Cerebral Metabolic Rate

Regional CBF and metabolism are tightly coupled. They involve a complex physiologic process regulated, not by a single mechanism, but by a combination of metabolic, glial, neural, and vascular factors. Increased neuronal activity results in increased local brain metabolism, and this increase in the CMR is associated with a proportional change in CBF referred to as neurovascular coupling . The traditional view of neurovascular coupling is that it is a positive feedback mechanism wherein increased neuronal activity results in a demand for energy; this demand is met by an increase in CBF. More recent data indicate that coupling is based on a feed-forward mechanism wherein neuronal activity directly increases CBF, thereby increasing energy supply. Although the precise mechanisms that mediate neurovascular coupling have not been defined, the data available implicate local by-products of metabolism (e.g., potassium ion [K ⁺ ], hydrogen ion [H ⁺ ], lactate, adenosine, and adenosine triphosphate [ATP]). Increased synaptic activity with the attendant release of glutamate leads to the downstream generation of a variety of mediators that affect vascular tone ( Fig. 11.4 ). Glutamate, released with increased neuronal activity, results in the synthesis and release of NO, a potent cerebral vasodilator that plays an important role in neurovascular coupling. Glia also play an important role in neurovascular coupling. Their processes make contact with neurons, and these processes may serve as conduits for the coupling of increased neuronal activity to increases in blood flow. Glutamate activation of metabotropic glutamate receptors (mGluR) in astrocytes leads to arachidonic acid (AA) metabolism and the subsequent generation of prostaglandins and epoxyeicosatrienoic acids. Oxygen modulates the relative contribution of these pathways, and in the setting of reduced oxygen tension at the tissue level, the release of adenosine can contribute to vascular dilation. The net result therefore on vascular tone is determined by the relative contribution of multiple signaling pathways. In addition, nerves that innervate cerebral vessels release peptide neurotransmitters such as vasoactive intestinal peptide (VIP), substance P, cholecystokinin, somatostatin, and calcitonin gene–related peptide. These neurotransmitters may also potentially be involved in neurovascular coupling.

Cerebral neurovascular coupling. Synaptic activity leads to glutamate release, activation of glutamatergic receptors, and calcium entry in neurons. This results in a release of arachidonic acid (AA) , prostaglandins (PGs) , and nitric oxide (NO) . Adenosine and lactate are generated from metabolic activity. These factors all lead to vascular dilation. Glutamate also activates metabotropic glutamate receptors (mGluR) in astrocytes, causing intracellular calcium entry, phospholipase A ₂ (PLA ₂ ) activation, release of AA and epoxyeicosatrienoic (EET) acid and prostaglandin E ₂ (PGE ₂ ) . The latter two AA metabolites contribute to dilation. By contrast, AA can also be metabolized to 20-hydroxyl-eicosatetraenoic acid (20-HETE) in vascular smooth muscle. 20-HETE is a potent vascular constrictor. cGMP, Cyclic guanosine monophosphate; eNOS, endothelial nitric oxide synthase; NMDAR, N -methyl d -aspartate (NMDA) glutamate receptor; nNOS, neuronal nitric oxide synthase.

Modified from Attwell D, Buchan AM, Charpak S, et al. Glial and neuronal control of brain blood flow. Nature . 2010;468(7321):232–243.

CMR is influenced by several phenomena in the neurosurgical environment, including the functional state of the nervous system, anesthetic drugs, and temperature.

Temperature

The effects of hypothermia on the brain have been reviewed in detail. The CMR decreases by 6% to 7% per degree Celsius of temperature reduction. In addition to anesthetic drugs, hypothermia can also cause complete suppression of the EEG (at approximately 18°C-20°C). However, in contrast to anesthetic drugs, temperature reduction beyond that at which EEG suppression first occurs does produce a further decrease in the CMR ( Fig. 11.5 ). This decrease occurs because anesthetic drugs reduce only the component of the CMR associated with neuronal function, whereas hypothermia decreases the rate of energy utilization associated with both electrophysiologic function and the basal component related to the maintenance of cellular integrity. Mild hypothermia preferentially suppresses the basal component of the CMR. The CMRO ₂ at 18°C is less than 10% of normothermic control values, which may explain the brain’s tolerance for moderate periods of circulatory arrest at these and colder temperatures.

Effect of temperature reduction on the cerebral metabolic rate of oxygen (CMRO ₂ ) in the cortex. Hypothermia reduces both of the components of cerebral metabolic activity identified in Fig. 11.2 ―that associated with neuronal electrophysiologic activity (Function) and that associated with the maintenance of cellular homeostasis (Integrity). This is in contrast to anesthetics that alter only the functional component. The ratio of cerebral metabolic rate (CMR) at 37°C to that at 27°C, the Q10 ratio, is shown in the graph. Note that the CMRO ₂ in the cortex (gray matter) is greater than global CMRO ₂ , considering the lower metabolic rate in white matter. EEG , Electroencephalogram.

Modified from Michenfelder JD. Anesthesia and the brain: clinical, functional, metabolic, and vascular correlates . New York: Churchill Livingstone; 1988.

Hyperthermia has an opposite influence on cerebral physiologic function. Between 37°C and 42°C, CBF and CMR increase. However, above 42°C, a dramatic reduction in cerebral oxygen consumption occurs, an indication of a threshold for a toxic effect of hyperthermia that may occur as a result of protein (enzyme) denaturation.

PaCO ₂

CBF varies directly with Pa co ₂ ( Fig. 11.6 A ), especially within the range of physiologic variation of Pa co ₂ . CBF changes 1 to 2 mL/100 g/min for each 1 mm Hg change in Pa co ₂ around normal Pa co ₂ values. This response is attenuated at a Pa co ₂ less than 25 mm Hg. Under normal circumstances, the sensitivity of CBF to changes in Pa co ₂ (ΔCBF/ΔPa co ₂ ) is positively correlated with resting levels of CBF. Accordingly, anesthetic drugs that alter resting CBF cause changes in the response of the cerebral circulation to CO ₂ . The magnitude of the reduction in CBF caused by hypocapnia is more intense when resting CBF is increased (as might occur during anesthesia with volatile agents). Conversely, when resting CBF is reduced, the magnitude of the hypocapnia-induced reduction in CBF is decreased slightly. It should be noted that CO ₂ responsiveness has been observed in normal brain during anesthesia with all the anesthetic drugs that have been studied.

A, Relationship between cerebral blood flow (CBF) and partial pressure of carbon dioxide (Pa co ₂₎ . CBF increases linearly with increases in arterial Pa co ₂ . Below a Pa co ₂ of 25 mm Hg, further reduction in CBF is limited. Similarly, the increase in CBF above a Pa co ₂ of approximately 75 to 80 mm Hg is also attenuated. The cerebrovascular responsiveness to Pa co ₂ is influenced significantly by blood pressure. With moderate hypotension (mean arterial pressure [MAP] reduction of <33%), the cerebrovascular responsiveness to changes in Pa co ₂ is attenuated significantly. With severe hypotension (MAP reduction of approximately 66%), CO ₂ responsiveness is abolished. B, The effect of Pa co ₂ variation on cerebral autoregulation. Hypercarbia induces cerebral vasodilation and, consequently, the autoregulatory response to hypertension is less effective. By contrast, hypocapnia results in greater CBF autoregulation over a wider MAP variation.

Modified from Willie and Rickards .

The role of MAP in the CO ₂ responsiveness of the cerebral circulation is further highlighted by the impact of modest and severe hypotension. With the former, the increase in CBF attendant upon hypercarbia is significantly reduced, whereas hypocapnia-induced vasoconstriction is only modestly affected. When hypotension is severe, a cerebrovascular response to changes in Pa co ₂ is not observed ( Fig. 11.6 A ). The level of Pa co ₂ also modulates cerebral autoregulation. With hypercarbia, cerebral autoregulatory response to hypertension is attenuated. By contrast, with the induction of hypocapnia, CBF is autoregulated over a wider MAP range ( Fig 11.6 B ).

The changes in CBF caused by Pa co ₂ are dependent on pH alterations in the extracellular fluid of the brain. NO, in particular NO of neuronal origin, is an important although not exclusive mediator of CO ₂ -induced vasodilation. The vasodilatory response to hypercapnia is also mediated in part by prostaglandins. The changes in extracellular pH and CBF rapidly occur after Pa co ₂ adjustments because CO ₂ freely diffuses across the cerebrovascular endothelium and the BBB. In contrast with respiratory acidosis, acute systemic metabolic acidosis has little immediate effect on CBF because the BBB excludes H ⁺ from the perivascular space. The CBF changes in response to alterations in Pa co ₂ rapidly occur, but they are not sustained. Despite the maintenance of an increased arterial pH, CBF returns toward normal over a period of 6 to 8 hours because the pH of CSF gradually returns to normal levels as a result of extrusion of bicarbonate (see Fig. 57.6). Consequently, a patient who has had a sustained period of hyperventilation or hypoventilation deserves special consideration. Acute restoration of a normal Pa co ₂ value will result in a significant CSF acidosis (after hypocapnia) or alkalosis (after hypercapnia). The former results in increased CBF with a concomitant increase in ICP that depends on the prevailing intracranial compliance. The latter conveys a theoretic risk for ischemia.

PaO ₂

Changes in Pa o ₂ from 60 to more than 300 mm Hg have little influence on CBF. A reduction in Pa o ₂ below 60 mm Hg rapidly increases CBF ( Fig. 11.7 A ). Below a Pa o ₂ of 60 mm Hg, there is a rapid reduction in oxyhemoglobin saturation. The relationship between oxyhemoglobin saturation, as evaluated by pulse oximetry, and CBF is inversely linear (see Fig. 11.7 B ). The mechanisms mediating cerebral vasodilation during hypoxia may include neurogenic effects initiated by peripheral and neuraxial chemoreceptors, as well as local humoral influences. A reduction in arterial oxygen content, and therefore cerebral oxygen delivery, can be achieved either by a reduction in Pa o ₂ (hypoxemic hypoxia) or by a reduction in hemoglobin concentration (anemia, hemodilution). Both hemodilution and hypoxemic hypoxia lead to cerebral vasodilation and an increase in CBF. Of the two variables, however, hypoxemic hypoxia is a far more potent variable in CBF augmentation than hemodilution. Cerebral oxygen delivery is better maintained during hypoxia when arterial content is equivalently reduced by hypoxia or hemodilution (see Fig. 11.7 C ). Deoxyhemoglobin plays a central role in hypoxia-induced increases in CBF by causing the release of NO and its metabolites, as well as ATP. Hypoxia-induced opening of ATP-dependent K ⁺ channels in vascular smooth muscle leads to hyperpolarization and vasodilation. The rostral ventrolateral medulla (RVLM) serves as an oxygen sensor within the brain. Stimulation of the RVM by hypoxia results in an increase in CBF (but not CMR), and lesions of the RVLM suppress the magnitude of the CBF response to hypoxia. The response to hypoxia is synergistic with the hyperemia produced by hypercapnia and acidosis. At high Pa o ₂ values, CBF modestly decreases. At 1 atmosphere of oxygen, CBF is reduced by approximately 12%.

(A) Relationship between cerebral blood flow (CBF) and partial pressure of oxygen (Pa o ₂₎ . Between the range of 60 and 200 mm Hg, Pa o ₂ has little impact on CBF. A reduction in Pa o ₂ to less than 60 mm Hg results in hemoglobin desaturation. There is significant cerebral vasodilation and a marked increase in CBF. (B) The relationship between hemoglobin saturation and CBF is inversely linear, with a gradual increase in CBF as saturation is decreased. (C) The impact of a reduction in cerebral oxygen delivery (CDO ₂ ) , either by hypoxemic hypoxia or by hemodilution, is depicted. CBF increases significantly either with hypoxia or hemodilution; however, the CBF response is much greater with hypoxia (upper panel) . The total cerebral oxygen delivery is better maintained with hypoxia than hemodilution at a comparable level of arterial oxygen content (CaO ₂ ) because of the greater CBF increase that occurs with the former.

Modified from Hoiland et al. and Todd et al. .

Systemic Vasodilators

Most drugs used to induce hypotension, including sodium nitroprusside, nitroglycerin, hydralazine, adenosine, and calcium channel blockers (CCBs), also cause cerebral vasodilation. As a result, CBF either increases or is maintained at pre-hypotensive levels. In addition, when hypotension is induced with a cerebral vasodilator, CBF is maintained at lower MAP values than when induced by either hemorrhage or a noncerebral vasodilator. In contrast to direct vasodilators, the ACE inhibitor enalapril does not have any significant effect on CBF. Anesthetics that simultaneously vasodilate the cerebral circulation cause increases in cerebral blood volume (CBV) with the potential to increase ICP. The effects of these anesthetics on ICP are less dramatic when hypotension is slowly induced, which probably reflects the more effective interplay of compensatory mechanisms (i.e., shifts in CSF and venous blood) when changes occur more slowly.

Catecholamine Agonists and Antagonists

Numerous drugs with agonist and antagonist activity at catecholamine receptors (α ₁ , α ₂ , β ₁ , β ₂ , and dopamine) are in common use. The effects of these vasoactive drugs on cerebral physiology are dependent on basal arterial blood pressure, the magnitude of the drug-induced arterial blood pressure changes, the status of the autoregulation mechanism, and the status of the BBB. A drug may have direct effects on cerebral vascular smooth muscle or indirect effects mediated by the cerebral autoregulatory response to changes in systemic blood pressure (or both types of effects). When autoregulation is preserved, increases in systemic pressure should increase CBF if basal blood pressure is outside the limits of autoregulation. When basal pressure is within the normal autoregulatory range, an increase in systemic arterial pressure does not significantly affect CBF because the normal autoregulatory response to a rising MAP entails cerebral vasoconstriction (i.e., an increase in cerebral vascular resistance) to maintain a constant CBF. When autoregulation is defective, CBF will vary in direct relation to arterial pressure. The information in the following paragraphs and in Table 11.2 emphasizes data obtained from investigations of vasopressors in intact preparations, and gives priority to the results obtained in humans and higher primates.

Barbiturates

A dose-dependent reduction in CBF and CMR occurs with barbiturates. With the onset of anesthesia, both CBF and CMRO ₂ are reduced by approximately 30%. When large doses of thiopental cause complete EEG suppression, CBF and CMR are reduced by approximately 50% to 60%. Further increases in the barbiturate dose have no additional effect on the CMR. These observations suggest that the major effect of nontoxic doses of depressant anesthetics is a reduction in the component of cerebral metabolism that is linked to electrical brain function (e.g., neurophysiologic activity) with only minimal effects on the second component, which is related to cellular homeostasis (see Fig. 11.2 ).

Tolerance to the CBF and CMR effects of barbiturates may quickly develop. In patients with severe head injury in whom barbiturate coma was maintained for 72 hours, the blood concentration of thiamylal required to maintain EEG burst suppression was observed to be increased by the end of the first 24 hours and continued to increase over the next 48 hours. During deep pentobarbital anesthesia, autoregulation and CO ₂ responsiveness are maintained.

Propofol

The effects of propofol (2,6-diisopropylphenol) on CBF and CMR are similar to those of barbiturates. Both CBF and CMR decrease after the administration of propofol in humans. In healthy volunteers, surgical levels of propofol reduced regional CBF by 53% to 79% in comparison with the awake state. Cerebral glucose metabolism in volunteers was evaluated by positron-emission tomography (PET) before and during infusion of propofol to the point of unresponsiveness, and resulted in a decrease of the whole-brain metabolic rate of 48% to 58%, with limited regional heterogeneity. When compared with isoflurane-fentanyl or sevoflurane-fentanyl anesthesia, a combination of propofol and fentanyl decreased subdural pressure in patients with intracranial tumors and decreased the arteriovenous oxygen content difference (AVDO ₂ ). Collectively, these investigations in human subjects indicate that propofol effects reductions in the CMR and secondarily decreases CBF, CBV, and ICP.

Both CO ₂ responsiveness and autoregulation are preserved in humans during the administration of propofol, even when administered in doses that produce burst suppression of the EEG. The magnitude of the reduction in CBF during hypocapnia is decreased during propofol administration. This effect is probably due to the cerebral vasoconstriction induced by suppression of CMR, which limits further hypocapnia-mediated vasoconstriction.

Etomidate

The effects of etomidate on CBF and CMR are also similar to those of barbiturates. Roughly parallel reductions in CBF and CMR occur in humans, and in general, they are accompanied by progressive suppression of the EEG. Induction of anesthesia with either thiopental or etomidate resulted in a similar reduction in MCAfv by approximately 27%. The changes in CBF and CMR are substantial. Etomidate, 0.2 mg/kg, reduced CBF and CMR by 34% and 45%, respectively, in adults. As is the case with barbiturates, no further reduction in the CMR occurs when additional drug is administered beyond a dose sufficient to produce EEG suppression. Although this latter phenomenon has not been demonstrated in humans, etomidate has been demonstrated to reduce ICP only when EEG activity is well preserved; etomidate is ineffective in reducing ICP when EEG activity is suppressed in head injured patients. The global CMR suppression attainable with etomidate is slightly less profound than that achieved with isoflurane and barbiturates. This finding is consistent with the observation that unlike barbiturates, which cause CMR suppression throughout the brain, the CMR suppression caused by etomidate is regionally variable and occurs predominantly in forebrain structures.

Etomidate is effective in reducing ICP without causing a reduction in CPP in patients with intracranial tumors and patients with head injuries. However, the administration of etomidate resulted in an exacerbation of brain tissue hypoxia and acidosis in patients in whom the MCA was temporarily occluded during surgery. Additional concerns regarding the occurrence of adrenocortical suppression caused by enzyme inhibition and renal injury caused by the propylene glycol vehicle will probably preclude more than episodic use.

Reactivity to CO ₂ is preserved in humans during the administration of etomidate. Autoregulation has not been evaluated. Myoclonus and epileptogenesis are discussed in the section, “Epileptogenesis.”

Narcotics

Inconsistencies can be found in the available information, but narcotics likely have relatively little effect on CBF and CMR in the normal, unstimulated nervous system. When changes do occur, the general pattern is one of modest reductions in both CBF and CMR. The inconsistencies in the literature may largely arise because the control states entailed paralysis and nominal sedation in many studies, often with N ₂ O alone. In these studies, in which substantial reductions in CBF and CMR were frequently observed, the effect of the narcotic was probably a combination of the inherent effect of the drug plus a substantial component attributable to reduction of arousal. Comparable effects related to reduction of arousal may occur and can be clinically important. However, they should be viewed as nonspecific effects of sedation or pain control, or both, rather than specific properties of narcotics. The following discussion emphasizes investigations in which control measurements were unlikely to have been significantly influenced by arousal phenomena.

Benzodiazepines

Benzodiazepines cause parallel reductions in CBF and CMR in humans. CBF and CMRO ₂ decreased by 25% when 15 mg of diazepam was given to patients with head injuries. The effects of midazolam on CBF (but not on CMR) have also been studied in humans. Administration of 0.15 mg/kg of midazolam to awake healthy human volunteers resulted in a 30% to 34% reduction in CBF. In an investigation using PET scanning, a similar dose of midazolam led to a global 12% reduction in CBF; the decreases occurred preferentially in the brain regions associated with arousal, attention, and memory. CO ₂ responsiveness was preserved.

The available data indicate that benzodiazepines cause a moderate reduction in CBF in humans, which is coupled to metabolism. The extent of the maximal reductions of CBF and CMR produced by benzodiazepines is probably intermediate between the decreases caused by narcotics (modest) and barbiturates (substantial). It appears that benzodiazepines should be safe to administer to patients with intracranial hypertension, provided that respiratory depression (and an associated increase in Pa co ₂ ) or hypotension do not occur.

Flumazenil is a highly specific, competitive benzodiazepine receptor antagonist. It had no effect on CBF when administered to nonanesthetized human volunteers. However, flumazenil reverses the CBF-, CMR-, and ICP-lowering effects of midazolam. When patients were aroused from midazolam anesthesia with flumazenil at the conclusion of craniotomy for brain tumor resection, no change in either CBF or CMR was observed. By contrast, severe increases in ICP occurred when flumazenil was given to patients with severe head injury in whom ICP was not well controlled. These latter observations are consistent with animal investigations during which flumazenil not only reversed the CBF and CMR effects of midazolam, but it also caused a substantial, although short-lived, overshoot above premidazolam levels in both CBF and ICP by 44% to 56% and 180% to 217%, respectively. The CMR did not rise above control levels, thus indicating that the increase in CBF was not metabolically coupled. The CBF overshoot effect is unexplained, but it may be a neurogenically mediated arousal phenomenon. Flumazenil should be used cautiously to reverse benzodiazepine sedation in patients with impaired intracranial compliance.

Droperidol

No human investigations of the CBF and CMR effects of droperidol have been conducted in isolation. However, the information available from animal investigations and combination drug administration in humans, taken together, suggests that droperidol is not a cerebral vasodilator and probably has little effect on CBF and CMR in humans. The occasional increases in ICP that have been observed probably reflect normal autoregulation-mediated vasodilation in response to an abrupt decrease in MAP.

Ketamine

Among the intravenous anesthetics, ketamine is unique in its ability to cause increases in both CBF and CMR. Animal studies indicate that the changes in the CMR are regionally variable; substantial increases occur in limbic system structures with modest changes or small decreases in cortical structures. PET studies in humans have demonstrated that subanesthetic doses of ketamine (0.2-0.3 mg/kg) can increase global CMR by approximately 25%. The greatest increase in the CMR occurred in the frontal and anterior cingulate cortex. A relative reduction in the CMR in the cerebellum was also observed. Commercially available formulations of ketamine contain both the (S) – and (R) -ketamine enantiomers. The (S) -ketamine enantiomer substantially increases CMR, whereas the (R) enantiomer tends to decrease the CMR, particularly in the temporomedial cortex and in the cerebellum. These changes in the CMR are accompanied by corresponding changes in CBF. Global, as well as regional, increases in CBF in humans that were not accompanied by similar increases in the CMRO ₂ after the administration of (S) -ketamine enantiomer have been observed. Both subanesthetic and anesthetic doses of ketamine increased global CBF by approximately 14% and 36%, respectively, without altering global CMRO ₂ . As expected, in the face of an unchanged CMR and increased CBF, the oxygen extraction ratio was reduced. The majority of investigations indicate that autoregulation is maintained during ketamine anesthesia, and CO ₂ responsiveness is preserved. A recent metaanalysis concluded that, in humans, ketamine administration increases CBF, particularly in the anterior cingulate gyrus, medial prefrontal cortex, and occipital lobes. In aggregate, the available data indicate that ketamine does increase CBF, and the accompanying increase in CMR is at best modest. Ketamine does not increase CBV.

The anticipated increase in ICP with an increase in CBF has not been confirmed to occur in humans. When examined in their entirety, the available data indicate that ketamine does not increase ICP in patients with nontraumatic neurologic illness nor in patients with traumatic brain injury. In fact, decreases in ICP occur when relatively large anesthetic doses of ketamine (1.5-5 mg/kg) are administered to patients with head injuries who are sedated with propofol. However, it should be noted that, in most of the studies in which the ICP effects of ketamine have been evaluated, patients received sedative agents in addition to ketamine. It has been established that anesthetic drugs (diazepam, midazolam, isoflurane-N ₂ O, propofol, opioids, methohexital) blunt or eliminate the increases in ICP or CBF associated with ketamine. Accordingly, although ketamine is probably best avoided as the sole anesthetic drug in patients with impaired intracranial compliance, it may be cautiously given to patients who are simultaneously receiving adjunctive sedative drugs.

Lidocaine

In nonanesthetized human volunteers, reductions in CBF and CMR of 24% and 20%, respectively, were observed after the administration of 5 mg/kg of lidocaine over a 30-minute period, followed by an infusion of 45 μg/kg/min. When very large doses (160 mg/kg) were given to dogs maintained on cardiopulmonary bypass, the reduction in the CMRO ₂ was apparently more than that observed with large-dose barbiturates. The membrane-stabilizing effect of lidocaine probably reduces the energy required for the maintenance of membrane integrity.

The effectiveness of bolus doses of thiopental, 3 mg/kg, and lidocaine, 1.5 mg/kg, in controlling the acute increase in ICP that occurred after the application of a pin head holder or skin incision in patients undergoing craniotomies has been assessed. The two regimens were equally effective in causing a reduction in ICP. However, the decrease in the MAP was greater with thiopental. Accordingly, a bolus dose of lidocaine is a reasonable adjunct to the prevention or treatment of acute increases in ICP and can prevent increases in ICP associated with endotracheal suctioning. Although large doses of lidocaine can produce seizures in humans, lidocaine-induced seizures have not been reported in anesthetized humans. Nonetheless, lidocaine doses should be adjusted to achieve serum levels less than the seizure threshold (>5-10 μg/mL) in awake humans. After a 2-mg/kg bolus, peak serum concentrations of 6.6 to 8.5 μg/mL are below the seizure threshold. Bolus doses of 1.5 to 2.0 mg/kg therefore seem appropriate.

Volatile Anesthetics

The pattern of volatile anesthetic effects on cerebral physiology is quite different than that of intravenous anesthetics, which generally cause parallel reductions in CMR and CBF. All volatile anesthetics, in a manner similar to intravenous sedative-hypnotic drugs, suppress cerebral metabolism in a dose-related fashion. Volatile anesthetics also possess intrinsic cerebral vasodilatory activity as a result of direct effects on vascular smooth muscle. The net effect of volatile anesthetics on CBF is therefore a balance between a reduction in CBF caused by CMR suppression and an augmentation of CBF caused by the direct cerebral vasodilation. When administered at a dose of 0.5 MAC, CMR suppression–induced reduction in CBF predominates, and net CBF decreases in comparison with the awake state. At 1 MAC, concentrations of isoflurane, sevoflurane, or desflurane, CBF remains unchanged; at this concentration, CMR suppression and vasodilatory effects are in balance. Beyond 1 MAC, the vasodilatory activity predominates, and CBF significantly increases, even though the CMR is substantially reduced ( Fig. 11.11 ). Vasodilation with increasing doses of volatile agents lead to an attenuation of cerebral autoregulation. With large doses, autoregulation is abolished and cerebral perfusion becomes pressure passive ( Fig. 11.12 ).

Relationship between changes in the cerebral metabolic rate of glucose (CMRg) and cerebral blood flow (CBF) in the motor-sensory cortex in rats during isoflurane anesthesia. The majority of the suppression in the CMR caused by isoflurane has occurred by 1 minimum alveolar concentration; CBF is not increased in this concentration range. Thereafter, additional isoflurane causes little further reduction in the CMR, and cerebral vasodilation occurs. These data (± standard deviation) from Maekawa and colleagues ¹³³ suggest the importance of metabolic coupling in determining the effects of isoflurane on CBF. MAP, Mean arterial pressure.

Schematic representation of the effect of increasing concentrations of a typical volatile anesthetic drug on autoregulation of cerebral blood flow. Dose-dependent cerebral vasodilation results in attenuation of autoregulatory response to increasing mean arterial pressure (MAP) . Both the upper and lower thresholds are shifted to the left.

The increase in CBF produced by volatile anesthetics at doses larger than 1 MAC has been referred to as reflecting a loss of neurovascular coupling. However, coupling (CBF adjustments paralleling changes in the CMR) persists during anesthesia with volatile anesthetics. Accordingly, the conclusion should be that the CBF/CMR ratio is altered (increased) by volatile anesthetics. This alteration is dose related, and under steady-state conditions, increasing doses of volatile agents lead to greater CBF/CMRO ₂ ratios —that is, higher MAC levels cause greater luxury perfusion.

The important clinical consequences of the administration of volatile anesthetics are derived from the increases in CBF and CBV—and consequently ICP—that can occur. Of the commonly used volatile anesthetics, the order of vasodilating potency is approximately halothane ≫ enflurane > desflurane ≈ isoflurane > sevoflurane.

Effects on cerebral blood flow

Volatile anesthetics possess intrinsic vasodilatory activity, and they not only modify cerebral autoregulation, but they also produce a dose-dependent decrease in arterial blood pressure. Hence, their effects on CBF and CMR are best evaluated when arterial blood pressure is maintained at a constant level. In addition, the cerebrovascular effects of volatile anesthetics are modulated by the simultaneous administration of other CNS-active drugs. The control state—awake, sedated, or anesthetized—against which the CBF and CMR effects of volatile anesthetics are compared, is important to recognize. The best information concerning the cerebrovascular effects of volatile anesthetics is obtained in studies during which a nonanesthetized (awake) control state is used.

Data on the cerebrovascular effects of halothane and enflurane are limited. Initial studies in humans demonstrated that the administration of 1 MAC halothane significantly increases CBF, even when systemic blood pressure is substantially reduced, in comparison with preanesthetic CBF. When the MAP is maintained at 80 mm Hg, 1.1 MAC levels of halothane increase CBF by as much as 191% and decrease the CMR by approximately 10% ( Fig. 11.13 ). When compared with awake values, 1.2 MAC enflurane also increased CBF and decreased CMR by 45% and 15%, respectively. The dramatic increases in CBF with a simultaneous modest reduction in the CMR attest to the cerebral vasodilatory properties of halothane and enflurane. Isoflurane, by contrast, does not increase CBF as much as halothane or enflurane. At concentrations of 1.1 MAC, isoflurane increases CBF by approximately 19% when arterial blood pressure is maintained within the normal range. The CMR is reduced by approximately 45%.

Estimated changes in cerebral blood flow (CBF) and the cerebral metabolic rate of oxygen (CMRO ₂ ) caused by volatile anesthetics. The CBF data for halothane, enflurane, and isoflurane were obtained during anesthesia (with blood pressure support) at 1.1 minimum alveolar concentration (MAC) in humans ³⁵⁶ and are expressed as percent change from awake control values. The CMRO ₂ data for halothane, enflurane, and isoflurane were obtained in cats and are expressed as percent change from N ₂ O-sedated control values. The data for sevoflurane were obtained during 1.1 MAC anesthesia in rabbits and are expressed as percent change from a morphine-N ₂ O–anesthetized control state. CBF values were obtained in patients who received 1 MAC sevoflurane anesthesia. Desflurane data were obtained in patients to whom 1 MAC desflurane was administered. CMR , Cerebral metabolic rate.

Both sevoflurane and desflurane can reduce CBF significantly in humans when compared with CBF in awake, nonanesthetized patients. At 1 MAC concentrations, sevoflurane and desflurane decreased CBF by 38% and 22% and CMR by 39% and 35%, respectively. These results, which suggest that the cerebral vasodilation produced by isoflurane is greater than that produced by sevoflurane and desflurane, were obtained with CBF measured by the Kety-Schmidt technique. This technique primarily measures CBF within the cortex and therefore may have substantially underestimated global CBF. PET studies in healthy humans have shown that sevoflurane dose-dependently suppresses the CMRO ₂ and CBF; at 1 MAC levels, the reduction in CBF and CMRO ₂ is approximately 50% and 50% to 60%, respectively. Even with a significant reduction in CBF, the administration of sevoflurane does not cause a decrease in CBV. Other investigations in humans, most using the measurement of MCAfv by transcranial Doppler, indicate that differences in the effects of isoflurane, desflurane ( Fig. 11.14 A ), and sevoflurane are modest. Unfortunately, a strictly quantitative comparison among these volatile anesthetics is not possible because of the variations in arterial blood pressure among study group patients. In addition, some discrepancy exists among studies in the literature regarding the magnitude of the effects of volatile anesthetics on CBF. Much of this inconsistency may occur as a result of the interaction of regionally selective CBF methods with the heterogeneity within the cerebrum of the CBF effects of volatile anesthetics. (See the later section, “Distribution of Changes in Cerebral Blood Flow/Cerebral Metabolic Rate.”)

Effect of volatile anesthetics on cerebral blood flow (CBF) (A) and the cerebral metabolic rate of oxygen (CMRO ₂ ) (B) in awake humans. The results are a composite of CBF and CMRO ₂ values obtained from a number of separate investigations. In these studies, arterial partial pressure of carbon dioxide (Pa co ₂ ) was maintained in the normocapnic range (∼35-40 mm Hg), and mean arterial pressure was supported. In most of the investigations, CBF was measured by a radioactive xenon washout technique; this technique primarily measures cortical CBF and, as such, may underestimate global CBF. This, in addition to species differences, probably account for the disparities between the data on the CBF effects attributed to volatile agents in this figure and Fig. 11.13 .

The anesthetic properties of xenon were recognized several decades ago, but this anesthetic is only now being evaluated for possible use in patients. The MAC of xenon has been estimated to be 63% to 71%, with female patients having significantly lower MAC values (51%). Xenon exerts its anesthetic effect via noncompetitive antagonism of the N -methyl- d -aspartate receptor (NMDAR), although activation of the TREK two-pore K ⁺ channel may also play a role. In healthy humans, the administration of 1 MAC xenon resulted in a reduction in CBF by approximately 15% in the cortex and by 35% in the cerebellum. Interestingly, CBF in white matter increased by 22%. This reduction in CBF is accompanied by a parallel reduction of the cerebral metabolic rate of glucose (CMRg) by 26%. Cerebral autoregulation and CO ₂ reactivity are preserved during xenon anesthesia in animals. Under background pentobarbital anesthesia in an experimental model of increased ICP, the administration of xenon did not increase ICP, and the response to both hypocapnia and hypercapnia was preserved. Diffusion of xenon into air-containing spaces such as the bowel does occur, although the magnitude of air expansion is considerably less than that with N ₂ O. Nonetheless, caution will have to be exercised with the use of xenon in patients with intracranial air. These data indicate that xenon has a favorable profile for neuroanesthesia.

Distribution of changes in cerebral blood flow and cerebral metabolic rate

The regional distribution of anesthetic-induced changes in CBF and CMR differs significantly between halothane and isoflurane. Halothane produces relatively homogeneous changes throughout the brain. CBF is globally increased, and CMR is globally depressed. The changes caused by isoflurane are more heterogeneous. Increases in CBF are greater in subcortical areas and hindbrain structures than in the neocortex. The converse is true for the CMR, with a larger reduction in the neocortex than in the subcortex. In humans, 1 MAC sevoflurane ( Fig. 11.15 ) results in a reduction in CBF within the cortex and the cerebellum. With an increase in sevoflurane dose, CBF within the cortex decreases further. By contrast, flow increases in the cerebellum with doses greater than 1.5 MAC. These effects of sevoflurane are similar to those produced by isoflurane. Desflurane has not been evaluated by local CBF studies. However, considering the similarity of its effects on the EEG (suggesting similar cortical CMR and CBF effects), an assumption of similar heterogeneity in CBF distribution seems reasonable, pending further investigation. These distribution differences may explain certain apparent contradictions in reported CBF effects in the existing literature for isoflurane. Methods that assess global hemodynamic effects reveal greater changes than those that emphasize the cortical compartment. For instance, when a xenon surface washout technique is employed (measurement of local cortical flow only), no increase in CBF occurred when isoflurane was administered to patients undergoing craniotomy.

Dose-dependent redistribution of cerebral blood flow (CBF) in humans. Positron-emission tomography (PET) scans demonstrate a dose-dependent reduction in CBF in both sevoflurane-anesthetized (left) and propofol-anesthetized (right) subjects. During sevoflurane anesthesia, there is a concentration dependent reduction in CBF within the cerebrum (indicated by blue color). An increase in concentration from 1.5 to 2 minimum alveolar concentration (MAC) leads to an increase in CBF within the cerebellum (indicated by the yellow-red color). A gradual reduction in the mean arterial pressure (MAP) occurred with increasing concentrations of sevoflurane, and the MAP was not supported. The CBF values would be expected to be considerably greater had blood pressure been maintained within the normal range. Therefore the CBF values represented in this figure probably underestimate true CBF during sevoflurane anesthesia. Propofol was administered in EC ₅₀ equivalents, defined as the plasma concentration that prevented movement in response to a surgical stimulus in 50% of patients. The target plasma propofol concentrations were 0, 6, 9, and 12 μg/mL. In propofol-anesthetized subjects, CBF was uniformly decreased and redistribution of CBF was not observed.

Modified from Kaisti K, Metsähonkala L, Teräs M, et al. Effects of surgical levels of propofol and sevoflurane anesthesia on cerebral blood flow in healthy subjects studied with positron emission tomography. Anesthesiology . 2002;96:1358–1370.

Cerebral blood volume

The extensive investigation of the influence of volatile anesthetics on CBF has been primarily based on the concern that the cerebral vasodilation produced by volatile anesthetics might increase ICP. However, it is CBV and not CBF, per se, that influences ICP. Most of the intracranial blood is within the cerebral venous circulation; although a reasonable correlation exists between vasodilation-induced increases in CBF and CBV, the magnitude of changes in CBF is considerably greater than that in CBV (see Fig. 11.9 ). Hence, changes in CBF do not reliably predict changes in CBV and, by extension, in ICP. CBV is considerably greater during isoflurane anesthesia than during propofol or pentobarbital anesthesia. In human volunteers, 1 MAC sevoflurane reduced regional CBF but not regional CBV; by contrast, propofol reduced both regional CBF and regional CBV ( Fig. 11.16 ). In addition, CBV responds to changes in Pa co ₂ by a reduction in CBV with hypocapnia and an increase in CBV with hypercapnia. The magnitude of the change in CBV is, however, less than the change in CBF. In aggregate, although the effect of anesthetics and interventions on CBF may parallel the effect on CBV, substantial qualitative and quantitative differences may well be observed.

Effect of anesthetic drugs on cerebral blood flow (CBF) and cerebral blood volume (CBV) . (A) When compared with isoflurane, propofol and pentobarbital effected substantial reductions in CBF. However, reductions in CBV were more modest. (B) Although sevoflurane effected a significant reduction in regional CBF (rCBF), regional CBV (rCBV) was unchanged. Had blood pressure been supported to normal levels, rCBV may have been greater than the awake state. By contrast, propofol effected a significant reduction in both rCBF and rCBV. These data indicate that the magnitude of the effect of anesthetics on rCBF is substantially greater than on rCBV. Hence, decreases in rCBF may not lead to equivalent reductions in rCBV. MAP, Mean arterial pressure; N ₂ O, nitrous oxide.

Nitrous Oxide

N ₂ O can cause increases in CBF, CMR, and ICP. At least a portion of the increases in CBF and CMR may be the result of a sympathoadrenal-stimulating effect of N ₂ O. The magnitude of the effect considerably varies according to the presence or absence of other anesthetic drugs ( Fig. 11.17 ). When N ₂ O is administered alone, substantial increases in CBF and ICP can occur. In sharp contrast, when N ₂ O is administered in combination with intravenous drugs, including barbiturates, benzodiazepines, narcotics, and propofol, its cerebral-vasodilating effect is attenuated or even completely inhibited. The addition of N ₂ O to anesthesia established with a volatile anesthetic will result in moderate increases in CBF.

Mean percent increases in cerebral blood flow velocity (CBFV) in the middle cerebral artery of normocapnic subjects exposed to 60% nitrous oxide (N ₂ O) after control recording in three conditions: awake; 1.1 minimum alveolar concentration (MAC) of isoflurane; and propofol, 150 μg/kg/min.

The most dramatic increases in ICP or CBF in humans and experimental animals have occurred when N ₂ O was administered alone or with minimal background anesthesia. For instance, before and during spontaneous breathing of 66% N ₂ O by patients with intracranial tumors, mean ICP increased from 13 to 40 mm Hg. The increases in CBF observed in humans are more modest than those observed in animals but are still substantial. Whether these substantial increases represent the effects of N ₂ O, per se, or whether they reflect the nonspecific effects of a second-stage arousal phenomenon is not known.

When N ₂ O is administered in conjunction with certain intravenous anesthetics, its CBF effect may be considerably attenuated. In an investigation of patients with intracranial tumors and poor intracranial compliance (mean preinduction ICP, 27 mm Hg), 50% N ₂ O introduced during barbiturate anesthesia and after the induction of hypocapnia had a negligible effect on ICP. Benzodiazepines administered alone have been shown to blunt the CBF response to N ₂ O in both animals and humans. Narcotics appear to have a similar effect. Anesthesia with 1 mg/kg morphine and 70% N ₂ O resulted in no change in CBF from awake control values. Because of the very minor effect of morphine on CBF, these data suggest that N ₂ O did not cause substantial cerebral vasodilation. Although the addition of N ₂ O to propofol anesthesia in children increased MCAfv in one study, similar increases were not demonstrated by other investigators.

In most investigations, including several in humans, during which N ₂ O has been added to a volatile anesthetic of 1 MAC or greater, substantial increases in CBF have been recorded. A comparison of an approximately equi-MAC substitution of N ₂ O for isoflurane revealed that CBF was greater by 43% with 0.75 MAC isoflurane and 65% N ₂ O in comparison to 1.5 MAC isoflurane. Several investigations have confirmed that CBF will be less with 1 MAC isoflurane than with a 1 MAC combination achieved with 50% to 65% N ₂ O and isoflurane. These observations are consistent with a substantial additive vasodilating effect of N ₂ O in the presence of a volatile agent.

This vasodilating effect of N ₂ O may be positively correlated with the concentration of inhaled drug and suggests that, in general, the increase in CBF caused by N ₂ O is exaggerated at higher concentrations of both halothane and isoflurane. Of importance, however, is the observation that the administration of 50% N ₂ O to healthy volunteers did not significantly alter CBV. In support of this observation, N ₂ O did not have any effect on CBV when added to a background of 1 MAC sevoflurane anesthesia. Although N ₂ O can increase CBF, these data indicate that its effect on CBV is modest.

Nondepolarizing Relaxants

The only recognized effect of nondepolarizing muscle relaxants on the cerebral vasculature occurs via the release of histamine. Histamine can result in a reduction in CPP because of the simultaneous increase in ICP (caused by cerebral vasodilation) and a decrease in the MAP. It is not entirely clear whether histamine directly causes cerebral vasodilation or whether it is a secondary (autoregulatory) response to a reduction in the MAP. d -Tubocurarine is the most potent histamine releaser among available muscle relaxants. Metocurine, atracurium, and mivacurium also release histamine in lesser quantities. This effect is likely to be clinically inconsequential unless these muscle relaxants are administered in the large doses necessary to achieve endotracheal intubation conditions rapidly. Of this group of drugs, cisatracurium has the least histamine-releasing effect. No evidence of histamine release was observed after the administration of 0.15 mg/kg of cisatracurium to neurosurgical patients in the intensive care unit. Yet, cisatracurium’s slow onset of action makes it less useful for a rapid sequence induction of anesthesia.

Vecuronium, in relatively large doses, does not have a significant effect on cerebral physiology in patients with brain tumors. The other aminosteroids, pipecuronium and rocuronium, should be similarly without direct effect, and no adverse events have been reported.

The indirect actions of relaxants may also have effects on cerebral physiology. Muscle relaxation may reduce ICP because coughing and straining are prevented, which decrease central venous pressure with a concomitant reduction in cerebral venous outflow impedance.

A metabolite of atracurium, laudanosine, may be epileptogenic. However, although large doses of atracurium caused an EEG arousal pattern in dogs, CBF, CMR, and ICP were unaltered. In rabbits, the administration of laudanosine did not increase the severity of the epileptoid activity caused by the direct application of a cephalosporin to the cortical surface. It appears highly unlikely that epileptogenesis will occur in humans with modest atracurium administration.

In summary, vecuronium, pipecuronium, rocuronium, atracurium, mivacurium, cisatracurium, metocurine, and pancuronium (if acute MAP increases are prevented with the latter) are all reasonable muscle relaxants for use in patients with or at risk for intracranial hypertension. Doses of metocurine, atracurium, and mivacurium should be limited to ranges not associated with hypotension.

Rocuronium is increasingly being used for the induction of anesthesia, as well as for intraoperative relaxation. It has the most rapid onset time of any nondepolarizing muscle relaxant. With sugammadex, even a profound neuromuscular blockade can be rapidly reversed (see Chapter 27, Chapter 28 ). The cerebrovascular effects of sugammadex have not yet been evaluated.

Succinylcholine

Succinylcholine can produce modest increases (∼5 mm Hg) in ICP in lightly anesthetized humans. This effect appears to be the result of cerebral activation (as evidenced by EEG changes and increases in CBF) caused by afferent activity from the muscle spindle apparatus. As might be expected with what appears to be an arousal phenomenon, deep anesthesia prevents succinylcholine-induced increases in ICP. The increase in ICP is also blocked by paralysis with vecuronium and by defasciculation with metocurine, 0.03 mg/kg. The efficacy of other defasciculating anesthetics has not been examined in humans.

Although succinylcholine can produce increases in ICP, it can still be used for a rapid sequence induction of anesthesia. No change in ICP was observed after the administration of succinylcholine, 1 mg/kg, to 10 nonparalyzed, ventilated neurosurgical patients in the intensive care unit, 6 of whom had sustained a head injury. Their observations are relevant because it is in precisely this population of patients that the issue of the use of succinylcholine arises most frequently. Considering that the ICP effects of succinylcholine may be an arousal phenomenon caused by increased afferent traffic from muscle spindles, it is reasonable to assume that disease processes that substantially blunt the level of consciousness might similarly blunt this response. As with many anesthetics, the concern should not be whether it is used but how it is used. When contraindications do not exist, with proper attention to the control of CO ₂ tension, arterial blood pressure, and depth of anesthesia and after defasciculation, little hazard should attend succinylcholine administration.

Volatile Anesthetics

Enflurane is potentially epileptogenic in clinical setting. Of particular relevance to neuroanesthesia is the observation that hypocapnia potentiates seizure-type discharges during enflurane anesthesia. A 50% decrease in the CMRO ₂ was noted in human volunteers anesthetized with 3% enflurane; however, with the onset of seizure activity, the CMRO ₂ returned to normal, thus indicating preservation of neurovascular coupling. No evidence suggests that this type of EEG activity is deleterious when oxygen delivery is maintained during the event. However, because seizure activity can elevate brain metabolism by as much as 400%, the use of enflurane, especially at high doses and with hypocapnia, should probably be avoided in patients predisposed to seizures.

The EEG-activating property of enflurane has been used intraoperatively to activate and identify seizure foci that are to be surgically resected, and in this situation, spike activity not preoperatively present has been observed to persist after surgery. However, adverse outcomes related to enflurane-induced seizures have not been reported.

Isoflurane can cause EEG spiking and myoclonus, but it has not been associated, in the experimental setting, with the frank epileptoid activity induced by enflurane. The clinical experience with isoflurane is extremely large, and unexplained seizure-like activity has been reported in only two patients. One occurrence was intraoperative, and the other was immediately postoperative. Therefore epileptogenesis does not appear to be a clinical concern with isoflurane. In fact, isoflurane has been successfully used to control EEG seizure activity in refractory status epilepticus.

Seizures occur during the induction of anesthesia with high concentrations of sevoflurane in children, including those without a recognized seizure diathesis. In two healthy humans, EEG burst suppression with 2 MAC sevoflurane was accompanied by epileptiform discharges that were observed during EEG monitoring. These discharges were associated with a significant increase in CBF, thus demonstrating that neurovascular coupling was preserved. In patients with temporal lobe epilepsy, the administration of 1.5 MAC sevoflurane elicited widespread paroxysmal EEG activity. Of note was the observation that the paroxysmal activity was not restricted to the ictal focus and that the administration of sevoflurane did not provide any assistance in localizing the epileptogenic region of the brain. The development of tonic-clonic movements suggestive of seizure activity has also been reported in otherwise healthy patients on emergence from sevoflurane anesthesia. In all of the reported cases of seizure activity attributable to sevoflurane anesthesia, untoward sequelae have not been documented. These reports highlight sevoflurane’s ability, albeit small, to evoke epileptiform activity; accordingly, the use of sevoflurane in patients with epilepsy should be undertaken with appropriate caution.

Methohexital

Myoclonic activity is sometimes observed with methohexital. Accordingly, this anesthetic has been used to activate seizure foci during cortical mapping. In neurosurgical patients to whom larger doses of methohexital were administered to produce burst suppression of the EEG, refractory seizures have occurred. Consequently, it appears that patients with seizures of temporal lobe origin, typically of the psychomotor variety or those to whom large doses are administered, are at risk for seizure activation by methohexital. However, prolonged seizure activity after single-dose methohexital administration has not been reported in patients who undergo ECT.

Ketamine

Ketamine can elicit seizures in patients with an epileptic diathesis. Depth electrode recordings in epileptic patients have revealed the occurrence of isolated subcortical seizure activity originating in the limbic and thalamic areas during ketamine anesthesia and demonstrated that this subcortical activation may not be reflected in surface EEG recordings. On only two occasions, seizures have also been reported after ketamine anesthesia in subjects who were neurologically normal; seizure thresholds may have been lowered by aminophylline in one of these instances. However, ketamine has also been employed for the purpose of controlling status epilepticus. Therefore, ketamine-induced seizure activity is not of significant concern.

Etomidate

Etomidate frequently produces myoclonus that is not associated with epileptiform activity on the EEG. A single instance of severe, sustained myoclonus immediately after anesthesia with etomidate by infusion has been reported. Etomidate has also been shown to precipitate generalized epileptic EEG activity in epileptic patients, and its use in this population should probably be avoided. However, it has been electively used in low doses to activate seizure foci for the purposes of intraoperative EEG localization. In the experience of the authors (unpublished), selective activation of a quiescent focus can be achieved with 0.1 mg/kg etomidate. Larger doses are more likely to lead to generalized activation.

Etomidate is also associated with longer seizures in response to ECT than seizures that occur after the administration of methohexital or propofol. Remarkably, etomidate, in the dose range of 0.15 to 0.3 mg/kg, does not cause dose-related seizure inhibition during ECT, as is readily demonstrated with methohexital or propofol.

The preceding information notwithstanding, no convincing reports indicate epileptogenesis in subjects who are neurologically normal, and the use of etomidate need not be restricted on this basis. In fact, etomidate has been used to control refractory status epilepticus.

Propofol

Abnormal body movements and opisthotonos can occur after propofol anesthesia. However, systematic studies in humans, although identifying the occurrence of occasional dystonic and choreiform movements, have failed to confirm propofol as a proconvulsant. Furthermore, ECT seizures were shorter after induction with propofol than after induction with methohexital, which is more consistent with an anticonvulsant effect. In addition, propofol sedation has been widely used during awake resection of seizure foci and other intracranial lesions. Although pronounced high-amplitude beta-frequency activity in the EEG has been observed, unexpected incidences of seizures have not been reported.

Narcotics

Seizures or limbic system hypermetabolism (or both) can be readily elicited in some animal species with narcotics. Although an increase in CBF in deep brain structures associated with pain processing has been observed in human volunteers, humans do not have a clinically apparent correlate of the hypermetabolism effect observed in animals. Several anecdotal accounts, unaccompanied by EEG recordings, have reported the occurrence of grand mal convulsions in patients who received both high and low doses of fentanyl. However, systematic investigations of EEG changes during the administration of relatively large doses of fentanyl, sufentanil, and alfentanil in humans have not documented neuroexcitatory activity, and the seizures may have been an exaggerated rigidity phenomenon. There are exceptions. Partial complex seizures on the induction of anesthesia with fentanyl in patients undergoing anterior temporal lobectomy have been reported. Eight of the nine patients displayed electrical seizure activity at a range of clinically relevant fentanyl doses (mean, 26 μg/kg). Another study found that alfentanil, 50 μg/kg, augmented temporal lobe spike activity in patients with temporal lobe epilepsy. Untreated rigidity may, itself, also have important CNS consequences. ICP elevation can occur during narcotic-induced rigidity, probably as a consequence of cerebral venous congestion.

Critical Cerebral Blood Flow Thresholds

The brain has a high rate of energy utilization and very limited energy storage capacity. The brain is therefore extremely vulnerable in the event of interruption of substrate (e.g., oxygen, glucose) supply. Under normal circumstances, global CBF is maintained at approximately 50 mL/100 g/min. In the face of a declining CBF and therefore oxygen supply, neuronal function deteriorates in a progressive manner rather than in an all-or-none fashion ( Fig. 11.18 ). There is substantial reserve below normal CBF levels, and not until EEG evidence of ischemia begins to appear is CBF decreased to approximately 20 mL/100 g/min. At a CBF level of approximately 15 mL/100 g/min, the cortical EEG is isoelectric. However, only when CBF is reduced to approximately 6 to 10 mL/100 g/min are indications of potentially irreversible membrane failure, such as increased extracellular potassium and a loss of the direct cortical response, rapidly evident. As CBF decreases in the flow range between 15 and 10 mL/100 g/min, a progressive deterioration in energy supply occurs and eventually leads to membrane failure and neuronal death at a time course that may last hours rather than minutes. The brain regions falling within this CBF range (6-15 mL/100 g/min) encompass brain tissue in which neuronal dysfunction is temporarily reversible but within which neuronal death will occur if flow is not restored; such regions are referred to as the ischemic penumbra . Studies defining progression to cerebral infarction within the penumbra have been performed principally in the cerebral cortex of primates, and the actual CBF levels at which the various decrements in function occur may vary with both anesthetic and species. However, in humans anesthetized with halothane and N ₂ O, the CBF threshold for the initial EEG change is similar to that observed in the animal investigations.

Relationships between cerebral perfusion, cerebral blood flow (CBF) , the electroencephalogram (EEG) , and the functional status and viability of neurons. Note that in the approximate CBF range of 6 to 12 mL/100 g/min, the energy supply is insufficient to support electrophysiologic activity (i.e., flat EEG) but can prevent complete membrane failure and neuronal death for extended periods. These areas are referred to as the ischemic penumbra . The data are derived from studies on the cerebral cortex of barbiturate-anesthetized baboons and nonanesthetized monkeys. The CBF and mean arterial pressure thresholds may vary with anesthetic and species.

Models of Cerebral Ischemia

How different is complete cerebral ischemia, as occurs during cardiac arrest, and incomplete cerebral ischemia, as may occur during occlusion of a major cerebral vessel or severe hypotension? From the clinician’s vantage, the important difference is that the residual (i.e., collateral) blood flow during incomplete ischemia may result in enough delivery of oxygen to allow some generation of ATP and thereby stave off the catastrophic irreversible membrane failure that occurs within minutes during normothermic complete cerebral ischemia. This difference in the rate of failure of the energy supply ( Fig. 11.19 ) can result in significantly greater apparent tolerance for focal or incomplete ischemia than for complete global ischemia (e.g., cardiac arrest).

Comparison of rates of failure of energy supply (adenosine triphosphate [ATP] ) in complete global ischemia in dogs (produced by decapitation ) and in incomplete focal ischemia in monkeys (middle cerebral artery [MCA] occlusion ). In the presence of residual cerebral blood flow (CBF) , energy supply failure is substantially delayed.

Energy Failure and Excitotoxicity

Energy failure is the central event that occurs during cerebral ischemia. ATP is required for the maintenance of the normal membrane ionic gradient, and energy failure is rapidly attended by membrane depolarization and influx of sodium (Na ⁺ ) and calcium (Ca ²⁺ ) into the neuron. Voltage-dependent Ca ²⁺ channels are then activated, and Ca ²⁺ gains entry into the cytosol. Depolarization of presynaptic terminals also results in the release of massive quantities of excitatory neurotransmitters, particularly glutamate, into the synaptic cleft. Activation of glutamatergic receptors, the NMDAR, and the α-amino-3-hydroxy-5-methyl-4-isoxazopropionic acid receptors (AMPARs), adds to the influx of Na ⁺ and Ca ²⁺ ( Fig. 11.20 ). Initiation of cellular signaling by the activation of the mGluR leads to the release of stored Ca ²⁺ from the endoplasmic reticulum (ER) via inositol 1,4,5-triphosphate (IP ₃ ) receptors. Ionic influx is accompanied by an influx of water, and neuronal swelling rapidly occurs after membrane depolarization. The injury that is initiated by excessive glutamatergic activity is referred to as excitotoxicity .

During ischemia, depletion of adenosine triphosphate (ATP) leads to neuronal depolarization and the subsequent release of supranormal quantities of neurotransmitters, especially glutamate. Excessive stimulation of ligand-gated channels and the simultaneous opening of voltage-dependent calcium (Ca ²⁺ ) channels permit rapid entry of Ca ²⁺ into neurons. Stimulation of metabotropic glutamate receptors (mGluRs) generates inositol 1,4,5-triphosphate (IP ₃ ) , which causes the release of Ca ²⁺ from the endoplasmic reticulum (ER) and mitochondria. Activation of the α-amino-3-hydroxy-5-methyl-4-isoxazopropionic acid receptors (AMPAR) –gated subset of glutamate receptors also permits excessive entry of sodium (Na ⁺ ) . Excessive free Ca ²⁺ results in the activation of numerous enzymes: protease activation causes the breakdown of the cytoskeleton of the neuron; lipases damage plasma membrane lipids and release arachidonic acid (AA), which is metabolized by cyclooxygenases and lipoxygenases to yield free radicals and other mediators of cell injury; activation of nitric oxide synthase (NOS) leads to the release of nitric oxide (NO) and, in turn, the generation of peroxynitrite (ONOO) , a highly reactive free radical; and activated endonucleases damage DNA, thereby rendering the neuron susceptible to apoptosis. Injury to the mitochondria leads to energy failure, generation of free radicals, and the release of cytochrome c ( cyt c ) from the mitochondria; the latter is one of the means by which neuronal apoptosis is initiated. mGluR, Metabotropic glutamate receptor; NAD ⁺ , oxidized form of nicotinamide adenine dinucleotide; NMDAR, N -methyl- d -aspartate receptor; PARP, poly-ADP-ribose polymerase; ROS, reactive oxygen species; VGCC, voltage-gated calcium channel.

Ca ²⁺ is a ubiquitous second messenger in cells and is a cofactor required for the activation of a number of enzyme systems. The rapid, uncontrolled increase in cytosolic Ca ²⁺ levels initiates the activation of a number of cellular processes that contribute to injury. Cytoskeletal proteins such as actin are cleaved by activated proteases. These enzymes also degrade a number of the protein constituents of the neuron. Lipases attack cellular lipids and produce membrane damage. An important lipase, phospholipase A ₂ , releases fatty acids such as AA from membranes. Metabolism of AA to prostaglandins and leukotrienes by cyclooxygenase and lipoxygenase is accompanied by the generation of superoxide free radicals. The latter, in combination with other free radicals generated in response to mitochondrial injury, can lead to lipid peroxidation and membrane injury. Prostaglandins and leukotrienes also evoke an inflammatory response and are powerful chemotactic drugs. Activation of platelets within cerebral microvessels, as well as an influx of white blood cells into damaged areas, aggravate the ischemic injury by occluding the vasculature.

Deoxyribonucleic acid (DNA) damage is also an important event during ischemic neuronal injury. Generation of free radicals from AA metabolism, from injured mitochondria, and from the production of peroxynitrite from NO leads to oxidative injury to DNA. Activation of endonucleases also produces DNA strand breaks. Under normal circumstances, DNA injury results in the activation of poly–adenosine diphosphate [ADP]–ribose polymerase (PARP), an enzyme that participates in DNA repair. With excessive DNA injury, PARP activity dramatically increases, which can lead to the depletion of nicotinamide adenine dinucleotide (NAD ⁺ ), a substrate of PARP. NAD ⁺ is also an important coenzyme in energy metabolism, and its depletion further exacerbates energy failure.

Lactate formation is an additional element of the pathophysiologic process. Lactic acid is formed as a result of the anaerobic glycolysis that takes place after failure of the supply of oxygen. The associated decrease in pH contributes to the deterioration of the intracellular environment. An increased preischemic serum glucose level may accelerate this process by providing additional substrate for anaerobic glycolysis.

NO, which has emerged as a probable mediator of CBF changes in many normal physiologic states (see the section “Cerebral Metabolic Rate”), is also of relevance to pathophysiologic ischemia. NO is, in fact, a weak free radical that in turn leads to the generation of a more reactive species (peroxynitrite), and it is the killer substance used by macrophages. In cerebral ischemia, NO is probably both friend and foe. During a period of focal ischemia, the vasodilating effect of NO (probably constitutively elaborated NO of endothelial origin) probably serves to augment collateral CBF. However, in the postischemic phase, NO (probably derived from neurons or macrophages) contributes to neuronal injury.

Collectively, the simultaneous and unregulated activation of a number of cellular pathways overwhelms the reparative and restorative processes within the neuron and ultimately leads to neuronal death.

The Nature of Neuronal Death

The neuronal death that occurs in response to these processes has been categorized as necrotic or apoptotic in nature. Necrotic death mediated by excitotoxic injury, is characterized by rapid cellular swelling, condensation and pyknosis of the nucleus, and swelling of the mitochondria and ER. A characteristic of these necrotic neurons is the presence of acidophilic cytoplasm. Necrotic neuronal death results in local infiltration of the brain by inflammatory cells. A considerable amount of collateral damage is a consequence of this inflammation.

Neuronal apoptosis, a form of cellular suicide , has also been demonstrated in a variety of models of cerebral ischemia. Apoptosis is characterized by chromatin condensation, involution of the cell membrane, swelling of mitochondria, and cellular shrinkage. In the later stages of apoptosis, neurons fragment into several apoptotic bodies, which are then cleared from the brain. The lack of a substantial inflammatory response to apoptotic death limits injury to surrounding neurons that have survived the initial ischemic insult.

A number of biochemical pathways that lead to apoptosis have been described. Initiation of apoptosis by the release of cytochrome c from injured mitochondria has been studied extensively ( Fig. 11.21 ). Cytochrome c is restricted from the cytoplasm by the outer mitochondrial membrane. When mitochondria are injured, pores within the outer membrane allow cytochrome c to be released into the cytoplasm, where it interacts with procaspase-9 and apoptosis-activating factor (APAF) to produce an apoptosome. Procaspase-9 undergoes activation by proteolytic cleavage. Activated caspase-9 then activates caspase-3. The latter serves as an executor of apoptosis by cleaving a number of protein substrates that are essential in DNA repair (such as PARP). Activation of caspase-3 can also occur by inflammatory signaling via tumor necrosis factor alpha (TNF-α) and the activation of caspase-8. It should be noted that the neuronal injury that occurs in response to ischemia cannot be easily divided into necrosis or apoptosis. The nature of neuronal death probably encompasses a spectrum in which some neurons undergo either necrosis or apoptosis, whereas others undergo cell death that has features of both necrosis and apoptosis.

Cellular processes that lead to neuronal apoptosis. Cytochrome c (cyt c) , which is normally restricted to the space between the inner and outer mitochondrial membranes, is released in response to mitochondrial injury. Cyt c, in combination with apoptosis-activating factor (APAF) , activates caspase-9 by proteolytic cleavage. Activated caspase-9 then leads to the activation of caspase-3. This enzyme cleaves a number of substrates, including those necessary for DNA repair. Within the mitochondria, Bax augments and Bcl prevents the release of cyt c. The release of cyt c can also be initiated by Bid, a substance that is activated by caspase-8 via tumor necrosis factor (TNF) signaling. In addition, caspase-8 can directly activate caspase-3. Excessive activation of poly-ADP-ribose polymerase, an enzyme integral to DNA repair, depletes cellular stores of oxidized nicotinamide adenine dinucleotide (NAD ⁺ ). Depletion of NAD ⁺ further exacerbates the energy failure because of its critical role in energy metabolism.

Timing of Neuronal Death

The traditional concept of ischemic injury was that neuronal death was restricted to the time of ischemia and during the early reperfusion period. However, more recent data indicate that postischemic neuronal injury is a dynamic process during which neurons continue to die for a long period after the initiating ischemic insult ( Fig. 11.22 ). This delayed neuronal death, which was first demonstrated in models of global cerebral ischemia, has been demonstrated during focal ischemia as well. The extent of delayed neuronal death depends on the severity of the ischemic insult. With severe ischemia, most neurons undergo rapid death. With more moderate insults, neurons that survive the initial insult undergo delayed death. This ongoing neuronal loss contributes to the gradual expansion of cerebral infarction after focal ischemia. In experimental studies, evidence of cerebral inflammation, which can theoretically contribute to further injury, has been demonstrated even 6 to 8 months after the primary ischemia.

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