- Email: [email protected]
Effect of mannitol on cerebral blood flow and microcirculation during experimental middle cerebral artery occlusion
Surg Neurol 1987;28:189-95
189
Effect of Mannitol on Cerebral Blood Flow and Microcirculation during Experimental Middle Cerebral Artery Occlusion Akira Tanaka, M.D., and Masamichi Tomonaga,
M.D.
Department of Neurosurgery, Fukuoka University, Fukuoka, Japan
Tanaka A, Tomonaga M. Effect of mannitol on cerebral blood flow and microcirculation during experimental middle cerebral artery occlusion. Surg Neurol 1987;28:189-95.
Regional cerebral blood flow (rCBF) was measured during and after a 2-3 hour occlusion period of the middle cerebral artery (MCA) in cats with the hydrogen clearance technique. The effects of mannitol upon rCBF were studied. Transient hypotension during occlusion dropped the blood flow to near zero on the occluded side, leading to postischemic hypoperfusion. Mannitol failed to modify blood flow during the occlusion period, but was effective in preventing any further decrease of blood flow during hypotension. Animals receiving mannitol had an improved postischemic recovery of blood flow. The correlation of ischemic severity and postischemic brain damage and the effects of mannitol on these parameters are discussed. KEY W O R D S : Brain edema; Cerebral blood flow; Mannitol; Microcirculation; Middle cerebral artery occlusion; Hypotension
In a prior communication, it was shown that acute brain swelling develops after middle cerebral artery (MCA) occlusion in animals with hypotension superimposed during occlusion. The swelling is due to edema in the infarcted cortex. This phenomena does not occur in normotensive animals [14]. In our second communication, it was shown that mannitol is effective in protecting the microcirculation during MCA occlusion and it prevents the development of acute brain swelling after release of the occlusion [ 15]. The beneficial effects of mannitol on cerebral ischemia may be related to enhancement o f cerebral blood flow, improved microcirculatory dynamics, or amelioration of cerebral edema [10]. In this study, serial measurements of regional cerebral blood flow (rCBF) were taken to investigate the mechAddress reprint requests to: Akira Tanaka, M.D., Department of Neurosurgery, Fukuoka University, Chikushi Hospital, 377-1, OhwazaZokumyouin, Chikushino-shi, Fukuoka, Japan. ©
1987 by Elsevier Science Publishing Co., Inc.
anisms of the aggravating effect of hypotension during MCA occlusion, and of the beneficial effect of mannitol.
Materials and Methods
Twenty adult cats were used for this study. After intramuscular administration of ketamine hydrochloride (25 mg/kg), the left MCA was clipped through a transorbital approach for a period of 2 - 3 hours. Transient hypotension was induced by withdrawal of venous blood in a group of animals. Aortic blood pressure was continuously monitored. The details of this procedure were described in our former report [14]. Arterial blood gases were also monitored in 12 of 20 animals. Body temperature was maintained at 36°-38°C with a heater. Regional cerebral blood flow was measured with a hydrogen clearance technique. Electrodes were composed of platinum and iridium wires, 0.3 mm in diameter, with a 0.5-mm Teflon-coated exposed tip. Four electrodes were placed in the cortex of the frontal, temporal, and parietal lobes on the left and in the cortex of the temporal lobe on the right through separate burr holes. A reference electrode was placed in the forehead. Hydrogen gas (about 10%) was inhaled through a plastic mask over the mouth for 3 minutes. The blood flow was calculated by the initial slope of the hydrogen washout curve over 2 minutes, disregarding the initial 1 minute. Blood flow was recorded every 30 or 60 minutes until 90 minutes after clip removal. Carbon black (50 mL) was infused intravenously upon completion of the blood flow measurements, and then the animals were killed with intravenous administration of potassium chloride. The animals were divided into the following four groups with five animals in each group. Group 1: Mannitol was not given and the clip was removed after 2 hours of occlusion time. There was no hypotension during the occlusion time. Group 2: Mannitol, 2.0 g/kg, was given just befi)re clipping the MCA, and the clip was removed 2 hours later. T h e r e was no hypotension during occlusion. 0090-~019/87/$3.50
190
Surg Neurol 1987;28:189-95
Tanaka and Tomonaga
Table 1. Means + Standard Deviations of Blood Pressure and Blood Gases before, during, and after MCA Occlusion, and during Hypotension Preocclusion
M A B P (mmHg ) Po2 ( m m H g ) Pco2 (mmHg ) pH
137.6 110.8 29.2 7.43
+_ -+ -+
M A B P (mmHg ) Po2 ( m m H g ) Pco2 (mmHg ) pH
132.7 108.0 29.0 7.42
-+ -+ -+ +
Occlusion
Hypotension
Untreated animals (groups 1 and 3) (6 cats) 24.5 131.0 +- 21.8 20.0 12.6 109.3 -+ 5.9 112.7 4.8 28.8 -+ 2.7 17.8 0.02 7.44 _+ 0.15 7.58 Mannitol-treated animals (groups 2 and 4) (6 cats) 25.0 130.3 -+ 19.6 19.5 14.8 105.0 -+ 8.9 120.0 5.4 28.9 -+ 1.2 19.2 0.04 7.43 -+ 0.06 7.54
Postocclusion
_+ + _+ -+
4.6 ~ 6. V 5.2 ~ 0.18 ~
140.0 111.5 29.4 7.43
+ _+ _+ _+
22.4 9.2 2.3 0.08
+-+ -+ +-
3.V 12.8 ~ 5.4 ~ 0.06 ~
141.2 112.3 28.3 7.43
+_ +_ -+ -+
21.7 12.3 4.1 0.07
Abbreviations: MABP, mean arterial blood pressure; MCA, middle cerebral artery. a3 cats.
Group 3: Mannitol was not given and the clip was removed 3 hours after MCA occlusion. There was transient hypotension during occlusion.
Group 1
Clipping the MCA promptly decreased the flow of blood in all three areas ipsilaterally and on the nonoccluded side (Table 2). The temporal lobe on the occluded side showed the greatest reduction in blood flow from 42.0 -+ 12.8 mL/100 g/min to 12.0 + 1.0 mL/100 g/min. During the occlusion period, blood flow remained relatively stable. It promptly increased above the preocclusion value upon clip removal and then returned to baseline levels in 90 minutes. Carbon black filled the hemispheres bilaterally in all the animals. Serial recordings of rCBF and a section of removed brain in an animal of this group are shown in Figure 1.
Group 4: Mannitol, 2.0 g/kg, was given just before clipping of the MCA and the clip was removed 3 hours later. There was transient hypotension during occlusion. The brains of the animals were removed and fixed in 10% formalin. One week later, the brains were cut into coronal sections. The impairment of carbon black filling was assessed in these specimens. Results Systemic Factors
Group 2
Mild hypertension, high Po2, and low Pco2 were characteristic findings in this study (Table 1). Animals were sedated, but not anesthetized, with ketamine hydrochloride during the experiment. Their breathing was unassisted and sometimes agitated as their extremities were restrained. This agitation and consequent hyperventilation were probably related to these deviated values of blood pressure and blood gases. Further increased ventilation during the hypotension period increased the alkalotic hypocapnea.
The extent of blood flow reduction after clipping the MCA was not modified by mannitol (Table 3). The blood flow returned to the preocclusion value after clip removal. However it rose abruptly 90 minutes later and was as high as 94.2 -+ 26.9 mL/100 g/min, which was 206.6% above the preocclusion value in the temporal lobe on the occluded side. Carbon black filled the hemispheres in all 5 animals and the temporal lobe on the occluded side showed hyperfilling in 4 of 5 animals.
Table 2. Means +- Standard Deviations of rCBF in Group 1 Postocclusion
Occlusion Electrode 1 2 3 4
Preocclusion 55.6 42.0 44.7 44.5
+ -4+-+
15.7 12.8 13.1 20.5
5 min 28.8 12.0 27.8 42.5
+ -+ -+ +-
5.2 1.0 3.8 26.2
120 min
60 rain 22.0 10.4 17.7 38.4
++ + +
2.6 0.8 3.1 23.1
18.9 10.8 19.3 39.5
Abbreviation: rCBF, regional cerebral blood flow. Electrode 1, left frontal; 2, left temporal; 3, left parietal; 4, right temporal lobe.
-+ -+ -+ +-
2.8 0.6 5.2 19.9
5 min 55.3 75.7 57.2 55.6
+-+-+ +
2.3 34.6 17.6 16.2
60 min 41.2 54.3 49.8 49.4
+ -+ -+ -+
10.6 29.1 15.9 14.5
90 min 33.6 40.0 43.6 44.6
++ -+ -4-
5.4 18.9 9.7 15.8
rCBF in MCA Occlusion and Mannitol
Surg Neurol 1987;28:189-95
191
CBF ml/100 g/min ELECTR(X
80-
60-
1
~ - - ~ - ~
:
-e 2
~-
~3
D
,0 4
_
40\
\\
.
.
20-
_ ...................... I . . . . . . . . . . . . . . . . . . .
CLIP
........
---0
1. . . . . . . . . . . . . . . . . .
4~
i. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CLIP OFF
Serial recordings of rCBF and a section of removed brain in an animal of this group are shown in Figure 2.
Group 3 Hypotension during MCA occlusion decreased the blood flow to near zero ipsilaterally (Table 4). The blood flow returned to the preocclusion value after clip removal. However, it fell abruptly 90 minutes later and was lower than 10 mL/100 g/min on the occluded side. Impairment of carbon black filling was within the entire area of the MCA in all the animals. Serial recordings of rCBF and a section of removed brain in an animal of this group are shown in Figure 3.
Group 4 The deterioration of blood flow during hypotension was minimized by mannitol (Table 5). Even the temporal lobe on the occluded side showed only a 14.2% reduction in flow (12.1 _+ 1.8 mL/100 g/min from 14.1 _+ 2.6 mL/100 g/min). The blood flow returned to the preocclusion value after clip removal. The whole hemisphere was completely filled with carbon black in all 5 animals and hyperfilling of the temporal lobe was noticed in 1 of them. Serial recordings of rCBF and a section of removed brain in an animal of this group are shown in Figure 4.
i ~
.
.
.
.
.
.
.
J
CARBON
Figure 1. An animal in group 1. There is a sharp decrease of blood flow in areas of the occluded side (1_,2, 3_)following MCA clipping. The temporal lobe (2) has the lowest value of 10.7 mL/lO0 g/min. Blood flow returns to the preocclusion value after clip removal. The whole hemisphere is filled with carbon black. Electrode 1, left frontal; 2, left temporal," 3, left parietal," 4, right temporal lobe.
Discussion The development of postischemic, irreversible brain damage depends upon the length of ischemia and its severity during arterial occlusion, although release of the occlusion always leads to restoration of normal or above normal cerebral blood flow. In the study of Morawetz et al [9], restoration of MCA flow led to improvement of hemiparesis after moderate reduction in local blood flow, but fatal infarction occurred despite restored flow after severe reduction in local blood flow. Jones et al [3] observed irreversible local brain damage when local blood flow fell below 10-12 mL/100 g/min for 2 to 3 hours or below 17-18 mL/100 g/min during permanent occlusion. Tamura and Sano [13] noted severe cortical damage in animals with marked reduction of blood flow during MCA occlusion, but little or no damage in animals with minimal reduction. There was a prompt and uniform recovery of blood flow after recirculation in the latter, whereas a marked diversity of blood flow was present (ranging from oligemia to hyperemia) in the former.
192
Surg Neurol 1987;28:189-95
Tanaka and Tomonaga
Table 3. Means +_ Standard Deviations of rCBF in Group 2 Occlusion Electrode l 2 3 4
Preocclusion 50.6 45.6 45.9 54.9
-+ + + -+
10.3 4.2 10.5 11.5
5 min 12.5 11.5 20.6 46.2
_+ +_ _+ _+
60 min
3.7 2.8 4.5 32.6
9.5 10.1 17.7 20.3
-+ + +_ -+
0.8 1.0 5.5 2.9
Postocclusion 120 min 9.4 10.3 16.3 20.0
-+ -+ -+ _+
1.1 2.6 3.7 1.8
5 rain 54.1 52.3 52.6 39.0
+ + + £
60 rain
18.7 12.7 13.5 15.9
47.4 45.4 38.4 33.4
+ -+ + -+
120 rain
12.5 17.5 9.6 13.4
80.2 94.2 65.6 57.2
-+ -+ -+ _+
24.5 26.9 23.7 18.3
Abbreviation: rCBF, regional cerebral blood flow.
In this experiment, the decrease in rCBF following MCA occlusion was always greatest in the temporal lobe on the occluded side, although a concomitant decrease was also observed on the nonoccluded side. In group 1, the regional blood flow stayed above 10.4 -+ 0.8 mL/100 g/min during 2 hours of MCA occlusion, and it returned to the preocclusion value after reopening the artery. Hemispheric carbon black filling was normal. Comparatively, in group 3, the blood flow decreased to near zero on the occluded side during transient hypotension,
F i g u r e 2. An animal in group 2. Mannitol does not modify the pattern and extent of bloodflow reductionfollowing MCA clipping. Bloodflow rises abruptly 90 minutes after clip removal. The temporal lobe on the occluded side (2) has the highest flow value, 210% of the preocclusion value. It shows the hyperfilling of carbon black (arrow).
CBF mllOOg
and it fell below 10 mL/100 g/min 90 minutes after reopening the artery. Carbon black filling defects were present in the entire MCA distribution. In a prior communication, it was shown that acute brain swelling develops after MCA occlusion in animals with transient hypotension during occlusion. Normotension during MCA occlusion prevents this phenomena [14]. The swelling is due to edema in the infarcted cortex. In the experiment of Mendelow et al [8], the combination of hypotension and unilateral carotid artery occlusion produced predominantly unilateral ischemic brain damage which correlated with regions of reduced cerebral blood flow in the rat. They postulate that the ischemic brain damage, whether reversible or irreversible, may be a consequence of the harmful effects that occur during subsequent reperfusion. Symon et al [12] dem-
min
80
14"
L~
60
40 ¸-
J
ELECTRODE
o
2O-
i
~iiiiii~
:
-
Lr~
o 1
•
o2
.-~
~3
~j
...... 6
3
c,,
CL.POFF
6
CARBON
4 HRS
rCBF in MCA Occlusion and Mannitol
Surg Neurol 1987;28:189-95
193
Table 4. Means +- Standard Deviations of rCBF in Group 3 Postocclusion
Occlusion Electrode
Preocclusion
1
42.4 +5.6 46.3 +16. l 34.3 _+4.9 29.9 _+3.2
2 3 4
5 min
60 min
120 rain
Hypotension
Normotension
150 min
5 min
60 min
90 min
16.1 +2.0 10.5 -+2.7 17.0 _+2.7 23.8 -+3.9
14.3 _+1.5 11.0 -+3.0 13.9 _+2.9 22.9 _+5.6
15.2 _+2.5 9.8 _+1.1 13.1 -+2.7 21.8 -+4.3
3.7 -+0.9 2.1 -+1.3 4.5 _+1.2 17.2 _+3.6
25.3 -+ 10.1 11.3 _+3.3 28.9 +8.1 41.4 _+16.1
14.2 -+3.9 7.1 _+4.2 12.3 _+2.1 21.8 -+6.1
30.4 -+9.6 32.5 ±12.7 28.9 _+9.9 24.6 -+7.3
31.4 _+19.6 22.2 +7.2 25.9 -+13.2 18.8 ±5.2
8.8 _+0.6 4.3 _+2.6 7.3 -+1.7 19.4 +6.8
Abbreviation: rCBF, regional cerebral blood flow.
clusion, hypoperfusion developed without preceding hyperperfusion. They suggest that the hyperperfusion is rather harmful in extending ischemic damage, leading eventually to hypoperfusion. From these findings, it is clear that blood flow preservation during arterial occlusion may prevent permanent ischemic injury during reperfusion. The afore-
onstrated that the water increase in a given cortical region is directly related to the degree of ischemia in that region. They suggest that the depth of ischemia is more important for final water content than the duration of the ischemic period. In our second communication, it was shown that the change in microcirculation during MCA occlusion is recovered by reopening the artery, but deteriorates if acute brain swelling develops during reperfusion [ 15]. In the study of Traupe et al [ 16], postischemic hyperperfusion was found regularly after 1 hour of MCA occlusion, but it was followed by hypoperfusion. After 2 hours of oc-
F i g u r e 3. An animal in group 3. Transient hypotension during occlusion drops the blood flow to near zero on the occluded side (1, 2, 3). Blood flow falls abruptly below 10 mL/lO0 g/min on that side 90 minutes after clip removal Impaired carbon black filling extends to the entire M C A distribution.
CBF m l 100g min 80
tl
c.,
ELECTROIDE
u
40
•
~-3 ~4
O LJ
20-
02
0
* i,
4 CLIP
HYPOTENSION CLIPOFF
CARBON
5 HR.S
194
Surg Neurol 1987;28:189-95
Table
Tanaka and Tomonaga
5. Means +_ Standard Deviations of rCBF in Group 4 Occlusion
Postocclusion
Electrode
Preocclusion
5 min
60 min
120 min
Hypotension
Normotension
150 min
5 min
60 min
90 rain
1
55.7 -+8.6 34.6 -+7.7 48,4 -+ 12.7 39,4 -+ 15,9
38.8 -+15.5 15.8 +2.3 26.7 -+ 5.4 35.1 -+ 18.0
19.2 -+3.3 14.3 -+ 3,0 21.7 -+4.7 27.1 -+11.8
21.7 -+4.0 14.1 -+ 2.6 19.0 -+3.2 26.1 -+12.3
20.9 -+8.5 12. l -+ 1.8 17.9 -+4.4 23.0 -+6.1
34.3 -+16.8 15.4 -+ 3,8 25.5 -+4.7 43.9 +23.2
20.7 +7.5 14.5 +4.9 18.3 -+6,7 25.8 -+5.7
49.2 --15.9 32.6 -+9.3 37.7 -+4.2 36.9 +4.2
38.5 -+22.4 41.0 -+12.2 42.1 -+18.8 32.2 -+4,7
38.1 +13.1 43.3 -+12.5 35.5 -+6.7 29.4 -+4.9
2 3 4
Abbreviation: rCBF, regional cerebral blood flow.
of cerebral blood flow, improved microcirculatory dynamics, or amelioration of cerebral edema [10]. However, it has not been proven whether or not the beneficial effect of mannitol on cerebral ischemia is due to enhancement of blood flow, although such enhancement was demonstrated in the normal brain of dogs and baboons [2,5,6]. In group 2 of this experiment, mannitol failed to minimize the reduction of cerebral blood flow during MCA occlusion. Restoration of flow was followed by hyperperfusion and hyperfilling with carbon black. On the other hand, in group 4, mannitol was effective in preventing the further deterioration of cerebral blood flow during transient hypotension, preserving the blood
mentioned progressive edema and secondary impairment of the microcirculation play a major role in the mechanism of postischemic brain damage. Mannitol has been shown to have beneficial effects on cerebral ischemia both experimentally [7,17] and clinically [1,18]. The beneficial effects have been supported by examination of microvascular patency and neuronal structure with light and electron microscopic analysis. The mechanism may be related to enhancement
F i g u r e 4. An animal in group 4. Mannitol minimizes the further reduction of bloodflow during transient hypotension and bloodflow returns to the preocclusion value after clip removal. The whole hemisphere is completely filled with carbon black.
CBF m1100g/min 80 ELECTRODE c~ cl 60 ~
': --~..~
20
-°
&
~
~ 3
c4
"O
L .....................................
°
4
g
MANNITOL CLIP
HYPOTENSION CUP OFF
5HRS
CARBON
rCBF in MCA Occlusion and Mannitol
flow above 12.1 _+ 1.8 mL/100 g/rain. The blood flow r e t u r n e d to the p r e o c c l u s i o n value after r e o p e n i n g the artery and c a r b o n black c o m p l e t e l y filled the h e m i sphere. T h e failure o f m a n n i t o l to significantly modify b l o o d flow d u r i n g arterial occlusion was also d e m o n s t r a t e d in o t h e r studies [4,10,1 1]. Kassell et al [6] suggest that it is difficult to correlate the e n h a n c e m e n t o f b l o o d flow with the beneficial effect o f m a n n i t o l d u r i n g cerebral ischemia, as this e n h a n c e m e n t is very small. In o u r second c o m m u n i c a t i o n , it was s h o w n that m a n nitol is effective in p r o t e c t i n g the m i c r o c i r c u l a t i o n during arterial occlusion, and it p r e v e n t s the d e v e l o p m e n t o f acute brain swelling in the p e r i o d o f r e p e r f u s i o n [ 15 ]. H y p e r f i l l i n g with c a r b o n black was observed. F r o m these findings, m a n n i t o l seems to play a role in preserving the critical value o f cerebral blood flow, which is a r o u n d 1 0 - 1 2 mL/100 g/min, and in p r o t e c t i n g the m i c r o c i r c u l a t i o n d u r i n g arterial occlusion, l e a d i n g to p r e v e n t i o n o f postischemic brain damage. Postischemic h y p e r p e r f u s i o n with m a n n i t o l a d m i n istration, as seen in g r o u p 2, was also o b s e r v e d in the e x p e r i m e n t o f K a g e y a m a [4], and the c o n c o m i t a n t hyperfilling with c a r b o n black was also d e m o n s t r a t e d in o u r f o r m e r study [15]. A l t h o u g h s u b s e q u e n t changes in b l o o d flow did n o t follow, it seems to be a harmless physiological a u t o r e g u l a t i v e o c c u r r e n c e [16].
References 1. Brown FD, Hanlon K, Mullan S. Treatment of aneurysmal hemiplegia with dopamine and mannitol. J Neurosurg 1978;49:525-9. 2. Johnston IH, Harper AM. The effect of mannitol on cerebral blood flow. An experimental study. J Neurosurg 1973;38:461-71. 3. Jones TH, Morawetz RB, Crowell RM, Marcoux FW, FitzGibbon SJ, DeGirolami U, Ojemann RG. Thresholds of focal cerebral ischemia in awake monkeys. J Neurosurg 1981;54:773-82. 4. KageyamaT. The effects of various agents for experimental cerebral ischemia evaluated by the regional cerebral blood flow and ultrastructural changes. Jpn J Stroke 1980;2:186-96.
Surg Neurol 1987;28:189-95
195
5. Kassell NF, Baumann KW, Hitchon PW, Gerk MK, Hill TR, Sokoll MD. Influence of a continuous high dose infusion of mannitol on cerebral blood flow in normal dogs. Neurosurgery 1981;9: 283-6, 6. Kassell NF, Baumann KW, Hitchon PW, Gerk MK, Hill TR, Sokoll MD. The effects of high dose mannitol on cerebral blood flow in dogs with normal intracranial pressure. Stroke 1982;13: 59-61. 7. Little JR. Modification of acute focal ischemia by treatment with mannitol. Stroke 1978;9:4-9. 8. Mendelow AD, Graham DI, McCulloch PJ, Mohamed AA. The distribution of ischaemic damage and cerebral blood flow after unilateral carotid occlusion and hypotension in the rat. Stroke 1984;15:704-1(/. 9. MorawetzRB, DeGirolami U, Ojemann RG, Marcoux FW, Crowell RM. Cerebral blood flow determined by hydrogen clearance during middle cerebral artery occlusion in unanesthetized monkeys. Stroke 1978;9:143-9. 10. Pena H, Gaines C, Suess D, Crowell RM, Waggener JD, DeGirolami U. Effect of mannitol on experimental focal ischemia in awake monkeys. Neurosurgery 1982; 11:477-81. 11. Seki H, Ogawa A, Yoshimoto T, Suzuki J. Effect of mannitol on rCBF in canine thalamic ischemia. An experimental study. Brain Nerve (Tokyo) 1981;33:110l-5. 12. Symon L, Branston NM, Chikovani O. lschemic brain edema following middle cerebral artery occlusion in baboons. Relationship between regional cerebral water content and blood flow at 1 to 2 hours. Stroke 1979;10:184-91. 13. Tamura A, Sano K. The temporary occlusion of middle cerebral artery in cats. The correlation between the rCBF and the histological changes. Brain Nerve (Tokyo) 1979;3 l :1005- l 5. 14. Tanaka A, Tomonaga M, Fukushima T. Acute brain swelling following the temporary occlusion of the middle cerebral artery in cats. lnfluence of hypotension during the occlusion. Med Bull Fukuoka Univ 1981;8:9-16. 15. Tanaka A, Tomonaga M. Microcirculation change during and after temporary occlusion of middle cerebral artery in cats and effect of mannitol (in press). 16. Traupe H, Kruse E, Heiss WD. Reperfusion of focal ischemia of varying duration. Postischemic hyper- and hypo-perfusion. Stroke 1982;13:615-22. 17. Watanabe T, Yoshimoto T, Ogawa A, Sakamoto T, SuzukiJ. The effect of mannitol in preventing the development of cerebral infarction. An electron microscopical investigation. Neurol Surg (Tokyo) 1979;7:859-66. 18. Yoshimoto T, Suzuki J. Intracranial definitive aneurysm surgery under normothermia and normotension utilizing temporary occlusion of major cerebral arteries and preoperative mannitol administration. Neurol Surg (Tokyo) 1976;4:775-83.
189
Effect of Mannitol on Cerebral Blood Flow and Microcirculation during Experimental Middle Cerebral Artery Occlusion Akira Tanaka, M.D., and Masamichi Tomonaga,
M.D.
Department of Neurosurgery, Fukuoka University, Fukuoka, Japan
Tanaka A, Tomonaga M. Effect of mannitol on cerebral blood flow and microcirculation during experimental middle cerebral artery occlusion. Surg Neurol 1987;28:189-95.
Regional cerebral blood flow (rCBF) was measured during and after a 2-3 hour occlusion period of the middle cerebral artery (MCA) in cats with the hydrogen clearance technique. The effects of mannitol upon rCBF were studied. Transient hypotension during occlusion dropped the blood flow to near zero on the occluded side, leading to postischemic hypoperfusion. Mannitol failed to modify blood flow during the occlusion period, but was effective in preventing any further decrease of blood flow during hypotension. Animals receiving mannitol had an improved postischemic recovery of blood flow. The correlation of ischemic severity and postischemic brain damage and the effects of mannitol on these parameters are discussed. KEY W O R D S : Brain edema; Cerebral blood flow; Mannitol; Microcirculation; Middle cerebral artery occlusion; Hypotension
In a prior communication, it was shown that acute brain swelling develops after middle cerebral artery (MCA) occlusion in animals with hypotension superimposed during occlusion. The swelling is due to edema in the infarcted cortex. This phenomena does not occur in normotensive animals [14]. In our second communication, it was shown that mannitol is effective in protecting the microcirculation during MCA occlusion and it prevents the development of acute brain swelling after release of the occlusion [ 15]. The beneficial effects of mannitol on cerebral ischemia may be related to enhancement o f cerebral blood flow, improved microcirculatory dynamics, or amelioration of cerebral edema [10]. In this study, serial measurements of regional cerebral blood flow (rCBF) were taken to investigate the mechAddress reprint requests to: Akira Tanaka, M.D., Department of Neurosurgery, Fukuoka University, Chikushi Hospital, 377-1, OhwazaZokumyouin, Chikushino-shi, Fukuoka, Japan. ©
1987 by Elsevier Science Publishing Co., Inc.
anisms of the aggravating effect of hypotension during MCA occlusion, and of the beneficial effect of mannitol.
Materials and Methods
Twenty adult cats were used for this study. After intramuscular administration of ketamine hydrochloride (25 mg/kg), the left MCA was clipped through a transorbital approach for a period of 2 - 3 hours. Transient hypotension was induced by withdrawal of venous blood in a group of animals. Aortic blood pressure was continuously monitored. The details of this procedure were described in our former report [14]. Arterial blood gases were also monitored in 12 of 20 animals. Body temperature was maintained at 36°-38°C with a heater. Regional cerebral blood flow was measured with a hydrogen clearance technique. Electrodes were composed of platinum and iridium wires, 0.3 mm in diameter, with a 0.5-mm Teflon-coated exposed tip. Four electrodes were placed in the cortex of the frontal, temporal, and parietal lobes on the left and in the cortex of the temporal lobe on the right through separate burr holes. A reference electrode was placed in the forehead. Hydrogen gas (about 10%) was inhaled through a plastic mask over the mouth for 3 minutes. The blood flow was calculated by the initial slope of the hydrogen washout curve over 2 minutes, disregarding the initial 1 minute. Blood flow was recorded every 30 or 60 minutes until 90 minutes after clip removal. Carbon black (50 mL) was infused intravenously upon completion of the blood flow measurements, and then the animals were killed with intravenous administration of potassium chloride. The animals were divided into the following four groups with five animals in each group. Group 1: Mannitol was not given and the clip was removed after 2 hours of occlusion time. There was no hypotension during the occlusion time. Group 2: Mannitol, 2.0 g/kg, was given just befi)re clipping the MCA, and the clip was removed 2 hours later. T h e r e was no hypotension during occlusion. 0090-~019/87/$3.50
190
Surg Neurol 1987;28:189-95
Tanaka and Tomonaga
Table 1. Means + Standard Deviations of Blood Pressure and Blood Gases before, during, and after MCA Occlusion, and during Hypotension Preocclusion
M A B P (mmHg ) Po2 ( m m H g ) Pco2 (mmHg ) pH
137.6 110.8 29.2 7.43
+_ -+ -+
M A B P (mmHg ) Po2 ( m m H g ) Pco2 (mmHg ) pH
132.7 108.0 29.0 7.42
-+ -+ -+ +
Occlusion
Hypotension
Untreated animals (groups 1 and 3) (6 cats) 24.5 131.0 +- 21.8 20.0 12.6 109.3 -+ 5.9 112.7 4.8 28.8 -+ 2.7 17.8 0.02 7.44 _+ 0.15 7.58 Mannitol-treated animals (groups 2 and 4) (6 cats) 25.0 130.3 -+ 19.6 19.5 14.8 105.0 -+ 8.9 120.0 5.4 28.9 -+ 1.2 19.2 0.04 7.43 -+ 0.06 7.54
Postocclusion
_+ + _+ -+
4.6 ~ 6. V 5.2 ~ 0.18 ~
140.0 111.5 29.4 7.43
+ _+ _+ _+
22.4 9.2 2.3 0.08
+-+ -+ +-
3.V 12.8 ~ 5.4 ~ 0.06 ~
141.2 112.3 28.3 7.43
+_ +_ -+ -+
21.7 12.3 4.1 0.07
Abbreviations: MABP, mean arterial blood pressure; MCA, middle cerebral artery. a3 cats.
Group 3: Mannitol was not given and the clip was removed 3 hours after MCA occlusion. There was transient hypotension during occlusion.
Group 1
Clipping the MCA promptly decreased the flow of blood in all three areas ipsilaterally and on the nonoccluded side (Table 2). The temporal lobe on the occluded side showed the greatest reduction in blood flow from 42.0 -+ 12.8 mL/100 g/min to 12.0 + 1.0 mL/100 g/min. During the occlusion period, blood flow remained relatively stable. It promptly increased above the preocclusion value upon clip removal and then returned to baseline levels in 90 minutes. Carbon black filled the hemispheres bilaterally in all the animals. Serial recordings of rCBF and a section of removed brain in an animal of this group are shown in Figure 1.
Group 4: Mannitol, 2.0 g/kg, was given just before clipping of the MCA and the clip was removed 3 hours later. There was transient hypotension during occlusion. The brains of the animals were removed and fixed in 10% formalin. One week later, the brains were cut into coronal sections. The impairment of carbon black filling was assessed in these specimens. Results Systemic Factors
Group 2
Mild hypertension, high Po2, and low Pco2 were characteristic findings in this study (Table 1). Animals were sedated, but not anesthetized, with ketamine hydrochloride during the experiment. Their breathing was unassisted and sometimes agitated as their extremities were restrained. This agitation and consequent hyperventilation were probably related to these deviated values of blood pressure and blood gases. Further increased ventilation during the hypotension period increased the alkalotic hypocapnea.
The extent of blood flow reduction after clipping the MCA was not modified by mannitol (Table 3). The blood flow returned to the preocclusion value after clip removal. However it rose abruptly 90 minutes later and was as high as 94.2 -+ 26.9 mL/100 g/min, which was 206.6% above the preocclusion value in the temporal lobe on the occluded side. Carbon black filled the hemispheres in all 5 animals and the temporal lobe on the occluded side showed hyperfilling in 4 of 5 animals.
Table 2. Means +- Standard Deviations of rCBF in Group 1 Postocclusion
Occlusion Electrode 1 2 3 4
Preocclusion 55.6 42.0 44.7 44.5
+ -4+-+
15.7 12.8 13.1 20.5
5 min 28.8 12.0 27.8 42.5
+ -+ -+ +-
5.2 1.0 3.8 26.2
120 min
60 rain 22.0 10.4 17.7 38.4
++ + +
2.6 0.8 3.1 23.1
18.9 10.8 19.3 39.5
Abbreviation: rCBF, regional cerebral blood flow. Electrode 1, left frontal; 2, left temporal; 3, left parietal; 4, right temporal lobe.
-+ -+ -+ +-
2.8 0.6 5.2 19.9
5 min 55.3 75.7 57.2 55.6
+-+-+ +
2.3 34.6 17.6 16.2
60 min 41.2 54.3 49.8 49.4
+ -+ -+ -+
10.6 29.1 15.9 14.5
90 min 33.6 40.0 43.6 44.6
++ -+ -4-
5.4 18.9 9.7 15.8
rCBF in MCA Occlusion and Mannitol
Surg Neurol 1987;28:189-95
191
CBF ml/100 g/min ELECTR(X
80-
60-
1
~ - - ~ - ~
:
-e 2
~-
~3
D
,0 4
_
40\
\\
.
.
20-
_ ...................... I . . . . . . . . . . . . . . . . . . .
CLIP
........
---0
1. . . . . . . . . . . . . . . . . .
4~
i. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CLIP OFF
Serial recordings of rCBF and a section of removed brain in an animal of this group are shown in Figure 2.
Group 3 Hypotension during MCA occlusion decreased the blood flow to near zero ipsilaterally (Table 4). The blood flow returned to the preocclusion value after clip removal. However, it fell abruptly 90 minutes later and was lower than 10 mL/100 g/min on the occluded side. Impairment of carbon black filling was within the entire area of the MCA in all the animals. Serial recordings of rCBF and a section of removed brain in an animal of this group are shown in Figure 3.
Group 4 The deterioration of blood flow during hypotension was minimized by mannitol (Table 5). Even the temporal lobe on the occluded side showed only a 14.2% reduction in flow (12.1 _+ 1.8 mL/100 g/min from 14.1 _+ 2.6 mL/100 g/min). The blood flow returned to the preocclusion value after clip removal. The whole hemisphere was completely filled with carbon black in all 5 animals and hyperfilling of the temporal lobe was noticed in 1 of them. Serial recordings of rCBF and a section of removed brain in an animal of this group are shown in Figure 4.
i ~
.
.
.
.
.
.
.
J
CARBON
Figure 1. An animal in group 1. There is a sharp decrease of blood flow in areas of the occluded side (1_,2, 3_)following MCA clipping. The temporal lobe (2) has the lowest value of 10.7 mL/lO0 g/min. Blood flow returns to the preocclusion value after clip removal. The whole hemisphere is filled with carbon black. Electrode 1, left frontal; 2, left temporal," 3, left parietal," 4, right temporal lobe.
Discussion The development of postischemic, irreversible brain damage depends upon the length of ischemia and its severity during arterial occlusion, although release of the occlusion always leads to restoration of normal or above normal cerebral blood flow. In the study of Morawetz et al [9], restoration of MCA flow led to improvement of hemiparesis after moderate reduction in local blood flow, but fatal infarction occurred despite restored flow after severe reduction in local blood flow. Jones et al [3] observed irreversible local brain damage when local blood flow fell below 10-12 mL/100 g/min for 2 to 3 hours or below 17-18 mL/100 g/min during permanent occlusion. Tamura and Sano [13] noted severe cortical damage in animals with marked reduction of blood flow during MCA occlusion, but little or no damage in animals with minimal reduction. There was a prompt and uniform recovery of blood flow after recirculation in the latter, whereas a marked diversity of blood flow was present (ranging from oligemia to hyperemia) in the former.
192
Surg Neurol 1987;28:189-95
Tanaka and Tomonaga
Table 3. Means +_ Standard Deviations of rCBF in Group 2 Occlusion Electrode l 2 3 4
Preocclusion 50.6 45.6 45.9 54.9
-+ + + -+
10.3 4.2 10.5 11.5
5 min 12.5 11.5 20.6 46.2
_+ +_ _+ _+
60 min
3.7 2.8 4.5 32.6
9.5 10.1 17.7 20.3
-+ + +_ -+
0.8 1.0 5.5 2.9
Postocclusion 120 min 9.4 10.3 16.3 20.0
-+ -+ -+ _+
1.1 2.6 3.7 1.8
5 rain 54.1 52.3 52.6 39.0
+ + + £
60 rain
18.7 12.7 13.5 15.9
47.4 45.4 38.4 33.4
+ -+ + -+
120 rain
12.5 17.5 9.6 13.4
80.2 94.2 65.6 57.2
-+ -+ -+ _+
24.5 26.9 23.7 18.3
Abbreviation: rCBF, regional cerebral blood flow.
In this experiment, the decrease in rCBF following MCA occlusion was always greatest in the temporal lobe on the occluded side, although a concomitant decrease was also observed on the nonoccluded side. In group 1, the regional blood flow stayed above 10.4 -+ 0.8 mL/100 g/min during 2 hours of MCA occlusion, and it returned to the preocclusion value after reopening the artery. Hemispheric carbon black filling was normal. Comparatively, in group 3, the blood flow decreased to near zero on the occluded side during transient hypotension,
F i g u r e 2. An animal in group 2. Mannitol does not modify the pattern and extent of bloodflow reductionfollowing MCA clipping. Bloodflow rises abruptly 90 minutes after clip removal. The temporal lobe on the occluded side (2) has the highest flow value, 210% of the preocclusion value. It shows the hyperfilling of carbon black (arrow).
CBF mllOOg
and it fell below 10 mL/100 g/min 90 minutes after reopening the artery. Carbon black filling defects were present in the entire MCA distribution. In a prior communication, it was shown that acute brain swelling develops after MCA occlusion in animals with transient hypotension during occlusion. Normotension during MCA occlusion prevents this phenomena [14]. The swelling is due to edema in the infarcted cortex. In the experiment of Mendelow et al [8], the combination of hypotension and unilateral carotid artery occlusion produced predominantly unilateral ischemic brain damage which correlated with regions of reduced cerebral blood flow in the rat. They postulate that the ischemic brain damage, whether reversible or irreversible, may be a consequence of the harmful effects that occur during subsequent reperfusion. Symon et al [12] dem-
min
80
14"
L~
60
40 ¸-
J
ELECTRODE
o
2O-
i
~iiiiii~
:
-
Lr~
o 1
•
o2
.-~
~3
~j
...... 6
3
c,,
CL.POFF
6
CARBON
4 HRS
rCBF in MCA Occlusion and Mannitol
Surg Neurol 1987;28:189-95
193
Table 4. Means +- Standard Deviations of rCBF in Group 3 Postocclusion
Occlusion Electrode
Preocclusion
1
42.4 +5.6 46.3 +16. l 34.3 _+4.9 29.9 _+3.2
2 3 4
5 min
60 min
120 rain
Hypotension
Normotension
150 min
5 min
60 min
90 min
16.1 +2.0 10.5 -+2.7 17.0 _+2.7 23.8 -+3.9
14.3 _+1.5 11.0 -+3.0 13.9 _+2.9 22.9 _+5.6
15.2 _+2.5 9.8 _+1.1 13.1 -+2.7 21.8 -+4.3
3.7 -+0.9 2.1 -+1.3 4.5 _+1.2 17.2 _+3.6
25.3 -+ 10.1 11.3 _+3.3 28.9 +8.1 41.4 _+16.1
14.2 -+3.9 7.1 _+4.2 12.3 _+2.1 21.8 -+6.1
30.4 -+9.6 32.5 ±12.7 28.9 _+9.9 24.6 -+7.3
31.4 _+19.6 22.2 +7.2 25.9 -+13.2 18.8 ±5.2
8.8 _+0.6 4.3 _+2.6 7.3 -+1.7 19.4 +6.8
Abbreviation: rCBF, regional cerebral blood flow.
clusion, hypoperfusion developed without preceding hyperperfusion. They suggest that the hyperperfusion is rather harmful in extending ischemic damage, leading eventually to hypoperfusion. From these findings, it is clear that blood flow preservation during arterial occlusion may prevent permanent ischemic injury during reperfusion. The afore-
onstrated that the water increase in a given cortical region is directly related to the degree of ischemia in that region. They suggest that the depth of ischemia is more important for final water content than the duration of the ischemic period. In our second communication, it was shown that the change in microcirculation during MCA occlusion is recovered by reopening the artery, but deteriorates if acute brain swelling develops during reperfusion [ 15]. In the study of Traupe et al [ 16], postischemic hyperperfusion was found regularly after 1 hour of MCA occlusion, but it was followed by hypoperfusion. After 2 hours of oc-
F i g u r e 3. An animal in group 3. Transient hypotension during occlusion drops the blood flow to near zero on the occluded side (1, 2, 3). Blood flow falls abruptly below 10 mL/lO0 g/min on that side 90 minutes after clip removal Impaired carbon black filling extends to the entire M C A distribution.
CBF m l 100g min 80
tl
c.,
ELECTROIDE
u
40
•
~-3 ~4
O LJ
20-
02
0
* i,
4 CLIP
HYPOTENSION CLIPOFF
CARBON
5 HR.S
194
Surg Neurol 1987;28:189-95
Table
Tanaka and Tomonaga
5. Means +_ Standard Deviations of rCBF in Group 4 Occlusion
Postocclusion
Electrode
Preocclusion
5 min
60 min
120 min
Hypotension
Normotension
150 min
5 min
60 min
90 rain
1
55.7 -+8.6 34.6 -+7.7 48,4 -+ 12.7 39,4 -+ 15,9
38.8 -+15.5 15.8 +2.3 26.7 -+ 5.4 35.1 -+ 18.0
19.2 -+3.3 14.3 -+ 3,0 21.7 -+4.7 27.1 -+11.8
21.7 -+4.0 14.1 -+ 2.6 19.0 -+3.2 26.1 -+12.3
20.9 -+8.5 12. l -+ 1.8 17.9 -+4.4 23.0 -+6.1
34.3 -+16.8 15.4 -+ 3,8 25.5 -+4.7 43.9 +23.2
20.7 +7.5 14.5 +4.9 18.3 -+6,7 25.8 -+5.7
49.2 --15.9 32.6 -+9.3 37.7 -+4.2 36.9 +4.2
38.5 -+22.4 41.0 -+12.2 42.1 -+18.8 32.2 -+4,7
38.1 +13.1 43.3 -+12.5 35.5 -+6.7 29.4 -+4.9
2 3 4
Abbreviation: rCBF, regional cerebral blood flow.
of cerebral blood flow, improved microcirculatory dynamics, or amelioration of cerebral edema [10]. However, it has not been proven whether or not the beneficial effect of mannitol on cerebral ischemia is due to enhancement of blood flow, although such enhancement was demonstrated in the normal brain of dogs and baboons [2,5,6]. In group 2 of this experiment, mannitol failed to minimize the reduction of cerebral blood flow during MCA occlusion. Restoration of flow was followed by hyperperfusion and hyperfilling with carbon black. On the other hand, in group 4, mannitol was effective in preventing the further deterioration of cerebral blood flow during transient hypotension, preserving the blood
mentioned progressive edema and secondary impairment of the microcirculation play a major role in the mechanism of postischemic brain damage. Mannitol has been shown to have beneficial effects on cerebral ischemia both experimentally [7,17] and clinically [1,18]. The beneficial effects have been supported by examination of microvascular patency and neuronal structure with light and electron microscopic analysis. The mechanism may be related to enhancement
F i g u r e 4. An animal in group 4. Mannitol minimizes the further reduction of bloodflow during transient hypotension and bloodflow returns to the preocclusion value after clip removal. The whole hemisphere is completely filled with carbon black.
CBF m1100g/min 80 ELECTRODE c~ cl 60 ~
': --~..~
20
-°
&
~
~ 3
c4
"O
L .....................................
°
4
g
MANNITOL CLIP
HYPOTENSION CUP OFF
5HRS
CARBON
rCBF in MCA Occlusion and Mannitol
flow above 12.1 _+ 1.8 mL/100 g/rain. The blood flow r e t u r n e d to the p r e o c c l u s i o n value after r e o p e n i n g the artery and c a r b o n black c o m p l e t e l y filled the h e m i sphere. T h e failure o f m a n n i t o l to significantly modify b l o o d flow d u r i n g arterial occlusion was also d e m o n s t r a t e d in o t h e r studies [4,10,1 1]. Kassell et al [6] suggest that it is difficult to correlate the e n h a n c e m e n t o f b l o o d flow with the beneficial effect o f m a n n i t o l d u r i n g cerebral ischemia, as this e n h a n c e m e n t is very small. In o u r second c o m m u n i c a t i o n , it was s h o w n that m a n nitol is effective in p r o t e c t i n g the m i c r o c i r c u l a t i o n during arterial occlusion, and it p r e v e n t s the d e v e l o p m e n t o f acute brain swelling in the p e r i o d o f r e p e r f u s i o n [ 15 ]. H y p e r f i l l i n g with c a r b o n black was observed. F r o m these findings, m a n n i t o l seems to play a role in preserving the critical value o f cerebral blood flow, which is a r o u n d 1 0 - 1 2 mL/100 g/min, and in p r o t e c t i n g the m i c r o c i r c u l a t i o n d u r i n g arterial occlusion, l e a d i n g to p r e v e n t i o n o f postischemic brain damage. Postischemic h y p e r p e r f u s i o n with m a n n i t o l a d m i n istration, as seen in g r o u p 2, was also o b s e r v e d in the e x p e r i m e n t o f K a g e y a m a [4], and the c o n c o m i t a n t hyperfilling with c a r b o n black was also d e m o n s t r a t e d in o u r f o r m e r study [15]. A l t h o u g h s u b s e q u e n t changes in b l o o d flow did n o t follow, it seems to be a harmless physiological a u t o r e g u l a t i v e o c c u r r e n c e [16].
References 1. Brown FD, Hanlon K, Mullan S. Treatment of aneurysmal hemiplegia with dopamine and mannitol. J Neurosurg 1978;49:525-9. 2. Johnston IH, Harper AM. The effect of mannitol on cerebral blood flow. An experimental study. J Neurosurg 1973;38:461-71. 3. Jones TH, Morawetz RB, Crowell RM, Marcoux FW, FitzGibbon SJ, DeGirolami U, Ojemann RG. Thresholds of focal cerebral ischemia in awake monkeys. J Neurosurg 1981;54:773-82. 4. KageyamaT. The effects of various agents for experimental cerebral ischemia evaluated by the regional cerebral blood flow and ultrastructural changes. Jpn J Stroke 1980;2:186-96.
Surg Neurol 1987;28:189-95
195
5. Kassell NF, Baumann KW, Hitchon PW, Gerk MK, Hill TR, Sokoll MD. Influence of a continuous high dose infusion of mannitol on cerebral blood flow in normal dogs. Neurosurgery 1981;9: 283-6, 6. Kassell NF, Baumann KW, Hitchon PW, Gerk MK, Hill TR, Sokoll MD. The effects of high dose mannitol on cerebral blood flow in dogs with normal intracranial pressure. Stroke 1982;13: 59-61. 7. Little JR. Modification of acute focal ischemia by treatment with mannitol. Stroke 1978;9:4-9. 8. Mendelow AD, Graham DI, McCulloch PJ, Mohamed AA. The distribution of ischaemic damage and cerebral blood flow after unilateral carotid occlusion and hypotension in the rat. Stroke 1984;15:704-1(/. 9. MorawetzRB, DeGirolami U, Ojemann RG, Marcoux FW, Crowell RM. Cerebral blood flow determined by hydrogen clearance during middle cerebral artery occlusion in unanesthetized monkeys. Stroke 1978;9:143-9. 10. Pena H, Gaines C, Suess D, Crowell RM, Waggener JD, DeGirolami U. Effect of mannitol on experimental focal ischemia in awake monkeys. Neurosurgery 1982; 11:477-81. 11. Seki H, Ogawa A, Yoshimoto T, Suzuki J. Effect of mannitol on rCBF in canine thalamic ischemia. An experimental study. Brain Nerve (Tokyo) 1981;33:110l-5. 12. Symon L, Branston NM, Chikovani O. lschemic brain edema following middle cerebral artery occlusion in baboons. Relationship between regional cerebral water content and blood flow at 1 to 2 hours. Stroke 1979;10:184-91. 13. Tamura A, Sano K. The temporary occlusion of middle cerebral artery in cats. The correlation between the rCBF and the histological changes. Brain Nerve (Tokyo) 1979;3 l :1005- l 5. 14. Tanaka A, Tomonaga M, Fukushima T. Acute brain swelling following the temporary occlusion of the middle cerebral artery in cats. lnfluence of hypotension during the occlusion. Med Bull Fukuoka Univ 1981;8:9-16. 15. Tanaka A, Tomonaga M. Microcirculation change during and after temporary occlusion of middle cerebral artery in cats and effect of mannitol (in press). 16. Traupe H, Kruse E, Heiss WD. Reperfusion of focal ischemia of varying duration. Postischemic hyper- and hypo-perfusion. Stroke 1982;13:615-22. 17. Watanabe T, Yoshimoto T, Ogawa A, Sakamoto T, SuzukiJ. The effect of mannitol in preventing the development of cerebral infarction. An electron microscopical investigation. Neurol Surg (Tokyo) 1979;7:859-66. 18. Yoshimoto T, Suzuki J. Intracranial definitive aneurysm surgery under normothermia and normotension utilizing temporary occlusion of major cerebral arteries and preoperative mannitol administration. Neurol Surg (Tokyo) 1976;4:775-83.