Cerebral protection
1 Department of Anesthesiology
2 Department of Neurobiology
3 Department 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{at}duke.edu
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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 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 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 beneficial 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 define limitations and efficacy of already available methods of intervention, aimed primarily at regulation of physiological homeostasis.
Keywords: brain, ischaemia; complications, cerebral ischaemia; recovery, neurological
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Introduction |
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Cerebral ischaemia/hypoxia can occur in a variety of perioperative circumstances. Outcomes from such events range from sub-clinical neurocognitive deficits 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 defined 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 inflammation, 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 (pre-conditioning)], 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 efficacy of various experimental post-ischaemic interventions, which have manifested either as 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).
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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 efficacy of an anaesthetic is dependent upon the severity of the ischaemic insult. If the insult were sufficiently 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 influx.
Many studies have supported this logic. Indeed, during abrupt onset of hypoxaemia, barbiturates and isoflurane 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 efficacy of pre-treatment with anaesthetics have proved difficult to acquire.
Early work testing intra-ischaemic anaesthetic efficacy was confounded by poor physiological control of experimental subjects. It was recognized later in the evolution of anaesthetic efficacy 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 confirm 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 field remained confused for more than a decade and insufficient data were generated to warrant human trials of anaesthetic efficacy when employed intraoperatively. Even then, the early results were mixed. One study found efficacy 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 efficacy,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.
Volatile anaesthetics
The efficacy 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 flow distal to the circle of Willis) and global (e.g. complete cessation of blood flow 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 Sevoflurane 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 is required for a surgical procedure, inclusion of volatile anaesthetics can be considered. Isoflurane and sevoflurane carry the largest data set to this decision. Desflurane also offers promise,33 38 but has been insufficiently 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-inflammatory properties.57 Propofol appears unique among anaesthetics in the laboratory setting because it offers efficacy with post-ischaemic therapy onset, although such treatment provides only transient protection.9 Propofol appears to offer efficacy similar to barbiturates but a dose-dependent study of its efficacy 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 efficacy for lidocaine, with perhaps its principle mechanism of action relating to inhibition of apoptosis.39 The efficacy of lidocaine appears dependent on dose, with doses in the range used to manage cardiac dysrhythmias having greatest efficacy.61 There have been no long-term outcome studies of lidocaine efficacy in experimental stroke. One small human trial found benefit 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, efficacy 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 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 difficult to recommend ketamine for the purposes of neuroprotection in the clinical environment at this time.
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Temperature
Hypothermia has been proposed to offer therapeutic benefit 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 benefit 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 efficacy, which reduced enthusiasm for the logistical issues necessary routinely to cool and re-warm a large patient population. Another factor may have been the influence 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 (32–35°C) 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 benefit. 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. 18–22°C) 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 findings.53 In contrast, it is widely observed that induction of deep hypothermia before circulatory arrest routinely allows the brain to tolerate intervals of no-flow 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 efficacy 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 defining 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 people's surprise, reduction in brain temperature by only a few degree Celsius provided major protection. These findings stimulated numerous clinical trials in both adults and newborns, which have since provided a scientific basis defining the opportunities and limitations of using off-bypass hypothermia to provide meaningful neuroprotection.
The first 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 definitive evidence was needed. Thus, a large-scale prospective human trial was conducted, but disappointing results were obtained.18 Cooling TBI patients within the first 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 efficacy only in certain patient populations and only when conducted with specific 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 significantly more patients with good outcome in the hypothermia group and negligible adverse events. Finally, convincing evidence is available that off-bypass hypothermia can appreciably improve outcome from at least cardiac arrest in humans.
These findings 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 efficacy 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 first employed selective head cooling and could only find a beneficial effect of hypothermia in a subset of the study population.27 The second employed total body cooling.60 In this study, the benefit 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 defining hypothermia efficacy, 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 sufficient 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 amplifies 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.
Arterial carbon dioxide partial pressure (PaCO2)
Because cerebral blood flow 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 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 benefit 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.
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 efficacy of hyperbaric oxygen (HBO) in rats undergoing a similar focal ischaemic insult.63 Evidence for HBO efficacy 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 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 benefit 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 insufficient evidence to define the role of glucocorticoids in focal ischaemic stroke.54 A large retrospective analysis found no benefit 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 efficacy in ischaemic brain, their use cannot be advocated.
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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 first was repeated demonstration that induced mild hypothermia reduces neurological morbidity and mortality associated with out-of-hospital ventricular fibrillation cardiac arrest. Beyond the immediate potential to apply this intervention is the larger message that post-ischaemic intervention can favourably influence outcome in humans. The second advance was recognition that efficacy 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 intervention, at least within the bounds of the clinical trial protocols employed.
Other than the use of mild hypothermia for ventricular fibrillation 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.
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