Cerebral Blood Flow and Its Regulation WALTER
D.
OBRIST,
PH.D.
In 1945, Kety and Schmidt (10) introduced a quantitative method for estimating cerebral blood flow (CBF) in man, utilizing the Fick principle with nitrous oxide as an inert diffusible tracer. Cerebral metabolic rate was also determined by simultaneous sampling of arteriovenous oxygen and glucose differences. During the next t\VO decades, this method gained wide acceptance and was applied to a host of physiological and clinical problems, including studies of the regulation of cerebral blood flow and its variation in health and disease. Thorough reviews of the early 'York have been published by Lassen (11) and by Sokoloff (24). Because the Kety-Schmidt technique yields blood flow measurements for the whole brain, it is not particularly suited to the investigation of focal disorders. In 1963, Lassen and Ingvar introduced a quantitative radioisotope technique for determining regional cerebral blood flow (rCBF) in man, involving the intracarotid injection of xenon-133 (133Xe) (7). This method, for the first time, made it possible to evaluate focal alterations of blood flow through the intact skull, thereby contributing substantially to our understanding of cerebral pathophysiology. The present paper attempts to summarize some of the recent findings based on these methods, with particular emphasis on derangement of blood flow regulation. REGULATION OF CEREBRAL BLOOD FLOW
Response to Changes in Arterial Blood Pressure
Historically, it has been assumed that maintenance of an adequate blood supply to the brain depends on the homeostatic regulation of systemic blood pressure, and that variations in blood pressure are accompanied by CBF changes. Recent human studies with the Kety-Schmidt technique (11), however, have shown a surprising constancy of cerebral blood flow over a wide range of arterial pressures. Maintenance of constant CBF despite blood pressure changes has been called "autoregulation." With a regional method, Harper (3) confirmed the independence of blood flow and blood pressure in dogs, and noted that rCBF fell only when mean arterial pressure dropped below 90 mm. Hg. Subsequent investigations have firmly established the existence of autoregulation in the normal brain while pointing to its impairment in certain pathological conditions. 106
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CHAPTER 8
CEREBRAL BLOOD FLOW
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Autoregulation of cerebral blood flow is achieved by compensatory changes in cerebral vascular resistance brought about by alterations in vessel caliber, i.e., vasodilatation and vasoconstriction (19). Given the equation, CBF = BPg/CVR, where BPg = the blood pressure gradient (arterial minus venous pressure) and CVR = cerebral vascular resistance, it is clear that an increase or decrease in BPg will have little effect on blood flow if CVR changes proportionately. This is true for the intact brain under normal physiological conditions. Impairment of the autoregulatory response has been found with both hypercapnia and hypoxia. Harper (3) observed that elevation of arterial pC0 2 to 60 mm. Hg or more resulted in a passive dependence of rCBF on blood pressure. He argued that hypercapnia produced maximal dilatation of the cerebral vessels, thus limiting their ability to compensate for blood pressure variations. A similar loss of autoregulation was observed by Freeman and Ingvar (2) in cats following episodes of severe hypoxia. Although impairment of autoregulation was associated with cerebral hyperemia, it persisted well beyond the posthypoxic return of rCBF to normal levels. These authors attributed the loss of autoregulation to tissue acidosis resulting from anaerobic metabolism. A more direct effect of hypoxia on vascular smooth muscle, however, must also be considered. Following earlier conflicting results, the question of a neurogenic influence on autoregulation has recently been re-examined. In a carefully controlled study on baboons, James and co-workers (9) demonstrated the role of the sympathetic nervous system in regulating cerebral vasomotor tone. Figure 8.1 compares normal rCBF responses to variations in arterial blood pressure with those obtained following: (a) ipsilateral cervical sympathectomy, and (b) stimulation of the cut sympathetic nerve. Whereas sympathectomy increased blood flow throughout the normal blood pressure range, sympathetic stimulation tended to decrease it. In contrast to the leveling-off of rCBF with increased pressure in the control condition (normal autoregulation), the sympathectomized preparations showed a continued rise in blood flow at elevated pressures (impaired autoregulation). These findings were interpreted as indicating involvement of sympathetic vasoconstrictor activity in the regulation of CBF. Support for a neurogenic influence has also been obtained by MchedlishviIi and co-workers (13) with a perfused carotid artery preparation in dogs. With nerves intact, calculated vascular resistance in the internal carotid artery revealed the expected rise with stepwise increases in perfusion pressure (normal autoregulation). After complete denervation, accomplished by sacrificing the animal and perfusing the artery from a donor dog, the vascular resistance no longer varied with changes in blood pressure (loss of autoregulation), in spite of a demonstrated vascular response to vasoactive
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FIG. 8.1. The relation between cortical blood flow and mean arterial pressure in 13 baboons. Blood gas tensions and pH were maintained within physiological limits throughout. Solid circles, response with nerves intact; open circles, after sympathectomy; solid squares, during sympathetic stimulation. (From M. J. Purves: The Physiology of the Cerebral Circulation, Fig. 6.6, p. 170. Cambridge University Press, London, 1972.)
drugs. These results were interpreted as indicating the primacy of neural mechanisms in regulating blood flow through major input arteries of the brain. As discussed in the clinical material below, impairment of cerebral blood flow autoregulation is a frequent accompaniment of brain insult. Factors affecting autoregulation, such as hypercapnia and hypoxia, as well as the mechanisms controlling it, are therefore important in understanding hemodynamic contributions to pathology. As indicated above, progress has been made in recent years toward such an understanding, which hopefully will have clinical implications. Response to Changes in Arterial pC02 It is widely recognized that carbon dioxide is one of the most potent agents acting upon the cerebral circulation in both animals and man (24). Because carbon dioxide is a product of the brain's metabolism, it serves to regulate blood flow homeostatically in accordance with the metabolic needs of the tissue. Whereas elevated tissue pC0 2 (resulting from a high metabolic rate) produces vasodilatation and increased CBF, reduced tissue pC0 2 produces vasoconstriction and decreased CBF. Similar blood flow responses
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occur with alterations in arterial carbon dioxide tension (pAC02 ) brought about by changes in respired gas, i.e., hyperventilation and CO2 inhalation. Recently, there has been considerable interest in the impairment of CBF responsiveness to CO2 in abnormal physiological and pathological conditions. In normotensive dogs, Harper and Glass (5) found more than a 2-fold increase in rCBF 'when pAC0 2 was varied from 30 to 70 mm. Hg. This response was reduced, however, by 50 per cent in hypotensive animals, and completely eliminated when mean arterial blood pressure fell to 50 mm. Hg. They speculated that the hypotension and associated hypoxia resulted in cerebral vasodilatation that limited further responses to increased pAC02 while overriding the vasoconstrictive effect of decreased pAC0 2 • Although arterial and tissue pC0 2 are believed to act directly on vascular smooth muscle, there is increasing evidence that the blood flow changes are at least partially modulated by neurogenic influences. Shalit and co-workers (23) were able to abolish or markedly diminish CBF responses to CO 2 by high medullary, pontine, and mesencephalic lesions in dogs, a finding that was reversible when cryogenic probes were employed. On the other hand, James and co-workers (9) found that cervical sympathectomy enhanced rCBF responses to CO2 in baboons. These results are presented in Figure 8.2, which also shows the converse, namely, a reduction in blood. flow response during stimulation of sympathetic nerves. In contrast to sympathectomy which increases cerebrovascular reactivity, vagotomy tends to impair rCBF responsiveness to CO2 (9). Evidence for a cholinergic neural mechanism was obtained by Rovere and co-workers (22), who found diminished blood flow responses in rats after intraperitoneal administration of atropine, and enhanced responses after eserine, a cholinesterase inhibitor. Interestingly, atropine did not affect the autoregulation of CBF to blood pressure changes, thereby suggesting that a different mechanism is involved. Taken together, the above results clearly indicate that blood flow responses to altered pAC02 are influenced by neural activity. Noting that there is now definitive evidence for autonomic innervation of cerebral vessels (15), Harper and associates (4) postulate a dual mechanism for control of the cerebral circulation. Whereas the larger extraparenchymal arteries are believed to be under neurogenic control, the smaller intraparenchymal (penetrating) vessels are considered to be under metabolic control ti:e., directly responsive to CO2 ) , with the pial vessels being influenced by both factors. Such a hypothesis may help to explain variations in CBF response at different CO2 levels. Since the two mechanisms operate essentially in series, it is possible for one to offset the effects of the other in maintaining a relatively constant vascular resistance. Thus, sympathectomy and sympathetic stimulation produce only slight changes in blood flow under nor-
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mocapnic conditions (Fig. 8.2) when presumably the intraparenchymal vessels, in response to local changes in pC0 2 , can compensate for dilatation or constriction of the extraparenchymal vessels. Under hypercapnic conditions, however, the intraparenchymal vessels are already dilated and can no longer compensate as effectively for variations in caliber of the input arteries, with the result that sympathectomy and sympathetic stimulation have a much greater effect on CBF. As in the case of autoregulation, reactivity of the cerebral vessels to CO2 may have important clinical implications, since the response is frequently impaired in brain-damaged patients. Some of the derangements of CBF regulation encountered in human pathological conditions are described in the following sections. CEREBRAL BLOOD FLOW STUDIES IN 1\1:AN
Relation to Age, Mental Status, and Sleep
Cerebral blood flow alterations are not limited to acute brain lesions but also occur with advancing age, in senile mental deterioration, and during normal sleep. Although previous studies, based primarily on hospitalized
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Focal Changes with Brain Lesions Regional cerebral blood flow studies have made a definite contribution to our understanding of hemodynamic alterations in a variety of human brain disorders. Hecdt-Rasmusscn and co-workers (6) found localized areas of hyperemia (increased rCBF) in the first two days following an acute stroke that were associated with angiographic evidence of early filling veins. This phenomenon, termed "luxury perfusion" by Lassen, was attributed to tissue acidosis resulting from either localized transient hypoxia or the spread of acid metabolites to areas surrounding an ischemic focus. The suggestion was made that hyperventilation may be of therapeutic value in counteracting local acidosis and preventing edema.
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patients, suggest a progressive decline of CBF with age, Sokoloff (25) observed that healthy old people did not differ significantly from young controls. Reduced blood flow was, however, found in elderly subjects with mild, asymptomatic vascular disease, which indicates that even in its early stages, this disorder is associated" ith CBF changes. Since the latter subjects revealed a normal cerebral metabolic rate for oxygen (CMR02 ) , Sokoloff speculated that the primary disturbance was circulatory insufficiency which, if chronic, could lead to tissue damage and impaired metabolism. In contrast, a group of elderly patients" ith organic dementia showed parallel declines in CBF and CMR0 2 • In this case it might be argued that the blood flow decline was secondary to a lower metabolism, thereby representing an adjustment to the lesser metabolic demands of the tissue. The issue of whether CBF reductions are the cause or the consequence of a lower CMR02 in old age is, however, still unresolved. With a regional method, Obrist and co-workers (16) found significant reductions in cerebral blood flow among patients with senile and presenile dementia in the absence of focal neurological signs. Although all regions were affected, the frontotemporal areas showed the greatest decline. The magnitude of the rCBF changes was reliably correlated with the degree of dementia. Cerebral blood flow may also vary with the functional state of the normal brain. In agreement with earlier studies on animals, Townsend and coworkers (26) found an increased rCBF during rapid eye movement (REM) sleep in healthy young subjects that could not be explained by changes in pAC02 or systemic blood pressure. EEG slow wave sleep, on the other hand, was associated with a significant decrease in rCBF relative to waking levels. Blood flow differences between sleep stages were believed to reflect changes in cerebral metabolic rate, although neurogenic alterations of vasomotor tone could not be ruled out. It is possible that the same mechanism responsible for the CBF changes may account for "plateau waves" during REM sleep in patients" ith increased intracranial pressure (8).
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FIG. 8.3. Regional cerebral blood flow (ml./IOO gm./min.) from the right hemisphere of a patient one day after cerebral infarction resulting in left hemiparesis. Heavy circles indicate localized findings. Top, an ischemic focus at rest; bottom left, focal impairment of CO 2 response; bottom right, global loss of autoregulation. (From N. A. Lassen and O. B. Paulson: Partial cerebral vasoparalysis in patients with apoplexy. In Cerebral Blood Flow, edited by M. Brock, C. Fieschi, D. H. Ingvar, N. A. Lassen, and K. Schiirmann, pp. 117-119. Springer-Verlag, Berlin, 1969.)
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In a larger series of acute strokes, Paulson and co-workers (18) confirmed the occurrence of hyperemic foci in the early postictal days. Ischemic foci (decreased rCBF) were also observed, but these were not confined to the acute phase. Focal vasoparalysis (loss of autoregulation and impaired CO 2 responsiveness) was found during the first two weeks following a stroke. In some cases, there was a global loss of autoregulation affecting the entire hemisphere. The interrelation, sequence, and time course of these events are of particular interest in relation to the progression or resolution of the pathophysiology. Serial studies, not possible with the invasive technique employed, are needed to establish more precise correlations" ith the clinical course of the illness. Figure, 8.3 illustrates a case described by Lassen and Paulson (12). The
CEREBRAL BLOOD FLOW
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heavy circles indicate an isch.emic focus at rest that showed a localized reduction in responsiveness to hypercapnia. This patient also revealed a global loss of autoregulation during Aramine-induced hypertension (metaraminol bitartrate= Aramine, Merck Sharp & Dohme, West Point, Pa.). A dissociation between CO 2 responsiveness and autoregulation was found in over one-half of the 15 patients studied by these authors within two weeks of the stroke. In most instances, CO2 responsiveness was preserved at a time when autoregulation was impaired. According to McHenry and co-workers (14), CO2 responsiveness is usually diminished rather than completely lost, the reduction being greatest in ischemic areas. Only two of 20 stroke patients in their series showed a generalized absence of reactivity to 5 per cent CO2 inhalation. Of particular interest was the occurrence of "intracerebral steal," i.e., a paradoxical focal decrease in blood flow accompanied by increased flow in other regions. Since such a decrease was encountered in only two of 140 regions studied, the phenomenon was considered rare. Nevertheless, the possibility of a steal, coupled with the poor responsiveness of ischemic areas, argues against CO2 as a useful therapeutic agent. It is "Tell known that acute head injury is associated with hemodynamic disturbances, particularly in comatose patients, where decreased CBF and CMR0 2 are usually found. Reivich and co-workers (21) observed a loss of autoregulation after mechanical brain trauma in cats that frequently extended beyond the locus of injury in the traumatized hemisphere. Bruce and co-workers (1) reported a consistent but topographically variable loss of autoregulation in comatose head-injured patients VI ith mass lesions, an example of which is shown in Figure 8.4. In this case, increasing arterial blood pressure with angiotensin revealed a focal impairment of autoregulation (increased rCBF) adjacent to a temporal lobe mass. Elsewhere in the hemisphere, the blood pressure change had little effect on rCBF (intact autoregulation). Intravenous administration of mannitol, on the other hand, resulted in a generalized increase in blood flow, somewhat greater adjacent to the lesion. Although loss of autoregulation might be expected to produce cerebral ischemia when perfusion pressure is low, its precise role in acute head injury is not fully understood. As in the case of stroke, serial rCBF studies are needed in order to determine the sequence and time course of hemodynamic changes and their relationship to other variables. In this brief review of some of the human findings, an attempt has been made to illustrate the application of regional cerebral blood flow methods to clinical research, including functional tests for autoregulation and CO 2 responsiveness. As noted above, further investigation is limited by the invasive nature of the best available technique, i.e., the intracarotid injection of 133Xe. Recently, efforts have been made to develop less traumatic
114
CLINICAL NEUROSURGERY
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FIG. 8.4. Regional cerebral blood flow (ml./l00 gm./min.) from the left hemisphere of a patient one day after head injury resulting in temporal lobe contusion and hematoma. Shaded area indicates location of the mass. Top, control values; middle, during angiotensin-induced blood pressure increase; bottom, after intravenous mannitol. CBF = cerebral blood flow, SAP = systemic arterial pressure, ICP = intracranial pressure, CPP = cerebral perfusion pressure, CVR = cerebral vascular resistance, Pa02, PaC0 2 (pA0 2, pAC0 2) = arterial oxygen and carbon dioxide tensions, AVD0 2 := cerebral arteriovenous oxygen difference, CMR0 2 = cerebral metabolic rate for oxygen. (From D. A. Bruce, T. W. Langfitt, J. D. Miller, H. Schutz, M. P. Vapalahti, A. Stanek, and H. I. Goldberg: Regional cerebral blood flow, intracranial pressure, and brain metabolism in comatose patients. J. Neurosurg., 38: 131-144, 1973.)
rCBF methods involving inhalation or intravenous injection of the isotope, that can safely and repeatedly be administered to acutely ill patients. Preliminary studies by Obrist and co-workers (17) with the 133Xe inhalation method appear to hold promise, as suggested by their work on carotid endarterectomy. This method has also been employed with some success in serial studies of acute stroke (20). Its application to research on head injury and other neurosurgical problems awaits further development.
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Control
CEREBRAL BLOOD FLOW
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REFERENCES 1. Bruce, D. A., Langfitt, T. W., Miller, J. D., Schutz, H., Vapalahti, M. P., Stanek, A., and Goldberg, H. I. Regional cerebral blood flow, intracranial pressure, and brain metabolism in comatose patients. J. Neurosurg., 38: 131-144, 1973. 2. Freeman, J., and Ingvar, D. H. Elimination by hypoxia of cerebral blood flow autoregulation and EEG relationship. Exp. Brain Res., 5: 61-71, 1968. 3. Harper, A. M. Autoregulation of cerebral blood flow: influence of the arterial blood pressure on the blood flow through the cerebral cortex. J. Neurol. Neurosurg. Psychiatry, 29: 398-403, 1966. 4. Harper, A. M., Deshmukh, V. D., Rowan, J. 0., and Jennett, W. B. The influence of sympathetic nervous activity on cerebral blood flow. Arch. N eurol., 27: 1-6, 1972. 5. Harper, A. M., and Glass, H. I. Effect of alterations in the arterial carbon dioxide tension on the blood flow through the cerebral cortex at normal and low arterial blood pressures. J. Neurol. Neurosurg. Psychiatry, 28: 449-452,1965. 6. Heedt-Rasmussen, K., Skinhej , E., Paulson, 0., Ewald, J., Bjerrum, J. K., Fahrenkrug, A., and Lassen, N. A. Regional cerebral blood flow in acute apoplexy: the "luxury perfusion syndrome" of brain tissue. Arch. Neurol., 17: 271-281, 1967. 7. Hoedt-Rasmussen, K., Sveinsdottir, E., and Lassen, N. A. Regional cerebral blood flow in man determined by intra-arterial inj ection of radioactive inert gas. Circ. Res., 18: 237-247,1966. 8. Hulme, A., and Cooper, R. Cerebral blood flow during sleep in patients with raised intracranial pressure. Prog. Brain Res., 30: 77-81, 1968. 9. James, I. M., Millar, R. A., and Purves, M. J. Observations on the extrinsic neural control of cerebral blood flow in the baboon. Circ. Res., 25: 77-93, 1969. 10. Kety, S. S., and Schmidt, C. F. The determination of cerebral blood flow in man by the use of nitrous oxide in low concentrations. Am. J. Physiol., 143: 53-66, 1945. 11. Lassen, N. A., Cerebral blood flow and oxygen consumption in man. Physiol. Rev., 39: 183-238, 1959. 12. Lassen, N. A., and Paulson, O. B. Partial cerebral vasoparalysis in patients with apoplexy: dissociation between carbon dioxide responsiveness and autoregulation. In Cerebral Blood Flow, edited by M. Brock, C. Fieschi, D. H. Ingvar, N. A. Lassen, and K. Schurmann, pp. 117-119. Springer-Verlag, Berlin, 1969. 13. Mchedlishvili, G. I., Mitagvaria, N. P., and Ormotsadze, L. G. Vascular mechanisms controlling a constant blood supply to the brain ("autoregulation"). Stroke, 4: 742-750, 1973. 14. McHenry, L. C., Jr., Goldberg, H. I., Jaffe, M. E., Kenton, E. J., West, J. W., and Cooper, E. S. Regional cerebral blood flow: response to carbon dioxide inhalation in cerebrovascular disease. Arch. Neurol., 27: 403-412,1972. 15. Nelson, E., and Rennels, M. Innervation of intracranial arteries. Brain, 93: 475-490, 1970. 16. Obrist, W. D., Chivian, E., Cronqvist, S., and Ingvar, D. H. Regional cerebral blood flow in senile and presenile dementia. Neurology (Minneap.), 20: 315-322, 1970. 17. Obrist, W. D., Silver, D., Wilkinson, W. E., Harel, D., Heyman, A., and Wang, H. S. The xenon-133 inhalation method: assessment of rCBF in carotid endarterectomy. In Cerebral Circulation and Metabolism, edited by T. W. Langfitt,
116
19. 20.
21.
22. 23. 24. 25. 26.
L. C. McHenry, M. Reivich, and H. Wollman. Springer-Verlag, New York, in press. Paulson, O. B., Lassen, N. A., and Skinhej , E. Regional cerebral blood flow in apoplexy without arterial occlusion. Neurology (Minneap.), 20: 125-138, 1970. Purves, M. J. The Physiology of the Cerebral Circulation, 420 pp. Cambridge University Press, London, 1972. Rao, N. S., Ali, Z. A., Omar, H. M'., and Halsey, J. H. Regional cerebral blood flow in acute stroke: preliminary experience with the 133xenon inhalation method. Stroke, 5: 8-12, 1974. Reivich, M., Marshall, W. J. S., and Kassell, N. Effects of trauma upon cerebral vascular autoregulation. In Cerebral Vascular Diseases, Seventh Conference, edited by J. F. Toole, J. Moossy, and R. Janeway, pp. 63-69. Grune & Stratton, New York, 1971. Rovere, A. A., Scremin, O. U., Beresi, M. R., Raynald, A. C., and Giardini, A. Cholinergic mechanism in the cerebrovascular action of carbon dioxide. Stroke, 4: 969-972, 1973. Shalit, M. N., Reinmuth, O. M., Shimojyo, S., and Scheinberg, P. Carbon dioxide and cerebral circulatory control. III. The effects of brain stem lesions. Arch. Neurol., 17: 342-353, 1967. Sokoloff, L. The action of drugs on the cerebral circulation. Pharmacol. Rev., 11: 1-85, 1959. Sokoloff, L. Cerebral circulatory and metabolic changes associated with aging. Res. Publ. Assoc. Res. Nerv. Ment. Dis., 41: 237-254,1966. Townsend, R. E., Prinz, P. N., and Obrist, W. D. Human cerebral blood flow during sleep and waking. J. Appl. Physiol., 35: 620-625, 1973.
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18.
CLINICAL NEUROSURGERY
D.
OBRIST,
PH.D.
In 1945, Kety and Schmidt (10) introduced a quantitative method for estimating cerebral blood flow (CBF) in man, utilizing the Fick principle with nitrous oxide as an inert diffusible tracer. Cerebral metabolic rate was also determined by simultaneous sampling of arteriovenous oxygen and glucose differences. During the next t\VO decades, this method gained wide acceptance and was applied to a host of physiological and clinical problems, including studies of the regulation of cerebral blood flow and its variation in health and disease. Thorough reviews of the early 'York have been published by Lassen (11) and by Sokoloff (24). Because the Kety-Schmidt technique yields blood flow measurements for the whole brain, it is not particularly suited to the investigation of focal disorders. In 1963, Lassen and Ingvar introduced a quantitative radioisotope technique for determining regional cerebral blood flow (rCBF) in man, involving the intracarotid injection of xenon-133 (133Xe) (7). This method, for the first time, made it possible to evaluate focal alterations of blood flow through the intact skull, thereby contributing substantially to our understanding of cerebral pathophysiology. The present paper attempts to summarize some of the recent findings based on these methods, with particular emphasis on derangement of blood flow regulation. REGULATION OF CEREBRAL BLOOD FLOW
Response to Changes in Arterial Blood Pressure
Historically, it has been assumed that maintenance of an adequate blood supply to the brain depends on the homeostatic regulation of systemic blood pressure, and that variations in blood pressure are accompanied by CBF changes. Recent human studies with the Kety-Schmidt technique (11), however, have shown a surprising constancy of cerebral blood flow over a wide range of arterial pressures. Maintenance of constant CBF despite blood pressure changes has been called "autoregulation." With a regional method, Harper (3) confirmed the independence of blood flow and blood pressure in dogs, and noted that rCBF fell only when mean arterial pressure dropped below 90 mm. Hg. Subsequent investigations have firmly established the existence of autoregulation in the normal brain while pointing to its impairment in certain pathological conditions. 106
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CHAPTER 8
CEREBRAL BLOOD FLOW
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Autoregulation of cerebral blood flow is achieved by compensatory changes in cerebral vascular resistance brought about by alterations in vessel caliber, i.e., vasodilatation and vasoconstriction (19). Given the equation, CBF = BPg/CVR, where BPg = the blood pressure gradient (arterial minus venous pressure) and CVR = cerebral vascular resistance, it is clear that an increase or decrease in BPg will have little effect on blood flow if CVR changes proportionately. This is true for the intact brain under normal physiological conditions. Impairment of the autoregulatory response has been found with both hypercapnia and hypoxia. Harper (3) observed that elevation of arterial pC0 2 to 60 mm. Hg or more resulted in a passive dependence of rCBF on blood pressure. He argued that hypercapnia produced maximal dilatation of the cerebral vessels, thus limiting their ability to compensate for blood pressure variations. A similar loss of autoregulation was observed by Freeman and Ingvar (2) in cats following episodes of severe hypoxia. Although impairment of autoregulation was associated with cerebral hyperemia, it persisted well beyond the posthypoxic return of rCBF to normal levels. These authors attributed the loss of autoregulation to tissue acidosis resulting from anaerobic metabolism. A more direct effect of hypoxia on vascular smooth muscle, however, must also be considered. Following earlier conflicting results, the question of a neurogenic influence on autoregulation has recently been re-examined. In a carefully controlled study on baboons, James and co-workers (9) demonstrated the role of the sympathetic nervous system in regulating cerebral vasomotor tone. Figure 8.1 compares normal rCBF responses to variations in arterial blood pressure with those obtained following: (a) ipsilateral cervical sympathectomy, and (b) stimulation of the cut sympathetic nerve. Whereas sympathectomy increased blood flow throughout the normal blood pressure range, sympathetic stimulation tended to decrease it. In contrast to the leveling-off of rCBF with increased pressure in the control condition (normal autoregulation), the sympathectomized preparations showed a continued rise in blood flow at elevated pressures (impaired autoregulation). These findings were interpreted as indicating involvement of sympathetic vasoconstrictor activity in the regulation of CBF. Support for a neurogenic influence has also been obtained by MchedlishviIi and co-workers (13) with a perfused carotid artery preparation in dogs. With nerves intact, calculated vascular resistance in the internal carotid artery revealed the expected rise with stepwise increases in perfusion pressure (normal autoregulation). After complete denervation, accomplished by sacrificing the animal and perfusing the artery from a donor dog, the vascular resistance no longer varied with changes in blood pressure (loss of autoregulation), in spite of a demonstrated vascular response to vasoactive
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FIG. 8.1. The relation between cortical blood flow and mean arterial pressure in 13 baboons. Blood gas tensions and pH were maintained within physiological limits throughout. Solid circles, response with nerves intact; open circles, after sympathectomy; solid squares, during sympathetic stimulation. (From M. J. Purves: The Physiology of the Cerebral Circulation, Fig. 6.6, p. 170. Cambridge University Press, London, 1972.)
drugs. These results were interpreted as indicating the primacy of neural mechanisms in regulating blood flow through major input arteries of the brain. As discussed in the clinical material below, impairment of cerebral blood flow autoregulation is a frequent accompaniment of brain insult. Factors affecting autoregulation, such as hypercapnia and hypoxia, as well as the mechanisms controlling it, are therefore important in understanding hemodynamic contributions to pathology. As indicated above, progress has been made in recent years toward such an understanding, which hopefully will have clinical implications. Response to Changes in Arterial pC02 It is widely recognized that carbon dioxide is one of the most potent agents acting upon the cerebral circulation in both animals and man (24). Because carbon dioxide is a product of the brain's metabolism, it serves to regulate blood flow homeostatically in accordance with the metabolic needs of the tissue. Whereas elevated tissue pC0 2 (resulting from a high metabolic rate) produces vasodilatation and increased CBF, reduced tissue pC0 2 produces vasoconstriction and decreased CBF. Similar blood flow responses
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occur with alterations in arterial carbon dioxide tension (pAC02 ) brought about by changes in respired gas, i.e., hyperventilation and CO2 inhalation. Recently, there has been considerable interest in the impairment of CBF responsiveness to CO2 in abnormal physiological and pathological conditions. In normotensive dogs, Harper and Glass (5) found more than a 2-fold increase in rCBF 'when pAC0 2 was varied from 30 to 70 mm. Hg. This response was reduced, however, by 50 per cent in hypotensive animals, and completely eliminated when mean arterial blood pressure fell to 50 mm. Hg. They speculated that the hypotension and associated hypoxia resulted in cerebral vasodilatation that limited further responses to increased pAC02 while overriding the vasoconstrictive effect of decreased pAC0 2 • Although arterial and tissue pC0 2 are believed to act directly on vascular smooth muscle, there is increasing evidence that the blood flow changes are at least partially modulated by neurogenic influences. Shalit and co-workers (23) were able to abolish or markedly diminish CBF responses to CO 2 by high medullary, pontine, and mesencephalic lesions in dogs, a finding that was reversible when cryogenic probes were employed. On the other hand, James and co-workers (9) found that cervical sympathectomy enhanced rCBF responses to CO2 in baboons. These results are presented in Figure 8.2, which also shows the converse, namely, a reduction in blood. flow response during stimulation of sympathetic nerves. In contrast to sympathectomy which increases cerebrovascular reactivity, vagotomy tends to impair rCBF responsiveness to CO2 (9). Evidence for a cholinergic neural mechanism was obtained by Rovere and co-workers (22), who found diminished blood flow responses in rats after intraperitoneal administration of atropine, and enhanced responses after eserine, a cholinesterase inhibitor. Interestingly, atropine did not affect the autoregulation of CBF to blood pressure changes, thereby suggesting that a different mechanism is involved. Taken together, the above results clearly indicate that blood flow responses to altered pAC02 are influenced by neural activity. Noting that there is now definitive evidence for autonomic innervation of cerebral vessels (15), Harper and associates (4) postulate a dual mechanism for control of the cerebral circulation. Whereas the larger extraparenchymal arteries are believed to be under neurogenic control, the smaller intraparenchymal (penetrating) vessels are considered to be under metabolic control ti:e., directly responsive to CO2 ) , with the pial vessels being influenced by both factors. Such a hypothesis may help to explain variations in CBF response at different CO2 levels. Since the two mechanisms operate essentially in series, it is possible for one to offset the effects of the other in maintaining a relatively constant vascular resistance. Thus, sympathectomy and sympathetic stimulation produce only slight changes in blood flow under nor-
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FIG. 8.2. The relation between cortical blood flow and pAC0 2 in a baboon. Solid circles, response with nerves intact; open circles, after sympathectomy; solid triangles, during sympathetic stimulation. (From M. J. Purves: The Physiology of the Cerebral Circulation, Fig. 7.11, p. 197. Cambridge University Press, London, 1972.)
mocapnic conditions (Fig. 8.2) when presumably the intraparenchymal vessels, in response to local changes in pC0 2 , can compensate for dilatation or constriction of the extraparenchymal vessels. Under hypercapnic conditions, however, the intraparenchymal vessels are already dilated and can no longer compensate as effectively for variations in caliber of the input arteries, with the result that sympathectomy and sympathetic stimulation have a much greater effect on CBF. As in the case of autoregulation, reactivity of the cerebral vessels to CO2 may have important clinical implications, since the response is frequently impaired in brain-damaged patients. Some of the derangements of CBF regulation encountered in human pathological conditions are described in the following sections. CEREBRAL BLOOD FLOW STUDIES IN 1\1:AN
Relation to Age, Mental Status, and Sleep
Cerebral blood flow alterations are not limited to acute brain lesions but also occur with advancing age, in senile mental deterioration, and during normal sleep. Although previous studies, based primarily on hospitalized
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Focal Changes with Brain Lesions Regional cerebral blood flow studies have made a definite contribution to our understanding of hemodynamic alterations in a variety of human brain disorders. Hecdt-Rasmusscn and co-workers (6) found localized areas of hyperemia (increased rCBF) in the first two days following an acute stroke that were associated with angiographic evidence of early filling veins. This phenomenon, termed "luxury perfusion" by Lassen, was attributed to tissue acidosis resulting from either localized transient hypoxia or the spread of acid metabolites to areas surrounding an ischemic focus. The suggestion was made that hyperventilation may be of therapeutic value in counteracting local acidosis and preventing edema.
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patients, suggest a progressive decline of CBF with age, Sokoloff (25) observed that healthy old people did not differ significantly from young controls. Reduced blood flow was, however, found in elderly subjects with mild, asymptomatic vascular disease, which indicates that even in its early stages, this disorder is associated" ith CBF changes. Since the latter subjects revealed a normal cerebral metabolic rate for oxygen (CMR02 ) , Sokoloff speculated that the primary disturbance was circulatory insufficiency which, if chronic, could lead to tissue damage and impaired metabolism. In contrast, a group of elderly patients" ith organic dementia showed parallel declines in CBF and CMR0 2 • In this case it might be argued that the blood flow decline was secondary to a lower metabolism, thereby representing an adjustment to the lesser metabolic demands of the tissue. The issue of whether CBF reductions are the cause or the consequence of a lower CMR02 in old age is, however, still unresolved. With a regional method, Obrist and co-workers (16) found significant reductions in cerebral blood flow among patients with senile and presenile dementia in the absence of focal neurological signs. Although all regions were affected, the frontotemporal areas showed the greatest decline. The magnitude of the rCBF changes was reliably correlated with the degree of dementia. Cerebral blood flow may also vary with the functional state of the normal brain. In agreement with earlier studies on animals, Townsend and coworkers (26) found an increased rCBF during rapid eye movement (REM) sleep in healthy young subjects that could not be explained by changes in pAC02 or systemic blood pressure. EEG slow wave sleep, on the other hand, was associated with a significant decrease in rCBF relative to waking levels. Blood flow differences between sleep stages were believed to reflect changes in cerebral metabolic rate, although neurogenic alterations of vasomotor tone could not be ruled out. It is possible that the same mechanism responsible for the CBF changes may account for "plateau waves" during REM sleep in patients" ith increased intracranial pressure (8).
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FIG. 8.3. Regional cerebral blood flow (ml./IOO gm./min.) from the right hemisphere of a patient one day after cerebral infarction resulting in left hemiparesis. Heavy circles indicate localized findings. Top, an ischemic focus at rest; bottom left, focal impairment of CO 2 response; bottom right, global loss of autoregulation. (From N. A. Lassen and O. B. Paulson: Partial cerebral vasoparalysis in patients with apoplexy. In Cerebral Blood Flow, edited by M. Brock, C. Fieschi, D. H. Ingvar, N. A. Lassen, and K. Schiirmann, pp. 117-119. Springer-Verlag, Berlin, 1969.)
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In a larger series of acute strokes, Paulson and co-workers (18) confirmed the occurrence of hyperemic foci in the early postictal days. Ischemic foci (decreased rCBF) were also observed, but these were not confined to the acute phase. Focal vasoparalysis (loss of autoregulation and impaired CO 2 responsiveness) was found during the first two weeks following a stroke. In some cases, there was a global loss of autoregulation affecting the entire hemisphere. The interrelation, sequence, and time course of these events are of particular interest in relation to the progression or resolution of the pathophysiology. Serial studies, not possible with the invasive technique employed, are needed to establish more precise correlations" ith the clinical course of the illness. Figure, 8.3 illustrates a case described by Lassen and Paulson (12). The
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heavy circles indicate an isch.emic focus at rest that showed a localized reduction in responsiveness to hypercapnia. This patient also revealed a global loss of autoregulation during Aramine-induced hypertension (metaraminol bitartrate= Aramine, Merck Sharp & Dohme, West Point, Pa.). A dissociation between CO 2 responsiveness and autoregulation was found in over one-half of the 15 patients studied by these authors within two weeks of the stroke. In most instances, CO2 responsiveness was preserved at a time when autoregulation was impaired. According to McHenry and co-workers (14), CO2 responsiveness is usually diminished rather than completely lost, the reduction being greatest in ischemic areas. Only two of 20 stroke patients in their series showed a generalized absence of reactivity to 5 per cent CO2 inhalation. Of particular interest was the occurrence of "intracerebral steal," i.e., a paradoxical focal decrease in blood flow accompanied by increased flow in other regions. Since such a decrease was encountered in only two of 140 regions studied, the phenomenon was considered rare. Nevertheless, the possibility of a steal, coupled with the poor responsiveness of ischemic areas, argues against CO2 as a useful therapeutic agent. It is "Tell known that acute head injury is associated with hemodynamic disturbances, particularly in comatose patients, where decreased CBF and CMR0 2 are usually found. Reivich and co-workers (21) observed a loss of autoregulation after mechanical brain trauma in cats that frequently extended beyond the locus of injury in the traumatized hemisphere. Bruce and co-workers (1) reported a consistent but topographically variable loss of autoregulation in comatose head-injured patients VI ith mass lesions, an example of which is shown in Figure 8.4. In this case, increasing arterial blood pressure with angiotensin revealed a focal impairment of autoregulation (increased rCBF) adjacent to a temporal lobe mass. Elsewhere in the hemisphere, the blood pressure change had little effect on rCBF (intact autoregulation). Intravenous administration of mannitol, on the other hand, resulted in a generalized increase in blood flow, somewhat greater adjacent to the lesion. Although loss of autoregulation might be expected to produce cerebral ischemia when perfusion pressure is low, its precise role in acute head injury is not fully understood. As in the case of stroke, serial rCBF studies are needed in order to determine the sequence and time course of hemodynamic changes and their relationship to other variables. In this brief review of some of the human findings, an attempt has been made to illustrate the application of regional cerebral blood flow methods to clinical research, including functional tests for autoregulation and CO 2 responsiveness. As noted above, further investigation is limited by the invasive nature of the best available technique, i.e., the intracarotid injection of 133Xe. Recently, efforts have been made to develop less traumatic
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FIG. 8.4. Regional cerebral blood flow (ml./l00 gm./min.) from the left hemisphere of a patient one day after head injury resulting in temporal lobe contusion and hematoma. Shaded area indicates location of the mass. Top, control values; middle, during angiotensin-induced blood pressure increase; bottom, after intravenous mannitol. CBF = cerebral blood flow, SAP = systemic arterial pressure, ICP = intracranial pressure, CPP = cerebral perfusion pressure, CVR = cerebral vascular resistance, Pa02, PaC0 2 (pA0 2, pAC0 2) = arterial oxygen and carbon dioxide tensions, AVD0 2 := cerebral arteriovenous oxygen difference, CMR0 2 = cerebral metabolic rate for oxygen. (From D. A. Bruce, T. W. Langfitt, J. D. Miller, H. Schutz, M. P. Vapalahti, A. Stanek, and H. I. Goldberg: Regional cerebral blood flow, intracranial pressure, and brain metabolism in comatose patients. J. Neurosurg., 38: 131-144, 1973.)
rCBF methods involving inhalation or intravenous injection of the isotope, that can safely and repeatedly be administered to acutely ill patients. Preliminary studies by Obrist and co-workers (17) with the 133Xe inhalation method appear to hold promise, as suggested by their work on carotid endarterectomy. This method has also been employed with some success in serial studies of acute stroke (20). Its application to research on head injury and other neurosurgical problems awaits further development.
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REFERENCES 1. Bruce, D. A., Langfitt, T. W., Miller, J. D., Schutz, H., Vapalahti, M. P., Stanek, A., and Goldberg, H. I. Regional cerebral blood flow, intracranial pressure, and brain metabolism in comatose patients. J. Neurosurg., 38: 131-144, 1973. 2. Freeman, J., and Ingvar, D. H. Elimination by hypoxia of cerebral blood flow autoregulation and EEG relationship. Exp. Brain Res., 5: 61-71, 1968. 3. Harper, A. M. Autoregulation of cerebral blood flow: influence of the arterial blood pressure on the blood flow through the cerebral cortex. J. Neurol. Neurosurg. Psychiatry, 29: 398-403, 1966. 4. Harper, A. M., Deshmukh, V. D., Rowan, J. 0., and Jennett, W. B. The influence of sympathetic nervous activity on cerebral blood flow. Arch. N eurol., 27: 1-6, 1972. 5. Harper, A. M., and Glass, H. I. Effect of alterations in the arterial carbon dioxide tension on the blood flow through the cerebral cortex at normal and low arterial blood pressures. J. Neurol. Neurosurg. Psychiatry, 28: 449-452,1965. 6. Heedt-Rasmussen, K., Skinhej , E., Paulson, 0., Ewald, J., Bjerrum, J. K., Fahrenkrug, A., and Lassen, N. A. Regional cerebral blood flow in acute apoplexy: the "luxury perfusion syndrome" of brain tissue. Arch. Neurol., 17: 271-281, 1967. 7. Hoedt-Rasmussen, K., Sveinsdottir, E., and Lassen, N. A. Regional cerebral blood flow in man determined by intra-arterial inj ection of radioactive inert gas. Circ. Res., 18: 237-247,1966. 8. Hulme, A., and Cooper, R. Cerebral blood flow during sleep in patients with raised intracranial pressure. Prog. Brain Res., 30: 77-81, 1968. 9. James, I. M., Millar, R. A., and Purves, M. J. Observations on the extrinsic neural control of cerebral blood flow in the baboon. Circ. Res., 25: 77-93, 1969. 10. Kety, S. S., and Schmidt, C. F. The determination of cerebral blood flow in man by the use of nitrous oxide in low concentrations. Am. J. Physiol., 143: 53-66, 1945. 11. Lassen, N. A., Cerebral blood flow and oxygen consumption in man. Physiol. Rev., 39: 183-238, 1959. 12. Lassen, N. A., and Paulson, O. B. Partial cerebral vasoparalysis in patients with apoplexy: dissociation between carbon dioxide responsiveness and autoregulation. In Cerebral Blood Flow, edited by M. Brock, C. Fieschi, D. H. Ingvar, N. A. Lassen, and K. Schurmann, pp. 117-119. Springer-Verlag, Berlin, 1969. 13. Mchedlishvili, G. I., Mitagvaria, N. P., and Ormotsadze, L. G. Vascular mechanisms controlling a constant blood supply to the brain ("autoregulation"). Stroke, 4: 742-750, 1973. 14. McHenry, L. C., Jr., Goldberg, H. I., Jaffe, M. E., Kenton, E. J., West, J. W., and Cooper, E. S. Regional cerebral blood flow: response to carbon dioxide inhalation in cerebrovascular disease. Arch. Neurol., 27: 403-412,1972. 15. Nelson, E., and Rennels, M. Innervation of intracranial arteries. Brain, 93: 475-490, 1970. 16. Obrist, W. D., Chivian, E., Cronqvist, S., and Ingvar, D. H. Regional cerebral blood flow in senile and presenile dementia. Neurology (Minneap.), 20: 315-322, 1970. 17. Obrist, W. D., Silver, D., Wilkinson, W. E., Harel, D., Heyman, A., and Wang, H. S. The xenon-133 inhalation method: assessment of rCBF in carotid endarterectomy. In Cerebral Circulation and Metabolism, edited by T. W. Langfitt,
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L. C. McHenry, M. Reivich, and H. Wollman. Springer-Verlag, New York, in press. Paulson, O. B., Lassen, N. A., and Skinhej , E. Regional cerebral blood flow in apoplexy without arterial occlusion. Neurology (Minneap.), 20: 125-138, 1970. Purves, M. J. The Physiology of the Cerebral Circulation, 420 pp. Cambridge University Press, London, 1972. Rao, N. S., Ali, Z. A., Omar, H. M'., and Halsey, J. H. Regional cerebral blood flow in acute stroke: preliminary experience with the 133xenon inhalation method. Stroke, 5: 8-12, 1974. Reivich, M., Marshall, W. J. S., and Kassell, N. Effects of trauma upon cerebral vascular autoregulation. In Cerebral Vascular Diseases, Seventh Conference, edited by J. F. Toole, J. Moossy, and R. Janeway, pp. 63-69. Grune & Stratton, New York, 1971. Rovere, A. A., Scremin, O. U., Beresi, M. R., Raynald, A. C., and Giardini, A. Cholinergic mechanism in the cerebrovascular action of carbon dioxide. Stroke, 4: 969-972, 1973. Shalit, M. N., Reinmuth, O. M., Shimojyo, S., and Scheinberg, P. Carbon dioxide and cerebral circulatory control. III. The effects of brain stem lesions. Arch. Neurol., 17: 342-353, 1967. Sokoloff, L. The action of drugs on the cerebral circulation. Pharmacol. Rev., 11: 1-85, 1959. Sokoloff, L. Cerebral circulatory and metabolic changes associated with aging. Res. Publ. Assoc. Res. Nerv. Ment. Dis., 41: 237-254,1966. Townsend, R. E., Prinz, P. N., and Obrist, W. D. Human cerebral blood flow during sleep and waking. J. Appl. Physiol., 35: 620-625, 1973.
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