MANAGEMENT OF ACUTE STROKE IN PRIMATES/Michenfelder et al.
tion of normal young men. J Clin Invest 27: 484-492, 1948
23. Yoshida K, Meyer JS, Sakamoto K, et al: Autoregulation of cerebral
blood flow. Electromagnetic flow measurements during acute hypertension in the monkey. Circulation Research 19: 726-738, 1966
24. Eklof B, Ingvar DH, Kagstrom E, et al: Persistence of cerebral blood
flow autoregulation following chronic bilateral cervical sympathectomy
in the monkey. Acta Physiol Scand 82: 172-176, 1971
25. Eklof B, Siesjo BK: Cerebral blood flow in ischemia caused by carotid
artery ligation in the rat. Acta Physiol Scand 87: 69-77, 1972
26. Yamaguchi T, Waltz AG: Non-uniform response of regional cerebral
blood flow to stimulation of cervical sympathetic nerve. J Neurol
Neurosurg Psychiat 34: 602-606, 1971
27. Aubineau P, Seylaz J, Sercombe R, Mama H: Evidence for regional
differences in the effects of beta-adrenergic stimulation on cerebral blood
flow. Brain Res 61: 153-161, 1973
28. Hassler O: A systematic investigation of the physiological intimal
cushions associated with the arteries in five human brains. Acta Soc Med
Upsal 67: 35-41, 1962
29. Takayanagi T, Rennels ML, Nelson E: An electron microscopic study of
intimal cushions in intracranial arteries of the cat. Am J Anat 133:
415-429, 1972
30. Lindvall O, Bjorklund A: The glyoxylic acid fluorescence histochemical
31.
32.
33.
34.
35.
36.
37.
87
method: A detailed account of the methodology for the visualization of
central catecholamine neurons. Histochemistry 39: 97-127, 1974
Wolff HG: The cerebral vessels — anatomical principles. Res Publ Assoc
Res Nerv Ment Dis 18: 29-68, 1938. Cited in Purves (1972)
Gerard RW: Brain metabolism and circulation. Res Publ Assoc Nerv
Ment Dis 18: 316-345, 1938
Sokoloff L: Local cerebral circulation at rest and during altered cerebral
activity induced by anesthesia or visual stimulation. In Kety SS, Elkes J
(eds): Regional Neurochemistry. New York, Pergamon, pp 107-117,
1961
Edvinsson L, Owman C, Rosengren E, et al: Concentration of
noradrenaline in pial vessels, choroid plexus, and iris during two weeks
after sympathetic ganglionectomy or decentralization. Acta Physiol
Scand 85: 201-206, 1972
Ronnberg AL, Edvinsson L, Larson LI, et al: Regional variation in the
presence of mast cells in the mammalian brain. Agents and Actions 3:
191, 1973
Folkow B: Nervous control of the blood vessels. Physiol Rev 35:
629-663, 1955
Bevan JA, Bevan RD, Purdy RE, et al: Comparison of adrenergic
mechanism in an elastic and muscular artery of the rabbit. Circulation
Research 30: 541-548, 1972
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Failure of Prolonged Hypocapnia, Hypothermia, or
Hypertension to Favorably Alter Acute Stroke in
Primates
JOHN
D.
MICHENFELDER,
M.D.,*
AND JAMES
H. MiLDEf
S U M M A R Y The effects of induced hypocapnia, hypothermia, and
hypertension were surveyed in a primate model of acute stroke during and following a 48-hour period of intensive care. The results were
compared to a group of nine control animals previously studied.
Hypocapnia ( P a c o 2 = 25 torr) was examined in five animals and did
not appear to alter the expected mortality, degree of neurological
deficit, or frequency of infarction. There was, however, a suggestion
that the size of infarction may be reduced. Hypothermia (29°C) in
five animals had a detrimental effect in that no animals survived
following the intensive care period and all had infarction with massive edema. We speculate that hypothermia caused a sufficient increase in blood viscosity as to compromise collateral flow, thereby accounting for this detrimental effect. Induced hypertension (to 20%
above control levels) was abandoned after three animals because of
severe systemic effects (cardiac failure and pulmonary edema) resulting in death during the period of intensive care.
Introduction
beneficial effects might be only transient or even ultimately
detrimental if the test treatment were continued.
Recognizing the validity of these criticisms, we have
studied Java monkeys after occlusion of a middle cerebral
artery via a transorbital approach which requires no brain
retraction and minimal disruption of the cranial vault.
Thereafter, these animals have been maintained for 48 hours
in a laboratory-created intensive care environment during
which time the test therapeutic intervention is introduced
and maintained and following which the effects are examined. Using this preparation, we previously studied the
effects of 48 hours of barbiturate anesthesia and demonstrated a significant beneficial effect in terms of mortality,
neurological deficit, and frequency and size of infarction.2
The present report details our observations in a survey of
three other proposed therapeutic interventions: hypocapnia,
hypothermia, and hypertension.
A VARIETY OF MEASURES has been proposed as
possibly being therapeutic in the management of acute
stroke.1 Recommendations have been variously based upon
laboratory investigations, theoretic considerations, and/or
clinical impression. Laboratory investigations which
attempt to document the effect of such measures in acute
stroke can often be criticized for any one of several reasons.
Studies of acute stroke in non-primates are vulnerable to
criticism since the observations are made in animals with a
collateral circulation that differs markedly from that of
man. The method of creating an ischemic lesion might invalidate any results if the surgical exposure requires brain
retraction, possible brain trauma, significant disruption of
the cranial vault, or insertion of a foreign body. Finally,
studies which examine only the acute effects of a proposed
therapeutic measure may be misleading, since any observed
•Professor of Anesthesiology, Mayo Medical School, Mayo Clinic,
Rochester, Minnesota 55901. fResearch Assistant, Department of
Anesthesiology, Mayo Clinic, Rochester, Minnesota 55901.
This investigation was supported in part by Research Grants NS-07507 and
GM-21729 from the National Institutes of Health, Public Health Service.
Methods
Thirteen Java monkeys of both sexes and weighing 1.0 to
1.9 kg were studied. The protocol for the study is summarized in table 1. The monkeys were studied in groups of two
STROKE
VOL 8, No
1, JANUARY-FEBRUARY
1977
TABLE 1 48-Hour Intensive Care Protocol
1. Induced with halo thane, 1.0%; intubated with succinylcholine, 40 mg
2. Transorbital exposure of MCA with operating microscope
3. MCA occluded; halothane discontinued; wound closed
After 30 minutes
i I i
i
5 hypocapnic monkeys
(Paco2 = 25 torr)
5 hypothermic
monkeys (29°C)
I
3 hypertensive
monkeys (20% >
control)
Streptomycin, 100 mg; penicillin, 300,000 units
Pancuronium, 0.05 mg/kg/hr
Diazepam, 0.1 mg/kg/hr
5% dextrose in 0.45% saline, 5.0 ml/kg/hr
Bicillin, 200,000 units (after 24 hours)
Drugs
and
fluids
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Monitors
Arterial blood pressure, continuous
MAP, CVP, HR, temp, urine output recorded, q 30 min
EEG, BCG recorded, q 2 hrs
Blood gases, Hb cone measured, q 4 hrs
Nursing
care
Controlled ventilation with 40% O2, 60% N2 (humidified)
Ventilation adjusted, prn (according to blood gases)
Extremities wrapped; heat lamp, prn
Turned, q 4 hrs
Trachea suctioned, prn
Pancuronium, 0.05 mg, prn (block monitor)
|
After 48 hours
1.
2.
3.
4.
Drugs, fluids, monitors discontinued
Extubated after return of spontaneous ventilation
Returned to cage after arousal; observed five days
Killed; brain removed, fixed, and sectioned
or three and were ultimately divided into three final groups
as determined by the test treatment. In all monkeys, anesthesia for the surgical preparation was induced and maintained with halothane (1%). Endotracheal intubation was accomplished following muscle paralysis with succinylcholine
(40 mg). Ventilation was controlled with a small Harvard
pump. A femoral artery and vein were exposed and cannulated for pressure measurements, blood samples, and drug
and fluid administration. A urinary catheter and rectal thermistor were inserted and secured. The right middle cerebral
artery (MCA) was exposed via a transorbital approach using
the operating microscope. A miniaturized Mayfield clip was
placed across the MCA just distal to the first anterior
branch which supplies an anterior-inferior portion of the
frontal lobe. The body of the clip remained extradural.
Thereafter, halothane was discontinued and the animals
were paralyzed with pancuronium (0.05 mg per kilogram),
and sedated with diazepam (0.1 mg per kilogram) intravenously. The dural incision was sealed with Surgicel and
glue (alpha cyanoacrylate) and the wound was closed. Streptomycin (100 mg) and penicillin (300,000 units) were administered intramuscularly. With completion of surgery, a
48-hour period of intensive care was initiated with fluids,
drugs, monitors, and nursing care as indicated in table 1.
The monkeys were continuously attended by two technicians under the supervision of a physician.
The test treatment was initiated 30 minutes after the
MCA had been occluded. Five monkeys were maintained
hypocapnic (Paco 2 = 25 torr), five hypothermic (29°C), and
three hypertensive (20% above control levels) for the 48-hour
period of intensive care or until death. In all other respects,
the 13 monkeys were managed identically (table 1). Hypocapnia (five animals) was rapidly achieved (within five
minutes) by an increase in both tidal volume and respiratory rate. Hypothermia (five animals) was induced and
maintained with surface cooling techniques (ice bags, alcohol sponging) and the target temperature of 29°C was
achieved within 15 to 25 minutes of initiating cooling. These
animals were ventilated in a manner to maintain Paco 2 at 35
to 40 torr as measured at 37°C (thus, corrected Paco 2 values
were all below 30 torr). Shivering was rigorously prevented
by additional doses of pancuronium as needed. Hypertension (three animals) was rapidly achieved (< five minutes)
initially with an infusion of phenylephrine (0.05%) delivered
by a Harvard pump. When resistance to phenylephrine
developed, levarterenol (0.05%) was next infused. This was
followed by angiotensin (0.05%) and finally adrenalin
(0.02%).
In the surviving monkeys, all drugs, fluids, and test treatments were discontinued after 48 hours. If spontaneous ventilation was judged adequate, the endotracheal tube was
removed, all catheters were removed, and monitoring was
discontinued. These monkeys were returned to their cage for
observation. If spontaneous ventilation remained inadequate (despite total reversal of muscle relaxants), the
monkeys were allowed to die (usually within two to three
hours of discontinued intensive care measures). The remaining monkeys were observed for five days (or until death) and
neurological deficits were graded daily by two independent
observers. After five days (seven days following MCA occlu-
MANAGEMENT OF ACUTE STROKE IN PRIMATES/M/c/fe*/e/rfer et al.
89
TABLE 2 48-Hour Values in Four Monkey Groups (Mean =*= SE)
No.
Group
Control
Hypocapnia
Hypothermia
Hypertension
monkeys
9
5
5
3
MAP
CVP
HR
(mm Hg) (mm Hg) (beats/min)
98
4
102
7
91
3
—
2
0
2
0
2
0
3
0
196
9
216
15
128
4
186
11
Downloaded from http://stroke.ahajournals.org/ by guest on June 18, 2017
sion), the monkeys were killed, the brains were removed,
fixed in formalin, identified by code number, and stored. In
monkeys that died prior to the end of the seven-day period,
the brains were similarly removed and stored. After all 13
monkeys had been studied, the brains were individually examined in sequence without knowledge of code identification. The size of each cerebral hemisphere was measured
by volume displacement before sectioning into 5-mm coronal slices. The end area of infarction in each slice was measured with a grid, and the total size of infarction was computed and then expressed as a percent of that hemisphere's
volume.
The mortality, frequency, and degree of neurological
deficit and frequency and magnitude of infarction were then
compared in each of the three treatment groups to a control
group of nine monkeys (previously reported).2
Results
The monitored variables among the three groups were
comparable and similar to control animals during the 48hour period of intensive care (table 2). Differences between
Temp
(°C)
37.1
Hb
(g/dl)
Pacoj
Paos
(mm Hg) (mm Hg)
10.9
160
0.0
0.7
5
37.1
10.8
0.1
0.5
29.4
10.0
0.1
1.0
9.7
1.5
151
12
116
2
103
10
36.9
0.0
35
1
23
1
24
1
36
1
pH
BB+
(mEq/L)
7.55
0.01
7.61
0.00
7.55
0.01
7.48
0.02
53
1
53
1
49
1
52
1
the groups were those accounted for by the different test
treatments. Thus, in the hypothermic animals, body
temperature, heart rate, and Paco 2 values (corrected for
temperature) all differed significantly from the previously
reported control group. In the hypocapnic animals, only
Paco 2 differed significantly. In the hypertensive group,
MAP was not tabulated because of the large variability that
occurred in these three animals (see fig. 1).
Comparing mortality, neurological deficit, and infarction
to control animals (tables 3 and 4) reveals little or no
therapeutic merit for any of the test treatments. Results in
the hypocapnic animals suggest a similar mortality rate,
degree of neurological deficit, and frequency of infarction as
seen in control animals. In two of these animals, gross infarction was not found, but edema, softening, and shift of
midline structures was found in each. Each of these had a
mild neurological deficit. In the remaining three, the infarcts
were small despite moderate to marked neurological deficits.
Compared to control animals there is a suggestion that the
size of infarction may be reduced by hypocapnia.
Hypothermia and hypertension were clearly detrimental.
None of the hypothermic animals survived more than three
hours following the 48 hours of intensive care (one died at 39
hours) and all had cerebral infarction with massive edema.
None of the hypertensive animals survived even the period of
intensive care with death occurring at 15, 22, and 39 hours,
respectively. Two of these animals had definite cerebral infarctions and the third had cerebral edema only. Death in
the hypertensive animals resulted from pulmonary complications secondary to congestive failure. At necropsy, all
showed massive atelectasis, pulmonary hemorrhagic edema,
and pericardial effusions. In each case, these animals had
progressive resistance to the vasopressor used. With initiation of a different vasopressor, a brief pressor effect was
usually observed (fig. 1) but was evanescent with ultimate
uncontrolled hypotension and death. In none of the animals
TABLE 3 Five-Day Survival, Neurological Deficit, and Size of
Infarction Following 48 Hours' Intensive Care in Control
Monkeys
FIGURE 1. Blood pressure record of one monkey (jf3) in the hypertensive group. An initial infusion of phenylephrine resulted in the
desired 20% increase in mean arterial pressure. This was maintained (with an increase in infusion rate) for about six hours. Thereafter, levarterenol had no pressor effect, while a brief response to
angiolensin was observed. Terminally (after 12 hours), adrenalin
was without particular effect and a repeat infusion of phenylephrine
was only briefly effective.
No.
Survived
1
2
3
4
5
6
7
8
9
Yes
No
Yes
No
Yes
Yes
No
Yes
Yes
Neurological deficit
0
-4
-2-3
-4
0-1
-2-3
-A
-1-2
-3
% Infarct
0
24
<1
100
0
2
4
18
20
90
STROKE
VOL 8, No 1, JANUARY-FEBRUARY
1977
TABLE 4 Five-Day Survival, Neurological Deficit and Size of Infarction in Monkeys Following 48 Hours of
Intensive Care
No. Survived
1
2
3
4
5
No
Yes
Yes
Yes
Yes
Hypocapnia
Neurological
%
deficit
Infarction
-4
-1
-1
-2-3
-1-2
1
?
?
<1
3
Hypothermia
Neurological
%
Infarction
deficit
No. SurvivedI
No
-4
No (39 hrs) - 4
-4
No
-4
No
-4
5 No
1
2
3
4
was a pressure greater than 20% above control mean arterial
pressure produced at any time.
Discussion
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Using a similar protocol in this same stroke model we had
previously demonstrated a beneficial effect of prolonged barbiturate anesthesia.2 In that study nine control monkeys
(table 3) were compared to nine pentobarbital-anesthetized
monkeys and the observed differences in mortality, neurological deficit, and infarction approached or exceeded
statistical significance (p < 0.06). It is unlikely that significant differences would have been demonstrable had fewer
animals been studied. In the present study, because of both
the expense and the scarcity of primates for laboratory investigation, we elected to survey other possible therapeutic
interventions which have been suggested (or clinically used)
in the treatment of acute stroke. The hope was to be able to
identify with only a relatively few animals the suggestion of
either a beneficial or detrimental effect. Any strong suggestion of a beneficial effect would have warranted an expanded
study. There was no such suggestion.
Hypocapnia
In 1968, Soloway et al.3 reported an apparent beneficial
effect of hypocapnia in acute strokes in dogs. In that study
cerebral infarction as produced by MCA occlusion was
significantly lessened if the animals were maintained hypocapnic for several hours at the time of MCA occlusion.
Several mechanisms have since been postulated whereby
hypocapnia might be beneficial.4 These include increased
flow to the ischemic brain (inverse steal effect), decreased
flow to the normal brain and, hence, a decrease in intracranial pressure, partial titration of the cerebral lactic
acidosis by the blood alkalosis, and a possible increased
resistance of cerebral tissue to hypoxia due to hypocapnia
per se. The results reported by Soloway et al. have not been
consistently confirmed by other investigators working with
different animal models of acute stroke.6"7 In common, however, these studies all examined the effects of hypocapnia for
a period of a few hours only. In 1973, Christensen et al.4
reported the failure of hypocapnia in a clinical study wherein acute stroke patients were maintained hypocapnic for
three days. As with any such clinical study, homogeneity of
control and experimental groups was lacking and on that
basis, the results may be questioned. In the present primate
study, homogeneity existed to the degree that it is experimentally possible. A 48-hour period of hypocapnia did
not appear to favorably alter the ischemic consequences of
MCA occlusion. Certainly in terms of mortality and neurological deficit, no benefit is apparent. There is a suggestion
6
3
2
1
No.
Hypertension
Neurological
%
Infarction
deficit
Survived
1 No (22 hrs)
2 No (39 hrs)
3 No (15 hrs)
-4
-4
-4
5
?
3
5
that the size of infarction may be reduced by hypocapnia in
that none of these animals had an infarct larger than 3%
while four of nine control animals had large infarctions. To
determine whether or not this suggested difference is a real
one would likely require many more animals in both control
and experimental groups. We elected not to pursue this
question further.
Hypothermia
The consistent detrimental effect of hypothermia was unexpected. In the absence of life-support measures, all of
these animals died; all had massive cerebral edema with underlying infarction. Since none of these animals survived
more than 51 hours, comparison of the percent infarction to
that in control animals which survived seven days is
probably misleading. Had the hypothermic animals survived the full seven days, the measured infarcts would likely
have been larger.
An explanation for the detrimental effect of hypothermia
is not immediately apparent. These animals were hemodynamically stable during the period of intensive care and
ventilation was well maintained. Acid-base balance was essentially normal and the low Paco 2 (24 torr) that we maintained was assumed to be appropriate for a body
temperature of 29°C. 8 At this temperature cerebral
metabolic rate (as well as whole body) should be reduced approximately 50%.9 Assuming no other effects, such a reduction in O2 requirements should have protected, at least partially, the ischemic brain.
The potential cerebral protective effect of hypothermia is
well established. Total cerebral ischemia or anoxia is
tolerated for increasing periods as temperature is lowered.
The relationship of O2 consumption to temperature is
probably an exponential one,9 such that for every 8° to 10°C
reduction in temperature O 2 consumption is halved and
tolerance to a period of anoxia is doubled. Thus, in a circumstance of temporary complete cerebral ischemia protection by hypothermia is unquestioned.
In the circumstance of prolonged incomplete focal
ischemia, a protective effect of hypothermia is often
assumed and has been reported in one canine study.10 However, differences between canine and primate collateral circulations may be sufficient to account for a different effect.
In the squirrel monkey following MCA occlusion, the
collateral flow is initially about 40% of the pre-occlusion
flow and is maintained for at least two hours." In the
absence of therapeutic intervention, infarction occurs some
time after two hours, presumably secondary to progressive
edema and failure of the collateral circulation. Reasonably,
if the O2 requirements of the ischemic brain could be
significantly reduced so as to match the reduced oxygen
MANAGEMENT OF ACUTE STROKE IN PRIMATES/Michenfelder et al.
delivery by way of the collaterals, infarction should be
preventable. On this basis, one would predict that a reduction in brain temperature to 29°C would prevent infarction
as long as collateral flow was maintained. Since an opposite
effect was observed, we conclude that collateral circulation
failed, at least in part, because of hypothermia itself. We
speculate that this might be accounted for by the increase in
blood viscosity that accompanies a temperature reduction
with a consequent reduced flow through the small collateral
vessels. If this is correct, then hypothermia might only be
protective if combined with hemodilution so as to maintain
or even reduce the normal blood viscosity.
Hypertension
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This protocol was abandoned after only three animals
because of the disastrous systemic consequences of artificially maintained hypertension in this species. Whether
such an effect might be expected in other primates is unknown. We selected an alpha agonist (phenylephrine) as our
initial vasopressor on the assumption that this would have
the least deleterious cardiac effects. This was effective for a
period of 6 to 20 hours but "resistance" was eventually encountered and thereafter a variety of vasoactive drugs
(levarterenol, angiotensin, and adrenalin) were only briefly
effective. Based upon the findings at necropsy, we suspect
that the development of "resistance" in fact signaled the
onset of cardiac failure presumably due to the prolonged
period of an artificially induced increase in peripheral
resistance and, hence, in the afterload on the heart. Whether
the same ultimate effect would have been seen had we initially used a mixed vasopressor, i.e., an alpha and beta
agonist, is unknown.
The theoretical merit of chronic induced hypertension in
incomplete focal ischemia is based upon the assumption that
flow in ischemic regions is pressure-dependent. Experimentally, this is demonstrable on an acute basis12 and clinically
transient periods of hypertension are commonly induced
during such procedures as carotid endarterectomy. To our
knowledge, chronic induced hypertension has not been
studied experimentally and reports of clinical efficacy are
anecdotal only.13
The results in the three animals of this study do not permit
any meaningful conclusions. Any possible beneficial cerebral effects were overwhelmed by the deleterious systemic
91
effects. That such might be expected to occur in man is not
suggested by clinical experience with prolonged vasopressor
therapy. However, for the most part, such therapy has been
used for the maintenance of normal blood pressure rather
than the production of chronic hypertension. It is reasonable
to expect the latter may introduce undesirable systemic
effects.
Conclusions
The results of this survey offer no support for the use of
prolonged hypocapnia, hypothermia, or hypertension in the
management of acute stroke. Whereas hypocapnia appeared
to have little or no beneficial effect, both hypothermia and
hypertension had detrimental effects. Among other
suggested therapeutic interventions, only barbiturate
anesthesia has been consistently demonstrated to favorably
alter the ischemic consequences of middle cerebral artery
occlusion in experimental animals.
References
1. Paulson OB: Cerebral apoplexy (stroke): Pathogenesis, pathophysiology
and therapy as illustrated by regional blood flow measurements in the
brain. Stroke 2: 327-360, 1971
2. Michenfelder JD, Milde JH, Sundt TM Jr: Cerebral protection by barbiturate anesthesia. Arch Neurol 33: 345-350 (May) 1976
3. Soloway M, Nadel W, Albin MS, et al: The effect of hyperventilation on
subsequent cerebral infarction. Anesthesiology 29: 975-980, 1968
4. Christensen MS, Paulson OB, Olesen J, et al: Cerebral apoplexy (stroke)
treated with or without prolonged artificial hyperventilation: 1. Cerebral
circulation, clinical course, and cause of death. Stroke 4: 568-619, 1973
5. Soloway M, Moriarty G, Fraser JG, et al: Effects of delayed hyperventilation on experimental cerebral infarction. Neurology (Minneap) 21:
479-485, 1971
6. Yamaguchi T, Regli F, Waltz AG: Effect of Paco 2 on hyperemia and
ischemia in experimental cerebral infarction. Stroke 2: 139-147, 1971
7. Michenfelder JD, Sundt TM Jr: The effect of Paco 2 on the metabolism of
ischemic brain in squirrel monkeys. Anesthesiology 38: 445-453, 1973
8. Rahn H: Body temperature and acid-base regulation. Pneumonologie
151: 87-94, 1974
9. Michenfelder JD, Theye RA: Hypothermia: Effect on canine brain and
whole-body metabolism. Anesthesiology 29: 1107-1112, 1968
10. Rosomoff HL: Hypothermia and cerebral vascular lesions. II. Experimental interruption followed by induction of hypothermia. Arch
Neurol Psychiat 78: 454-464, 1957
11. Sundt TM Jr, Waltz AG: Cerebral ischemia and reactive hyperemia:
Studies of cortical blood flow and microcirculation before, during, and
after temporary occlusion of middle cerebral artery of squirrel monkeys.
Circulation Research 28: 426-433, 1971
12. Denny-Brown D, Meyer JS: The cerebral collateral circulation. 2.
Production of cerebral infarction by ischemic anoxia and its reversibility
in early stages. Neurology (Minneap) 7: 567-579, 1957
13. Farhat SM, Schneider RC: Observations on the effect of systemic blood
pressure on intracranial circulation in patients with cerebrovascular insufficiency. J Neurosurg 27: 441-445, 1967
Failure of prolonged hypocapnia, hypothermia, or hypertension to favorably alter acute
stroke in primates.
J D Michenfelder and J H Milde
Stroke. 1977;8:87-91
doi: 10.1161/01.STR.8.1.87
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