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Cerebral Physiology and the Effects of Anesthetic Drugs
Key Points
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The brain has a high metabolic rate and receives approximately 12% to 15% of cardiac output. Under normal circumstances, cerebral blood flow (CBF) is approximately 50 mL/100 g/min. Gray matter receives 80% and white matter receives 20% of this blood flow.
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Approximately 60% of the brain’s energy consumption supports electrophysiologic function. The remainder of the energy consumed by the brain is involved in cellular homeostatic activities.
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CBF is tightly coupled to local cerebral metabolism, a process called neurovascular coupling. When cerebral activity in a particular region of the brain increases, a corresponding increase in blood flow to that region takes place. Conversely, suppression of cerebral metabolism leads to a reduction in blood flow.
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CBF is autoregulated and remains constant over a mean arterial pressure (MAP) range estimated at 65 to 150 mm Hg, given normal venous pressure. CBF becomes pressure passive when MAP is either less than the lower limit or more than the upper limit of autoregulation. The lower and upper limits, as well as the range and slope of the plateau, manifest significant variability between individuals.
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CBF is also under chemical regulation. CBF varies directly with arterial carbon dioxide tension (Pa co 2 ) in the range of 25 to 70 mm Hg. When arterial partial pressure of oxygen (Pa o 2 ) decreases to less than 60 mm Hg, CBF increases dramatically. Reductions in body temperature influence CBF primarily by the suppression of cerebral metabolism.
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Systemic vasodilators (e.g., nitroglycerin, nitroprusside, hydralazine, and calcium channel blockers) vasodilate the cerebral circulation and can, depending on the MAP, increase CBF. Vasopressors such as phenylephrine, norepinephrine, ephedrine, and dopamine do not have appreciable direct effects on the cerebral circulation. Their effect on CBF is via their effect on arterial blood pressure. When the MAP is less than the lower limit of autoregulation, vasopressors increase the MAP and thereby increase CBF. If the MAP is within the limits of autoregulation, then vasopressor-induced increases in systemic pressure have little effect on CBF.
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All volatile anesthetics suppress cerebral metabolic rate (CMR) and, with the exception of halothane, can produce burst suppression of the electroencephalogram. At that level, the CMR is reduced by approximately 60%. Volatile anesthetics have dose-dependent effects on CBF. In doses less than the minimum alveolar concentration (MAC), CBF is modestly decreased. In doses larger than 1 MAC, direct cerebral vasodilation results in an increase in CBF and cerebral blood volume (CBV).
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Barbiturates, etomidate, and propofol decrease the CMR and can produce burst suppression of the electroencephalogram. At that level, the CMR is reduced by approximately 60%. Because neurovascular coupling is preserved, CBF is decreased. Opiates and benzodiazepines effect minor decreases in CBF and CMR. In contrast, ketamine can increase CBF significantly, in association with a modest increase in CMR.
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Brain stores of oxygen and substrates are limited, and the brain is extremely sensitive to decreases in CBF. Severe decreases in CBF (<6-10 mL/100 g/min) lead to rapid neuronal death. Ischemic injury is characterized by early excitotoxicity and delayed apoptosis.
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Barbiturates, propofol, ketamine, volatile anesthetics, and xenon have neuroprotective efficacy and can reduce ischemic cerebral injury in experimental models. This anesthetic neuroprotection is sustained only when the severity of the ischemic insult is mild; with moderate-to-severe injury, long-term neuroprotection is not achieved. The neuroprotective efficacy of anesthetics in humans is limited. Administration of etomidate can decrease regional blood flow, which can exacerbate ischemic brain injury.
This chapter reviews the effects of anesthetic drugs and techniques on cerebral physiology—in particular, their effects on cerebral blood flow (CBF) and metabolism. The final section presents a brief discussion of pathophysiologic states, including cerebral ischemia and cerebral protection. Attention is directed to the rationale for selection and appropriate use of the anesthetic agents for neuroanesthetic management. Chapter 57 presents the clinical management of these patients in detail. Neurologic monitoring, including the effects of anesthetics on the electroencephalogram (EEG) and evoked responses, is reviewed in Chapter 39 .
The Anatomy of the Cerebral Circulation
The arterial blood supply to the brain is composed of paired right and left internal carotid arteries, which give rise to the anterior circulation, and paired right and left vertebral arteries, which give rise to the posterior circulation. The connection of the two vertebral arteries forms the basilar artery. The internal carotid arteries and the basilar artery connect to form a vascular loop called the circle of Willis at the base of the brain that permits collateral circulation between both the right and left and the anterior and posterior perfusing arteries. Three paired arteries that originate from the circle of Willis perfuse the brain: anterior, middle, and posterior cerebral arteries. The posterior communicating arteries and the anterior communicating artery complete the loop. The anterior and the posterior circulations contribute equally to the circle of Willis.
Under normal circumstances, blood from the anterior and posterior circulations does not admix because the pressures in the two systems are equal. Similarly, side-to-side admixing of blood across the circle is limited. The vessels that originate from the circle provide blood flow to well-delineated regions of the brain. However, in pathologic circumstances during which occlusion of one of the arterial branches occurs, the circle of Willis can provide anterior-posterior or side-to-side collateralization to deliver flow to the region of the brain with reduced perfusion.
A complete circle of Willis is shown in Fig. 11.1 A . However, substantial variability exists in the anatomy of the circle of Willis, and a significant proportion of individuals may have an incomplete circular loop. The variations in the circle and their prevalence are shown in Fig. 11.1 B .
Three sets of veins drain blood from the brain. The superficial cortical veins are within the pia mater on the brain’s surface. Deep cortical veins drain the deeper structures of the brain. These veins drain into dural sinuses, of which the superior and inferior sagittal sinuses and the straight, transverse and sigmoid sinuses are the major dural sinuses. These ultimately drain into the right and left internal jugular veins.A schematic representation of the cerebral venous circulation is shown in Fig. 11.1 C .
There is considerable asymmetry in the blood flow between the right and left internal jugular veins. In approximately 65% of patients, flow in the right IJV is greater than in the left; in the remainder, the left IJV is dominant. The pattern of venous drainage may have implications for insertion of jugular venous catheters for the measurement of jugular venous oxygen saturation (SjVO 2 ). To ensure accurate measurement of SjVO 2 , it has been advocated that the catheter be inserted into the dominant jugular vein. In most patients, the right IJV will be the dominant vein.
Cerebrospinal Fluid Formation and Circulation
Cerebrospinal fluid (CSF) is produced primarily by the choroid plexus in the lateral, third, and fourth ventricles; there are small contributions from the endothelial cells and from fluid that is produced as a consequence of metabolic activity. CSF production is the result of hydrostatic efflux from capillaries into the perivascular space, and then active transport into the ventricles. CSF reabsorption occurs primarily via the arachnoid granulations present in the dural sinuses. A smaller proportion of CSF, which tracks along cranial and peripheral nerves, perivascular routes, and along white matter tracts, gains access to the cerebral venous system by transependymal flow. The total CSF space is approximately 150 mL and total daily CSF production averages 450 mL. Therefore, there is a substantial daily turnover of CSF. CSF production is also under the influence of the circadian rhythm, with the peak production of CSF occurring during sleep.
Recently, the concept of the glymphatic pathway as a means by which waste products are removed from the brain has been advanced. Conceptually, the glymphatic pathway can be visualized as a system akin to the lymphatic system in the systemic circulation (note, however, that the brain does not contain lymphatics other than those present in the meninges). Functionally, CSF enters the periarterial space, a space that is bounded by the vessels and the end-feet of astrocytes. Aquaporin channels on the end-feet facilitate this water exchange. From the periarterial space, CSF is transported to the brain parenchyma, and from there to the perivenous space and on to the ventricles. As such, the glymphatic system serves as a waste disposal system. Of considerable interest is the observation that the periarterial space increases significantly during sleep and during general anesthesia; hence, glymphatic transport and waste clearance is increased during these states. Among anesthetic agents, glymphatic transport is reduced by volatile agents but is less affected by dexmedetomidine.
Regulation of Cerebral Blood Flow
Anesthetic drugs cause dose-related and reversible alterations in many aspects of cerebral physiology, including CBF, cerebral metabolic rate (CMR), and electrophysiologic function (EEG, evoked responses). The effects of anesthetic drugs and techniques have the potential to adversely affect the diseased brain and are thus of clinical importance in patients with neurosurgical disease. Conversely, the effects of general anesthesia on CBF and CMR can be altered to improve both the surgical course and the clinical outcome of patients with neurologic disorders.
The adult human brain weighs approximately 1350 g and therefore represents approximately 2% of total body weight. However, it receives 12% to 15% of cardiac output. This high flow rate is a reflection of the brain’s high metabolic rate. At rest, the brain consumes oxygen at an average rate of approximately 3.5 mL of oxygen per 100 g of brain tissue per minute. Whole-brain oxygen consumption (50 mL/min) represents approximately 20% of total body oxygen utilization. Normal values for CBF, CMR, and other physiologic variables are provided in Box 11.1 .
BOX 11.1
Normal Cerebral Physiologic Values (Values Updated)
| CBF | |
| Global | 45-55 mL/100 g/min |
| Cortical (mostly gray matter) | 75-80 mL/100 g/min |
| Subcortical (mostly white matter) | 8-20 mL/100 g/min |
| CMRO 2 | 3-3.5 mL/100 g/min |
| CVR | 1.5-2.1 mm Hg/100 g/min/mL |
| Cerebral venous P o 2 | 32-44 mm Hg |
| Cerebral venous S o 2 | 55%-70% |
| rSO2 | 55%-80% |
| SjV o 2 | 60%-70% |
| ICP (supine) | 8-12 mm Hg |
CBF, Cerebral blood flow; CMRO 2 , cerebral metabolic rate of oxygen; CVR, cerebral vascular resistance; ICP, intracranial pressure; P o 2 , partial pressure of oxygen; rSO 2 , regional oxygen saturation measured by near-infrared spectroscopy; S o 2 , oxygen saturation; SjV o 2 , jugular venous oxygen saturation.
Approximately 60% of the brain’s energy consumption supports electrophysiologic function. The depolarization-repolarization activity that occurs, reflected in the EEG, requires expenditure of energy for the maintenance and restoration of ionic gradients and for the synthesis, transport, release, and reuptake of neurotransmitters. The remainder of the energy consumed by the brain is involved in cellular homeostatic activities ( Fig. 11.2 ). Local CBF and CMR within the brain are very heterogeneous, and both are approximately four times greater in gray matter than in white matter. The cell population of the brain is also heterogeneous in its oxygen requirements. Glial cells make up approximately one half of the brain’s volume and require less energy than neurons. Besides providing a physically supportive latticework for the brain, glial cells are important in the reuptake of neurotransmitters, in the delivery and removal of metabolic substrates and wastes, and in blood-brain barrier (BBB) function.
Given the limited local storage of energy substrate, the brain’s substantial demand for substrate must be met by adequate delivery of oxygen and glucose. However, the space constraints imposed by the noncompliant cranium and meninges require that blood flow not be excessive. Not surprisingly, elaborate mechanisms regulate CBF. These mechanisms, which include myogenic, chemical, and autonomic neural factors, are listed in Table 11.1 .
TABLE 11.1
Factors Influencing Cerebral Blood Flow
| Factor | Comment |
|---|---|
| Chemical, Metabolic, Humoral | |
| CMR | CMR influence assumes intact flow-metabolism coupling, the mechanism of which is not fully understood. |
| Anesthetics | |
| Temperature | |
| Arousal; seizures | |
| Paco 2 | |
| Pao 2 | |
| Cardiac output | |
| Vasoactive drugs | |
| Anesthetics | |
| Vasodilators | |
| Vasopressors | |
| Myogenic | |
| Autoregulation; MAP | The autoregulation mechanism is fragile; in many pathologic states, CBF is regionally pressure passive. |
| Rheologic | |
| Blood viscosity | |
| Neurogenic | |
| Extracranial sympathetic and parasympathetic pathways | Contribution and clinical significance are poorly defined. |
| Intraaxial pathways | |
See text for discussion.
CBF, Cerebral blood flow; CMR, cerebral metabolic rate; MAP, mean arterial pressure; Pa co 2 , arterial partial pressure of carbon dioxide; Pa o 2 , arterial partial pressure of oxygen.
Myogenic Regulation (Autoregulation) of Cerebral Blood Flow
The conventional view of autoregulation is that the cerebral circulation adjusts its resistance to maintain CBF relatively constant over a wide range of mean arterial pressure (MAP) values. In normal human subjects, CBF is autoregulated between 70 mm Hg (lower limit of autoregulation, LLA) and 150 mm Hg (upper limit of autoregulation, ULA) ( Fig. 11.3 ). There is, however, considerable variation between subjects in the autoregulation limits. Cerebral perfusion pressure is the difference between the MAP and the intracranial pressure (ICP). Because ICP is not usually measured in normal subjects, cerebral perfusion pressure (CPP = MAP − ICP) is rarely available. Assuming a normal ICP of 5 to 10 mm Hg in a supine subject, an LLA of 70 mm Hg expressed as MAP corresponds to a LLA of approximately 60 to 65 mm Hg expressed as CPP. Above and below the autoregulatory plateau, CBF is pressure-dependent (pressure-passive) and linearly varies with CPP. Autoregulation is influenced by the time course over which the changes in CPP occur. Even within the range over which autoregulation normally occurs, a rapid change in arterial pressure will result in a transient (i.e., 3-4 minute) alteration in CBF.
The limits of autoregulation and the autoregulatory plateau are conceptual frameworks for the purpose of analysis. They do not represent physiologic “all-or-none” responses. There is considerable variability in the LLA and ULA as well as in the limits of the plateau (see the section on “An Integrated Contemporary View of Cerebral Autoregulation”).
The precise mechanisms by which autoregulation is accomplished and its overlap with neurovascular coupling are not known. According to the myogenic hypothesis, changes in CPP lead to direct changes in the tone of vascular smooth muscle; this process appears to be passive. Nitric oxide (NO) and calcium channels may participate in the vasodilation associated with hypotension.
Chemical Regulation of Cerebral Blood Flow
Several factors, including changes in CMR, arterial partial pressure of carbon dioxide (Pa co 2 ), and arterial partial pressure of oxygen (Pa o 2) cause alterations in the cerebral biochemical environment that result in adjustments in CBF.
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.
CMR is influenced by several phenomena in the neurosurgical environment, including the functional state of the nervous system, anesthetic drugs, and temperature.
Functional state
CMR decreases during sleep and increases during sensory stimulation, mental tasks, or arousal of any cause. During epileptic activity, increases in the CMR may be extreme, whereas regionally, after brain injury and globally with coma, the CMR may be substantially reduced.
Anesthetic drugs
The effect of individual anesthetic drugs on the CMR is presented in greater detail in the second section of this chapter. In general, anesthetic drugs suppress the CMR, with the exception of ketamine and nitrous oxide (N 2 O). The component of the CMR on which they act is electrophysiologic function. With several anesthetics, including barbiturates, isoflurane, sevoflurane, desflurane, propofol, and etomidate, increasing plasma concentrations cause progressive suppression of EEG activity and a concomitant reduction in the CMR. However, increasing the plasma level beyond what is required to first achieve suppression of the EEG results in no further depression of the CMR. The component of the CMR required for the maintenance of cellular integrity, the “housekeeping” component, is unaltered by anesthetic drugs (see Fig. 11.2 ).
When the complete suppression of EEG is achieved, the cerebral metabolic rate of oxygen (CMRO 2 ) is similar irrespective of the anesthetic agent used to achieve EEG suppression. Yet anesthetic-induced EEG suppression is not a single physiologic state and is influenced by the drug used to produce suppression. When barbiturates are administered to the point of EEG suppression, a uniform depression in the CBF and CMR occurs throughout the brain. When suppression occurs during the administration of isoflurane and sevoflurane, the relative reductions in the CMR and CBF are more intense in the neocortex than in other portions of the cerebrum. Electrophysiologic responsiveness also varies. Cortical somatosensory evoked responses to median nerve stimulation can be readily recorded at doses of thiopental far in excess of those required to cause complete suppression of the EEG but are difficult to elicit at concentrations of isoflurane associated with a burst-suppression pattern (∼1.5 minimum alveolar concentration [MAC]). In addition, the EEG characteristics of the burst-suppression states that occur just before complete suppression differ among anesthetic drugs. These differences may be of some relevance to discussions of differences in the neuroprotective potential of drugs that can produce EEG suppression.
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.
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.
![Fig. 11.6, 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.](https://storage.googleapis.com/dl.dentistrykey.com/clinical/CerebralPhysiologyandtheEffectsofAnestheticDrugs/5_3s20B9780323596046000110.jpg "Fig. 11.6, 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.")
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%.
Neurogenic Regulation of Cerebral Blood Flow
The cerebral vasculature is extensively innervated. The density of innervation declines with vessel size, and the greatest neurogenic influence appears to be exerted on larger cerebral arteries. This innervation includes cholinergic (parasympathetic and nonparasympathetic), adrenergic (sympathetic and nonsympathetic), serotoninergic, and VIPergic systems of extraaxial and intraaxial origin. An extracranial sympathetic influence via the superior cervical ganglion, as well as parasympathetic innervation via the sphenopalatine ganglion, certainly exists in animals. The intraaxial pathways likely result from innervation arising from several nuclei, including the locus coeruleus, the fastigial nucleus, the dorsal raphe nucleus, and the basal magnocellular nucleus of Meynert. Evidence of the functional significance of neurogenic influences has been derived from studies of CBF autoregulation and ischemic injury. Hemorrhagic shock, a state of high sympathetic tone, results in less CBF at a given MAP than occurs when hypotension is produced with sympatholytic drugs. During shock, a sympathetically mediated vasoconstrictive effect shifts the lower end of the autoregulatory curve to the right. It is not clear what the relative contributions of humoral and neural mechanisms are to this phenomenon; however, a neurogenic component certainly exists because sympathetic denervation increases CBF during hemorrhagic shock. Moreover, sympathetic denervation produced by a blockade of the stellate ganglion can increase CBF in humans. Activation of cerebral sympathetic innervation also shifts the ULA to the right and offers some protection against hypertension-induced increases in CBF (which can in certain circumstances lead to a breakdown of the BBB). Experimental interventions that alter these neurogenic control pathways influence outcome after standardized ischemic insults, presumably by influences on vascular tone and therefore CBF. The nature and influence of such pathways in humans are not known, and their manipulation for the purposes of clinical management remains to be systematically investigated.
Effects of Blood Viscosity on Cerebral Blood Flow
Blood viscosity can influence CBF. Hematocrit is the single most important determinant of blood viscosity. In healthy humans, variation of the hematocrit within the normal range (33%-45%) probably results in only modest alterations in CBF. Beyond this range, changes are more substantial. In anemia, cerebral vascular resistance is reduced and CBF increases. However, this may result not only from a reduction in viscosity but also as a compensatory response to reduced oxygen delivery. Although arterial oxygen content can be reduced by both hypoxia and by hemodilution, the increase in CBF that accompanies hypoxia is of a greater magnitude than that by hemodilution induced reduction in oxygen delivery. The effect of a reduction in viscosity on CBF is more important with focal cerebral ischemia, a condition in which vasodilation in response to impaired oxygen delivery is probably already maximal. In this situation, reducing viscosity by hemodilution increases CBF in the ischemic territory. In patients with focal cerebral ischemia, a hematocrit of 30% to 34% will result in optimal delivery of oxygen. However, manipulation of viscosity in patients with acute ischemic stroke is not of benefit in reducing the extent of cerebral injury. Therefore, viscosity is not a target of manipulation in patients at risk as a result of cerebral ischemia, with the possible exception of those with hematocrit values higher than 55%.
Cardiac Output
The conventional view of cerebral hemodynamics is that perfusion pressure (MAP or CPP) is the primary determinant of CBF and that the influence of cardiac output is limited. More recent data suggest that cardiac output impacts cerebral perfusion. In several investigations in which central blood volume was modulated, either reduced by application of lower body negative pressure, or increased by the infusion of fluid, a linear relationship between cardiac output and CBF, as measured as middle cerebral artery flow velocity (MCAfv) by transcranial Doppler, was clearly demonstrated. An analysis of the pooled data from these investigations indicates that a reduction in cardiac output of approximately 30% leads to a decrease in CBF by about 10%. In patients undergoing hip arthroplasty under hypotensive epidural anesthesia, the administration of epinephrine led to a maintenance of CBF even though the MAP was below the LLA. Presumably, this maintenance of CBF was due to an epinephrine-induced increase in cardiac output. An association between CO and CBF has also been observed in acute stroke, subarachnoid hemorrhage-induced vasospasm, and sepsis. However, the CO–CBF relationship has not been demonstrated uniformly; in fact, augmentation of CO does not increase CBF in several disease states, including traumatic head injury, neurologic surgery, and cardiac surgery. Collectively, the available data suggest that CO does influence CBF and that this effect may be of particular relevance in situations in which circulating volume is reduced and in shock states.
An Integrated Contemporary View of Cerebral Autoregulation
The conventional view of cerebral autoregulation is that CBF is held constant as MAP increases between the lower limit and ULA. The currently available data, however, indicate that this view is now outmoded and is in need of revision. As discussed previously, CBF and the cerebral vasculature are influenced by a variety of variables. Clearly, MAP (perfusion pressure) is a major determinant of CBF. Cardiac output is increasingly being recognized as an important determinant of CBF. Cardiac output in turn is dependent on adequate circulatory volume, cardiac preload, contractility, afterload, and heart rate and rhythm. The presence of cardiovascular disease, in particular congestive heart failure, will limit the capacity of autoregulatory mechanisms to maintain CBF in response to hypotension. Arterial blood gas tensions affect vasomotor tone, and both hypercarbia and hypoxia attenuate autoregulation. The contribution of the sympathetic nervous system is of importance in the cerebrovascular response to hypertension. At the same time, sympathetic nerves reduce the vasodilatory capacity of the cerebral vessels during hypotension. A variety of medications can impact autoregulation, either through modulation of sympathetic nervous system activity (β-antagonists, α 2 -agonists) or by direct reduction of vasomotor tone (calcium channel antagonists, nitrates, angiotensin receptor blockers, angiotensin converting enzyme [ACE] inhibitors). Anesthetics modulate autoregulation by a number of means, including suppression of metabolism, alteration of neurovascular coupling to a higher flow–metabolism ratio, suppression of autonomic neural activity, and by direct effect on cerebral vasomotor tone, and alteration of cardiac function and systemic circulatory tone.
Cerebrovascular tone and CBF are therefore under the control of a complex regulatory system ( Fig. 11.8 ). Given the multitude of factors that determine the capacity of the cerebral circulation to respond to changes in perfusion pressure, the premise that cerebral autoregulation is static is now untenable. Rather, cerebral autoregulation should be viewed as a dynamic process and that the morphologic form of the autoregulatory curve is the result of the integration of all the variables that affect cerebrovascular tone in an interdependent manner. Therefore, a continuum of vascular responsiveness in both the lower and upper limits and in the plateau probably exists as the ability of the cerebrovascular bed to dilate or constrict is exhausted. In a review of the available data from investigations in humans, the range of pressures that defined the LLA spanned from 33 mm Hg to as high as 108 mm Hg. In healthy humans subjected to lower body negative pressure to reduce central blood volume and to reduce blood pressure, the autoregulatory plateau spanned a range of only 10 mm Hg (± 5 mm Hg from baseline) as opposed to a range of 100 mm Hg in the once conventional representations of autoregulation. Above and below this narrow plateau, CBF was pressure passive. Even within this narrow plateau, a modest increase in CBF with increases in blood pressure is observable—that is, the plateau is not flat. The slope of the percentage change in MAP to percentage change in CBF relationship has been demonstrated to be 0.81 ± 0.77 with induction of hypotension and 0.21 ± 0.47 with the induction of hypertension. These data are consistent with the premise that the capacity of the cerebral circulation to adapt to increases in blood pressure is considerably greater than adaptation to hypotension. Based on these more recent observations, the conventional view of autoregulation is probably not applicable to most subjects, and a revision of the framework of cerebral circulatory control along the lines of recent data is needed. In this respect, it is the view of the authors that cerebral autoregulation should be accurately represented by a family of autoregulatory curves rather than a single static curve (see Fig. 11.8 ). In these dynamic autoregulatory curves, there is considerable heterogeneity in the LLA and ULA, as well as in the limits and slope of the plateau.
Clinical implications : Maintenance of cerebral perfusion is essential, and identification of a target range of MAP in individual patients is a key part of anesthetic management. Given the substantial variability in cerebral autoregulatory capacity, it may be difficult to identify the target range based on an LLA in most patients. Selection of the target range based on the baseline pressure, after due consideration of comorbid conditions that may impact cerebrovascular and cardiovascular performance, may be preferable. In attempts to maintain adequate perfusion pressure, the traditional approach of systemic vasoconstriction, for example with α 1 -agonists, is reasonable. However, the adequate maintenance of circulatory volume and of cardiac output should also be considered; administration of agents that can also increase cardiac output may be of value. This may be of particular relevance in patients with compromised cardiac function.
Vasoactive Drugs
Many drugs with intrinsic vascular effects are used in contemporary anesthetic practice, including both anesthetic drugs and numerous vasoactive drugs specifically used for hemodynamic manipulation. This section deals with the latter. The actions of anesthetics are discussed in the “Effects of Anesthetics on Cerebral Blood Flow and Cerebral Metabolic Rate” section.
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.
TABLE 11.2
Best Estimates of the Influence of Pure Catecholamine Receptor Agonists and Specific Pressor Substances on Cerebral Blood Flow and Cerebral Metabolic Rate
| Agonist | Cerebral Blood Flow | Cerebral Metabolic Rate |
|---|---|---|
| Pure | ||
| α 1 | 0/− | 0 |
| α 2 | − | − |
| β | + | + |
| β (BBB open) | +++ | +++ |
| Dopamine | ++ | 0 |
| Dopamine (high dose) | − | ?0 |
| Fenoldopam | − | ?0 |
| Mixed | ||
| Norepinephrine | 0/− | 0/+ |
| Norepinephrine (BBB open) | + | + |
| Epinephrine | + | + |
| Epinephrine (BBB open) | +++ | +++ |
The number of symbols indicates the magnitude of the effect.
Where species differences occurred, data from primates were given preference. See text for complete discussion.
BBB, Blood-brain barrier; +, increase; −, decrease; 0, no effect.
α 1 -Agonists
Will the administration of α 1 -agonists (phenylephrine, norepinephrine) reduce CBF?
Studies in humans and nonhuman primates do not confirm this concern. Intracarotid infusions of norepinephrine in doses that significantly increase the MAP result in no change in CBF. Norepinephrine can increase CBF, but such increases might occur if autoregulation were defective or its limit exceeded. β-Mimetic drugs (norepinephrine has β 1 activity) may cause activation of cerebral metabolism with a coupled increase in CBF. This effect is more apparent when these drugs can gain greater access to the brain parenchyma via a defective BBB (see Table 11.2 ). Administration of phenylephrine to patients undergoing cardiopulmonary bypass does not decrease CBF. In spinal cord–injured patients with relative hypotension, the administration of the α 1 -agonist midodrine increased perfusion pressure and increased flow velocity in the middle cerebral artery (MCA) and the posterior cerebral artery. In healthy patients, and in those undergoing surgery in the beach chair position, the administration of phenylephrine maintains or augments MCAfv. Collectively, these data suggest that norepinephrine and phenylephrine maintain cerebral perfusion.
The traditional view that CBF can be maintained by the administration of α 1 -agonists without any adverse effect on cerebral oxygenation has been challenged. In anesthetized patients, phenylephrine administration by bolus modestly reduced regional cerebral oxygen saturation (rSO 2 ), measured by near-infrared oximetry. Ephedrine, although increasing arterial blood pressure to a similar extent as phenylephrine, did not reduce rSO 2 , presumably because of its ability to maintain cardiac output. In human volunteers, a norepinephrine-induced increase in arterial blood pressure slightly reduced MCAfv and cerebral oxygen saturation (S co 2 ) and SjV o 2 . By contrast, although phenylephrine decreased rSO 2 , MCAfv was increased and SjV o 2 was unchanged. These data have led to the question of whether phenylephrine and norepinephrine administration negatively impact cerebral oxygenation. Several factors argue against this possibility. The first concern is methodology. Near-infrared spectroscopy (NIRS) measures oxygenated and deoxygenated blood in a defined region of brain and is a composite of arterial, capillary, and venous blood. Vasopressors affect both arterial and venous tone. Even a minor change in the volume of arterial and venous volumes within the region of the brain can affect the rSO 2 measurement. Moreover, extracranial contamination is a significant component of the rSO 2 values reported by the currently available NIRS monitors. This contamination is more important than the slight reduction in S co 2 observed in these investigations. In the absence of direct measurement of brain tissue oxygenation, a modest reduction in S co 2 in the face of increasing arterial blood pressure cannot be taken as evidence of impairment of cerebral oxygenation. In addition, phenylephrine did not decrease SjV o 2 , a more global measurement of cerebral oxygenation. Although norepinephrine decreased SjV o 2 by approximately 3% (a mild reduction at best), its administration has been previously shown to increase the CMRO 2 . Finally, the minor reduction in rSO 2 effected by phenylephrine is no longer apparent when an increase in the CMRO 2 is concurrent. Phenylephrine apparently does not prevent an increase in CBF when such an increase is warranted by increased brain metabolism.
These studies were conducted in patients with a normal central nervous system (CNS). Although unlikely, the concern is that α 1 -agonists might reduce cerebral perfusion in the injured brain. In patients with a head injury, the administration of phenylephrine increased CPP and did not reduce regional CBF. Transient changes may occur in CBF and rSO 2 (on the order of 2-5 minutes) in response to bolus doses of phenylephrine; however, with a continuous infusion, α 1 -agonists have little direct influence on CBF and cerebral oxygenation in humans. Thus maintenance of CPP with these vasopressors does not have an adverse effect on the brain.
α 2 -Agonists
α 2 -Agonists have both analgesic and sedative effects. This class of drugs includes dexmedetomidine and clonidine, with the latter being a significantly less specific and less potent α 2 -agonist. Two investigations in human volunteers have confirmed the ability of dexmedetomidine to decrease CBF. Dexmedetomidine dose-dependently decreased MCAfv, with the maximum reduction being approximately 25%. Dexmedetomidine (1 μg/kg loading dose and infusion at either 0.2 or 0.6 μg/kg/hr) decreased CBF by approximately 30% in healthy human volunteers. In both these investigations, the CMR was not measured; whether the reduction in CBF was due to a direct vasoconstrictor activity of dexmedetomidine or to suppression of the CMR with a corresponding reduction in CBF is not clear. In a more recent study of dexmedetomidine during which both MCAfv and the CMR were measured in healthy humans, dexmedetomidine decreased MCAfv in parallel with a reduction in the CMR. Similarly, in healthy patients and those with traumatic brain injury undergoing sedation with dexmedetomidine, the reduction in CBF was matched by a parallel reduction in CMR. Thus the effects of dexmedetomidine on CBF were primarily mediated by its ability to suppress the CMR; the reduction in CBF is commensurate with the reduction in CMR, and there is no evidence that dexmedetomidine causes cerebral ischemia. However, the well-known effect of dexmedetomidine in decreasing arterial blood pressure merits careful consideration if used in patients who are critically dependent on collateral perfusion pressure, especially in the recovery phase of an anesthetic.
β-Agonists
β-receptor agonists, in small doses, have little direct effect on the cerebral vasculature. In larger doses and in association with physiologic stress, they can cause an increase in the CMR with an accompanying increase in CBF. The β 1 -receptor is probably the mediator of these effects. In doses that do not result in substantial changes in the MAP, intracarotid epinephrine does not change CBF in nonanesthetized humans. However, with larger doses that lead to an increase in the MAP, both CBF and CMRO 2 can increase by approximately 20%. A recent investigation has demonstrated that the administration of epinephrine in patients undergoing surgery under hypotensive epidural anesthesia can increase MCAfv, presumably by augmenting cardiac output (as discussed previously).
Dobutamine can increase CBF and CMR by 20% and 30%, respectively. Dobutamine can increase CBF independent of its effect on blood pressure; the increase in CBF has been attributed to the augmentation of cardiac output by dobutamine.
Evidence suggests that a defect in the BBB enhances the effect of β-agonists. Intracarotid norepinephrine, which does not normally affect CBF and CMR, increases CBF and CMR when BBB permeability is increased with hypertonic drugs. Epinephrine caused an elevation in the CMRO 2 , but only when the BBB was made permeable. These observations beg the interpretation that β-agonists will increase CBF and CMR only when the BBB is injured. However, when epinephrine was given in doses that did not significantly increase the MAP, increases in CBF and CMR occurred. Accordingly, BBB injury may exaggerate but is not a necessary condition in humans for the occurrence of β-mediated increases in CBF and CMR.
β-Blockers
β-Adrenergic blockers either reduce or have no effect on CBF and CMR. In two investigations in humans, propranolol, 5 mg intravenously, and labetalol, 0.75 mg/kg intravenously, had no effect on CBF and cerebral blood flow velocity (CBFV), respectively. Modest reductions in CBF occur after the administration of labetalol to patients undergoing craniotomy who become hypertensive during emergence from anesthesia. Esmolol shortens seizures induced by electroconvulsive therapy (ECT), which suggests that esmolol does cross the normal BBB. Catecholamine levels at the time of β-blocker administration or the status of the BBB (or both) may influence the effect of these drugs. β-Adrenergic blockers are unlikely to have adverse effects on patients with intracranial pathology, other than effects secondary to changes in perfusion pressure.
Dopaminergic agents
Dopamine can be used for the treatment of hemodynamic dysfunction. It also augments the function of the normal cardiovascular system when an increase in the MAP is desired as an adjunct to the treatment of focal cerebral ischemia, especially in the setting of vasospasm. Nonetheless, its effects on CBF and CMR have not been defined with certainty. The likely predominant effect of dopamine in the normal cerebral vasculature, when administered in small doses, is probably slight vasodilation with a minimal change in the CMR. Increased CMR in discrete regions of the brain, such as the choroid plexus and basal ganglia, can occur. However, overall cortical blood flow is not influenced. Vasoconstriction of the cerebral circulation is not observed even when dopamine is administered in doses of up to 100 μg/kg/min. Fenoldopam is a dopamine agonist with activity at the DA 1 -receptor and α 2 -receptor. The administration of fenoldopam leads to systemic vasodilation and a decrease in arterial blood pressure. In humans, fenoldopam decreased systemic blood pressure to a level that was above the LLA; however, a modest (≈15%) reduction was observed in CBF that did not increase to normal levels when systemic blood pressure was supported. The reason for the reduction of CBF is not clear.
Calcium channel blockers
CCBs are frequently used to treat acute hypertension in the neurologically injured patient population. Cerebral vessels are richly endowed with calcium channels, in particular the L-type calcium channel. CCBs therefore induce vasodilation of the pial and cerebral arteries. In healthy humans, intravenous administration of nimodipine does not change CBF; however, when the slight decrease in MAP and changes in Pa co 2 are taken into consideration, CBF increased by approximately 5% to 10%. CMR and CO 2 reactivity are maintained. Nimodipine in human subjects does, however, blunt autoregulation moderately. Intraarterial nimodipine for the treatment of cerebral vasospasm after subarachnoid hemorrhage increased regional CBF significantly provided MAP was maintained, indicating that nimodipine is a cerebral vasodilator.
Nicardipine is perhaps the most commonly used CCB for perioperative blood pressure control because of its short half-life and easy titratability. Nicardipine is a modest cerebral vasodilator and has repeatedly been shown to increase CBF or CBFV while reducing systemic MAP. Cerebral CO 2 reactivity appears to be well preserved in the presence of nicardipine.
Clevidipine is a third generation dihydropyridine CCB that has an ultrashort half-life because it undergoes rapid esterase-mediated metabolism. Its use in both the cardiac and neurologic patient populations has increased significantly given its rapid titratability. In healthy volunteers, clevidipine did not increase MCAfv. However, a substantial reduction in MAP of approximately 25% occurred. The lack of increase in MCAfv in the face of hypotension suggests that clevidipine is a cerebral vasodilator and, like nicardipine, probably attenuates autoregulation to a moderate extent. CO 2 reactivity is preserved.
The available data indicate that CCBs are moderate cerebral vasodilators. Their net impact on CBF is therefore dependent on the extent of systemic vasodilation and MAP. When MAP is maintained, increases in CBF should be expected.
Angiotensin II, Angiotensin-Converting Enzyme Inhibitors, and Angiotensin Receptor Antagonists
There has been a renaissance of the use of angiotensin II (AII) for the treatment of vasodilatory shock that is refractory to conventional vasopressor agents. In these shock states, AII increased MAP and reduced the need for other vasopressors including norepinephrine and vasopressin. The acute effect of AII on the cerebral circulation has received only modest attention. Acute administration of AII increases cerebral microvascular constriction without affecting CBF; this effect precedes its impact on blood pressure. However, AII attenuates regional hyperemia that occurs with an increase in regional metabolism, thereby adversely impacting neurovascular coupling. Given that CBF is maintained in the face of increased blood pressure, autoregulation and CO 2 responsivity appear to be maintained.
Both ACE inhibitors and angiotensin-receptor blockers (ARBs) are commonly used to treat hypertension. In the surgical setting and in the neurocritical care unit, these drugs are administered to control arterial blood pressure acutely. ACE inhibitors and ARBs reduce arterial blood pressure when hypertension is present. However, they do not affect resting CBF, and autoregulation is maintained. However, acute administration of ACE inhibitors and ARBs decreases the LLA (left shift of the autoregulatory curve in experimental animals); the significance of this finding in humans is not clear. In patients with acute stroke, ACE inhibitors and ARBs reduce arterial blood pressure but do not acutely affect CBF. Apparently, these drugs do not reduce CBF when arterial blood pressure is modestly decreased.
Age
The loss of neurons is progressive in the normally aging brain from young adulthood to advanced age. There is approximately 10% neuronal loss in healthy aged brain. The loss of myelinated fibers results in reduced white matter volume. By contrast, the loss of synapses in the aged brain is considerably greater. The majority of excitatory synapses in the brain are on dendritic spines. Dendrite branching and volume decrease progressively, and the number of dendritic spines is reduced by approximately 25% to 35%. Concomitant with the loss of neuropil, both CBF and CMRO 2 decrease by 15% to 20% at the age of 80 years. Cerebral circulatory responsiveness to changes in Pa co 2 and to hypoxia are slightly reduced in the healthy aged brain.
Effects of Anesthetics on Cerebral Blood Flow and Cerebral Metabolic Rate
This section discusses the effects of anesthetic drugs on CBF and CMR. It includes limited mention of the influences on autoregulation, CO 2 responsiveness, and CBV. Effects on CSF dynamics, the BBB, and epileptogenesis are discussed later in the chapter.
In the practice of neuroanesthesia, the manner in which anesthetic drugs and techniques influence CBF receives prime attention. The rationale is twofold. First, the delivery of energy substrates is dependent on CBF, and modest alterations in CBF can influence neuronal outcome substantially in the setting of ischemia. Second, control and manipulation of CBF are central to the management of ICP because as CBF varies in response to vasoconstrictor-vasodilator influences, CBV varies with it. With respect to ICP, CBV is the more critical variable. In the normal brain, CBV is approximately 5 mL/100 g of brain, and over a Pa co 2 range of approximately 25 to 70 mm Hg, CBV changes by approximately 0.049 mL/100 g for each 1 mm Hg change in Pa co 2 . In an adult brain weighing approximately 1400 g, this change can amount to 20 mL in total CBV for a Pa co 2 range of 25 to 55 mm Hg. Because CBV is more difficult to measure than CBF few data exist, especially in humans.
Although CBV and CBF usually vary in parallel, the magnitude of change in CBV is less than the magnitude of change in CBF ( Fig. 11.9 ). In addition, CBV and CBF vary independently under some circumstances. During cerebral ischemia, for example, CBV increases, whereas CBF is reduced significantly. Autoregulation normally serves to prevent MAP-related increases in CBV. In fact, as the cerebral circulation constricts to maintain a constant CBF in the face of an increasing MAP, CBV actually decreases. When autoregulation is impaired or its upper limit (≈150 mm Hg) is exceeded, CBF and CBV then increase in parallel as arterial blood pressure increases (see Fig. 11.8 ). A decreasing MAP results in a progressive increase in CBV as the cerebral circulation dilates to maintain constant flow, and exaggerated increases in CBV occur as the MAP decreases to less than the LLA. In normal subjects, the initial increases in CBV do not increase ICP because there is latitude for compensatory adjustments by other intracranial compartments (e.g., translocation of venous blood and CSF to extracerebral vessels and the spinal CSF space, respectively). When intracranial compliance ∗
∗ Note a well-entrenched misuse of terminology. 64 The “compliance” curve that is commonly drawn to describe the ICP-volume relationship (see Fig. 57-3) actually depicts the relationship ?P/?V (elastance) and not ?V/?P (compliance). References to “reduced compliance” in this text would more correctly be rendered as “increased elastance.” However, because the existing literature most commonly uses the “compliance” terminology, the authors have left the misuse uncorrected herein.
is reduced, an increase in CBV can cause herniation or sufficiently reduce CPP to cause ischemia.
Intravenous Anesthetic Drugs
The action of most intravenous anesthetics leads to parallel reductions in CMR and CBF. Ketamine, which causes an increase in the CMR and CBF, is the exception. The effects of selected intravenous anesthetic drugs on human CBF are compared in Fig. 11.10 . ,
Intravenous anesthetics maintain neurovascular coupling, and consequently changes in CBF induced by intravenous anesthetics are largely the result of the effects on the CMR with parallel (coupled) changes in CBF. Intravenous anesthetics have direct effects on vascular tone. Barbiturates, for example, cause relaxation of isolated cerebral vessels in vitro. However, in vivo , barbiturates suppress CMR, and the net effect at the point of EEG suppression is vasoconstriction and a substantial decrease in CBF. In general, autoregulation and CO 2 responsiveness are preserved during the administration of intravenous anesthetic drugs.
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.
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