British Journal of Anaesthesia 99 (1): 1017 (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 management of these problems. However, current practice remains largely founded on extrapolation from animal studies and limited clinical investigation. A major step was made with demonstration that rapid induction of mild sustained hypothermia in comatose survivors of outof-hospital ventricular brillation cardiac arrest reduces death and neurological morbidity with negligible adverse events. This provides the rst 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 ischaemic 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 benecial in transient focal ischaemia but deleterious in global ischaemia. 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 dene limitations and efcacy of already available methods of intervention, aimed primarily at regulation of physiological homeostasis. Br J Anaesth 2007; 99: 1017 Keywords: brain, ischaemia; complications, cerebral ischaemia; recovery, neurological

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Cerebral ischaemia/hypoxia can occur in a variety of perioperative circumstances. Outcomes from such events range from sub-clinical neurocognitive decits to catastrophic neurological morbidity or death. Although certain surgical procedures present greater risk for ischaemic/hypoxic brain injury, most insults are not presaged but instead arise as unintended complications of either the surgical procedure or the anaesthetic. It has been the investigative interest of surgeons and anaesthesiologists to reduce perioperative brain injury for more than 60 yr.12 Classically, such intervention has been categorized as either neuroprotection or neuroresuscitation. Neuroprotection was dened as treatment initiated before onset of ischaemia, intended to modify intra-ischaemic cellular and vascular biological responses to deprivation of energy supply so as to increase tolerance of tissue to ischaemia resulting in improved outcome. Neuroresuscitation, in contrast, implied treatment begun after the ischaemic insult had occurred with the intent of optimizing reperfusion.

However, it has become increasingly clear that an ischaemic/hypoxic insult does not simply constitute energy failure with consequent interruption of ongoing metabolic events. Indeed this does occur. In addition, though, ischaemia and hypoxia stimulate active responses in the brain, which persist long after substrate delivery has been restored. These responses include activation of transcription factors which up-regulate expression of genes contributing to apoptosis and inammation, inhibition of protein synthesis, sustained oxidative stress, and neurogenesis. Although some of these responses may have a teleological advantage [e.g. elimination of dead or dysfunctional tissue or increased tolerance to a subsequent insult ( preconditioning)], most responses aggravate damage caused by the primary insult. Consequently, the concept that neuroprotection can be extended well into the reperfusion phase seems appropriate, albeit with different targets other than preservation of energy stores. This possibility may, in part, explain the efcacy of various experimental postischaemic interventions, which have manifested either as

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Cerebral protection

Table 1 Evidence-based status of plausible interventions to reduce perioperative ischaemic brain injury. , Repeated physiologically controlled studies in animals/randomized, prospective, adequately powered clinical trials; , consistent suggestion by case series/retrospective or prospective small sample size trials, or data extrapolated from other paradigms; 2/, inconsistent ndings in clinical trials; may be dependent on characteristics of insult; 2, well-dened absence of benet; 22, absence of evidence in physiologically controlled studies in animals/randomized, prospective, adequately powered clinical trials; 222, evidence of potential harm; *, out-of-hospital ventricular brillation cardiac arrest Intervention Pre-ischaemic efcacy in experimental animals 222 22 222 2 222 Post-ischaemic efcacy in experimental animals 222 22 22 22 2 22 22 22 22 22 22 22 22 Pre-ischaemic efcacy in humans Post-ischaemic efcacy in humans Sustained protection in experimental animals 222 22 22 22 22 22 22 22 22 22 22 Sustained protection in humans

Moderate hypothermia Mild hyperthermia Hyperventilation Normoglycaemia Hyperbaric oxygen Barbiturates Propofol Etomidate Nitrous oxide Isourane Sevourane Desurane Lidocaine Ketamine Glucocorticoids

2/ 22 22 22 2 22 22 22 22 22 22 22

* 22 22 2/ 2 22 22 22 22 22 22 22 22 22

22 22 22 22

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22 2 22 22 22 22 22 22 22 22

clinically available therapies (e.g. mild hypothermia) or instead as promising candidates for future clinical use targeting events, such as oxidative stress, apoptosis, and neurogenesis. The above logic is presented as a taste of where we are going with investigations aimed at ameliorating long-term improvement from an ischaemic/hypoxic insult that may occur in the perioperative period. However, the rest of this article will focus on the opportunities and limitations of currently available interventions (Table 1).

Anaesthetics
Barbiturates
It has been postulated for more than 50 yr that anaesthetics increase the tolerance of brain to an ischaemic insult.28 The logic is simple. Most drugs selected to be anaesthetics suppress neurotransmission. This suppression reduces energy requirement, and reduction in energy requirement should allow tissue better to preserve energy balance during a transient interruption of substrate delivery. Since adenosine triphosphate (ATP) synthesis recovers rapidly after restoration of substrate delivery, anaesthetics would be expected to be protective if present during ischaemia but not if given after restoration of substrate delivery. It would also follow that efcacy of an anaesthetic is dependent upon the severity of the ischaemic insult. If the insult were sufciently severe to cause loss of all electrical activity, there would be no activity for anaesthetics to suppress and thus no mechanism for such drugs to increase tolerance to ischaemia. In

contrast, in less severe insults, suppression of activity by the anaesthetic before onset of ischaemia should delay decay of ATP concentrations and thus also delay loss of ionic gradients and calcium inux. Many studies have supported this logic. Indeed, during abrupt onset of hypoxaemia, barbiturates and isourane slow deterioration of ATP concentrations.43 48 Furthermore, post-ischaemic treatment with either barbiturates or volatile anaesthetics has no effect on outcome.1 59 Surprisingly, irrefutable data supporting efcacy of pre-treatment with anaesthetics have proved difcult to acquire. Early work testing intra-ischaemic anaesthetic efcacy was confounded by poor physiological control of experimental subjects. It was recognized later in the evolution of anaesthetic efcacy studies that factors such as blood glucose, brain temperature, and perfusion pressure were important determinants of ischaemic outcome and that anaesthetics independently modulated these factors. In addition, early studies typically compared one anaesthetic against another. The assumption was that the control anaesthetic was not protective and thus failure to improve outcome by the test anaesthetic indicated lack of a protective state. However, little work was done to conrm that the control anaesthetic was not protective. Subsequent studies, which became feasible as experimental models evolved, often found considerable protection from the control anaesthetic when compared with an awake state. Thus, the eld remained confused for more than a decade and insufcient data were generated to warrant human trials of anaesthetic efcacy when employed intraoperatively. Even then, the early results were mixed. One

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study found efcacy from thiopental when given in cardiac surgical patients, whereas another did not.50 67 However, only short-term outcomes were assessed, which prevented assessment of the full evolution of the ischaemic injury. Furthermore, surgical procedures and cardiopulmonary bypass conditions were markedly different between the two trials. Numerous other explanations have been offered, but perhaps the overall potency of barbiturates as neuroprotective agents is weak in the face of severe ischaemic insults.65 One problem with barbiturates is their prolonged duration of action. It was believed that optimal protection would be present only when massive doses were administered to abolish electroencephalographic (EEG) activity, thereby eliciting maximal suppression of cerebral metabolic rate (CMR) before onset of the insult. Some practitioners still adhere to this principle when using barbiturates to protect the brain but such large doses can markedly delay anaesthesia emergence, which has limited their clinical application. Although it is unlikely that these massive doses are necessary to obtain maximal efcacy,65 recognition that volatile anaesthetics can also produce EEG isoelectricity at doses which still allow rapid anaesthesia emergence was greeted with optimism because such compounds could be more widely applied in clinical settings.

is required for a surgical procedure, inclusion of volatile anaesthetics can be considered. Isourane and sevourane carry the largest data set to this decision. Desurane also offers promise,33 38 but has been insufciently studied to determine whether it should be equally considered in this class of potential neuroprotective compounds.

Other anaesthetics
Other anaesthetics possess properties that suggest potential for intra-ischaemic neuroprotection. These include propofol, etomidate, and lidocaine. Study of these drugs has not been as extensive as for either barbiturates or volatile anaesthetics. The principle feature of propofol and etomidate is suppression of CMR by inhibition of synaptic activity.19 35 Propofol may also have free radical scavenging and anti-inammatory properties.57 Propofol appears unique among anaesthetics in the laboratory setting because it offers efcacy with post-ischaemic therapy onset, although such treatment provides only transient protection.9 Propofol appears to offer efcacy similar to barbiturates but a dose-dependent study of its efcacy has not been completed, leaving little guidance for potential clinical use. Furthermore, propofol infused to induce EEG burst suppression failed to improve outcome in cardiac valve surgery patients.56 Etomidate, although initially heralded as a substitute for barbiturates,8 has never met rigorous evaluation for neuroprotective properties. In fact, some work has indicated that etomidate may paradoxically exacerbate ischaemic injury by inhibiting nitric oxide synthase, thereby intensifying the ischaemic insult.21 As a result of this and other studies, the use of etomidate for neuroprotection has fallen out of favour in clinical settings. Lidocaine also suppresses CMR, but this effect is only meaningful at doses beyond those typically employed in clinical environments. Numerous laboratory studies have found efcacy for lidocaine, with perhaps its principle mechanism of action relating to inhibition of apoptosis.39 The efcacy of lidocaine appears dependent on dose, with doses in the range used to manage cardiac dysrhythmias having greatest efcacy.61 There have been no long-term outcome studies of lidocaine efcacy in experimental stroke. One small human trial found benet from low-dose lidocaine infusion during cardiac surgery on long-term neuropsychological impairment.44 Lidocaine should be further evaluated for neuroprotective properties since its use is supported by a litany of laboratory successes such as short-duration of action and ease of use. However, because it has not been evaluated in a large-scale clinical trial, efcacy in clinical environments remains speculative. Ketamine offers potent inhibition of glutamatergic neurotransmission at the N-methyl-D-aspartate (NMDA) receptor. There is a long history of NMDA receptor antagonists as potential neuroprotective agents but, overall, such compounds offer little or no protection against global

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Volatile anaesthetics
The efcacy of volatile anaesthetics as neuroprotective agents has undergone more than 30 yr of scrutiny and still no human outcome trials have been conducted to guide clinical practice. We know the following facts from the laboratory. Volatile anaesthetics provide major improvement in ischaemic outcome. The dose required to obtain this protection is within a clinically relevant range, with higher doses potentially worsening outcome.46 Volatile anaesthetics protect against both focal (e.g. obstruction of ow distal to the circle of Willis) and global (e.g. complete cessation of blood ow to the brain or forebrain) ischaemia. However, the improvement in outcome is transient in global ischaemia,23 whereas it is persistent in focal ischaemia.58 Sevourane has also been shown to provide long-term protection in one experimental model.51 The mechanism by which volatile anaesthetics protect is, in part, attributable to suppression of energy requirements.47 Both inhibition of excitatory neurotransmission and potentiation of inhibitory receptors are likely to be involved.15 22 30 It is also likely that volatile anaesthetics have other important effects that include regulation of intracellular calcium responses during ischaemia,29 and activation of TREK-1 two-pore-domain K channels.25 Although a great deal has been learned from the laboratory, in the absence of human outcome data, it cannot be stated that volatile anaesthetics improve outcome from perioperative ischaemic insults. However, if an anaesthetic

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insults. Protection against focal insults is substantial, but only if the drug is given before ischaemia onset. Because ketamine is clinically available, it is tempting to argue that it should be considered when a focal ischaemic insult is anticipated. To date, however, there are no human data supporting this practice. Little is also known about dose response properties, even in animals. Thus, it is difcult to recommend ketamine for the purposes of neuroprotection in the clinical environment at this time.

Physiological management
Temperature
Hypothermia has been proposed to offer therapeutic benet for more than 60 yr.24 Early investigators examined its effects in both neurosurgery and cardiac surgery patients. In the same era, it was also considered to offer benet in survivors of cardiac arrest and hypoxic insults.10 It remains unclear why hypothermia fell out of favour in subsequent decades. One factor may have been its apparent lack of efcacy, which reduced enthusiasm for the logistical issues necessary routinely to cool and re-warm a large patient population. Another factor may have been the inuence of mechanistic studies conducted in the laboratory.42 That work examined effects of hypothermia on brain energy metabolism and found hypothermia to reduce CMR in a temperature-dependent fashion, which became the presumed mechanism of action. The most impressive effects on CMR were at very low temperatures, and those temperatures required use of cardiopulmonary bypass. The effects of mild (32 358C) hypothermia on CMR were negligible. In contrast, barbiturates can reduce CMR by 50 60% without the use of cardiopulmonary bypass and were therefore viewed as having a greater potential benet. Perhaps for those reasons, the use of perioperative hypothermia persisted only in the context of caring for some cardiac surgical patients. There is no doubt that deep hypothermia (e.g. 18 228C) is highly neuroprotective. We know that only a few minutes of complete global ischaemia will cause neuronal death in normothermic brain. This has been best examined in the laboratory, but human evidence is consistent with those ndings.53 In contrast, it is widely observed that induction of deep hypothermia before circulatory arrest routinely allows the brain to tolerate intervals of no-ow exceeding 40 min, and substantially greater intervals of arrest with complete or near-complete neurological recovery are frequently reported. As a result of this prima facie evidence, the efcacy of deep hypothermia has not been subjected to randomized controlled trials. However, there is still much to be learned with respect to optimizing cooling and re-warming methods, optimal magnitude of hypothermia, determination of brain temperature using surrogate sites, and dening within individual patients when

the duration of circulatory arrest approaches the limits of deep hypothermic neuroprotection. The story might have ended there had it not been for several laboratory studies that ignored the CMR hypothesis. Those studies re-visited the possibility that mild hypothermia could protect the brain against ischaemia insults.14 40 To most peoples surprise, reduction in brain temperature by only a few degree Celsius provided major protection. These ndings stimulated numerous clinical trials in both adults and newborns, which have since provided a scientic basis dening the opportunities and limitations of using off-bypass hypothermia to provide meaningful neuroprotection. The rst reported work related to traumatic brain injury (TBI). Three pilot studies provided suggestive evidence that mild hypothermia improved either brain physiology or outcome. However, those studies employed small sample sizes and more denitive evidence was needed. Thus, a large-scale prospective human trial was conducted, but disappointing results were obtained.18 Cooling TBI patients within the rst several hours after injury failed to improve outcome. The design and conduct of this trial have been vigorously debated but what is clear is that induced hypothermia is not a panacea for TBI. If it is proven effective in later trials, it will probably be shown to have efcacy only in certain patient populations and only when conducted with specic protocols. Such work is ongoing. If the TBI study had been performed in isolation, perhaps off-bypass hypothermia would have been abandoned in the clinic again. However, other studies were already underway, two of which markedly altered the mood of the investigative community. Both studies were reported simultaneously and used similar experimental designs wherein comatose survivors of out-of-hospital cardiac arrest were randomized to normothermia or mild hypothermia, which involved rapid surface cooling as soon as spontaneous circulation was restored.2 11 Both studies found signicantly more patients with good outcome in the hypothermia group and negligible adverse events. Finally, convincing evidence is available that offbypass hypothermia can appreciably improve outcome from at least cardiac arrest in humans. These ndings have prompted publication of guidelines recommending that comatose survivors of out-of-hospital cardiac arrest undergo cooling after restoration of spontaneous circulation.3 49 The extent to which the efcacy of induced hypothermia can be extrapolated to other conditions of cardiac arrest (loss of airway, asphyxia, and drowning) may never be known given the sporadic and relatively rare nature of those events. However, such intervention may be considered.41 In addition, there is an increasing evidence that peripartum neonatal asphyxial brain injury favourably responds to treatment with hypothermia. Two trials have been reported. The rst employed selective head cooling and

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could only nd a benecial effect of hypothermia in a subset of the study population.27 The second employed total body cooling.60 In this study, the benet of induced mild hypothermia was clear. Despite this, some feel additional trials are required before such intervention can be widely advocated.32 In the course of dening hypothermia efcacy, it has also become apparent that hyperthermia has adverse effects on post-ischaemic brain. Spontaneous post-ischaemic hyperthermia is common4 and, in animals, intra-ischaemic or even delayed post-ischaemic hyperthermia dramatically worsens outcome. Spontaneous hyperthermia has also been associated with poor outcome in humans.36 These facts provide sufcient evidence to advocate frequent temperature monitoring in patients with cerebral injury (and those at risk for cerebral injury). Aggressive treatment of hyperthermia should be considered.

Glucose
Glucose is a fundamental substrate for brain energy metabolism. Deprivation of glucose in the presence of oxygen can result in neuronal necrosis, but the presence of glucose in the absence of oxygen carries a worse fate. The mechanistic basis for this dichotomy remains unclear. The most persistent hypothesis is that glucose, in the absence of oxygen, undergoes anaerobic glycolysis resulting in intracellular acidosis, which amplies the severity of other deleterious cascades initiated by the ischaemic insult. Many animal studies have demonstrated adverse effects of hyperglycaemia from a wide variety of brain insults. Human studies remain principally correlative in nature, that is, patients having worse outcomes from stroke, TBI, etc. also tend to have higher blood glucose concentrations on hospital admission. For some time, it was unclear whether admission hyperglycaemia simply represented a stress response to the brain insult, or instead was contributing to a worsened injury. The animal data clearly favour the latter interpretation. More importantly, human research has demonstrated more rapid expansion of ischaemic lesions in hyperglycaemic, compared with normoglycaemic patients.6 52 In addition, there is accumulating evidence that regulation of blood glucose yields a higher incidence of good outcome in stroke patients.26 For all of these reasons, it is rational to maintain normoglycaemia in all patients at risk for, or recovering from acute brain injury.

practice can be appreciated, in fact, it is contradicted by direct examination of cerebral well being. The most salient evidence is derived from TBI investigations. These studies support a different concept, that being worsening of perfusion by hyperventilation-induced vasoconstriction in ischaemic tissue. Indeed, the volume of ischaemic tissue, elegantly assessed with positron emission tomography in TBI patients, was markedly increased when moderate hypocapnia was induced.20 This is consistent with the only prospective trial of hyperventilation on TBI outcome, which observed a decreased number of patients with good or moderate disability outcomes when chronic hyperventilation was employed.45 It remains unevaluated whether acute hyperventilation improves outcome from pending transtentorial herniation or when rapid surgical decompression of a haematoma (e.g. epidural) is anticipated. Within the context of focal ischaemic stroke, clinical trials have found no benet from induced hypocapnia,17 62 although hyperventilation is sometimes employed in cases of refractory brain oedema. Use of hyperventilation during cardiopulmonary resuscitation may serve to increase mean intrathoracic pressure thereby decreasing perfusion pressure and is not advocated.5 Consequently, there are few data to support use of hyperventilation in the context of cerebral resuscitation.

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Arterial oxygen partial pressure

It makes sense that optimization of oxygen delivery to ischaemic tissue should improve outcome. Indeed, oxygen deprivation is the fundamental fault leading to tissue demise. However, reperfusion presents deranged oxygen metabolism with the opportunity to increase formation of reactive oxygen species that plausibly induce secondary insults, thereby worsening outcome. There are few human data regarding the effects of normobaric hyperoxaemia in human resuscitation. One retrospective perinatal resuscitation analysis found worse long-term outcome in children when either hyperoxaemia or hypocapnia was present during resuscitation or early recovery.37 Others found more rapid normalization of Apgar scores when 40% oxygen compared with 100% oxygen was used for resuscitation.31 In animal models, it is becoming evident that the effect of hyperoxaemia is dependent on the nature of the ischaemic insult. Rats subjected to middle cerebral artery occlusion had smaller infarcts when normobaric hyperoxaemia was present during both ischaemia and reperfusion. This is consistent with the demonstrated efcacy of hyperbaric oxygen (HBO) in rats undergoing a similar focal ischaemic insult.63 Evidence for HBO efcacy in humans is weak.16 In contrast, in dogs subjected to cardiac arrest, it has been repeatedly observed that outcome is worsened by normobaric hyperoxaemia present during early recirculation.64 This has been attributed to oxidation and decreased pyruvate dehydrogenase activity, the enzymatic link between anaerobic and aerobic glycolysis.55 Management of oxygen

Arterial carbon dioxide partial pressure (PaCO2)

Because cerebral blood ow and PaCO2 are linearly related within physiologically relevant ranges, hyperventilation had become an entrenched practice in cerebral resuscitation. Reduction in PaCO2 was presumed to augment cerebral perfusion pressure favourably by reducing the cross-sectional diameter of the arterial circulation and thus cerebral blood volume. This would offset increases in intracranial pressure. Although the logic behind this

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delivery after restoration of spontaneous circulation, so as to maintain pulse oximeter values within the range of 94 96, optimized short-term neurological outcome.7 These compelling data should serve as a stimulus for a randomized clinical trial and stimulates re-consideration of the necessity for hyperoxaemia in the early post-resuscitation interval.

Steroids
Steroids such as dexamethasone reduce oedema surrounding brain tumours. Beyond that, evidence for benet from the use of steroids is weak. Evidence that methylprednisolone improves outcome from acute spinal cord trauma is controversial,13 but some surgeons have extended this observation to intraoperative use in spinal cord surgery. There is insufcient evidence to dene the role of glucocorticoids in focal ischaemic stroke.54 A large retrospective analysis found no benet from glucocorticoid treatment in patients with cardiac arrest.34 In fact, there is animal evidence that such glucocorticoids exacerbate injury from global ischaemia by increasing plasma glucose concentration.66 Given the potential adverse effects of steroids and lack of demonstrable efcacy in ischaemic brain, their use cannot be advocated.

intervention, at least within the bounds of the clinical trial protocols employed. Other than the use of mild hypothermia for ventricular brillation cardiac arrest, practice of clinical neuroprotection rests on extrapolation from animal studies and weak clinical trials. Review of these data allows some recommendations to be made (Table 2). Such recommendations are likely to be advanced with increased understanding of cellular responses to ischaemia and appropriately conducted clinical trials.

References
1 Randomized clinical study of thiopental loading in comatose survivors of cardiac arrest. Brain Resuscitation Clinical Trial I Study Group. N Engl J Med 1986; 314: 397 403 2 Hypothermia after Cardia Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002; 346: 549 56 3 Part 7.5: Postresuscitation support. Circulation 2005; 112: IV84 8 4 Albrecht RF 2nd, Wass CT, Lanier WL. Occurrence of potentially detrimental temperature alterations in hospitalized patients at risk for brain injury. Mayo Clin Proc 1998; 73: 629 35 5 Aufderheide TP, Sigurdsson G, Pirrallo RG, et al. Hyperventilation-induced hypotension during cardiopulmonary resuscitation. Circulation 2004; 109: 1960 5 6 Baird TA, Parsons MW, Phanh T, et al. Persistent poststroke hyperglycemia is independently associated with infarct expansion and worse clinical outcome. Stroke 2003; 34: 2208 14 7 Balan IS, Fiskum G, Hazelton J, Cotto-Cumba C, Rosenthal RE. Oximetry-guided reoxygenation improves neurological outcome after experimental cardiac arrest. Stroke 2006; 37: 3008 13 8 Batjer HH, Frankfurt AI, Purdy PD, Smith SS, Samson DS. Use of etomidate, temporary arterial occlusion, and intraoperative angiography in surgical treatment of large and giant cerebral aneurysms. J Neurosurg 1988; 68: 234 40 9 Bayona NA, Gelb AW, Jiang Z, Wilson JX, Urquhart BL, Cechetto DF. Propofol neuroprotection in cerebral ischemia and its effects on low-molecular-weight antioxidants and skilled motor tasks. Anesthesiology 2004; 100: 1151 9 10 Benson DW, Williams GR Jr, Spencer FC, Yates AJ. The use of hypothermia after cardiac arrest. Anesth Analg 1959; 38: 423 8 11 Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002; 346: 557 63 12 Bigelow WG, Lindsay WK, Greenwood WF. Hypothermia; its possible role in cardiac surgery: an investigation of factors governing survival in dogs at low body temperatures. Ann Surg 1950; 132: 849 66 13 Bracken MB, Shepard MJ, Holford TR, et al. Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury. Results of the Third National Acute Spinal Cord Injury Randomized Controlled Trial. National Acute Spinal Cord Injury Study. JAMA 1997; 277: 1597 604 14 Busto R, Dietrich WD, Globus M-T, Ginsberg MD. The importance of brain temperature in cerebral ischemic injury. Stroke 1989; 20: 1113 14 15 Canas PT, Velly LJ, Labrande CN, et al. Sevourane protects rat mixed cerebrocortical neuronal-glial cell cultures against transient oxygen-glucose deprivation: involvement of glutamate uptake and reactive oxygen species. Anesthesiology 2006; 105: 990 8

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Conclusion
Ischaemic brain injury remains a potentially devastating disorder, although progress is being made in resuscitation science. Two key advances occurred in the past decade. The rst was repeated demonstration that induced mild hypothermia reduces neurological morbidity and mortality associated with out-of-hospital ventricular brillation cardiac arrest. Beyond the immediate potential to apply this intervention is the larger message that post-ischaemic intervention can favourably inuence outcome in humans. The second advance was recognition that efcacy of mild hypothermia depends at least in part upon the type of ischaemic lesion being treated. Trauma and focal ischaemia could not be shown to be amenable to hypothermic

Table 2 Considerations when anticipating or managing a perioperative ischaemic insult Assure absence of hyperthermia Manage blood glucose with insulin to induce normoglycaemia Optimize haemoglobin-oxygen saturation (increasing concern that hyperoxaemia may be adverse in global ischaemia) Establish normocapnia Consider the use of volatile anaesthetics if surgery ongoing (consistent sustained benet in experimental animal studies, reversible allowing neurological examination, human trials not performed) Resist the use of glucorticoids (no evidence of efcacy, preclinical evidence of adverse effect in global ischaemia) Consider the use of postoperative sustained induced moderate hypothermia if global ischaemia (not tested by clinical trials in perioperative environment, but supported by consistent evidence of efcacy when used in out-of-hospital ventricular brillation cardiac arrest)

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