Introduction

Neuroprotection describes strategies to protect neuronal elements against damage and impairment of neurologic function. One of the essentials of neuroanesthesia practice is to provide the patient with neuroprotective measures. It is hoped that these measures will reduce poor neurologic outcomes, i.e., motor and sensory deficits and cognitive dysfunction resulting from inevitable surgical brain injury during neurosurgical procedures. The most common forms of brain injury during neurosurgical procedures are (1) brain retraction, (2) incising and removing brain tissue, and (3) temporary vascular occlusion. For instance, eliminating pathological brain tissue and brain retraction will inevitably lead to injury of normal brain structures. Moreover, clamping of a carotid artery during carotid endarterectomy or temporary clipping of intracerebral arteries can simulate unilateral global ischemia or acute ischemic stroke, respectively ( Table 5.1 ).

Neuroprotective strategies can be classified into nonpharmacological and pharmacological ( Table 5.2 ). Some of these strategies are based on laboratory evidence and are either target specific or with indeterminate targets. Other neuroprotective approaches are “empiric” meaning that they are guided by experience not precepts or theory.

Nonpharmacological Strategies

Nonpharmacological strategies signify the manipulation of homeostatic processes in a manner that will have neuroprotective effects ( Table 5.2 ).

Mild Hypothermia

Hypothermia has been commonly classified into three levels: mild from 32 to 35°C, moderate from 32 to 28°C, and deep under 28°C. Deep hypothermia associated with circulatory arrest was previously used during clipping of giant complex intracerebral aneurysms without favorable but detrimental outcomes. Such disappointing experience has steered the evolution of mild hypothermia as a neuroprotective strategy based on encouraging results shown in many laboratory investigations. The mechanisms of the presumed hypothermic neuroprotection are multifaceted and include changes in various cellular processes including its ability to decrease the cerebral metabolic rate by about 10% for every degree Celsius. Hypothermia maintains the integrity of the blood–brain barrier after ischemic insults and constricts cerebral blood vessels and thus reduces brain edema and cerebral blood volume and decreases intracranial pressure (ICP). Additionally, it inhibits excitotoxicity by decreasing glutamate release resulting in decrease of cellular depolarization and inhibition of deleterious calcium influx through voltage- and receptor-operated calcium channels. Also, hypothermia depresses the delayed responses to brain injury, namely reactive oxygen species production and mitochondrial dysfunction that triggers neuronal tissue inflammation and programmed cell death (apoptosis), respectively. Finally, hypothermia can ameliorate secondary neuronal damage by downregulating certain gene-induced proteomic responses leading to cell damage and upregulating a small subset of cold-shock proteins that depress apoptosis and promote cell proliferation.

Despite the various neuroprotective mechanisms of mild hypothermia reported in the laboratory, its clinical efficacy is still indefinable. A recent carefully conducted metaanalysis showed that among patients undergoing craniotomy for various neurosurgical indications including aneurysm clipping, traumatic brain injury, and ischemic stroke there was no evidence that intraoperative or postoperative hypothermia significantly reduces or increases mortality or significantly alters the risk of severe neurologic disability. Application of mild hypothermia did not alter the risk for postoperative complications, i.e., intracranial hemorrhage, ischemic stroke, congestive cardiac failure, or myocardial infarction. There was some weak evidence that postoperative hypothermia may increase the risk of infective complications. Such lack of efficacy and relative safety of mild hypothermia has been in agreement with other systematic reviews. It should be noted that mild hypothermia might be beneficial in the case of comatose survivors of out-of-hospital cardiac arrest and peripartum asphyxia-induced brain injury.

To date, there is no convincing clinical evidence to establish the value of mild hypothermia as a neuroprotective strategy during neurosurgery. Anesthesiologists who opt to use mild hypothermia for their patients because of its favorable safety profile and efficacy in nonneurosurgical situations of global brain ischemia should consider the following precautions: core temperature should be monitored at two sites to avoid inadvertent excessive cooling, target temperature has to be reached before opening the dura, rewarming should start after brain tissue handling has ended, rewarming should continue in the postoperative period until core temperature normalizes, and active cooling equipment should be calibrated and tested before use.

Blood Pressure Control

During neurosurgical procedures, regional and global cerebral blood flow (CBF) is compromised mainly due to brain retraction and surgical bleeding, respectively ( Table 5.2 ). Regional CBF was shown to decrease during brain retraction in swine animal models by about 50% of baseline during normoventilation or hyperventilation. Global CBF decrements are not uncommon during neurosurgery and can lead to surgical brain injury and unfavorable outcomes. CBF is autoregulated, i.e., sustained within a normal range (50–60 mL per 100 g brain tissue per minute) provided that the mean arterial pressure (MAP) is between 60 and 150 mmHg and the ICP is about 10 mmHg. CBF is correlated to the cerebral perfusion pressure (CPP) and CPP = MAP-ICP (normal CPP is 70–90 mmHg). During neurosurgery, the autoregulatory mechanisms for CBF maintenance are not optimal and the extent of its dysfunction is unknown. In fact, the relationship between CBF and CPP may become linear due to loss of vessel reactivity that is responsible for autoregulation. Therefore, decrements in MAP should be avoided and kept above 80 mmHg to maintain CPP near 70 mmHg during neurosurgery. Recent reports provide important indirect evidence of the deleterious effects of intraoperative regional and global brain hypoperfusion. In patients with severe traumatic brain injury, who had neurosurgical intervention in the form of decompressive craniotomies, the autoregulatory curves were determined. Data from these patients revealed constant brain perfusion over a wide CPP range (50–90 mmHg) and a 100% incidence of ischemia when CPPs fell below the lower limit of autoregulation. As CPPs increased there was a corresponding decrease in the incidence of ischemia, potentially mediated through an associated force-dependent dilation of the cerebral vessels. In another population of patients who undergo endovascular treatment of acute ischemic stroke, a relatively consistent conclusion from studies is that general anesthesia appears to be associated with higher mortality and morbidity compared with monitored anesthesia care. This has been attributed to the hypotensive actions of general anesthesia resulting from anesthetic agents and positive pressure ventilation, and such depressive cardiovascular effects will lead to decrements in brain perfusion. Additionally, data from the International Stroke Trial suggest that for every 10 mmHg below asystolic blood pressure of 150 mmHg early death increased by about 18%. Finally, acute reductions in MAP in patients with intracerebral hemorrhage caused diminishing cerebral tissue diffusion on MRI and were associated with cerebral ischemia, disability, and mortality.

In conclusion, during neurosurgical procedures moderate and severe intraoperative hypotension should be avoided and MAP should be maintained close to the patient’s baseline pressure. Elevation of MAP could be achieved by using a combination of measures including volume resuscitation, decreasing anesthetic levels and vasopressors, i.e., alpha agonists and ephedrine.

Induced Arterial Hypertension

Induced (or permissive) hypertension is a technique that can achieve stable and adequate collateral CPP during neurosurgical procedures associated with localized ischemic compromise of brain tissue. Such technique uses vasopressors to raise the arterial blood pressure by 20–40% to recruit cerebral collateral networks including the leptomeningeal circulation particularly in patients who have incomplete circle of Willis. Hence, induced hypertension will be potentially beneficial to reduce the incidence of perioperative cerebral ischemic events during: (1) interventional neuroradiology procedures, (2) temporary clipping or clamping during cerebral aneurysmal surgery or carotid endarterectomy, respectively, (3) extracranial to intracranial bypass surgery, (4) surgery in patients with cerebral vasospasm and (5) surgery in patients with conditions leading to significant cerebral autoregulation dysfunction, e.g., intracranial pathology with mass effect, severe systemic hypertensive disease and traumatic brain injury.

Several reports allude to the potential benefits of induced hypertension. Actually, increased middle cerebral artery mean blood flow velocity by intentional hypertension during dissection of the carotid artery in carotid endarterectomy prevented the postoperative development of new cerebral ischemic lesions as detected by diffusion weighted MRI imaging. In another recent study, reactionary approach to malperfusion, i.e., selective shunting or elevation of blood pressure was compared to a preemptive routine protocol for induced hypertension during carotid clamping to maintain adequate collateral CBF during carotid endarterectomy. The risk of temporary neurologic malperfusion was 18.1% in the groups where a reactionary approach to malperfusion was addressed by shunt, or the elevation of blood pressure, as compared with 0.86% of patients with pretreated collateral CPP with a standard induced hypertension protocol. Additionally, the safety of induced hypertension has been described in several reports. For example, induced hypertension did not cause rupture in small, intact, unprotected intracranial aneurysms in subarachnoid hemorrhage patients. Similarly, there were no reported events of myocardial infarction, congestive heart failure, intracranial hemorrhage, or hyperperfusion syndrome.

Phenylephrine (50–200 μg IV boluses) and ephedrine (5–10 mg IV boluses) are the primary vasoconstrictors used to raise blood pressure during induced hypertension. Phenylephrine is a pure α ₁ -adrenergic receptor agonist and causes reflex bradycardia. It does not have chronotropic or inotropic effect. It has an immediate onset of action and a short half-life of approximately 5 min that makes it suitable for use as a variable rate infusion. If severe bradycardia occurs, anticholinergic agents can be administered to antagonize the baroreceptor-mediated vagotonic effect of phenylephrine. Ephedrine is a sympathomimetic amine. It indirectly stimulates the adrenergic receptor system by increasing the activity of norepinephrine at the postsynaptic α and β receptors thus causing vasoconstriction and week chronotropic and inotropic effects. Other sympathomimetic agents have been used to induce hypertension particularly in the ICU, e.g., dopamine, dobutamine, and vasopressin.

Normoglycemia

Perioperative hyperglycemia may occur in diabetic as well as nondiabetic patients. In nondiabetic patients, perioperative hyperglycemia exists in two forms: stress hyperglycemia and glucose variability. The latter is a measure of the magnitude of glucose excursions over time and can occur in diabetic patients. Perioperative hyperglycemia results from neuroendocrine responses activated by surgery or trauma that includes an increase in the stress hormones such as catecholamines, cortisol, and glucagon providing conditions for tissue recuperation. Nonetheless, the intensification of such homeostatic response mechanisms can trigger organ damage of its own accord. In fact, the evidence consistently suggests that perioperative hyperglycemia leads to unfavorable neurologic and nonneurologic outcomes after various neurosurgical procedures. A recent study showed that after surgical intervention in diabetics with cervical spondylosis myelopathy, perioperative glucose levels were linearly associated with impaired improvement in Nurick score that is based on the extent of walking disability. In carotid endarterectomy, patients with operative day glucose more than 11.1 mmol/L (200 mg/dL) were 2.8-, 4.3-, and 3.3-fold more likely to experience perioperative stroke or transient ischemic attack, myocardial infarction, or death, respectively. Additionally, patients with elevated fasting blood sugar 6.1 mmol/L (>110 mg/dL) undergoing carotid artery stenting are at a greater risk for worse major acute events, namely stroke, myocardial infarction, and death in both the short and long term. The Intraoperative Hypothermia for Aneurysm Surgery Trial (IHAST) concluded that blood glucose levels more than 7.2 and 8.4 mmol/L (130 and 150 mg/dL) at the time of clipping of a ruptured cerebral aneurysm are associated with long-term changes in cognition and gross neurologic dysfunction, respectively. In the pediatric population, patients who developed postoperative complications exhibited higher mean blood glucose levels on admission to the intensive care unit 9 mmol/L (162.0 mg/dL) and mean peak blood glucose levels on postoperative day one 9.6 mmol/L (171.9 mg/dL).

Because the brain tissue is vulnerable at the extremes of blood sugar values, a consensus pertaining to the blood sugar target is still controversial in neurosurgical patients. However, to date most evidence cannot support intensive insulin therapy with tight glucose control in the neurosurgical population during the perioperative period. Tight glucose control has been shown to cause much higher incidence of severe hypoglycemic episodes, stroke, myocardial infarction, and death as well as brain energy crisis that correlates with increased mortality. Consequently, a consensus statement by the American Association of Clinical Endocrinologists and the American Diabetes Association has recommended that treatment should be initiated at a threshold of >10.0 mmol/L (>180 mg/dL), preferably with IV insulin therapy, and maintain the glucose level between 7.8 and 10.0 mmol/L (140 and 180 mg/dL). The consensus also conveyed that (1) greater benefit may be obtained at the lower end of this range, (2) glucose concentrations <6.0 mmol/L (110 mg/dL) are not recommended, and (3) the suggested glucose targets should be flexible and individualized to the patient and the clinical situations relating to the speed of achieving normoglycemia and the insulin regimen used. Several insulin regimens have been proposed. A modified guideline is suggested in Table 5.3 .

Table 5.3

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