Carbon Dioxide and the Cerebral Circulation 

(Brian) Associate Professor.Dennis M. Fisher, M.D., EditorTHE arterial partial pressure of carbon dioxide (PaCO(2)) is an important regulator of the cerebral circulation, and a large body of literature describes this relation. This review summarizes the current state of knowledge of the effect of CO2on cerebral physiology, focusing first on mechanisms of CO2-induced alteration of vascular tone, then on the effect of CO2on cerebral vascular regulation, and finally on CO2manipulation in patient care.This section summarizes information regarding the site of action of CO2on the cerebral circulation and cellular mechanisms important in CO2-mediated changes in cerebral vascular tone. The CO2-mediated alteration of brain extracellular pH is the initial step leading to changes in vascular tone. The effect of pH on cerebral vascular tone is mediated by nitric oxide (NO), prostanoids, cyclic nucleotides, potassium channels, and intracellular calcium. Most data available support an important role for each of these mediators in the response of the cerebral circulation to CO2. However, contradictory data exist, and there is no comprehensive understanding of how these mediators interact to control cerebral vascular tone. Further, mechanisms differ in neonates and adults.Increased carbon dioxide tension (PCO2) relaxes cerebral arteries in vitro, which indicates that CO2can cause cerebral vascular relaxation independent of extravascular cells. 1,2In vivo, cerebral arteries respond to highly localized perivascular alteration of PCO2and pH, which indicates that the mechanisms that affect cerebral vascular tone are localized to the area of the blood vessel wall. 3–5Cellular elements that could contribute to the cerebral vascular response to CO2include vascular cells (endothelium and smooth muscle) and extravascular cells (perivascular nerves, parenchymal neurons, and glia). In adult animals, removal of the endothelium in vitro 1or endothelial damage in vivo 6does not alter the response of cerebral arteries to hypercapnia. This suggests that in adults the endothelium is not involved in the response to CO2. In neonates, however, the endothelium does contribute to cerebral vasodilatation during hypercapnia. 7,8Tetrodotoxin, which blocks sodium channels and prevents neuronal depolarization, does not reduce CO2-mediated cerebral vasodilation, indicating that depolarization of perivascular nerves or parenchymal neurons is not important. 6,9Selective destruction of cortical neurons also does not alter the cerebral vascular response to hypercapnia. 10Although these data in adults suggest that the endothelium, parenchymal neurons, and perivascular nerves are not important during hypercapnia-induced cerebral vasodilation, it is also possible that these cells produce overlapping vasodilator messengers, and removal of an individual messenger is not sufficient to alter the response. No data exist regarding a potential role for glia in the CO2response of the cerebral circulation.In vitro data suggest that extravascular cells are not important in the response of cerebral arteries to increased PaCO(2). However, the relative contribution of vascular and extravascular cells to CO2-mediated vasodilation cannot be assessed by comparing in vivo and in vitro studies. Although isolated cerebral vessels relax with increased PCO2, technical differences between in vivo and in vitro studies make it impossible to know if vasodilation is equal in isolated vessels compared with in vivo blood vessels. Thus, in vivo, it is possible that dilation is larger, and some of the effect of CO2on cerebral vessels is mediated by extravascular cells.When cerebral vascular tone is altered by a change in PCO2, it is possible that CO2itself, a CO2-mediated change in pH, or both are signals leading to a change in vascular tone. Applying acidotic or alkalotic solutions to the brain dilates or constricts cerebral arteries in vivo, which indicates that pH can affect cerebral vascular tone. 4In humans, Severinghaus et al. 11showed that cerebral blood flow (CBF) was normal during chronic hypocapnia, which suggests that CO2itself does not alter cerebral vascular tone. Kontos et al. 3,12offered the best evidence that pH rather than CO2is the controlling messenger for CO2-mediated alterations of cerebral vascular tone. Applying artificial cerebrospinal fluid (CSF) topically to the cerebral cortex of anesthetized cats, they showed that the diameter of cerebral arterioles responded only to changes in pH, regardless of fluid PCO2. During alterations of fluid PCO2, the pH of the artificial CSF was held constant by altering its bicarbonate concentration. Because CO2diffuses freely through cell membranes and bicarbonate does not, these data suggest that extracellular pH is more important than intracellular pH in altering cerebral vascular tone. Data in isolated cerebral arteries also indicate that extracellular pH is more important than intracellular pH in hypercapnic-induced dilation of cerebral arteries. 13However, changes in extracellular pH do affect intracellular pH in cerebral vascular smooth muscle, 13and due to complex interactions between extracellular and intracellular pH, 14it is not known whether extracellular or intracellular pH controls cerebral vascular tone.Changes in pH can exert effects on smooth muscle tone through second messenger systems and by altering vascular smooth muscle calcium concentration directly. This section reviews the role of prostanoids, NO, cyclic nucleotides, potassium channels, and intracellular calcium concentration in CO2-mediated changes in cerebral vascular tone.Prostanoids. Production of prostaglandins is controlled by the availability of arachidonic acid, which is cleaved from membrane lipids by phospholipase. Cyclo-oxygenase converts arachidonic acid to prostaglandin H2, which is subsequently modified by other enzymes to yield both vasoconstrictor and vasodilator prostanoids. The principle vasoactive prostanoids in the brain are prostaglandin E2(PGE2) and prostacyclin (PGI2), both dilator prostanoids, and the constrictor prostanoid prostaglandin F2alpha (PGF2alpha). 15In adult humans and animals, some studies reported that indomethacin, a cyclooxygenase inhibitor, reduces hypercapnia-induced cerebral vasodilation. 16–19However, other studies reported that indomethacin does not reduce hypercapnia-induced cerebral vasodilation. 20–23Although indomethacin reduces hypercapnia-induced increase in CBF in humans, aspirin and naproxen have no effect, even when there is an equal degree of cyclo-oxygenase inhibition. 16Other have reported in animals and humans that the cyclo-oxygenase inhibitors aspirin, sulindac, amfenac, and dicolfenac do not alter the response of the cerebral circulation to hypercapnia. 19,20,24,25In adult humans and animals, brain arachidonic acid, PGI2, and PGE2concentrations do not increase during hypercapnia. 16,26–28Overall, data in adults indicate that cyclooxygenase products are not responsible for cerebral vasodilation during hypercapnia. The effect of indomethacin on hypercapnia-induced cerebral vasodilation is difficult to resolve. However, indomethacin does inhibit enzymes other than cyclo-oxygenase, including phosphodiesterase, phospholipase A2, and cyclic adenosine monophosphate (cAMP)-dependent protein kinase, which indicate that the effect of indomethacin is nonselective. 26The neonatal and adult cerebral circulation responds to CO (2) in a similar way, although the magnitude of the response may be less in neonates (see below). In neonates, prostanoids are important in regulating the cerebral circulation. 29In neonatal animals, damage in vivo to cerebral vascular endothelium prevents hypercapnia-mediated increases in CSF PGI2concentration and dilation of cerebral blood vessels. 8Inhibition of phospholipase, which prevents the release of arachidonic acid and the production of prostanoids, abolishes the response of the neonatal circulation to hypercapnia and extracellular acidosis. 30Further, indomethacin inhibits hypercapnia-induced cerebral vasodilation and increases in CSF PGI2and PGE2concentrations in newborn animals. 31,32In human neonates, indomethacin abolishes hypercapnic-induced increases in CBF. 33These data support the concept that in neonates, vasodilator prostaglandins derived from the vascular endothelium are important in the response to hypercapnia. However, an alternative role for prostaglandins has been suggested by some investigators, who report in newborn animals that after inhibition of cyclo-oxygenase or endothelial injury, application to the brain of a very low concentration of vasodilator prostanoids restores hypercapnia-induced cerebral vasodilation. 7,34These data suggest that prostanoids may not be direct mediators of hypercapnia-induced cerebral vasodilation, but rather that a basal level of prostanoids is necessary to “permit” hypercapnia to dilate cerebral blood vessels. Overall, data indicate that cyclo-oxygenase products are important regulators in the hypercapnic response of the newborn but not adult cerebral circulation.Nitric Oxide. Nitric oxide is an important regulator of cerebral vascular tone and is produced by a family of NO-synthase enzymes in brain vascular endothelial cells, some perivascular nerves, parenchymal neurons, and glia. 35,36Nitric oxide activates guanylate cyclase in vascular smooth muscle, increasing the intracellular concentration of cyclic guanosine monophosphate (cGMP), causing vasorelaxation. 36In adult animals, inhibition of NO-synthase activity reduces cerebral vasodilation during hypercapnia 37–41and extracellular acidosis-mediated cerebral vasodilation. 39This indicates that NO is one vasodilator important in the response of the cerebral circulation to hypercapnia and acidosis. Although these studies indicate that NO is important in CO2-induced cerebral vasodilation, they also suggest that NO is not the only vasodilator signal, because after inhibition of NO-synthase, 10–70% of hypercapnia-mediated cerebral vasodilation remains. The wide range in the reduction of cerebral vasodilation may reflect use of different NO-synthase inhibitors, doses of inhibitors, timing of doses, degree of hypercapnia, and species differences. During severe hypercapnia (PaCO2> 100 mmHg), CO2-mediated dilation of cerebral arterioles cannot be reduced by inhibition of NO-synthase, which indicates that cerebral vasodilation during severe hypercapnia does not depend on NO. 37In contrast to adults, NO does not play a role in hypercapnia-induced cerebral vasodilation in neonatal animals. 32Although it might be surmised from these studies that hypercapnia increases the synthesis of NO, which leads to cerebral vasodilation, some investigations suggest an alternative explanation. The brain tonically produces NO, creating a constant vasodilator signal. 36Inhibition of NO-synthase removes tonic NO and increases the resting tone in cerebral blood vessels, which could alter the response to other vasoactive signals, such as hypercapnia. Thus inhibition of NO-synthase could cause a direct effect by preventing hypercapnia-mediated activation of NO-synthase and indirect effects by reducing basal NO and cGMP levels and increasing resting tone of blood vessels. After inhibition of NO-synthase, low concentrations of NO-dependent and NO-independent vasodilators can restore cerebral vascular tone to baseline. 9However, NO-dependent but not NO-independent vasodilators can restore the response to hypercapnia. 9Furthermore, a cell-permeable cGMP analog can also restore basal vascular tone and the response to hypercapnia after inhibition of NO-synthase. 9These data suggest that changes in basal tone are not important, because NO-independent vasodilators cannot restore the response to hypercapnia. These data indicate that NO and cGMP are important in CO2-mediated dilation of cerebral blood vessels. However, NO and cGMP may not be the final mediators of vasodilation, but rather that basal levels of NO and cGMP “permit” hypercapnia to dilate cerebral vessels. Nitric oxide may also function in a “permissive” role for other vasodilators in the cerebral circulation. 42,43In the brain, vascular endothelium expresses the endothelial isoform of NO-synthase, and some perivascular nerves, parenchymal neurons, and glia express the neuronal isoform of NO-synthase. 36,44–46All are potential sources of NO important for hypercapnia-induced cerebral vasodilation. 36Damage to vascular endothelium in vivo does not reduce hypercapnia-induced vasodilation, 6which indicates that the endothelial isoform of NO-synthase is not the source of NO involved in hypercapnia-induced cerebral vasodilation. Selective inhibition of the neuronal isoform of NO-synthase reduces hypercapnia-induced cerebral vasodilation, which indicates that the activity of neuronal NO-synthase is important. 47Cerebral perivascular nerves originating from the sphenopalatine ganglia release NO but do not appear to be important in hypercapnia, because destruction of these nerves does not alter the cerebral vascular response to hypercapnia. 48Furthermore, tetrodotoxin, which blocks sodium channels and prevents neuronal depolarization, does not reduce hypercapnia-induced cerebral vasodilation. 9This indicates that the activation of neuronal NO-synthase by depolarization of perivascular nerves or parenchymal neurons is not important in hypercapnia-induced cerebral vasodilation. The NO responsible for hypercapnia-induced cerebral vasodilation could arise either from parenchymal neurons producing NO in the absence of depolarization or from glia. However, selective destruction of cortical neurons does not alter hypercapnia-induced cerebral vasodilation, which indicates that parenchymal neurons are not involved in the response to hypercapnia. 10Thus data suggest that, in adult animals, the vascular endothelium, parenchymal neurons, and perivascular nerves are not the source of NO important in hypercapnia-mediated vasodilation. Neuronal NO-synthase appears to be the source of NO involved in hypercapnia-induced cerebral vasodilation, but the cellular location is not known. Glia, which express neuronal NO-synthase, could be the source of NO, but it is also possible that multiple, overlapping sources of NO may be involved in hypercapnia-induced cerebral vasodilation.In contrast to hypercapnia, alterations in cerebral vascular tone during hypocapnia do not depend on NO. In adult rabbits and rats, cerebral vasoconstriction during hypocapnia is not altered by inhibition of NO-synthase. 38,49Cyclic Nucleotides. Changes in cyclic nucleotide concentrations are important in the signaling cascade leading from pH to changes in vascular smooth muscle tone. Nitric oxide activates guanylate cyclase in vascular smooth muscle, increasing the cGMP concentration while vasodilator prostanoids (PGE2, PGI2) activate adenylate cyclase and increase the cAMP concentration. 32,36In adult rats, hypercapnia increases brain cGMP concentration, consistent with the theory that hypercapnia increases NO production, which then increases cGMP. 40However, in isolated cerebral arteries from adult rats, increased PCO2relaxes arteries but does not increase cGMP, consistent with the “permissive” hypothesis in which increases in NO and cGMP are not required for CO2-mediated dilation of cerebral blood vessels. 1Cyclic GMP is important in hypercapnia; however, as after inhibition of NO-synthase, infusion of a low concentration of a stable cGMP analog restores hypercapnia-induced vasodilation in the brain. 9As with NO, it is not clear in adult animals whether cGMP functions as a vasodilator mediator during hypercapnia or whether basal levels of cGMP are necessary to “permit” hypercapnia-induced cerebral vasodilation to occur.In neonatal pigs, hypercapnia causes cerebral vasodilation and increased brain PGI2 and cAMP concentration; inhibition of cyclo-oxygenase prevents these changes. 32These data suggest that cAMP mediates vasodilation during hypercapnia in neonates. Although vasodilator prostanoids can act permissively for hypercapnia in neonates, it is not known whether cAMP can play a similar permissive role.Potassium Channels. Recent evidence suggests that vascular smooth muscle potassium channels play an important role in regulating cerebral vascular tone. 50In vascular smooth muscle, the opening of potassium channels allows potassium (the major intracellular cation) to diffuse out of the cell, making the interior of the cell more negative (hyperpolarized). When the cell is hyperpolarized, voltage-gated calcium channels reduce the influx of extracellular calcium, decreasing intracellular calcium concentration and reducing vascular smooth muscle tone.One subgroup of potassium channels is ATP sensitive (KATP). Decreasing pH increases the open-state probability of KATPchannels (which would hyperpolarize cells), supporting the concept that during hypercapnia, activation of KATPchannels could cause vascular smooth muscle hyperpolarization and cerebral vasodilation. 51Furthermore, extracellular acidosis hyperpolarizes cerebral vascular smooth muscle, also supporting the concept that changes in vascular smooth muscle membrane potential are important during hypercapnia. 2In large cerebral arteries in vitro, acidosis-reduced relaxation depends partially on activation of KATPchannels. 52In adult animals, cerebral vasodilation during modest (PaCO2nearly = 55 mmHg), but not marked, hypercapnia can be attenuated by blockade of K (ATP) channels. 41,53A second potassium channel is the large conductance calcium-activated potassium channel. This channel can be activated by cGMP and NO, hyperpolarizing vascular smooth muscle and reducing intracellular calcium. 54,55It contributes to cGMP-dependent vasodilation in small cerebral arterioles 56but not in large cerebral arteries. 57In contrast to KATPchannels, large conductance calcium-activated potassium channels do not contribute to acidosis-induced vasodilation in isolated large cerebral arteries. 52The lack of importance of these channels during acidosis-induced vasodilation in large cerebral arteries may reflect the regional heterogeneity of potassium channel distribution.A third potassium channel is the delayed rectifier potassium channel (KV). This channel is normally activated by membrane depolarization, resulting in repolarization by allowing potassium to exit the cell. 50In cerebral vascular smooth muscle, KVchannels are pH sensitive, and acidosis increases KVconductance, hyperpolarizing the cell. 58This suggests that KVchannels should be activated during hypercapnia and contribute to dilation. However, in isolated large cerebral arteries, blockade of KVchannels does not alter dilation to acidosis. 52As with large conductance calcium-activated potassium channels, this discrepancy may reflect regional differences in potassium channel distribution in the cerebral circulation.Intracellular Calcium. Vascular smooth muscle tone is controlled by intracellular calcium concentration. Under baseline conditions, intracellular calcium is approximately 0.1 micro Meter, which is 10,000 times less than extracellular calcium. Small changes in plasma membrane calcium conductance may have a significant effect on both intracellular calcium concentration and vascular smooth muscle tone. During alkalosis, cerebral vascular smooth muscle intracellular calcium concentration increases, which increases tone. 59In cerebral vascular smooth muscle, changes in extracellular pH affect intracellular calcium concentration and vascular tone. 60Extracellular acidosis-induced dilation of cerebral arterioles can be prevented by elevation of extracellular calcium, which suggests that reduced entry of calcium into vascular smooth muscle is important in the reduction of vascular tone by acidosis. 5Cyclic nucleotides (cAMP and cGMP) affect vascular tone in part by altering smooth muscle calcium concentration. 54,61Both cAMP and cGMP appear to activate their respective protein kinases and phosphorylate calcium channels, which reduces the entry of calcium into vascular smooth muscle. 61,62Cyclic nucleotides also activate potassium channels, leading to membrane hyperpolarization and inactivation of voltage-gated calcium channels, reducing intracellular calcium concentration. 61The system of mediators that link extracellular pH to cerebral vascular tone is complex and interrelated (Figure 1). The initial step is alteration of extracellular pH, and the final common mediator is intracellular calcium concentration. In adults, cerebral vasodilation during hypercapnia is mediated in part by NO, which increases cGMP concentration. Cyclic GMP exerts several effects to decrease intracellular calcium, including activation of KATPchannels and the direct reduction of calcium entry through calcium channels. Nitric oxide can also activate potassium channels directly and thereby hyperpolarize and relax vascular smooth muscle. Some data suggest that NO and cGMP are not the direct mediators during hypercapnia but rather function in a “permissive” way to allow vasodilation. The cellular source of NO important during hypercapnia is unknown but appears to involve the neuronal isoform of NO-synthase. In neonates, prostanoids and cAMP function in a way that is analogous to NO and cGMP during hypercapnia. However, in neonates the source of prostanoids is the vascular endothelium. Other than changes in pH and vascular smooth muscle intracellular calcium concentration, little is known about subcellular mechanisms that are important during cerebral vasoconstriction from hypocapnia.Alteration of PaCO2affects CBF and may interact with several physiologic or pathophysiologic processes in the brain. This section reviews (1) the effect of CO2on CBF and cerebral blood volume (CBV), (2) the effect of anesthetics on the CO2response of the cerebral circulation, (3) the potential interactions of CO2with other processes that regulate CBF, and (4) the possibility for hypocapnia-induced cerebral ischemia in the normal brain.The relative change in CBF during variations of PaCO2depends on several factors, including baseline CBF, cerebral perfusion pressure, and anesthetic drugs. However, in a wide variety of subjects and conditions, most studies report a change in global CBF of 1–2 ml center dot 100 g-1center dot min-1for each 1 mmHg change in PaCO2. 24,63–82Reducing PaCO2to 20–25 mmHg decreases the global CBF by 40–50%, and further reductions of PaCO(2) do not reduce CBF any further. 83,84Increasing the PaCO(2) to 80 mmHg or more produces a maximal increase in CBF of 100–200% in anesthetized animals. 37,83In awake animals, however, increasing the PaCO2to 80 mmHg increases CBF by six times, but one half of the increase in CBF is a result of endogenous catecholamine release and activation of neuronal metabolism. 85This suggests that in awake subjects, severe hypercapnia may increase the flow by two mechanisms, with a direct effect of CO2on cerebral blood vessels and an indirect effect by increasing brain metabolism and blood flow.Brain blood flow is not homogeneous, and areas of the brain that receive more blood flow have a steeper flow response to changes in PaCO2. For example, in cats with a baseline cortical blood flow of 86 ml center dot 100 g-1center dot min-1, the slope of the CO2response was a 1.7-ml change in CBF for each 1-mmHg change in PaCO2. In contrast, spinal cord blood flow was 46 ml center dot 100 g-1center dot min-1with a slope of 0.9. 67Similar findings have been reported in animals 68and humans. 76The observation that baseline CBF influences the response of CBF to changes in PaCO2also holds true when CBF is elevated artificially, as by inhalational anesthetics.In awake humans, active hyperventilation to a PaCO2of 16 mmHg initially reduced CBF by 40%, but during 4 h of sustained hypocapnia, CBF recovered to within 10% of baseline. 86Similar findings have been demonstrated in goats 87and piglets. 88Recovery of CBF during sustained hypocapnia appears to be mediated by a reduction in CSF (and extracellular) bicarbonate concentration and correction of extracellular pH (Figure 2). 89Glial cells appear to be important in the regulation of extracellular bicarbonate concentration because these cells contain large amounts of carbonic anhydrase, which can convert bicarbonate to CO2and water. 90Bicarbonate is the only buffer in extracellular brain fluid, and the reduction of bicarbonate concentration during sustained hypocapnia leads to a greater reduction in brain extracellular pH and a greater increase in CBF during any subsequent increase in CO2. In support of this concept, after 6 h of sustained hypocapnia in awake goats, normocapnia caused marked cerebral hyperemia. 87Chronic hypocapnia in awake rabbits reduces the bicarbonate concentration of CSF and enhances the dilation of cerebral vessels to hypercapnia. 91Thus, in humans, acute termination of sustained hyperventilation could result in cerebral hyperemia and increased intracranial pressure (ICP). To avoid these events, termination of sustained hypocapnia is best accomplished by normalizing PaCO2over a period of hours, which allows the brain to increase the extracellular bicarbonate concentration and buffer the change in extracellular pH.In anesthetized dogs, CBF returned to baseline values during 6 h of sustained hypercapnia, accompanied by an increase in CSF bicarbonate concentration and partial correction of CSF pH. 92In awake rabbits, chronic hypercapnia increased CSF bicarbonate concentration and attenuated the response of the cerebral circulation to further hypercapnia. 91In unanesthetized animals, however, hypercapnia can increase brain catecholamines and activate cerebral metabolism, indirectly causing an increase in CBF. 85,93Anesthetics may influence the response to hypercapnia by suppressing catecholamine release and preventing increased cerebral metabolism.When hypocapnia is used to reduce ICP, it does so by reducing CBV and not CBF per se. Technical difficulties have limited the number of studies of PaCO2and CBV. Evidence indicates that during alterations of PaCO2, changes in CBV are qualitatively similar to changes in CBF. In humans, baseline CBV is 3 or 4 ml per 100 g 94–96and is similar to values reported in baboons and monkeys when measurement techniques are similar. 71,97Other investigators have reported that CBV was larger in monkeys, dogs, and goats 78,98,99and smaller in rats. 100In humans, hyperventilation reduces CBV by 0.049 ml center dot 100 g-1center dot mmHg CO2-1, 96which is similar to values in monkeys 71and goats. 78Smaller changes in CBV have been reported in rats 100and dogs. 99Variations in CBV measurements likely reflect the intrinsic difficulty of measuring CBV and the measurement techniques. During sustained hyperventilation in dogs, CBV returns to baseline during a period of 4 h. 101The effect of PaCO2on CBV is attenuated during hypotension. 98Inhaled Anesthetics. In awake humans, hyperventilation decreased CBF by 0.9 ml center dot 100 g-1center dot min-1center dot mmHg CO2-1, and during with (and hyperventilation decreased CBF by ml center dot 100 g-1center dot min-1center dot mmHg CO hyperventilation caused a greater reduction of CBF during with because increased CBF from to ml center dot 100 g-1center dot min-1, CBF was greater during hyperventilation with compared with hyperventilation in the awake humans with a CBF of ml center dot 100 g-1center dot min-1, CBF was reduced by ml for each 1 mmHg reduction in PaCO2. animals, hyperventilation reduces CBF, and the slope of the reduction is directly to the CBF. data indicate that the cerebral circulation responds to hyperventilation during and the response is increased when CBF is humans, reductions in CBF by hyperventilation was greater during than in the awake importance of CBF in the response to hyperventilation during was demonstrated in dogs, CBF during is approximately that during and the reduction of CBF by hypocapnia during is also approximately that during humans and animals anesthetized with CBF is reduced by and the degree of reduction is directly to CBF. humans and anesthetized with or hypocapnia reduces CBF, and the degree of reduction is also to CBF. humans to oxide CBF is ml center dot 100 g-1center dot and hypocapnia reduced CBF by approximately 1 ml center dot 100 g-1center dot min-1center dot mmHg decrease in CBF is in goats to humans, the of to a anesthetic does not alter cerebral flow or the response of the cerebral circulation to the of to a anesthetic in rabbits increased CBF and the slope of the response to studies support the concept that by increasing CBF, anesthetics the response of the cerebral circulation to