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A Method for the Study of Experimental Cerebral Vasospasm
63
A Method for the Study of Experimental Cerebral Vasospasm LINDSAY SYMON The Department of Neurosurgical Studies, The NationaI Hospital, Queen Square, London
Narrowing of cerebral arteries is seen in the area of intracranial aneurysms after subarachnoid haemorrhage. It has been regarded as arterial spasm and associated by some surgeons with the narrowing of cerebral vessels which can be produced at operation by traumatic stimuli (Pool, 1958; Gillingham, 1958; Johnson et al., 1958). Experimentally produced traumatic arterial spasm has been much studied therefore, since spasm has been thought to be important in the production of ischaemic symptoms after subarachnoid haemorrhage. Most of this experimental work has confined itself to visual description of spasm without quantitation and the concept has remained scientifically vague as a result. The present work attempts to study experimental spasm in a form in which numerical analysis is possible so that its character and its variability may be analysed. There is no proof that experimental and clinical spasm are the same, but angiographically they are indistinguishable (Symon, 1967). The method of production and recording of spasm has been fully described elsewhere (Symon, 1963, 1967). A small catheter is introduced into a leptomenhgeal branch of the middle cerebral artery, and the pulse pressure and intravascular pressure in the middle cerebral field continuously measured. The main middle cerebral artery is bared of arachnoid within the first 5 mm of its course and stimulated by light repetitive occlusions using a stopped non-toothed dissecting forceps to produce approximately the same pressure at each occlusion. The resulting spasm produces the appearance shown in Fig. 1. Shortly after the stimulus there is a reduction in intravascular pressure and pulse pressure increasing to a maximum and then slowly decreasing. This gives three measurements, the total duration of spasm, the time it takes to reach its maximum and the intensity of the spasm measured as a percentage reduction in pulse pressure. Other recordings essential from the control point of view are endtidal CO2 monitored continuously, arterial pCO2 quantitatively from time to time, and systemic blood pressure continuously. A further recording shown is a superficial thermistor recording from a small pial artery of similar size to that catheterised indicating that blood flow is reduced during the period of spasm. The mean values obtained from these three measurements in a group of 15 animals are shown in Table 1. The variation from one animal to the next is not inconsiderable. Mean duration varies from 12to 29 min, the time of development from nearly 2 min to over 7 min, and the intensity from a pulse pressure reducReferences p . 67
64
L. S Y M O N
A
Fig. 1. Records of systemic blood pressure (S.B.P.), endtidal COa tension (ETCOa) and middle cerebral pressure and flow (M.C.P., M.C.F.) from a parietal branch of the middle cerebral artery, in a baboon under chloralose anaesthesia. Traumatic stimulus at S.
tion of 24% to one of over 50%. The mean and standard errors for the group as a whole are shown. In a group of five animals which formed the first in Table I, the control observations were the only ones made, and a series of spasms were produced over a prolonged period of time. The analysis of this group in which five control episodes were made in each case is shown in Table 11. There is appreciable variation from maximum to minimum, both in the duration of spasm, in the time of the development of the spasm, and in the intensity of the spasm. In most cases there is a narrow standard error for the TABLE I Experiment number
Number of observations
Mean duration (min)
Mean time to maximum (min)
Mean % reduction in pulse pressure
11 12 13 16 17 18 19 20 21 22 24 26 27 29 30
5 5 5 5 5 3 3 3 3 3 3 3 3 3 3
22.6 12.6 15.1 15.3 20.7 13.3 14.4 20.3 20.3 19.0 16.2 28.0 28.6 22.4 18.5 19.2 f4.9
3.9 3.8 3.3 4.1 3.9 2.7 3.3 3.3 3.4 1.8 1.9 6.0 6.5 3.4 4.4 3.7 f0.4
41.6 44.5 29.4 33.4 53.2 53 37 41.5 47 46 49 54 30 45
Mean S.D.
40
43.6 f8.1
P u h
m X
v m
TABLE I1 Experiment
Number of
Duration of spasm (min) Max.
~
Min.
Mean & S.D.
Reduction in pial puhe pressure ( %)
Time to maximum (min) Max.
Min.
Mean
z ti
S.D.
Max.
Min.
z,
Mean & S.D. -
~~
11
5
34.5
14.0
22.6 i- 10.8
8.4
2.6
3.9 f 2.6
50
38
41.6 f 8.5
12
5
19.3
10.6
12.6 f 3.8
4.0
3.6
3.8 & 0.6
66
20
44.5 f 18.6
13
5
16.6
12.2
15.1 f 3.0
4.9
1.8
3.3 i-1.2
33
20
29.4 f 5.4
16
5
18.3
11.9
15.3 & 2.5
5.0
3.5
4.1 & 0.6
56
20
33.4 f 13.7
17
5
26.2
14.8
20.7 f 5.3
5.0
3.2
3.9 & 2.7
61
30
53.2 i. 10.9
?
r 0
m
w
m W
0 ?
r
c
66
L. S Y M O N
duration of spasm. The variability of the time of development of spasm is rather large and the variability in the intensity of the spasm is also seen tc be considerable. Electrical and more complicated mechanical methods of applying the stimulus did not prove satisfactory. Electrical stimuli in particular applied in the region of the base of the brain considerably altered the animal’s systemic blood pressure during the passage of the current. Thus, descriptive experimentswhich do not provide adequate objective and statistical evidence of the standards of variation to be expected in a particular preparation, are unlikely to be of scientific value. The range of random variation in the experimental preparation used must be stated. Using this method I have analysed the reproducibilityof arterial spasm at high and low levels of arterial pCOz. The normocapnic controls were artificially ventilated to maintain an arterial p C 0 ~between 35 and 45 mm Hg. Hypocapnic animals were hyperventilated to reduce the arterial p C 0 z to less than 20 mm Hg. Hypercapnic animals had COz added to the respiratory inlet to raise the arterialPC02 to more than 50 mm Hg. The three parameters of spasm were not significantly different in any case. A troublesome complicating factor was the production of clear emboli from the area of artery traumatised. This may be associated with the appearance of whiteness and narrowness of the main trunk indistinguishable photographically from severe arterial spasm. The picture is different on the end arterial recording, however, as is shown in Fig. 2 where a traumatic stimulus results in the appearance of severe spasm which appears to be resolving. Suddenly it progresses to obliteration of the pulse and instead of resolving in about 20 min intravascular pressure remains very low until 30 min when it suddenly recovers, unlike the gradual recovery of arterial spasm. Repeated trauma again abolished the pulse for a prolonged period of time. Each sudden reappearance of the pulse in this instance was associated with a shower of clear bodies in the peripheral circulation similar to those described by Denny Brown after carotid
-
M.C.I?(F)
6
TIME(M1N.I
&
2
6
j,
2k
Lo
j,
Fig. 2. Records of systemic blood pressure (S.B.P.), middle cerebral arterial pressure (M.C.P.) and middle cerebral flow (M.C.F.) in a baboon under chloralose anaesthesia. Traumatic stimulus at A.
E X P E R I M E N T A L CEREBRAL VASOSPASM
67
trauma. I believe them to be platelet emboli from the area of damage to the artery. Histological examination of the traumatised area of artery shows that the intima is damaged and the internal elastic lamina broken up into spirals which project into the lumen and contain small aggregates of structureless granular material suggesting that these may be aggregates of platelets. The histological appearances are independent of the production of spasm since spasm has been produced in animals which subsequently show no histological changes. Animals who have proceeded to apparent complete obliteration of the artery which has subsequently resolved do not show thrombosis of the vessel but they show the histological damage to the intima. Using this preparation also, various agents have been applied to the middle cerebral artery in an attempt to produce or encourage traumatic arterial spasm. These have included fresh and stored blood, serum, CSF from subarachnoid cases, haemolysed blood, concentrations of catecholamine up to 100 pg/ml, of 5-HT up to 100pg/ml and of bradykinin and histamine. None of these produced the appearances of reduced peripheral blood flow, or of reduced pulse and intravascular pressures such as are associated with traumatic arterial spasm. The appearances of the wave of spasm coming on and slowly relaxing is very suggestiveof focal liberation of some pharmacologically active material, as yet uncertain in nature. It may be that although vaso-active material externally applied does not produce significant spasm in this preparation, the liberation of some vaso-active compound intra-murally from the area of damaged arterial wall may yet be effective in producing spasm. REFERENCES GILLINGHAM, F. J. (1958) The management of ruptured intracranial aneurysm. Ann. Roy. Coll. Surg. Eng., 23, 89-1 17. JOHNSON,R. J., POITER,J. M. AND REID,R. C. (1958) Arterial spasm in subarachnoid haemorrhage: mechanical considerations. J . Neurol. Neurosurg. Psychiat., 21, 68. POOL,J. L. (1958) Cerebral vasospasm. New Engl. J. Med., 259, 1259-1264. L. (1963) Cerebral arterial pressure recording in dogs and macacus rhesus. J. Physiol., 165, SYMON, 62P. -, (1967) Vascular spasm in the cerebral circulation. Proc. First Migraine Symposium (in press). -, (1967) A comparativestudy of middle cerebral arterial pressure in dogs and macaaues. J. Physiol. (in press).
References p. 67
A Method for the Study of Experimental Cerebral Vasospasm LINDSAY SYMON The Department of Neurosurgical Studies, The NationaI Hospital, Queen Square, London
Narrowing of cerebral arteries is seen in the area of intracranial aneurysms after subarachnoid haemorrhage. It has been regarded as arterial spasm and associated by some surgeons with the narrowing of cerebral vessels which can be produced at operation by traumatic stimuli (Pool, 1958; Gillingham, 1958; Johnson et al., 1958). Experimentally produced traumatic arterial spasm has been much studied therefore, since spasm has been thought to be important in the production of ischaemic symptoms after subarachnoid haemorrhage. Most of this experimental work has confined itself to visual description of spasm without quantitation and the concept has remained scientifically vague as a result. The present work attempts to study experimental spasm in a form in which numerical analysis is possible so that its character and its variability may be analysed. There is no proof that experimental and clinical spasm are the same, but angiographically they are indistinguishable (Symon, 1967). The method of production and recording of spasm has been fully described elsewhere (Symon, 1963, 1967). A small catheter is introduced into a leptomenhgeal branch of the middle cerebral artery, and the pulse pressure and intravascular pressure in the middle cerebral field continuously measured. The main middle cerebral artery is bared of arachnoid within the first 5 mm of its course and stimulated by light repetitive occlusions using a stopped non-toothed dissecting forceps to produce approximately the same pressure at each occlusion. The resulting spasm produces the appearance shown in Fig. 1. Shortly after the stimulus there is a reduction in intravascular pressure and pulse pressure increasing to a maximum and then slowly decreasing. This gives three measurements, the total duration of spasm, the time it takes to reach its maximum and the intensity of the spasm measured as a percentage reduction in pulse pressure. Other recordings essential from the control point of view are endtidal CO2 monitored continuously, arterial pCO2 quantitatively from time to time, and systemic blood pressure continuously. A further recording shown is a superficial thermistor recording from a small pial artery of similar size to that catheterised indicating that blood flow is reduced during the period of spasm. The mean values obtained from these three measurements in a group of 15 animals are shown in Table 1. The variation from one animal to the next is not inconsiderable. Mean duration varies from 12to 29 min, the time of development from nearly 2 min to over 7 min, and the intensity from a pulse pressure reducReferences p . 67
64
L. S Y M O N
A
Fig. 1. Records of systemic blood pressure (S.B.P.), endtidal COa tension (ETCOa) and middle cerebral pressure and flow (M.C.P., M.C.F.) from a parietal branch of the middle cerebral artery, in a baboon under chloralose anaesthesia. Traumatic stimulus at S.
tion of 24% to one of over 50%. The mean and standard errors for the group as a whole are shown. In a group of five animals which formed the first in Table I, the control observations were the only ones made, and a series of spasms were produced over a prolonged period of time. The analysis of this group in which five control episodes were made in each case is shown in Table 11. There is appreciable variation from maximum to minimum, both in the duration of spasm, in the time of the development of the spasm, and in the intensity of the spasm. In most cases there is a narrow standard error for the TABLE I Experiment number
Number of observations
Mean duration (min)
Mean time to maximum (min)
Mean % reduction in pulse pressure
11 12 13 16 17 18 19 20 21 22 24 26 27 29 30
5 5 5 5 5 3 3 3 3 3 3 3 3 3 3
22.6 12.6 15.1 15.3 20.7 13.3 14.4 20.3 20.3 19.0 16.2 28.0 28.6 22.4 18.5 19.2 f4.9
3.9 3.8 3.3 4.1 3.9 2.7 3.3 3.3 3.4 1.8 1.9 6.0 6.5 3.4 4.4 3.7 f0.4
41.6 44.5 29.4 33.4 53.2 53 37 41.5 47 46 49 54 30 45
Mean S.D.
40
43.6 f8.1
P u h
m X
v m
TABLE I1 Experiment
Number of
Duration of spasm (min) Max.
~
Min.
Mean & S.D.
Reduction in pial puhe pressure ( %)
Time to maximum (min) Max.
Min.
Mean
z ti
S.D.
Max.
Min.
z,
Mean & S.D. -
~~
11
5
34.5
14.0
22.6 i- 10.8
8.4
2.6
3.9 f 2.6
50
38
41.6 f 8.5
12
5
19.3
10.6
12.6 f 3.8
4.0
3.6
3.8 & 0.6
66
20
44.5 f 18.6
13
5
16.6
12.2
15.1 f 3.0
4.9
1.8
3.3 i-1.2
33
20
29.4 f 5.4
16
5
18.3
11.9
15.3 & 2.5
5.0
3.5
4.1 & 0.6
56
20
33.4 f 13.7
17
5
26.2
14.8
20.7 f 5.3
5.0
3.2
3.9 & 2.7
61
30
53.2 i. 10.9
?
r 0
m
w
m W
0 ?
r
c
66
L. S Y M O N
duration of spasm. The variability of the time of development of spasm is rather large and the variability in the intensity of the spasm is also seen tc be considerable. Electrical and more complicated mechanical methods of applying the stimulus did not prove satisfactory. Electrical stimuli in particular applied in the region of the base of the brain considerably altered the animal’s systemic blood pressure during the passage of the current. Thus, descriptive experimentswhich do not provide adequate objective and statistical evidence of the standards of variation to be expected in a particular preparation, are unlikely to be of scientific value. The range of random variation in the experimental preparation used must be stated. Using this method I have analysed the reproducibilityof arterial spasm at high and low levels of arterial pCOz. The normocapnic controls were artificially ventilated to maintain an arterial p C 0 ~between 35 and 45 mm Hg. Hypocapnic animals were hyperventilated to reduce the arterial p C 0 z to less than 20 mm Hg. Hypercapnic animals had COz added to the respiratory inlet to raise the arterialPC02 to more than 50 mm Hg. The three parameters of spasm were not significantly different in any case. A troublesome complicating factor was the production of clear emboli from the area of artery traumatised. This may be associated with the appearance of whiteness and narrowness of the main trunk indistinguishable photographically from severe arterial spasm. The picture is different on the end arterial recording, however, as is shown in Fig. 2 where a traumatic stimulus results in the appearance of severe spasm which appears to be resolving. Suddenly it progresses to obliteration of the pulse and instead of resolving in about 20 min intravascular pressure remains very low until 30 min when it suddenly recovers, unlike the gradual recovery of arterial spasm. Repeated trauma again abolished the pulse for a prolonged period of time. Each sudden reappearance of the pulse in this instance was associated with a shower of clear bodies in the peripheral circulation similar to those described by Denny Brown after carotid
-
M.C.I?(F)
6
TIME(M1N.I
&
2
6
j,
2k
Lo
j,
Fig. 2. Records of systemic blood pressure (S.B.P.), middle cerebral arterial pressure (M.C.P.) and middle cerebral flow (M.C.F.) in a baboon under chloralose anaesthesia. Traumatic stimulus at A.
E X P E R I M E N T A L CEREBRAL VASOSPASM
67
trauma. I believe them to be platelet emboli from the area of damage to the artery. Histological examination of the traumatised area of artery shows that the intima is damaged and the internal elastic lamina broken up into spirals which project into the lumen and contain small aggregates of structureless granular material suggesting that these may be aggregates of platelets. The histological appearances are independent of the production of spasm since spasm has been produced in animals which subsequently show no histological changes. Animals who have proceeded to apparent complete obliteration of the artery which has subsequently resolved do not show thrombosis of the vessel but they show the histological damage to the intima. Using this preparation also, various agents have been applied to the middle cerebral artery in an attempt to produce or encourage traumatic arterial spasm. These have included fresh and stored blood, serum, CSF from subarachnoid cases, haemolysed blood, concentrations of catecholamine up to 100 pg/ml, of 5-HT up to 100pg/ml and of bradykinin and histamine. None of these produced the appearances of reduced peripheral blood flow, or of reduced pulse and intravascular pressures such as are associated with traumatic arterial spasm. The appearances of the wave of spasm coming on and slowly relaxing is very suggestiveof focal liberation of some pharmacologically active material, as yet uncertain in nature. It may be that although vaso-active material externally applied does not produce significant spasm in this preparation, the liberation of some vaso-active compound intra-murally from the area of damaged arterial wall may yet be effective in producing spasm. REFERENCES GILLINGHAM, F. J. (1958) The management of ruptured intracranial aneurysm. Ann. Roy. Coll. Surg. Eng., 23, 89-1 17. JOHNSON,R. J., POITER,J. M. AND REID,R. C. (1958) Arterial spasm in subarachnoid haemorrhage: mechanical considerations. J . Neurol. Neurosurg. Psychiat., 21, 68. POOL,J. L. (1958) Cerebral vasospasm. New Engl. J. Med., 259, 1259-1264. L. (1963) Cerebral arterial pressure recording in dogs and macacus rhesus. J. Physiol., 165, SYMON, 62P. -, (1967) Vascular spasm in the cerebral circulation. Proc. First Migraine Symposium (in press). -, (1967) A comparativestudy of middle cerebral arterial pressure in dogs and macaaues. J. Physiol. (in press).
References p. 67