- Email: [email protected]
Influence of Systemic Blood Pressure on Blood Flow and Microcirculation of Ischemic Cerebral Cortex: a Failure of Autoregulation*
107
Influence of Systemic Blood Pressure on Blood Flow and Microcirculation of Ischemic Cerebral Cortex : a Failure of Autoregulation * A R T H U R G. WALTZ**
AND
T H O R A L F M. S U N D T . JR.***
Mayo Clinic and Mayo Foundation, Rochester, Minnesota ( U.S.A.)
Previously1 we described the changes of the superficial microvasculature and microcirculation of the frontal and anterior parietal regions of the cerebral cortex of cats and squirrel monkeys (Suimiri sciurea) which we observed and photographed after acute occlusion of the ipsilateral middle cerebral artery, exposed by an extradural approach with the aid of an operation microscopez. Early ischemic changes in cortical surface vessels included darkening of the blood in surface veins and venules, a decrease in the velocity of the flow of blood through arterial and venous channels, and aggregation of formed elements of the blood, producing “sludging” and stasis. Occasionally dilatation of arteries and arterioles was associated. A few minutes to a few hours after occlusion, pallor of the cortex developed because of the disappearance of small surface vessels. Cortical pallor, either focal or generalized, was the earliest definite sign of cortical ischemia. Once pallor was established, spontaneous recolorization of the cortex rarely occurred. Constriction or “spasm” of superficial cortical arteries and arterioles frequently accompanied ischemia. It was not determined whether the constriction was truly a response to ischemia or simply an artefact1. White thrombi, composed largely of platelets, often formed in veins. Rarely, venous blood became distinctly reddish, particularly in areas (focal or generalized) in which ischemic changes were progressing. Late ischemic changes included collapse of venous and arterial vessels and stasis or disappearance of the column of blood from larger vessels. Ischemic changes occurring in the superficial cortical microvasculature and microcirculation after occlusion of the ipsilateral middle cerebral artery probably were representative of the process of cerebral infarction1. In our studies ischemic changes occurred regularly after arterial occlusion, even though systemic blood pressure remained at normotensive levels. There was considerable variation from animal to animal and between the two species. In general, ischemic changes in the surface vessels
* This investigxtion was supported in part by Research Grants FR-5530 and NB-6663 from the National Institutes of Health, Public Health Service. * * Cerebrovascular Clinical Research Center, Section of Neurology. *** Fellow in Basic Neurological Sciences, Mayo Graduate School of Medicine (University of Minnesota), Rochester. References p . 111-112
108
A. G. W A L T Z A N D TH. M. S U N D T NON ISCHEMIC CORTEX
2.00-
160
I
120 -
o.80 040
0
t1 20
40
60
80
100
120
, 140
~
160
I 180
MABP,mmHg
Fig. 1. Effect of changes of mean arterial pressure on blood flow of cerebral cortex of cats.
of the frontal and anterior parietal areas of the brain were more severe in squirrel monkeys than in cats. In cats occlusion of a middle cerebral artery more often produced an infarct deep in the brain or in the temporal lobe2. The variation of effects between species was confirmed by measurements of cortical blood flow by determination of the rate of clearance from the cortex of radioactive krypton-85 injected into the brachiocephalic artery or aortic arch. When measured over the frontal and anterior parietal areas after occlusion of the ipsilateral middle cerebral artery, cortical blood flow in squirrel monkeys was found to be too low to be calculated; in cats, blood flow after occlusion was reduced to about one half the preocclusion values. All observations of the superficial cortical microvasculature and microcirculation and measurements of cortical blood flow which we describe subsequently in this paper were made in the areas of the brain mentioned above: the frontal and anterior parietal regions.
Influence of Hypotension In our studies of the superficial cortical microvasculature and microcirculation after occlusion of the ipsilateral middle cerebral artery, hypotension occasionally occurred spontaneously during the surgical procedure, before or after arterial occlusion, or the systemic blood pressure purposely was lowered by the removal of blood from a femoral artery. Hypotension did not produce a qualitative change in the response of the superficial cortical microcirculation to ischemia. When hypotension occurred, ischemic changes developed in cortical vessels more quickly and were more severe than if blood pressure was maintained at normotensive levels. The character ofthe ischemic changes, however, was not altered. In a separate series of experiments in cats we measured blood flow (by the krypton-
109
A F A I L U R E OF A U T O R E G U L A T I O N
85 clearance method) in the cortex made ischemic by occlusion of the ipsilateral middle cerebral artery. As stated above, when systemic blood pressure remained at normotensive levels, cortical blood flow was reduced after occlusion to about half the pre-occlusion value. When systemic hypotension was produced by the intravenous injection of small amounts of sodium nitroprusside or trimethaphan camsylate (Arfonad), an additional reduction in cortical blood flow took place, often to values too low to be calculated by the method. We did not find a “threshold” level of hypotension below which the flow of blood through the ischemic cortex decreased precipitously. Rather, in the ischemic cortex the reduction in systemic blood pressure appeared to result in a passive reduction in the flow of blood, as determined by observation of the severity of ischemic changes in surface vessels or by measurement of the clearance of krypton-85 from the cortex. The response of the ischemic cortex to systemic hypotension was different from the response of the cortex of the cerebral hemisphere opposite the occluded middle cerebral artery. In the nonischemic cortex, blood flow remained relatively unaffected by hypotension until very low levels of blood pressure were reached (approximately 50 mm Hg mean arterial pressure, as measured by a manometer or strain gauge through a catheter placed in a femoral artery or the abdominal aorta). In the ischemic cortex, autoregulation of cortical blood flow for variations in blood pressure was impaired or abolished. The vascular mechanisms responsible for autoregulation of flow either were severely damaged by ischemia or had reacted maximally to ischemia and hence could not respond further to hypotension. Influence of Hypertension
Elevations of systemic blood pressure, occurring spontaneously or produced by the intravenous injection of phenylephrine (Neo-Synephrine), usually did not influence changes in the microcirculation or blood flow in the cortex madeischemic by occlusion 2.00
1.60
1.20
ISCHEMIC CORTEX
I
‘-1
--
1
’ . ..
li
8
.
. .
0.40
0
* .
20
40
60
80
I
100
I
120
I
140
I
160
MABP,mm Hg
Fig. 2. Effect of changes of mean arterial blood pressure on blood flow of cortex made ischemic by occlusion of middle cerebral artery. References p . 111-112
110
A. G. W A L T Z A N D TH. M. S U N D T
of the ipsilateral middle cerebral artery. Ischemic changes in surface vessels were not retarded or lessened, and values for blood flow calculated from the ischemic cortex were not increased by hypertension. However, when a slight rise in systemic blood pressure occurred in the presence of platelet thrombosis in veins, venous hemorrhage often developed. The failure of cortical blood flow to increase in consonancewith increasing systemic blood pressure probably was not caused by autoregulation of flow for variations in pressure. It seems more likely that cortical blood flow (through channels collateral to the occluded middle cerebral artery) already was maximal in response to ischemia and hence could not respond further to hypertension. C22 D Nonischemic cortex
0
0
.
;.c , o k
. z L
200-
Ischemic cortex X Red venous blood
9
& 100
150: 50
0
I
I
I
I
I
Occurrence of “Red Venous Blood” With Variations in Systemic Blood Pressure As stated above, blood flow through the ischemic cortex (measured by the krypton-85 clearance method) was further reduced when systemic hypotension was produced by the intravenous injection of sodium nitroprusside. If the blood pressure was then allowed to return to normotensive levels by discontinuation of the use of sodium nitroprusside, cortical blood flow often would approach or exceed the values found for the ischemic cortex before hypotension. When systemic blood pressure increased
A F A I L U R E OF A U T O R E G U L A T I O N
111
from hypotensive levels and the cortical blood flow increased, the unusual phenomenon of reddening of blood in veins was seen. Lassen4,at this Congress, has stated that ‘‘luxury perfusion” of the brain, manifested by red venous blood, indicates a disturbance of autoregulation for oxygen availability and utilization. In the experiments we are reporting, when the cortical blood flow increased more oxygen apparently was supplied to the ischemic, partially damaged tissue than could be used, resulting in a higher venous oxygen saturation and red venous blood. We have reported previously’ that red blood at times is seen in surface veins in ischemic cortex without known variations in systemic blood pressure. In both situations the lack of response of autoregulatory mechanisms to increased cortical venous oxygen saturation may have been the result of ischemic damage or deficiency of an essential substance other than oxygen (such as glucose) or an excess of a metabolite (such as carbon dioxide). CONCLUSIONS AND SUMMARY
In cats and squirrel monkeys occlusion of a middle cerebral artery produces ischemic changes in the ipsilateral superficial cortical microvasculature and microcirculation. These ischemic changes, which probably are representative of the process of cere bra1 infarction, include darkening of venous blood, slowing of the velocity of the flow of blood, aggregation of formed elements of the blood, pallor of the cortex, dilatation or constriction, or both, of arterial vessels, formation of white (platelet) thrombi in veins and venules, reddening of the blood in veins and collapse of vessels. Blood flow through the ischemic cortex, measured by the krypton-85 clearance method, is markedly reduced. Systemic hypotension, spontaneous or produced by drugs or the removal of blood, speeds the development and increases the severity of ischemic changes in the microcirculation, but does not alter the character of such changes. Hypotension after arterial occlusion results in a further reduction of cortical blood flow which appears to be passive, indicating a failure of autoregulation of flow. Autoregulation may fail because of tissue damage or because there is a maximal response to ischemia. Systemic hypertension, spontaneous or produced by drugs, does not influence ischemic changes in the microcirculation, except for the fact that when platelet thrombi are present in veins, venous hemorrhage often occurs. An increase in systemic blood pressure does not produce an increase in blood flow through the ischemic cortex, except when hypotension previously has been present. In the latter instance, blood in veins may become redder, also indicating a failure of autoregulation of cortical blood flow. REFERENCES 1 WALTZ,A. G. AND SUNDT,T. M., JR. (1967) The microvasculature and microcirculation of the cerebral cortex after arterial occlusion. Brain (In press). 2 SUNDT,T. M., JR. AND WALTZ,A. G. (1966) Experimental cerebral infarction: retro-orbital, extradural approach for occluding the middle cerebral artery. Mayo Clin. Proc., 41, 159-168. References p. 111-112
112
A. G . WALTZ AND TH. M. SUNDT
3 WALTZ,A. G., SUNDT,T. M.,JR. AND OWEN,C. A., JR. (1967) Effect of middle cerebral artery occlusion on cortical blood flow in animals. Neurology, 16,1185-1 190. 4 LASSEN,N.A. (1967) On the regulation of cerebral blood flow in diseases of the brain with special regard to “the acute brain syndrome” characterizedby luxury perfusion. This volume pp. 121-124.
Influence of Systemic Blood Pressure on Blood Flow and Microcirculation of Ischemic Cerebral Cortex : a Failure of Autoregulation * A R T H U R G. WALTZ**
AND
T H O R A L F M. S U N D T . JR.***
Mayo Clinic and Mayo Foundation, Rochester, Minnesota ( U.S.A.)
Previously1 we described the changes of the superficial microvasculature and microcirculation of the frontal and anterior parietal regions of the cerebral cortex of cats and squirrel monkeys (Suimiri sciurea) which we observed and photographed after acute occlusion of the ipsilateral middle cerebral artery, exposed by an extradural approach with the aid of an operation microscopez. Early ischemic changes in cortical surface vessels included darkening of the blood in surface veins and venules, a decrease in the velocity of the flow of blood through arterial and venous channels, and aggregation of formed elements of the blood, producing “sludging” and stasis. Occasionally dilatation of arteries and arterioles was associated. A few minutes to a few hours after occlusion, pallor of the cortex developed because of the disappearance of small surface vessels. Cortical pallor, either focal or generalized, was the earliest definite sign of cortical ischemia. Once pallor was established, spontaneous recolorization of the cortex rarely occurred. Constriction or “spasm” of superficial cortical arteries and arterioles frequently accompanied ischemia. It was not determined whether the constriction was truly a response to ischemia or simply an artefact1. White thrombi, composed largely of platelets, often formed in veins. Rarely, venous blood became distinctly reddish, particularly in areas (focal or generalized) in which ischemic changes were progressing. Late ischemic changes included collapse of venous and arterial vessels and stasis or disappearance of the column of blood from larger vessels. Ischemic changes occurring in the superficial cortical microvasculature and microcirculation after occlusion of the ipsilateral middle cerebral artery probably were representative of the process of cerebral infarction1. In our studies ischemic changes occurred regularly after arterial occlusion, even though systemic blood pressure remained at normotensive levels. There was considerable variation from animal to animal and between the two species. In general, ischemic changes in the surface vessels
* This investigxtion was supported in part by Research Grants FR-5530 and NB-6663 from the National Institutes of Health, Public Health Service. * * Cerebrovascular Clinical Research Center, Section of Neurology. *** Fellow in Basic Neurological Sciences, Mayo Graduate School of Medicine (University of Minnesota), Rochester. References p . 111-112
108
A. G. W A L T Z A N D TH. M. S U N D T NON ISCHEMIC CORTEX
2.00-
160
I
120 -
o.80 040
0
t1 20
40
60
80
100
120
, 140
~
160
I 180
MABP,mmHg
Fig. 1. Effect of changes of mean arterial pressure on blood flow of cerebral cortex of cats.
of the frontal and anterior parietal areas of the brain were more severe in squirrel monkeys than in cats. In cats occlusion of a middle cerebral artery more often produced an infarct deep in the brain or in the temporal lobe2. The variation of effects between species was confirmed by measurements of cortical blood flow by determination of the rate of clearance from the cortex of radioactive krypton-85 injected into the brachiocephalic artery or aortic arch. When measured over the frontal and anterior parietal areas after occlusion of the ipsilateral middle cerebral artery, cortical blood flow in squirrel monkeys was found to be too low to be calculated; in cats, blood flow after occlusion was reduced to about one half the preocclusion values. All observations of the superficial cortical microvasculature and microcirculation and measurements of cortical blood flow which we describe subsequently in this paper were made in the areas of the brain mentioned above: the frontal and anterior parietal regions.
Influence of Hypotension In our studies of the superficial cortical microvasculature and microcirculation after occlusion of the ipsilateral middle cerebral artery, hypotension occasionally occurred spontaneously during the surgical procedure, before or after arterial occlusion, or the systemic blood pressure purposely was lowered by the removal of blood from a femoral artery. Hypotension did not produce a qualitative change in the response of the superficial cortical microcirculation to ischemia. When hypotension occurred, ischemic changes developed in cortical vessels more quickly and were more severe than if blood pressure was maintained at normotensive levels. The character ofthe ischemic changes, however, was not altered. In a separate series of experiments in cats we measured blood flow (by the krypton-
109
A F A I L U R E OF A U T O R E G U L A T I O N
85 clearance method) in the cortex made ischemic by occlusion of the ipsilateral middle cerebral artery. As stated above, when systemic blood pressure remained at normotensive levels, cortical blood flow was reduced after occlusion to about half the pre-occlusion value. When systemic hypotension was produced by the intravenous injection of small amounts of sodium nitroprusside or trimethaphan camsylate (Arfonad), an additional reduction in cortical blood flow took place, often to values too low to be calculated by the method. We did not find a “threshold” level of hypotension below which the flow of blood through the ischemic cortex decreased precipitously. Rather, in the ischemic cortex the reduction in systemic blood pressure appeared to result in a passive reduction in the flow of blood, as determined by observation of the severity of ischemic changes in surface vessels or by measurement of the clearance of krypton-85 from the cortex. The response of the ischemic cortex to systemic hypotension was different from the response of the cortex of the cerebral hemisphere opposite the occluded middle cerebral artery. In the nonischemic cortex, blood flow remained relatively unaffected by hypotension until very low levels of blood pressure were reached (approximately 50 mm Hg mean arterial pressure, as measured by a manometer or strain gauge through a catheter placed in a femoral artery or the abdominal aorta). In the ischemic cortex, autoregulation of cortical blood flow for variations in blood pressure was impaired or abolished. The vascular mechanisms responsible for autoregulation of flow either were severely damaged by ischemia or had reacted maximally to ischemia and hence could not respond further to hypotension. Influence of Hypertension
Elevations of systemic blood pressure, occurring spontaneously or produced by the intravenous injection of phenylephrine (Neo-Synephrine), usually did not influence changes in the microcirculation or blood flow in the cortex madeischemic by occlusion 2.00
1.60
1.20
ISCHEMIC CORTEX
I
‘-1
--
1
’ . ..
li
8
.
. .
0.40
0
* .
20
40
60
80
I
100
I
120
I
140
I
160
MABP,mm Hg
Fig. 2. Effect of changes of mean arterial blood pressure on blood flow of cortex made ischemic by occlusion of middle cerebral artery. References p . 111-112
110
A. G. W A L T Z A N D TH. M. S U N D T
of the ipsilateral middle cerebral artery. Ischemic changes in surface vessels were not retarded or lessened, and values for blood flow calculated from the ischemic cortex were not increased by hypertension. However, when a slight rise in systemic blood pressure occurred in the presence of platelet thrombosis in veins, venous hemorrhage often developed. The failure of cortical blood flow to increase in consonancewith increasing systemic blood pressure probably was not caused by autoregulation of flow for variations in pressure. It seems more likely that cortical blood flow (through channels collateral to the occluded middle cerebral artery) already was maximal in response to ischemia and hence could not respond further to hypertension. C22 D Nonischemic cortex
0
0
.
;.c , o k
. z L
200-
Ischemic cortex X Red venous blood
9
& 100
150: 50
0
I
I
I
I
I
Occurrence of “Red Venous Blood” With Variations in Systemic Blood Pressure As stated above, blood flow through the ischemic cortex (measured by the krypton-85 clearance method) was further reduced when systemic hypotension was produced by the intravenous injection of sodium nitroprusside. If the blood pressure was then allowed to return to normotensive levels by discontinuation of the use of sodium nitroprusside, cortical blood flow often would approach or exceed the values found for the ischemic cortex before hypotension. When systemic blood pressure increased
A F A I L U R E OF A U T O R E G U L A T I O N
111
from hypotensive levels and the cortical blood flow increased, the unusual phenomenon of reddening of blood in veins was seen. Lassen4,at this Congress, has stated that ‘‘luxury perfusion” of the brain, manifested by red venous blood, indicates a disturbance of autoregulation for oxygen availability and utilization. In the experiments we are reporting, when the cortical blood flow increased more oxygen apparently was supplied to the ischemic, partially damaged tissue than could be used, resulting in a higher venous oxygen saturation and red venous blood. We have reported previously’ that red blood at times is seen in surface veins in ischemic cortex without known variations in systemic blood pressure. In both situations the lack of response of autoregulatory mechanisms to increased cortical venous oxygen saturation may have been the result of ischemic damage or deficiency of an essential substance other than oxygen (such as glucose) or an excess of a metabolite (such as carbon dioxide). CONCLUSIONS AND SUMMARY
In cats and squirrel monkeys occlusion of a middle cerebral artery produces ischemic changes in the ipsilateral superficial cortical microvasculature and microcirculation. These ischemic changes, which probably are representative of the process of cere bra1 infarction, include darkening of venous blood, slowing of the velocity of the flow of blood, aggregation of formed elements of the blood, pallor of the cortex, dilatation or constriction, or both, of arterial vessels, formation of white (platelet) thrombi in veins and venules, reddening of the blood in veins and collapse of vessels. Blood flow through the ischemic cortex, measured by the krypton-85 clearance method, is markedly reduced. Systemic hypotension, spontaneous or produced by drugs or the removal of blood, speeds the development and increases the severity of ischemic changes in the microcirculation, but does not alter the character of such changes. Hypotension after arterial occlusion results in a further reduction of cortical blood flow which appears to be passive, indicating a failure of autoregulation of flow. Autoregulation may fail because of tissue damage or because there is a maximal response to ischemia. Systemic hypertension, spontaneous or produced by drugs, does not influence ischemic changes in the microcirculation, except for the fact that when platelet thrombi are present in veins, venous hemorrhage often occurs. An increase in systemic blood pressure does not produce an increase in blood flow through the ischemic cortex, except when hypotension previously has been present. In the latter instance, blood in veins may become redder, also indicating a failure of autoregulation of cortical blood flow. REFERENCES 1 WALTZ,A. G. AND SUNDT,T. M., JR. (1967) The microvasculature and microcirculation of the cerebral cortex after arterial occlusion. Brain (In press). 2 SUNDT,T. M., JR. AND WALTZ,A. G. (1966) Experimental cerebral infarction: retro-orbital, extradural approach for occluding the middle cerebral artery. Mayo Clin. Proc., 41, 159-168. References p. 111-112
112
A. G . WALTZ AND TH. M. SUNDT
3 WALTZ,A. G., SUNDT,T. M.,JR. AND OWEN,C. A., JR. (1967) Effect of middle cerebral artery occlusion on cortical blood flow in animals. Neurology, 16,1185-1 190. 4 LASSEN,N.A. (1967) On the regulation of cerebral blood flow in diseases of the brain with special regard to “the acute brain syndrome” characterizedby luxury perfusion. This volume pp. 121-124.