Journal of Cerebral Blood Flow and Metabolism 10:327-336 © 1990 Raven Press, Ltd., New York
Autoregulation of Cerebral Blood Flow in Experimental Focal Brain Ischemia
Ulrich Dirnagl and William Pulsinelli Cerebrovascular Disease Research Center, Department of Neurology and Neuroscience, Cornell University Medical College, New York, New York, U.S.A.
Summary: The relationship between systemic arterial pressure (SAP) and neocortical microcirculatory blood flow (CBF) in areas of focal cerebral ischemia was stud ied in 15 spontaneously hypertensive rats (SHRs) anes thetized with halothane (0.5%). Ischemia was induced by ipsilateral middle cerebral artery/common carotid artery occlusion and CBF was monitored continuously in the ischemic territory using laser-Doppler flowmetry during manipulation of SAP with I-norepinephrine (hyperten sion) or nitroprusside (hypotension). In eight SHRs not subjected to focal ischemia, we demonstrated that 0.5% halothane and the surgical manipUlations did not impair autoregulation. Autoregulation was partly preserved in ischemic brain tissue with a CBF of > 30% of preocclu sion values. In areas where ischemic CBF was 30%, 100 measurements, eight probes in seven animals). Third-order regression for each animal. (Solid lines), hypertension before hypotension; (Dashed lines), hypotension before hypertension.
for first-order regression, also indicating improved fit due to the cubic model. Relationship in moderately ischemic brain tissue (group B). A total of 130 measurements at nine probe sites in seven animals detected brain tissue in which rCBF fell to a level between 15 and 30% of baseline values after MCAICCA occlusion. Mean rCBF after MCAICCA occlusion was 18.2% of baseline, with a range of 15-29% (SD ± 9%). The rCBF/SAP relationship was linear (Fig. 3), and the AI was 0. 88 (extrapolated from the pooled data from seven independent probes). The l3-coeffi cients, calculated for a third-order regression of rCBF on SAP for each animal, did not reach statis tical significance (p > 0.1). r values for the first order regressions shown in Fig. 3 ranged from 0.36 to 0.98. Third-order regression did not improve r values, and the lines fit by the cubic model were 50
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FIG. 3. Mean systemic arterial pressure (MSAP; mm Hg) and regional CBF (rCBF; % of preocclusion values) in moderately ischemic cortex (rCBF between 15 and 30%, 130 measure ments, 11 probes in 10 animals). First-order regression for . each animal. (Solid lines), hypertension before hypotension; (dashed lines), hypotension before hypertension.
AUTOREGULATION IN CEREBRAL ISCHEMIA
almost straight, indicating linear relationships be tween SAP and rCBF. Relationship in severely ischemic brain tissue (group C). A total of 102 measurements at nine probe sites in seven animals showed rCBF values below 15% of baseline after MCAICCA occlusion. The mean rCBF after MCA/CCA occlusion in this group equaled 10.8% of baseline (range 4-14%; SD ± 4%). Figure 4 shows the data, analyzed with a linear regression for each animal. The cubic model (third-order polynomial regression) did not improve the curve fit (no statistical significance of the l3-coefficients, p > 0.2). ? values for the first-order regressions shown in Fig. 4 ranged from 0.51 to 0.94. Third-order regression did not improve r2 val ues, and the lines fit by this model were almost straight, indicating linear relationships between SAP and rCBF. The AI of 0.60 (extrapolated from the pooled data from seven independent probes; see Fig. 5) was less than in zones of moderate ischemia where autoregulation was also lost. DISCUSSION
Our study shows that rCBF in the neocortex of SHRs anesthetized with 0.5% halothane is auto regulated to nitroprusside- and norepinephrine induced changes in SAP. The SAP within which autoregulation was maintained ranged from 80 to 175 mm Hg. These values are consistent with the limits of autoregulation reported for the SHR (see below). In ischemic neocortex, autoregulation was atten uated but not abolished in tissue areas where rCBF after MCAICCA occlusion fell to levels between 30 and 60% of preocclusion values. In tissue areas where post-MCA/CCA occlusion rCBF was 30%), estimated postocclusion CBF would approximate >40 ml/100 g/min, that for group B (15% < CBF < 30%) be tween 20 and 40 mll100 g/min, and for group C (CBF < 15%) 30% of pre occlusion values; autoregulation was completely lost when CBF fell below 30% of normal values. SAP had a greater influence on CBF in moderately ischemic brain tissue (CBF between 15 and 30% of baseline) than in severely ischemic brain tissue (CBF < 15% of baseline). Moderately ischemic tis sue (CBF between 15 and 30% of baseline) might benefit from raising SAP in the first hours after ce rebral infarction. Acknowledgment: Dr. U. Dirnagl is a recipient of a Ger man Academic Exchange Service (DAAD) research scholarship. This research was supported in part by NIH grant NS-03346. We are grateful to Dr. Martin Lesser, Assistant Professor of Biostatistics, for statistical advice.
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physiology and Pharmacotherapy of Cerebrovascular Dis orders (Betz E, Grote J, Heuser D, Wuellenweber R, eds, Baden-Baden, Witzstrock, pp 37-38 Anderson RE, Michenfelder JD, Sundt TM (1980) Brain intra cellular pH, blood flow, and blood-brain barrier differences with barbiturate and halothane anesthesia. Anesthesiology
52:201-206 Arbit E, DiResta GR, Bedford RF, Shah NK, Galicich JH (1989) Intraoperative measurement of cerebral and tumor blood flow with laser-Doppler flowmetry. Neurosurgery 24:166-
170 Aspey BS, Ehteshami S, Hurst CM, McCoy AL, Harrison MJG (1987) The effect of increased blood pressure on hemispheric lactate and water content during acute cerebral ischemia in the rat and gerbil. J Neurol Neurosurg Psychiatry 50:1493-
1498 Ayoagi M, Meyer JS, Deshmukh VD, Ott EO, Tagashira Y, Kawamura Y, Matsuda M, Achari, AN, Chee ANC (1975) Central cholinergic control of cerebral blood flow in the ba boon. J Neurosurg 43:689-705 Barry DI, Strandgaard S, Svendsen 0, Braendstrup 0, Graham 01, Hemmingsen R, Bolwig TG (1981) Adaptive changes in the lower limit of cerebral blood flow autoregulation in hy pertensive rats. J Cereb Blood Flow Metab I(suppl I):S263 Barry DI, Strandgaard S, Graham 01, Braendstrup 0, Svendsen UG, Vorstrup S, Hemmingsen R, Bolwig TG (1982) Cerebral blood flow in rats with renal and spontaneous hypertension: resetting of the lower limit of autoregulation. J Cereb Blood
Flow and Metab 2:347-353 Bleyaert AL, Sands PA, Safar P, Nemoto M, Stezoski SW, Moossy J, Rao GR (1980) Augmentation of postischemic brain damage by severe intermittent hypertension. Crit Care
Med 8:41-47 Bonner RF (1987) Model for photon migration in turbid biologi cal media. J Opt Soc Am 4:423-432
J
Cereb Blood Flow Metab, Vol. 10, No.3, 1990
Brint S, Jacewicz M, Kiessling M, Tanabe J, Pulsinelli W (1988) Focal brain ischemia in the rat: methods for reproducible neocortical infarction using tandem occlusion of the distal middle cerebral and ipsilateral common carotid arteries. J
Cereb Blood Flow Metab 8:474-485 Brown FB, Hanlon K, Crockard HA, Mullan S (1977) Effect of sodium nitroprusside on cerebral blood flow in conscious human beings. Surg Neurol 7:67-70 Brown FB, Crockard HA, Johns LM, Mullan S (1978) The effect of sodium nitroprusside and trimethaphan camsylate on ce rebral blood flow in rhesus monkeys. Neurosurgery 2:31-34 Candia GJ, Heros RC, Lavyne MH, Zervas NT, Nelson CN (1978) Effect of intravenous sodium nitroprusside in cerebral blood flow and intracranial pressure. Neurosurgery 3:50-53 Chien S, Usami S, Skalak R (1984) Blood flow in small tubes. In: Handbook of Physiology, Sec 2, Vol 4, Pt 1 (Renkin EM, Michel CC, eds) Bethesda, American Physiological Society, pp 217-249 Crockard HA, Brown FD, Mullan JF (1976) Effects of tri methaphane and sodium nitroprusside on cerebral blood flow in rhesus monkeys. Acta Neurochir 35:83-89 Diaz FG, Ausmann JI (1980) Experimental cerebral ischemia.
Neurosurgery 6:436-445 Dirnagl U, Kaplan B, Jacewicz M, Pulsinelli W (1989) Continu ous measurement of cerebral cortical blood flow by laser Doppler flowmetry in a rat stroke model. J Cereb Blood
Flow Metab 9:589-596 Drummond JC, Oh YS, Cole OJ, Shapiro HM (1988) Phenyleph rine-induced hypertension decreases the extent of ischemia following middle cerebral artery occlusion in the rat. Anes
thesiol Rev 15:38-39 Farhat SM, Schneider RC (1967) Observations on the effect of systemic blood pressure on intracranial circulation in pa tients with cerebrovascular insufficiency. J Neurosurg 27:
441-445 Fenske A, Kohl J, Fischer M, Regli F, Reulen HJ (1975) The effect of arterial hypertension following occlusion of the middle cerebral artery. In: Blood Flow and Metabolism in the Brain (Harper AM, Jennet B, Miller D, Rowan J, eds), London, Churchill Livingstone, pp 6.25-6.26 Fieschi C, Agnioli A, Battistini N, Bozzao L, Prencipe M (1968) Derangement of regional cerebral blood flow and of its reg ulatory mechanisms in acute cerebrovascular lesions. Neu
rology 18:1166-1179 Fujishima M, Omae T (1976) Lower limit of cerebral autoregu lation in normotensive and spontaneously hypertensive rats.
Experientia 32: 1019-1021 Fujishima M, Sadoshima S, Ogato J, Yoshida F, Ibayashi S, Shiokawa 0, Omae T (1983) Autoregulation of cerebral blood flow during development of spontaneous hyperten sion. J Cereb Blood Flow Metab 3(suppl I):S667-S668 Gottstein U, Seel AW (1977) Antihypertensive therapy in stroke patients. Acta Neurol Scand 56(suppl 64):174-175 Grotta JC (1987) Can raising cerebral blood improve outcome after acute cerebral infarction? Stroke 18:264-267 Haberl RL, Heizer ML, Marmarou A, Ellis EF (1989) Laser Doppler assessment of the brain microcirculation. Am J
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Morita H, Nemoto EM, Bleyaert AL, Stezoski SW (1977) Brain blood flow autoregulation and metabolism during halothane anesthesia in monkeys. Am J Physiol 233:H670-H676 Murphy 1M, Sage 11 (1988) Trimethaphane or nitroprusside in the setting of intracranial hypertension. Clin Neuropharma colli :436-442 Norusis Ml (1988) SPSS/PC+ V2.0 Chicago, SPSS Inc., pp B219-B220 Okada Y, McDowall DG, Ali MM, Lane lR (1975) Effects of halothane- induced hypotension on CO2 responsiveness and on autoregulation of the cerebral circulation. In: Blood Flow and Metabolism in the Brain (Harper AM, Jennet B, Miller D, Rowan 1, eds), London, Churchill Livingstone, pp 11.911.13 Okada Y, Shima T, Matsumura S, Nishida M, Yamada T, Okita S (1987) Comparison of autoregulatory responses in the ver tebral and carotid arterial system by induced hypotension, hypertension, and epidural anesthesia. J Cereb Blood Flow Metab 7(suppl 1):S252 Olesen 1 (1973) Quantitative evaluation of normal and pathologic cerebral blood flow regulation to perfusion pressure. Arch Neurol 28:143-149 Olesen 1 (1974) Cerebral blood flow: methods for measurement, regulation, effects of drugs, and changes in disease. Acta Neurol Scand 50(suppl 57) Olsen TS (1982) Should induced hypertension or hypotension ever be used in the treatment of stroke? Acta Med Scand (suppl 678):113-120 Reivich M, Marshall WIS, Kassel N (1969) Loss of autoregula tion produced by cerebral trauma. In: Cerebral Blood Flow (Brock M, Fieschi C, Ingvar DH, eds), New York, Springer, pp 205-208 Rogers MC, Traystman Rl (1979) Cerebral hemodynamic effects of nitroglycerin and nitroprusside. Acta Neurol Scand 60(suppl 72):600-601 Safar P, Stezoski W, Nemoto EM (1976) Amelioration of brain damage after 12 minutes' cardiac arrest in dogs. Arch Neurol 33:91-95 Schuier Fl, Hossmann K-A (1980) Experimental brain infarcts in cats. II. Ischemic brain edema. Stroke 11:593-601 Shinohara Y, Takagi S, Yamamoto M, Haida M, Taniguchi R, Hamano H (1987) Topographical distribution of autoregula tory ability and CO2 reactivity in monkey brain. J Cereb Blood Flow Metab 7(suppl 1):S285 Skarphedisson 10, Harding H, Thoren P (1988) Repeated mea surements of cerebral blood flow in rats. Comparisons be tween the hydrogen clearance method and laser Doppler flowmetry. Acta Physiol Scand 134:133-142 Smith AL, Larson CP, Hoff JT (1973) Effects of halothane on regional cerebral blood flow in experimental focal ischemia. Anesthesiology 39:377-381 Spatz M, Mrsulja BB, Ito U, Fujimoto T, Klatzo (1976) Effects of hypertension on postischemic brain injury in mongolian gerbils. Stroke 7:4 Stern MD (1975) In vivo evaluation of microcirculation by co herent light scattering. Nature 254:56-58 Strandgaard S, Olesen 1, Skinhoj E, Lassen NA (1973) Autoreg ulation of brain circulation in severe arterial hypertension. Br Med J 1:507-510 Symon L, Pasztor E, Dorsch NWC, Branston NM (1973) Phys iological responses of local areas of the cerebral circulation in experimental primates determined by the method of hy drogen clearance. Stroke 4:632--642 Symon L, Branston NM, Strong Al (1976) Autoregulation in acute focal ischemia: an experimental study. Stroke 7:547554 Tsukada T, Hashimoto T, Imai S (1979) Effects of adenosine and catecholamines upon the cerebral blood flow. Acta Neurol Scand 60(suppl 72):152-153 Tyson GW, Teasdale GM, Graham or, McCulloch 1 (1982) Ce rebrovascular permeability following MCA occlusion in the rat. J Neurosurg 57:186-196 van Dellen lR, Buchanan N (1977) Prolonged induced hyperten-
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U. DIRNAGL AND W. PULSINELLI sion in the management of incipient cerebral infarction. Surg
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Autoregulation of Cerebral Blood Flow in Experimental Focal Brain Ischemia
Ulrich Dirnagl and William Pulsinelli Cerebrovascular Disease Research Center, Department of Neurology and Neuroscience, Cornell University Medical College, New York, New York, U.S.A.
Summary: The relationship between systemic arterial pressure (SAP) and neocortical microcirculatory blood flow (CBF) in areas of focal cerebral ischemia was stud ied in 15 spontaneously hypertensive rats (SHRs) anes thetized with halothane (0.5%). Ischemia was induced by ipsilateral middle cerebral artery/common carotid artery occlusion and CBF was monitored continuously in the ischemic territory using laser-Doppler flowmetry during manipulation of SAP with I-norepinephrine (hyperten sion) or nitroprusside (hypotension). In eight SHRs not subjected to focal ischemia, we demonstrated that 0.5% halothane and the surgical manipUlations did not impair autoregulation. Autoregulation was partly preserved in ischemic brain tissue with a CBF of > 30% of preocclu sion values. In areas where ischemic CBF was 30%, 100 measurements, eight probes in seven animals). Third-order regression for each animal. (Solid lines), hypertension before hypotension; (Dashed lines), hypotension before hypertension.
for first-order regression, also indicating improved fit due to the cubic model. Relationship in moderately ischemic brain tissue (group B). A total of 130 measurements at nine probe sites in seven animals detected brain tissue in which rCBF fell to a level between 15 and 30% of baseline values after MCAICCA occlusion. Mean rCBF after MCAICCA occlusion was 18.2% of baseline, with a range of 15-29% (SD ± 9%). The rCBF/SAP relationship was linear (Fig. 3), and the AI was 0. 88 (extrapolated from the pooled data from seven independent probes). The l3-coeffi cients, calculated for a third-order regression of rCBF on SAP for each animal, did not reach statis tical significance (p > 0.1). r values for the first order regressions shown in Fig. 3 ranged from 0.36 to 0.98. Third-order regression did not improve r values, and the lines fit by the cubic model were 50
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60
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200
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FIG. 3. Mean systemic arterial pressure (MSAP; mm Hg) and regional CBF (rCBF; % of preocclusion values) in moderately ischemic cortex (rCBF between 15 and 30%, 130 measure ments, 11 probes in 10 animals). First-order regression for . each animal. (Solid lines), hypertension before hypotension; (dashed lines), hypotension before hypertension.
AUTOREGULATION IN CEREBRAL ISCHEMIA
almost straight, indicating linear relationships be tween SAP and rCBF. Relationship in severely ischemic brain tissue (group C). A total of 102 measurements at nine probe sites in seven animals showed rCBF values below 15% of baseline after MCAICCA occlusion. The mean rCBF after MCA/CCA occlusion in this group equaled 10.8% of baseline (range 4-14%; SD ± 4%). Figure 4 shows the data, analyzed with a linear regression for each animal. The cubic model (third-order polynomial regression) did not improve the curve fit (no statistical significance of the l3-coefficients, p > 0.2). ? values for the first-order regressions shown in Fig. 4 ranged from 0.51 to 0.94. Third-order regression did not improve r2 val ues, and the lines fit by this model were almost straight, indicating linear relationships between SAP and rCBF. The AI of 0.60 (extrapolated from the pooled data from seven independent probes; see Fig. 5) was less than in zones of moderate ischemia where autoregulation was also lost. DISCUSSION
Our study shows that rCBF in the neocortex of SHRs anesthetized with 0.5% halothane is auto regulated to nitroprusside- and norepinephrine induced changes in SAP. The SAP within which autoregulation was maintained ranged from 80 to 175 mm Hg. These values are consistent with the limits of autoregulation reported for the SHR (see below). In ischemic neocortex, autoregulation was atten uated but not abolished in tissue areas where rCBF after MCAICCA occlusion fell to levels between 30 and 60% of preocclusion values. In tissue areas where post-MCA/CCA occlusion rCBF was 30%), estimated postocclusion CBF would approximate >40 ml/100 g/min, that for group B (15% < CBF < 30%) be tween 20 and 40 mll100 g/min, and for group C (CBF < 15%) 30% of pre occlusion values; autoregulation was completely lost when CBF fell below 30% of normal values. SAP had a greater influence on CBF in moderately ischemic brain tissue (CBF between 15 and 30% of baseline) than in severely ischemic brain tissue (CBF < 15% of baseline). Moderately ischemic tis sue (CBF between 15 and 30% of baseline) might benefit from raising SAP in the first hours after ce rebral infarction. Acknowledgment: Dr. U. Dirnagl is a recipient of a Ger man Academic Exchange Service (DAAD) research scholarship. This research was supported in part by NIH grant NS-03346. We are grateful to Dr. Martin Lesser, Assistant Professor of Biostatistics, for statistical advice.
REFERENCES Acar U, Pickard JD (1980) Angiotensin and pial arterioles: im plications for the study of CBF autoregulation. In: Patho
physiology and Pharmacotherapy of Cerebrovascular Dis orders (Betz E, Grote J, Heuser D, Wuellenweber R, eds, Baden-Baden, Witzstrock, pp 37-38 Anderson RE, Michenfelder JD, Sundt TM (1980) Brain intra cellular pH, blood flow, and blood-brain barrier differences with barbiturate and halothane anesthesia. Anesthesiology
52:201-206 Arbit E, DiResta GR, Bedford RF, Shah NK, Galicich JH (1989) Intraoperative measurement of cerebral and tumor blood flow with laser-Doppler flowmetry. Neurosurgery 24:166-
170 Aspey BS, Ehteshami S, Hurst CM, McCoy AL, Harrison MJG (1987) The effect of increased blood pressure on hemispheric lactate and water content during acute cerebral ischemia in the rat and gerbil. J Neurol Neurosurg Psychiatry 50:1493-
1498 Ayoagi M, Meyer JS, Deshmukh VD, Ott EO, Tagashira Y, Kawamura Y, Matsuda M, Achari, AN, Chee ANC (1975) Central cholinergic control of cerebral blood flow in the ba boon. J Neurosurg 43:689-705 Barry DI, Strandgaard S, Svendsen 0, Braendstrup 0, Graham 01, Hemmingsen R, Bolwig TG (1981) Adaptive changes in the lower limit of cerebral blood flow autoregulation in hy pertensive rats. J Cereb Blood Flow Metab I(suppl I):S263 Barry DI, Strandgaard S, Graham 01, Braendstrup 0, Svendsen UG, Vorstrup S, Hemmingsen R, Bolwig TG (1982) Cerebral blood flow in rats with renal and spontaneous hypertension: resetting of the lower limit of autoregulation. J Cereb Blood
Flow and Metab 2:347-353 Bleyaert AL, Sands PA, Safar P, Nemoto M, Stezoski SW, Moossy J, Rao GR (1980) Augmentation of postischemic brain damage by severe intermittent hypertension. Crit Care
Med 8:41-47 Bonner RF (1987) Model for photon migration in turbid biologi cal media. J Opt Soc Am 4:423-432
J
Cereb Blood Flow Metab, Vol. 10, No.3, 1990
Brint S, Jacewicz M, Kiessling M, Tanabe J, Pulsinelli W (1988) Focal brain ischemia in the rat: methods for reproducible neocortical infarction using tandem occlusion of the distal middle cerebral and ipsilateral common carotid arteries. J
Cereb Blood Flow Metab 8:474-485 Brown FB, Hanlon K, Crockard HA, Mullan S (1977) Effect of sodium nitroprusside on cerebral blood flow in conscious human beings. Surg Neurol 7:67-70 Brown FB, Crockard HA, Johns LM, Mullan S (1978) The effect of sodium nitroprusside and trimethaphan camsylate on ce rebral blood flow in rhesus monkeys. Neurosurgery 2:31-34 Candia GJ, Heros RC, Lavyne MH, Zervas NT, Nelson CN (1978) Effect of intravenous sodium nitroprusside in cerebral blood flow and intracranial pressure. Neurosurgery 3:50-53 Chien S, Usami S, Skalak R (1984) Blood flow in small tubes. In: Handbook of Physiology, Sec 2, Vol 4, Pt 1 (Renkin EM, Michel CC, eds) Bethesda, American Physiological Society, pp 217-249 Crockard HA, Brown FD, Mullan JF (1976) Effects of tri methaphane and sodium nitroprusside on cerebral blood flow in rhesus monkeys. Acta Neurochir 35:83-89 Diaz FG, Ausmann JI (1980) Experimental cerebral ischemia.
Neurosurgery 6:436-445 Dirnagl U, Kaplan B, Jacewicz M, Pulsinelli W (1989) Continu ous measurement of cerebral cortical blood flow by laser Doppler flowmetry in a rat stroke model. J Cereb Blood
Flow Metab 9:589-596 Drummond JC, Oh YS, Cole OJ, Shapiro HM (1988) Phenyleph rine-induced hypertension decreases the extent of ischemia following middle cerebral artery occlusion in the rat. Anes
thesiol Rev 15:38-39 Farhat SM, Schneider RC (1967) Observations on the effect of systemic blood pressure on intracranial circulation in pa tients with cerebrovascular insufficiency. J Neurosurg 27:
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