bothcontext of caring for some cardiac surgical patients. studies found significantly more patients with good There is no doubt that deep hypothermia (e.g. 18– outcome in the hypothermia group and negligible adverse228C) is highly neuroprotective. We know that only a few events. Finally, convincing evidence is available that off-minutes of complete global ischaemia will cause neuronal bypass hypothermia can appreciably improve outcomedeath in normothermic brain. This has been best examined from at least cardiac arrest in humans.in the laboratory, but human evidence is consistent with These findings have prompted publication of guidelinesthose findings.53 In contrast, it is widely observed that recommending that comatose survivors of out-of-hospitalinduction of deep hypothermia before circulatory arrest cardiac arrest undergo cooling after restoration of spon-routinely allows the brain to tolerate intervals of no-flow taneous circulation.3 49 The extent to which the efficacy ofexceeding 40 min, and substantially greater intervals of induced hypothermia can be extrapolated to other con-arrest with complete or near-complete neurological recov- ditions of cardiac arrest (loss of airway, asphyxia, andery are frequently reported. As a result of this prima facie drowning) may never be known given the sporadic andevidence, the efficacy of deep hypothermia has not been relatively rare nature of those events. However, such inter-subjected to randomized controlled trials. However, there vention may be considered.41is still much to be learned with respect to optimizing In addition, there is an increasing evidence that peripar-cooling and re-warming methods, optimal magnitude of tum neonatal asphyxial brain injury favourably responds tohypothermia, determination of brain temperature using sur- treatment with hypothermia. Two trials have beenrogate sites, and defining within individual patients when reported. The first employed selective head cooling and 13
  5. 5. Fukuda and Warnercould only find a beneficial effect of hypothermia in a practice can be appreciated, in fact, it is contradicted bysubset of the study population.27 The second employed direct examination of cerebral well being. The most salienttotal body cooling.60 In this study, the benefit of induced evidence is derived from TBI investigations. These studiesmild hypothermia was clear. Despite this, some feel support a different concept, that being worsening of per-additional trials are required before such intervention can fusion by hyperventilation-induced vasoconstriction inbe widely advocated.32 ischaemic tissue. Indeed, the volume of ischaemic tissue, In the course of defining hypothermia efficacy, it has elegantly assessed with positron emission tomography inalso become apparent that hyperthermia has adverse effects TBI patients, was markedly increased when moderate hypo-on post-ischaemic brain. Spontaneous post-ischaemic capnia was induced.20 This is consistent with the only pro-hyperthermia is common4 and, in animals, intra-ischaemic spective trial of hyperventilation on TBI outcome, whichor even delayed post-ischaemic hyperthermia dramatically observed a decreased number of patients with good or mod-worsens outcome. Spontaneous hyperthermia has also been erate disability outcomes when chronic hyperventilationassociated with poor outcome in humans.36 These facts was employed.45 It remains unevaluated whether acuteprovide sufficient evidence to advocate frequent tempera- hyperventilation improves outcome from pending transten-ture monitoring in patients with cerebral injury (and those torial herniation or when rapid surgical decompression of a Downloaded from http://bja.oxfordjournals.org/ at McGill University Libraries on March 8, 2012at risk for cerebral injury). Aggressive treatment of haematoma (e.g. epidural) is anticipated. Within thehyperthermia should be considered. context of focal ischaemic stroke, clinical trials have found no benefit from induced hypocapnia,17 62 although hyper-Glucose ventilation is sometimes employed in cases of refractory brain oedema. Use of hyperventilation during cardiopul-Glucose is a fundamental substrate for brain energy metab- monary resuscitation may serve to increase mean intrathor-olism. Deprivation of glucose in the presence of oxygen acic pressure thereby decreasing perfusion pressure and iscan result in neuronal necrosis, but the presence of not advocated.5 Consequently, there are few data to supportglucose in the absence of oxygen carries a worse fate. The use of hyperventilation in the context of cerebralmechanistic basis for this dichotomy remains unclear. The resuscitation.most persistent hypothesis is that glucose, in the absenceof oxygen, undergoes anaerobic glycolysis resulting inintracellular acidosis, which amplifies the severity of other Arterial oxygen partial pressuredeleterious cascades initiated by the ischaemic insult. It makes sense that optimization of oxygen delivery toMany animal studies have demonstrated adverse effects of ischaemic tissue should improve outcome. Indeed, oxygenhyperglycaemia from a wide variety of brain insults. deprivation is the fundamental fault leading to tissueHuman studies remain principally correlative in nature, demise. However, reperfusion presents deranged oxygenthat is, patients having worse outcomes from stroke, TBI, metabolism with the opportunity to increase formation ofetc. also tend to have higher blood glucose concentrations reactive oxygen species that plausibly induce secondaryon hospital admission. For some time, it was unclear insults, thereby worsening outcome. There are few humanwhether admission hyperglycaemia simply represented a data regarding the effects of normobaric hyperoxaemia instress response to the brain insult, or instead was contribut- human resuscitation. One retrospective perinatal resuscita-ing to a worsened injury. The animal data clearly favour tion analysis found worse long-term outcome in childrenthe latter interpretation. More importantly, human research when either hyperoxaemia or hypocapnia was presenthas demonstrated more rapid expansion of ischaemic during resuscitation or early recovery.37 Others found morelesions in hyperglycaemic, compared with normoglycaemic rapid normalization of Apgar scores when 40% oxygenpatients.6 52 In addition, there is accumulating evidence that compared with 100% oxygen was used for resuscitation.31regulation of blood glucose yields a higher incidence of In animal models, it is becoming evident that the effectgood outcome in stroke patients.26 For all of these reasons, of hyperoxaemia is dependent on the nature of the ischae-it is rational to maintain normoglycaemia in all patients at mic insult. Rats subjected to middle cerebral artery occlu-risk for, or recovering from acute brain injury. sion had smaller infarcts when normobaric hyperoxaemia was present during both ischaemia and reperfusion. This isArterial carbon dioxide partial pressure (PaCO2) consistent with the demonstrated efficacy of hyperbaricBecause cerebral blood flow and PaCO2 are linearly related oxygen (HBO) in rats undergoing a similar focal ischaemicwithin physiologically relevant ranges, hyperventilation insult.63 Evidence for HBO efficacy in humans is weak.16had become an entrenched practice in cerebral resuscita- In contrast, in dogs subjected to cardiac arrest, it has beention. Reduction in PaCO2 was presumed to augment cer- repeatedly observed that outcome is worsened by normoba-ebral perfusion pressure favourably by reducing the ric hyperoxaemia present during early recirculation.64 Thiscross-sectional diameter of the arterial circulation and thus has been attributed to oxidation and decreased pyruvatecerebral blood volume. This would offset increases in dehydrogenase activity, the enzymatic link between anaero-intracranial pressure. Although the logic behind this bic and aerobic glycolysis.55 Management of oxygen 14
  6. 6. Cerebral protectiondelivery after restoration of spontaneous circulation, so as intervention, at least within the bounds of the clinical trialto maintain pulse oximeter values within the range of protocols employed.94– 96, optimized short-term neurological outcome.7 These Other than the use of mild hypothermia for ventricularcompelling data should serve as a stimulus for a random- fibrillation cardiac arrest, practice of clinical neuroprotectionized clinical trial and stimulates re-consideration of the rests on extrapolation from animal studies and weaknecessity for hyperoxaemia in the early post-resuscitation clinical trials. Review of these data allows some recommen-interval. dations to be made (Table 2). Such recommendations are likely to be advanced with increased understanding ofSteroids cellular responses to ischaemia and appropriately conducted clinical trials.Steroids such as dexamethasone reduce oedema surround-ing brain tumours. Beyond that, evidence for benefit fromthe use of steroids is weak. Evidence that methylpredniso- Referenceslone improves outcome from acute spinal cord trauma is 1 Randomized clinical study of thiopental loading in comatose sur-controversial,13 but some surgeons have extended this vivors of cardiac arrest. Brain Resuscitation Clinical Trial I Studyobservation to intraoperative use in spinal cord surgery. Downloaded from http://bja.oxfordjournals.org/ at McGill University Libraries on March 8, 2012 Group. N Engl J Med 1986; 314: 397 – 403There is insufficient evidence to define the role of gluco- 2 Hypothermia after Cardia Arrest Study Group. Mild therapeuticcorticoids in focal ischaemic stroke.54 A large retrospec- hypothermia to improve the neurologic outcome after cardiactive analysis found no benefit from glucocorticoid arrest. N Engl J Med 2002; 346: 549 – 56 3 Part 7.5: Postresuscitation support. Circulation 2005; 112: IV84 – 8treatment in patients with cardiac arrest.34 In fact, there is 4 Albrecht RF 2nd, Wass CT, Lanier WL. Occurrence of potentiallyanimal evidence that such glucocorticoids exacerbate detrimental temperature alterations in hospitalized patients atinjury from global ischaemia by increasing plasma glucose risk for brain injury. Mayo Clin Proc 1998; 73: 629– 35concentration.66 Given the potential adverse effects of 5 Aufderheide TP, Sigurdsson G, Pirrallo RG, et al.steroids and lack of demonstrable efficacy in ischaemic Hyperventilation-induced hypotension during cardiopulmonarybrain, their use cannot be advocated. resuscitation. Circulation 2004; 109: 1960 – 5 6 Baird TA, Parsons MW, Phanh T, et al. Persistent poststroke hyperglycemia is independently associated with infarct expansionConclusion and worse clinical outcome. Stroke 2003; 34: 2208 – 14 7 Balan IS, Fiskum G, Hazelton J, Cotto-Cumba C, Rosenthal RE.Ischaemic brain injury remains a potentially devastating Oximetry-guided reoxygenation improves neurological outcomedisorder, although progress is being made in resuscitation after experimental cardiac arrest. Stroke 2006; 37: 3008 – 13science. Two key advances occurred in the past decade. 8 Batjer HH, Frankfurt AI, Purdy PD, Smith SS, Samson DS. Use ofThe first was repeated demonstration that induced mild etomidate, temporary arterial occlusion, and intraoperativehypothermia reduces neurological morbidity and mortality angiography in surgical treatment of large and giant cerebral aneurysms. J Neurosurg 1988; 68: 234– 40associated with out-of-hospital ventricular fibrillation 9 Bayona NA, Gelb AW, Jiang Z, Wilson JX, Urquhart BL,cardiac arrest. Beyond the immediate potential to apply Cechetto DF. Propofol neuroprotection in cerebral ischemia andthis intervention is the larger message that post-ischaemic its effects on low-molecular-weight antioxidants and skilledintervention can favourably influence outcome in humans. motor tasks. Anesthesiology 2004; 100: 1151 – 9The second advance was recognition that efficacy of mild 10 Benson DW, Williams GR Jr, Spencer FC, Yates AJ. The use ofhypothermia depends at least in part upon the type of hypothermia after cardiac arrest. Anesth Analg 1959; 38: 423 – 8ischaemic lesion being treated. Trauma and focal ischae- 11 Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypother-mia could not be shown to be amenable to hypothermic mia. N Engl J Med 2002; 346: 557 – 63 12 Bigelow WG, Lindsay WK, Greenwood WF. Hypothermia; its possible role in cardiac surgery: an investigation of factors gov-Table 2 Considerations when anticipating or managing a perioperative erning survival in dogs at low body temperatures. Ann Surg 1950;ischaemic insult 132: 849 – 66Assure absence of hyperthermia 13 Bracken MB, Shepard MJ, Holford TR, et al. Administration ofManage blood glucose with insulin to induce normoglycaemia methylprednisolone for 24 or 48 hours or tirilazad mesylate forOptimize haemoglobin-oxygen saturation (increasing concern that 48 hours in the treatment of acute spinal cord injury. Results ofhyperoxaemia may be adverse in global ischaemia) the Third National Acute Spinal Cord Injury RandomizedEstablish normocapniaConsider the use of volatile anaesthetics if surgery ongoing (consistent Controlled Trial. National Acute Spinal Cord Injury Study. JAMAsustained benefit in experimental animal studies, reversible allowing 1997; 277: 1597 – 604neurological examination, human trials not performed) 14 Busto R, Dietrich WD, Globus M-T, Ginsberg MD. The import-Resist the use of glucorticoids (no evidence of efficacy, preclinical evidence ance of brain temperature in cerebral ischemic injury. Strokeof adverse effect in global ischaemia) 1989; 20: 1113– 14Consider the use of postoperative sustained induced moderate hypothermia if 15 Canas PT, Velly LJ, Labrande CN, et al. Sevoflurane protects ratglobal ischaemia (not tested by clinical trials in perioperative environment,but supported by consistent evidence of efficacy when used in out-of-hospital mixed cerebrocortical neuronal-glial cell cultures against transientventricular fibrillation cardiac arrest) oxygen-glucose deprivation: involvement of glutamate uptake and reactive oxygen species. Anesthesiology 2006; 105: 990 – 8 15
  7. 7. Fukuda and Warner16 Carson S, McDonagh M, Russman B, Helfand M. Hyperbaric improve neurological recovery following cardiac arrest. Brain oxygen therapy for stroke: a systematic review of the evidence. Resuscitation Clinical Trial I Study Group. JAMA 1989; 262: Clin Rehabil 2005; 19: 819 – 33 3427– 3017 Christensen MS, Paulson OB, Olesen J, et al. Cerebral apoplexy 35 Kaisti KK, Langsjo JW, Aalto S, et al. Effects of sevoflurane, pro- (stroke) treated with or without prolonged artificial pofol, and adjunct nitrous oxide on regional cerebral blood flow, hyperventilation. 1. Cerebral circulation, clinical course, and oxygen consumption, and blood volume in humans. Anesthesiology cause of death. Stroke 1973; 4: 568 –631 2003; 99: 603 – 1318 Clifton GL, Miller ER, Choi SC, et al. Lack of effect of induction 36 Kammersgaard LP, Jorgensen HS, Rungby JA, et al. Admission of hypothermia after acute brain injury. N Engl J Med 2001; 344: body temperature predicts long-term mortality after acute 556– 63 stroke: the Copenhagen Stroke Study. Stroke 2002; 33: 1759 – 6219 Cold GE, Eskesen V, Eriksen H, Blatt Lyon B. Changes in CMRO2, 37 Klinger G, Beyene J, Shah P, Perlman M. Do hyperoxaemia and EEG and concentration of etomidate in serum and brain tissue hypocapnia add to the risk of brain injury after intrapartum during craniotomy with continuous etomidate supplemented with asphyxia? Arch Dis Child Fetal Neonatal Ed 2005; 90: F49– 52 N2O and fentanyl. Acta Anaesthesiol Scand 1986; 30: 159–63 38 Kurth CD, Priestley M, Watzman HM, McCann J, Golden J.20 Coles JP, Fryer TD, Coleman MR, et al. Hyperventilation following Desflurane confers neurologic protection for deep hypothermic head injury: effect on ischemic burden and cerebral oxidative circulatory arrest in newborn pigs. Anesthesiology 2001; 95: 959–64 metabolism. Crit Care Med 2007; 35: 568 – 78 39 Lei B, Popp S, Capuano-Waters C, Cottrell JE, Kass IS. Lidocaine Downloaded from http://bja.oxfordjournals.org/ at McGill University Libraries on March 8, 201221 Drummond JC, McKay LD, Cole DJ, Patel PM. The role of nitric attenuates apoptosis in the ischemic penumbra and reduces oxide synthase inhibition in the adverse effects of etomidate in infarct size after transient focal cerebral ischemia in rats. the setting of focal cerebral ischemia in rats. Anesth Analg 2005; Neuroscience 2004; 125: 691 – 701 100: 841– 6 40 Leonov Y, Sterz F, Safar P, et al. Mild cerebral hypothermia during22 Elsersy H, Mixco J, Sheng H, Pearlstein RD, Warner DS. Selective and after cardiac arrest improves neurologic outcome in dogs. gamma-aminobutyric acid type A receptor antagonism reverses iso- J Cereb Blood Flow Metab 1990; 10: 57 – 70 flurane ischemic neuroprotection. Anesthesiology 2006; 105: 81–90 41 McDonagh DL, Allen IN, Keifer JC, Warner DS. Induction of23 Elsersy H, Sheng H, Lynch JR, Moldovan M, Pearlstein RD, hypothermia after intraoperative hypoxic brain insult. Anesth Warner DS. Effects of isoflurane versus fentanyl-nitrous oxide Analg 2006; 103: 180 –1 anesthesia on long-term outcome from severe forebrain ischemia 42 Michenfelder J, Terry HJ, Daw E, Uihlein A. Induced hypothermia: in the rat. Anesthesiology 2004; 100: 1160 – 6 physiologic effects, indications, and techniques. Surg Clin North24 Fay T. Observations on generalized refrigeration in cases of severe Am 1965; 45: 889 cerebral trauma. Assoc Res Nerv Ment Dis Proc 1943; 24: 611–19 43 Michenfelder JD, Theye RA. Cerebral protection by thiopental25 Franks NP, Honore E. The TREK K2P channels and their role in during hypoxia. Anesthesiology 1973; 39: 510 – 7 general anaesthesia and neuroprotection. Trends Pharmacol Sci 44 Mitchell SJ, Pellett O, Gorman DF. Cerebral protection by lido- 2004; 25: 601 – 8 caine during cardiac operations. Ann Thorac Surg 1999; 67:26 Gentile NT, Seftchick MW, Huynh T, Kruus LK, Gaughan J. 1117– 24 Decreased mortality by normalizing blood glucose after acute 45 Muizelaar JP, Marmarou A, Ward JD, et al. Adverse effects of pro- ischemic stroke. Acad Emerg Med 2006; 13: 174 – 80 longed hyperventilation in patients with severe head injury: a ran-27 Gluckman PD, Wyatt JS, Azzopardi D, et al. Selective head domized clinical trial. J Neurosurg 1991; 75: 731– 9 cooling with mild systemic hypothermia after neonatal encephalo- 46 Nasu I, Yokoo N, Takaoka S, et al. The dose-dependent effects of pathy: multicentre randomised trial. Lancet 2005; 365: 663 – 70 isoflurane on outcome from severe forebrain ischemia in the rat.28 Goldstein A, Jr, Wells BA, Keats AS. Increased tolerance to Anesth Analg 2006; 103: 413 – 8 cerebral anoxia by pentobarbital. Arch Int Pharmacodyn Ther 1966; 47 ˚ Nellgard B, Mackensen GB, Pineda J, Wellons JC 3rd, Pearlstein RD, 161: 138– 43 Warner DS. Anesthetic effects on cerebral metabolic rate predict29 Gray JJ, Bickler PE, Fahlman CS, Zhan X, Schuyler JA. Isoflurane histologic outcome from near-complete forebrain ischemia in the neuroprotection in hypoxic hippocampal slice cultures involves rat. Anesthesiology 2000; 93: 431–6 increases in intracellular Ca2þ and mitogen-activated protein 48 Newberg LA, Michenfelder JD. Cerebral protection by isoflurane kinases. Anesthesiology 2005; 102: 606 – 15 during hypoxemia or ischemia. Anesthesiology 1983; 59: 29 – 3530 Harada H, Kelly PJ, Cole DJ, Drummond JC, Patel PM. Isoflurane 49 Nolan JP, Morley PT, Vanden Hoek TL, et al. Therapeutic reduces N-methyl-D-aspartate toxicity in vivo in the rat cerebral hypothermia after cardiac arrest: an advisory statement by the cortex. Anesth Analg 1999; 89: 1442 –7 advanced life support task force of the International Liaison31 Hellstrom-Westas L, Forsblad K, Sjors G, et al. Earlier Apgar Committee on Resuscitation. Circulation 2003; 108: 118 – 21 score increase in severely depressed term infants cared for in 50 Nussmeier NA, Arlund C, Slogoff S. Neuropsychiatric compli- Swedish level III units with 40% oxygen versus 100% oxygen cations after cardiopulmonary bypass: cerebral protection by a resuscitation strategies: a population-based register study. barbiturate. Anesthesiology 1986; 64: 165 – 70 Pediatrics 2006; 118: e1798 – 804 51 Pape M, Engelhard K, Eberspacher E, et al. The long-term effect32 Higgins RD, Raju TN, Perlman J, et al. Hypothermia and perinatal of sevoflurane on neuronal cell damage and expression of apop- asphyxia: executive summary of the National Institute of Child totic factors after cerebral ischemia and reperfusion in rats. Health and Human Development workshop. J Pediatr 2006; 148: Anesth Analg 2006; 103: 173 – 9 170– 5 52 Parsons MW, Barber PA, Desmond PM, et al. Acute hyperglyce-33 Hoffman WE, Charbel FT, Edelman G, Ausman JI. Thiopental and mia adversely affects stroke outcome: a magnetic resonance desflurane treatment for brain protection. Neurosurgery 1998; 43: imaging and spectroscopy study. Ann Neurol 2002; 52: 20– 8 1050– 3 53 Petito CK, Feldmann E, Pulsinelli WA, Plum F. Delayed hippocam-34 Jastremski M, Sutton-Tyrrell K, Vaagenes P, Abramson N, pal damage in humans following cardiorespiratory arrest. Heiselman D, Safar P. Glucocorticoid treatment does not Neurology 1987; 37: 1281 – 6 16
  8. 8. Cerebral protection54 Qizilbash N, Lewington SL, Lopez-Arrieta JM. Corticosteroids 61 Shokunbi MT, Gelb AW, Wu XM, Miller DJ. Continuous lidocaine for acute ischaemic stroke. Cochrane Database Syst Rev 2002: infusion and focal feline cerebral ischemia. Stroke 1990; 21: CD000064 107 – 1155 Richards EM, Rosenthal RE, Kristian T, Fiskum G. Postischemic 62 Simard D, Paulson OB. Artifical hyperventilation in stroke. Trans hyperoxia reduces hippocampal pyruvate dehydrogenase activity. Am Neurol Assoc 1973; 98: 309 – 10 Free Radic Biol Med 2006; 40: 1960 – 70 63 Veltkamp R, Sun L, Herrmann O, et al. Oxygen therapy in perma-56 Roach GW, Newman MF, Murkin JM, et al. Ineffectiveness of nent brain ischemia: potential and limitations. Brain Res 2006; burst suppression therapy in mitigating perioperative cerebrovas- 1107: 185 –91 cular dysfunction. Multicenter Study of Perioperative Ischemia 64 Vereczki V, Martin E, Rosenthal RE, Hof PR, Hoffman GE, Fiskum G. (McSPI) Research Group. Anesthesiology 1999; 90: 1255 – 64 Normoxic resuscitation after cardiac arrest protects against hippo-57 Rodriguez-Lopez JM, Sanchez-Conde P Lozano FS, et al. , campal oxidative stress, metabolic dysfunction, and neuronal death. Laboratory investigation: effects of propofol on the systemic J Cereb Blood Flow Metab 2006; 26: 821–35 inflammatory response during aortic surgery. Can J Anaesth 2006; 65 Warner DS, Takaoka S, Wu B, et al. Electroencephalographic 53: 701 – 10 burst suppression is not required to elicit maximal neuroprotec-58 Sakai H, Sheng H, Yates RB, Ishida K, Pearlstein RD, Warner DS. tion from pentobarbital in a rat model of focal cerebral ischemia. Isoflurane provides long-term protection against focal cerebral Anesthesiology 1996; 84: 1475 – 84 ischemia in the rat. Anesthesiology 2007; 106: 92 – 99 66 Wass CT, Scheithauer BW, Bronk JT, Wilson RM, Lanier WL. Downloaded from http://bja.oxfordjournals.org/ at McGill University Libraries on March 8, 201259 Sarraf-Yazdi S, Sheng H, Brinkhous AD, Pearlstein RD, Warner DS. Insulin treatment of corticosteroid-associated hyperglycemia and Effects of postischemic halothane administration on outcome from its effect on outcome after forebrain ischemia in rats. transient focal cerebral ischemia in the rat. J Neurosurg Anesthesiol Anesthesiology 1996; 84: 644 – 51 1999; 11: 31–6 67 Zaidan JR, Klochany A, Martin WM, Ziegler JS, Harless DM,60 Shankaran S, Laptook AR, Ehrenkranz RA, et al. Whole-body Andrews RB. Effect of thiopental on neurologic outcome follow- hypothermia for neonates with hypoxic-ischemic encephalopathy. ing coronary artery bypass grafting. Anesthesiology 1991; 74: N Engl J Med 2005; 353: 1574 –84 406 – 11 17