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Effects of Anesthetic Agents and Other Drugs on Cerebral Blood Flow, Metabolism, and Intracranial Pressure
Introduction
The major goals in neurosurgical anesthesia are to provide adequate tissue perfusion to the brain (and spinal cord) so that the regional metabolic demand is met and to provide adequate surgical conditions (a “relaxed brain”). If anesthetic drugs or anesthetic techniques are improperly used, they can worsen the existing intracranial pathologic condition and may produce new damage. Some anesthetics or anesthetic techniques may help protect the brain subjected to metabolic stress or even ameliorate damage from such an insult. Thus, knowledge of the effects of anesthetics and anesthetic techniques on cerebral circulation, metabolism, and intracranial pressure (ICP) both in normal and pathologic conditions is important. In addition, special attention must be paid in the case of functional neurosurgery or minimally invasive surgery, such as awake surgery, stereotaxic surgery, identification of epileptic foci, and neuroradiological interventional procedures, in which anesthesiologists should consider using anesthetics and adjuvant drugs that allow control of asleep-awake-asleep status or sedation with analgesia and no or minimal interference with brain electrophysiologic monitoring or neurologic findings. While providing such a state, the anesthesiologist should ensure patency of the airway with well-maintained ventilation and circulatory stability.
In this chapter, physiologic and pharmacologic considerations in relation to neurosurgical anesthesia are summarized, followed by a review of the effects of anesthetics and other drugs on cerebral blood flow (CBF), cerebral metabolism, and ICP, focusing on human data. Data from animal studies are cited only when there are not sufficient human data. The clinical relevance of these issues to the practice of neurosurgical anesthesia is discussed.
Physiologic and pharmacologic considerations in relation to neurosurgical anesthesia
Blood Flow and Metabolism Changes in Relation to Functional Changes
Under physiologic conditions, the brain vessel diameter changes within seconds in response to the changes in neuronal activity that immediately influence metabolic demand. Although the cellular mechanisms underlying the coupling of neuronal activation to cerebral blood vessel responses are not fully determined, it has been proposed that the energy (metabolic) demand caused by neuronal activity increases blood flow. The underlying metabolic signals could be a lack of O 2 or glucose, or the production of CO 2 . However, studies have demonstrated that blocking the enzymes that generate nitric oxide (NO) and arachidonic acid derivatives downstream of glutamate receptors greatly reduces functional hyperemia with little effect on the energy use associated with neuronal activity. , From these data, a “feed-forward mechanism” has been proposed in which glutamate released from presynaptic nerve terminals activates both neurons and astrocytes, leading to the release of vasoactive substances from both cell types. As this feed-forward mechanism is not driven by energy demand, the fractional increase in blood flow induced by sustained neuronal activity is greater than the increase in neuronal adenosine triphosphate (ATP) consumption. The vasoactive substances include NO, prostaglandin E 2 (PGE 2 ), potassium ions (K + ), epoxyeicosatrienoic acid (EET), and arachidonic acid. NO, PGE 2 , K + , and EET dilate vessels. In contrast, arachidonic acid released from astrocytes is converted to 20-hydroxy- eicosatetraenoic acid (20-HETE) in vascular smooth muscle cells, which constricts vessels. Whether astrocytic activation leads to vasodilation or vasoconstriction may depend on preexisting vessel tone.
Traditionally, blood flow is controlled solely by arteriole smooth muscle. However, recent evidence suggests that vasodilatory substances, such as PGE 2 or related substances, can actively relax the pericytes that regulate the diameter of capillaries. In an animal study, it was demonstrated that capillaries dilate before arterioles in response to neuronal activity and that most of the increase in blood flow can be attributed to capillary dilation. The role of pericytes in controlling cerebral blood flow remains to be determined.
As neurons have a limited energy reserve, sufficient ATP should be generated to match energy demand, which changes dramatically with neuronal activity. To explain how ATP is generated on demand, the “astrocyte-neuron lactate shuttle hypothesis” was proposed, in which astrocytic activation by glutamate released from neurons stimulates glucose uptake into astrocytes; glucose is processed glycolytically, resulting in a release of lactate as an energy substrate for neurons. This hypothesis is based on the finding that cerebral activation resulted in a much greater increase in glucose consumption than in oxygen consumption. However, a smaller discrepancy between the increase of glucose and oxygen use was also reported. Recent quantitative work has shown that most of the ATP produced in response to increased neuronal activity is generated by oxidative phosphorylation. It appears that the extent to which astrocytes feed neurons still remains controversial.
Anesthetics cause functional alterations in the central nervous system and produce metabolic changes. In general, intravenous anesthetics decrease cerebral metabolic rate (CMR) and CBF in parallel fashion, whereas most inhalational anesthetics decrease CMR with an increase in CBF. At first sight, the coupling of CMR and CBF is maintained with intravenous anesthetics, whereas it is lost with inhalational anesthetics. However, a strong correlation exists between CMR and CBF within individual brain structures during anesthesia. Indeed, during burst and suppression phases of electroencephalogram (EEG) with isoflurane anesthesia, cerebral blood flow velocity of middle cerebral artery (Vmca) appears to increase and decrease, respectively. , In addition, seizure activity or noxious stimuli during anesthesia produce parallel increases in CBF and CMR. Because the net effect of anesthetics on CBF is a balance between their direct effects on cerebral vessels and indirect effects caused by CMR changes, it is probable that the coupling of CMR and CBF is maintained with anesthetics but is modified by direct effects of anesthetics on vascular tone.
Blood Flow Changes in Relation to Cerebral Perfusion Pressure and CO 2
Cerebral perfusion pressure (CPP) and carbon dioxide tension in the arterial blood (PaCO 2 ) are the important variables that influence CBF. Autoregulation is the physiologic maintenance of constant CBF over a wide range of CPP values. Traditionally, CPP is determined as the difference between mean arterial blood pressure (MABP) and the greater of ICP or CVP. In the patient with intracranial hypertension, effective downstream pressure is determined by ICP. Advances in flow measurement techniques have demonstrated beat-to-beat flow changes and the concept of apparent zero flow pressure, at which flow ceases. Apparent zero flow pressure has been proposed as an estimate of critical closing pressure that may better estimate CPP. Zero-flow pressure is extrapolated by linear regression analysis of the arterial blood-pressure–Vmca relationship. The arterial blood pressure-axis intercept of the regression line determines zero-flow pressure. In conditions of increased cerebrovascular tone, such as hypocapnia or pharmacologically induced vasoconstriction, ICP does not uniquely determine effective downstream pressure.
CO 2 can produce marked changes in cerebrovascular resistance (CVR) and CBF. Over a range of PaCO 2 values of 20 to 80 mmHg, for each 1 mmHg increase or decrease in PaCO 2 there is a 2% to 4% increase or decrease in CBF. Changes in the extracellular hydrogen ion (H + ) concentration, NO, prostanoids, cyclic nucleotides, intracellular calcium, and potassium channel activity have been regarded as regulatory factors for cerebrovascular reactivity to CO 2 . Compared with adults, children have less cerebral reactivity to CO 2 changes. Whether this difference is related to possible domination of prostaglandin and cyclic guanosine monophosphate in regulating vascular tone in children remains to be determined.
As CO 2 affects CVR and CBF, the autoregulation curve changes according to CO 2 levels. During hypercapnia, the plateau ascends and shortens, the lower limit shifts rightward, and the upper limit shifts leftward. In contrast, during hypocapnia, the plateau descends and the lower limit remains unchanged. How the upper limit moves during hypocapnia is not clear.
Changes in Cerebral Blood Flow and Intracranial Pressure Regulation in Pathologic Conditions
Patients who undergo neurosurgery may have various types of intracranial pathologic conditions as well as systemic diseases, and their responses to anesthetics may be different from those of normal subjects. Brain tissue hypoxia, acidosis, and edema are the main pathologic consequences of most brain disorders. Cerebral vasoparalysis occurs, and coupling between blood flow and metabolism is impaired. Under these circumstances, autoregulation and CO 2 reactivity are also disturbed. Strict blood pressure control and respiratory management are required.
In the event of focal cerebral ischemia, hypercapnia can dilate the vessels in the normal area but not in the damaged area, and, consequently, blood flow may be shunted from the ischemic to the normal area (intracerebral steal or the “reversed Robin Hood effect”). As intracerebral steal has been documented in acute ischemic stroke patients, hypercapnia should be avoided in these patients. Conversely, hypocapnia can divert blood from the normal area to the ischemic area (inverse intracerebral steal, or the “Robin Hood effect”). However, no beneficial effect was found in an animal experiment when hyperventilation was initiated at 1 hour after focal cerebral ischemia. Because of a lack of evidence indicating the possible beneficial effect on outcome, hyperventilation cannot be recommended in patients who have experienced stroke.
Although the effect is not confirmed for every anesthetic, experimental data in animals suggest that intracerebral steal or inverse intracerebral steal may also be induced pharmacologically. However, the effect of anesthetics on cerebral blood flow redistribution is unpredictable because anesthetics modulate cerebral vessel diameter by both their direct vasoactive property and indirect effects caused by CMR changes.
Anesthesia alters ICP through changes in cerebral blood volume (CBV). Although correlation between CBV and CBF does not always exist, the changes in CBV, in general, appear to be proportional to the changes in CBF. Therefore, an increase in CBF causes an increase in CBV and, thus ICP. Increases in blood pressure, especially when autoregulation is impaired, also produce an increase in CBV. Mechanical effects, such as the patient’s position and respiratory pattern (by influencing intrathoracic pressure) also may affect ICP. , Muscle activity during the patient’s movement may raise central venous pressure (CVP) and ICP. Anesthetic agents also affect ICP by changing the rate of production and reabsorption of cerebrospinal fluid (CSF) (see Chapter 3 ). Intracranial physiology and pathophysiology in relation to the use of anesthetics and adjuvant drugs are summarized in Fig. 4.1 .
Effects of specific anesthetic drugs and other drugs
Inhalational Anesthetics
In general, all inhalational anesthetics are cerebral vasodilators and possess the capability of increasing ICP. Inhalational anesthetics, with the possible exception of nitrous oxide (N 2 O), usually depress metabolism. Although the coupling of neuronal activation to cerebral blood vessel responses seems to work even with high concentrations of inhalational anesthetics, direct vasodilation surpasses indirect vasoconstriction by the reduction of CMRO 2 , resulting in a higher CBF/CMRO 2 ratio. Table 4.1 summarizes the effects of inhalational anesthetics on CBF, CMR, and ICP.
Table 4.1
Summary of the Effects of Inhalational Anesthetics on Cerebral Blood Flow, Cerebral Metabolic Rate, and Intracranial Pressure
| Cerebral Blood Flow | Cerebral Metabolic Rate | Intracranial Pressure | |
|---|---|---|---|
| N 2 O | ↑↑ | ↑ or → | ↑↑ |
| Xenon | ↓ (Gray) ↑ (White) | ↓ | ↑ or → |
| Isoflurane | ↑ or → | ↓↓ | → or ↗ or ↑ |
| Sevoflurane | ↓ or → or ↗ | ↓ or ↓↓ | → or ↗ or ↑ |
| Desflurane | ↓ or ↑ | ↓↓ | ↑ or → |
Nitrous Oxide
It is generally agreed that N 2 O increases CBF, CMR, and ICP; however, in humans, some studies did not observe an increase in CMR. The magnitude of changes varies substantially. The cause of this variation may be the concentrations examined and its use in combination with other drugs that may modify its original effect. The most dramatic increases in CBF and ICP occurred when N 2 O was administered alone or with minimal background anesthetics. The increases in CBF and CMRO 2 with N 2 O do not appear to be related solely to the sympathetic hyperactivity. N 2 O appears to have no direct vasodilating effect.
Marked heterogeneity in regional cerebral blood flow (rCBF), regional CBV (rCBV), and regional CMR (rCMR) during administration of N 2 O alone has been revealed with positron emission tomography (PET) and magnetic resonance imaging (MRI). Subanesthetic concentrations of N 2 O (20%) increase rCBF and rCMR in the anterior cingulate cortex, with opposite effects occurring in the posterior cingulate, hippocampus, parahippocampal gyrus, and visual cortices. N 2 O 30% increased CBF in the global gray matter by 22%, with no change detected in global CMRO 2 . At N 2 O 50%, rCBF and rCBV increased in all gray-matter regions, although the increase in rCBF was less pronounced in basal ganglia. Global cerebral metabolic rates for glucose (CMRg) was unchanged with N 2 O 50%, but regional metabolism was changed; regional CMRg increased in the basal ganglia and thalamus and this effect was present 1 hour after discontinuation of N 2 O.
N 2 O, when added to volatile anesthetics, raises CBF, but CMR is either increased or unchanged. Indirect evidence—measurements of Vmca—has shown that N 2 O raises CBF. , In patients with brain tumors, N 2 O increased Vmca, but the increase was completely reversed by hyperventilation. ,
The addition of N 2 O 70% to anesthesia with propofol (EEG isoelectric) in non-neurosurgical patients produced a 20% increase in Vmca with greater oxygen and glucose use in association with EEG activation. A PET study in humans showed that N 2 O 70% counteracted almost all rCBF reductions and some of rCMRO 2 reductions produced by propofol at a dose of clinical anesthesia (EEG activity remained). In contrast, in animal studies, a high dose of thiamylal or pentobarbital has been shown to abolish the N 2 O-induced increases in CBF or CMRO 2 . Regional metabolic studies in rats demonstrated that N 2 O 67% did not change local cerebral metabolic rates for glucose (lCMR g ), with a nearly isoelectric EEG by pentobarbital. Whether the differences in modification of N 2 O-induced increases in CBF or CMR by other anesthetics are due to the differences in species, methods, or the dose ranges of the anesthetics examined is not clear.
An increase in ICP caused by N 2 O has been repeatedly demonstrated. The rise in ICP can be attenuated by prior administration of thiopental, diazepam, or morphine, or by induction of hypocapnia. It is advisable to use hypocapnia, cerebral vasoconstricting drugs, or both, when N 2 O is administered, especially in patients with reduced intracranial compliance.
Some authorities have proposed that N 2 O has neurotoxic properties based on data from experimental animals. It has been reported that N -methyl- d -aspartate (NMDA) receptor blockade during synaptogenesis in the immature brain can induce neuronal degeneration. This effect occurs not only with anesthetics with an NMDA receptor blocking property (N 2 O, xenon, and ketamine) but also with those acting as gamma- aminobutyric acid (GABA) receptor modulators (propofol, midazolam, barbiturates, and isoflurane). However, it has been demonstrated that NMDA receptor antagonists protect against ischemic brain injuries. N 2 O may have both neuroprotective and neurotoxic properties. In humans, post-hoc analysis of data acquired as part of the Intraoperative Hypothermia for Aneurysm Surgery Trial (IHAST) showed no detrimental effect on the long-term gross neurological or neuropsychological outcome with the use of N 2 O during cerebral aneurysm clipping. ,
N 2 O enlarges the volume of potential air space, and thus its use is restricted in patients with intracranial or intravascular air compartment. Further, the incidence of nausea and vomiting appears to increase in patients exposed to N 2 O for more than 1 hour, which may also restrict its use in neurosurgical patients. Since drugs that provide easily controllable analgesia are available, such as remifentanil, the use of N 2 O in neurosurgical anesthesia has decreased.
Xenon
PET showed that xenon 1 MAC decreases absolute rCBF by 11% in the gray matter and increases it by 22% in the white matter, with greater reductions in the cerebellum (by 35%), thalamus (by 23%), and cortical areas (by 9%). The decreased rCBF in the gray matter may be a result of reduced metabolism, as evidenced by the comparable reductions in CMRg in the corresponding brain areas. A later study that determined concomitant changes in rCBF and rCMRg in the same individuals during 1 MAC xenon anesthesia supported the results of these studies. Xenon anesthesia induces a uniform reduction in rCMRg, whereas rCBF decreased in 7 of 13 brain regions. The mean decreases in gray matter were 32% and 15% for rCMRg and rCBF, respectively, resulting in signs of moderate luxury perfusion in some brain areas including the pre- and postcentral gyri, insula, and anterior and posterior cingulate. Though the reduction in CMR is less pronounced than those reported with volatile anesthetics, the metabolic pattern produced with xenon resembles those produced with volatile anesthetics rather than with N 2 O. , ,
During steady state xenon 70% inhalation in rats, having achieved stable cardiovascular conditions, mean values of CBF and CMRg did not change from conscious control values, but during short inhalation of xenon 70%, CBF increased by 40–50%. In pigs, xenon 79% increased rCBF approximately 40% more than total intravenous anesthesia control. However, xenon (30–70%) was reported to have no effect on rCBF and autoregulation in pigs sedated with propofol. It should be noted that MAC of xenon varies among species (71% in humans, 98% in monkeys, 119% in pigs, 85% in rabbits, 161% in rats), and this variation may explain the different results among the species.
The effects of xenon on ICP in patients with head injury are variable; ICP has been found to either increase by 7 mmHg or not to change with xenon 0.45 MAC. In animals either with normal ICP or with elevated ICP, , xenon (0.34–0.7 MAC) did not change ICP. At present, in humans, xenon appears to be a mild cerebral metabolic depressant and its effect on CBF and ICP is mild. In a newborn global hypoxic- ischemic pig model under propofol and remifentanil anesthesia, post-insult administration of xenon reportedly preserves autoregulation.
Because xenon is an antagonist of the NMDA receptor, it may have neuroprotective effects. Indeed, neuroprotection by inhalation of xenon before injury was demonstrated in both in-vitro and in-vivo cerebral ischemia , and traumatic brain injury models, the effect being observed even with post-treatment after hypoxic-ischemic insult in neonatal rats and after traumatic brain injury in adult mice. In combination with either hypothermia (35 °C) or the α 2 - adrenergic agonist dexmedetomidine, xenon exhibited neuroprotection in the same model. Also, it was reported that preconditioning by xenon (70%) reduced brain damage from hypoxia-ischemia in neonatal rats. A later study has demonstrated that xenon (50%) provides long-term neuroprotection in a neonatal hypoxia-ischemia model and that this protection is augmented by concomitant application of moderate hypothermia (32 °C). In a rat transient middle cerebral artery occlusion model, the combination of 30% xenon and subtherapeutic hypothermia (36 °C) after reperfusion has also been demonstrated to provide long-term neuroprotection. However, xenon was also reported to cause neuronal cell death in an in-vitro model of the developing rodent brain at 1 MAC, as does isoflurane and sevoflurane at similarly potent concentrations.
With its low blood/gas partition coefficient of 0.115, xenon may offer advantage for neuroanesthesia use, because early neurologic examination after the emergence period is possible and may be desirable. However, this agent’s effects when combined with other anesthetics should be further determined.
Halothane
Most studies demonstrated that halothane induces cerebral vasodilation and increases CBF, provided that the systemic blood pressure is maintained. The increase in cortical CBF appears greater with halothane than with isoflurane at equi-MAC concentrations. It is probably true that the potency of overall vasodilating property of halothane appears to be most prominent among available volatile anesthetics.
A dose-related cerebral metabolic depressive effect of halothane has been demonstrated repeatedly. At clinical levels of anesthesia, the decrease in global CMRO 2 ranges from 10% to 30%. A study using PET demonstrated that halothane anesthesia titrated to a point just beyond the loss of consciousness is associated with a 40% reduction of whole-brain glucose metabolism, the magnitude of reduction being similar to that with isoflurane.
Halothane raises ICP in a dose-related fashion, and the rise in ICP is parallel to that in CBF. The elevation of ICP with halothane appears to be most prominent among the commonly used volatile anesthetics. However, at 0.5 MAC or less, the effect on ICP is minimal. The increased ICP that, with halothane, often occurs in association with systemic hypotension results in reduced CPP. This response may augment the risk of cerebral ischemia. The increase in ICP may be attenuated either by hyperventilation or by barbiturates. However, the beneficial effects of hypocapnia may not be obtained when the initial ICP is very high or reactivity to CO 2 is lost globally.
In summary, although halothane in low concentrations (less than 1%) can be safely used in clinical neuroanesthesia practice when PaCO 2 is reduced and barbiturates (and probably propofol) also are given, the margin of safety is probably wider with isoflurane, desflurane, or sevoflurane than with halothane.
Isoflurane
In general, the increase in global CBF is smaller with isoflurane than with halothane. However, at a given level of metabolic rate, isoflurane possesses greater cerebral vasodilating capabilities than halothane. It has been demonstrated that halothane, isoflurane, and desflurane at 0.5 MAC produces a similar increase in Vmca in humans during propofol-induced isoelectric EEG, whereas at 1.5 MAC, isoflurane and desflurane have greater vasodilating effects than halothane. The net effect of inhalational anesthetics on CBF is a balance between a reduction in CBF caused by CMR suppression and augmentation of CBF due to direct cerebral vasodilation; the reported smaller increases in CBF with isoflurane than with halothane may occur from a more potent cerebral metabolic depressive effect of isoflurane. The hypothetical illustrations of changes in CBF with rising concentrations of halothane and isoflurane are shown in Fig. 4.2 .
In PET studies in humans, isoflurane (0.2–1.0 MAC) was reported to produce no change in global CBF but to cause regional increase (anterior cingulate and insula regions) and decrease (cerebellum, thalamus, and lingual gyrus) in relative CBF. Additionally, isoflurane (0.5%) was reported to reduce whole brain metabolism by almost 50%, and this reduction was fairly uniform throughout the brain.
It is unlikely that any single mechanism is entirely responsible for the vasodilative property of isoflurane. Some investigators speculate that the vasodilative property of isoflurane may be related to NO. It was also reported that approximately one-third of the cortical hyperemic response to isoflurane measured by laser Doppler flowmetry is mediated by NO, prostaglandins, and epoxyeicosatrienoic acid, and that the remaining part of the response appears to be mediated by a direct action on smooth muscle. A study using a closed cranial window model demonstrated that an adenosine triphosphate (ATP)-sensitive K + channel blocker, glibenclamide, attenuates isoflurane (and sevoflurane)-induced cerebral vasodilation, suggesting that vasodilation with these anesthetics is mediated, at least in part, via activation of ATP-sensitive K + channels.
Gray matter rCBV is increased with isoflurane when the systemic blood pressure is maintained (0.45%), and thus ICP can increase. Data on ICP appear to be inconsistent, and lumbar cerebrospinal fluid pressure (CSFP) increased in one study, while ICP did not change in another. Because ICP was reported to be lower in the patients anesthetized with propofol- fentanyl than those anesthetized with isoflurane-fentanyl, propofol-fentanyl may be preferable in the setting of unstable ICP. In the intensive care unit (ICU) setting, two studies have showed that isoflurane (0.5–0.8 MAC) does not cause a clinically relevant increase in ICP in patients with subarachnoid hemorrhage, intracerebral hemorrhage, or ischemic stroke if baseline ICP values are low or only moderately elevated. ,
Because of the potent cerebral metabolic depressive effect, isoflurane was predicted to have cerebral protective effects, which may be produced by a variety of the mechanisms, including inhibition of excitatory neurotransmission, potentiation of GABA A receptor, regulation of intracellular calcium responses, and activation of TWIK (tandem of P domains in a weak inwardly rectifying K + channel)-related K + (TREK)-1 two-pore-domain K + channels. Indeed, many animal studies demonstrated the neuroprotective properties of isoflurane within clinically relevant concentrations. However, the protection with isoflurane is only applicable to mild insults, being inferior to and less durable than mild hypothermia in its neuroprotective effect. Also, it is important to note that isoflurane has preconditioning , and postconditioning effects. In the developing brain, the neurotoxicity of isoflurane has been reported.
In the clinical setting, there is no good evidence that isoflurane uniquely protects against ischemic central nervous system injury. Suggestive observations include those in a large retrospective review of changing anesthetic management practices during carotid endarterectomy in humans. The critical CBF below which ischemic EEG changes occur was greater in patients anesthetized with halothane than in patients anesthetized with isoflurane. At a comparable level of rCBF, the incidence of EEG ischemic changes with isoflurane has been reported to be significantly lower than that seen with halothane.
In summary, isoflurane appears to produce a mild increase in CBF and a pronounced decrease in cerebral metabolism. The accumulated evidence in basic research strongly suggests that isoflurane has a cerebral protective effect, although it is not proven clinically. However, isoflurane may be a desirable anesthetic for many neurosurgical procedures, including carotid endarterectomy. The increase in ICP caused by isoflurane, if it occurs, may be mild and can be prevented by hypocapnia. However, when ICP elevation should definitely be avoided, propofol in combination with synthetic opioid may be preferable.
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