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Global Brain Ischemia: A Reproducible Monkey Model
EDWIN M. NEMOTO, PH.D., ACHIEL L. BLEYAERT,
S. W. STEZOSKI, JOHN MOOSSY, M.D.,
AND PETER SAFAR,
M.D.,
GUTTI R. RAO,
M.D.,
M.D.
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SUMMARY We developed a monkey model of 16 minutes global
brain ischemia (GBI) resulting in reproducible, severe, permanent
functional neurologic deficit with long term (7 days) postischemic
(PI) survival made possible by standardized intensive care with 24
hour coverage by trained personnel. Quantitated neurologic deficit
(ND) and brain histopathological examinations were developed. Fifteen minutes GBI resulted in rapid recovery within 12-24 hours PI
without residual neurologic sequelae. Twenty minutes GBI caused
severe neurologic deficit and within 4 days PI, a delayed Cushing
response eventually leading to cardiac arrest. Sixteen minutes GBI
resulted in severe neurologic deficit (monkeys unable to sit, stand,
walk, or feed themselves), but with long term survival. Brain histopathological analyses revealed a combination of cortical and brainstem
lesions. Severest changes were observed in the occipital (calcarine)
cortex with less severe damage in the frontal and temporal regions.
Oculomotor nuclei and medial longitudinal fasciculus in the midbrain
were regularly affected. With this model we can test the efficacy of
promising therapies in terms of clinically relevant variables.
UNDERSTANDING the pathogenesis of postischemic
(PI) encephalopathy and its amelioration by promising
therapies has been hampered by the variability in degree of
neurologic recovery1 and brain histopathology2 after
seemingly comparable durations of global brain ischemia
(GBI). Earlier studies suggested that 6 minutes GBI caused
severe permanent brain damage*'4 but recent studies indicate that the brain is capable of functional recovery after
201 and 60 minutes6 of GBI. Data of past studies are difficult
to interpret because recovery was evaluated in terms of acute
physiological, biochemical or neuropathological changes not
necessarily related to functional neurologic recovery6' *•7
and the methods for arresting brain circulation were highly
invasive and probably contributed to PI morbidity and mortality.1
Using a simple, and noninvasive method for GBI in the
rhesus monkey we determined the duration of ischemia
resulting in severe ND with long-term PI survival. Our
earlier observations in dogs8- • and those of Myers, et al.1-10
in monkeys provided an estimate of the "threshold" of
ischemic brain damage of 15 minutes. Sixteen minutes GBI
resulted in severe neurologic deficit with survival, 15 minutes
in complete recovery and 20 minutes in death within 7 days
PI.
and 5% dextrose/0.45 NaCl infused IV at 3-5 ml/kg/hr.
Femoral artery and vein catheters were inserted for monitoring of mean arterial pressure (MAP), blood sampling and
drug infusion. Frontal, parietal and occipital bipolar EEG
was monitored via stainless steel screw electrodes. A subdural supracortical catheter was inserted for intracranial
pressure (ICP) monitoring.
Methods
Anesthesia and Surgical Preparations
Prequarantined female rhesus monkeys 4 to 5 kg body
weight (Primate Imports, Inc.) were fasted overnight with
water ad libitum. Anesthesia was induced with 4% halothane
(Fluothane, Ayerst, Inc.)/O2 followed by intubation and IM
injection of 0.4 mg atropine and .06 mg/kg pancuronium
bromide and mechanical ventilation (Harvard Apparatus,
Inc.) on 1% halothane/33% O2/66% N2O plus CO2 to maintain end-tidal CO2 (continuously monitored by an LB-1
Beckman infrared analyzer) at about 5-6%. ECG, rectal
temperature, and urine output were continuously monitored
From University of Pittsburgh School of Medicine, Departments of
Anesthesiology/Critical Care Medicine Program and Pathology, Pittsburgh,
PA 15261.
Supported in part by the Medical Research Service of the Veterans Administration Hospital, Pittsburgh, PA, The Addison Gibson Foundation, A.
Laerdal, and NIH Grant No. NS10974.
Ischemia
A pediatric tourniquet (Zimmer Warsaw, Inc.) wrapped
around the neck and inflated to 30 psi and trimethaphan
camsylate (Arfonad, Roche Laboratories) induced hypotension (MAP about 50 torr) were used to arrest brain circulation with blood pressure control throughout the ischemic
episode. The effectiveness of this method in completely
arresting brain circulation has been tested by brain scan with
mm
Tc and lack of brain 133Xe clearance after intra-arterial
injection. An isoelectric EEG (50 jtV/cm) within 15 seconds
after the start of ischemia verified complete ischemia in each
study.
Postischemia
The monkey was continuously ventilated on 100% O2 for
up to 6 hours and thereafter on 40% O2/N2 then weaned
from the ventilator when: (a) level of consciousness — normal or stuporous; (b) vigorous response to carinal stimulation; (c) vigorous gag reflex; and (d) arterial PO2 of 350 torr
or greater on 100% O2 and PaCO2 less than 40 torr. Five cm
H2O PEEP was applied continuously while intubated and on
spontaneous ventilation.
Fluid and electrolyte balance were maintained by IV infusion of 5% dextrose/0.45% NaCl (3-5 cc/kg/hr) for up to 24
hours PI, then switched to 10% dextrose/0.24% NaCl and
nasogastric feeding of a prepared diet containing 1
calorie/ml (Sustacal, Meade Johnson). A total of about 250
calories/day was administered in the form of Sustacal and
10% dextrose/0.24% NaCl. IVfluidcomposition was altered
according to serum electrolytes and osmolality.
The following pharmacologic interventions were used in
the intensive care of the monkeys: (a) diphenylhydantoin
(Dilantin, Parke Davis) 10 mg IM and phenobarbital
(Elkins-Sinn, Inc.) 5 mg/kg, as needed for nausea; (b)
trimethaphan camsylate for MAP > 125 torr; (c)
GLOBAL BRAIN ISCHEMIA MONKEY MODEL/Nemoto et al.
TABLE 1 Neurologic Deficit Scoring Sheet (Maximum Deficit
= 500 Points)
I.
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LEVEL OF CONSCIOUSNESS
normal 0, clouded or delirious 30,
stupor 60, coma 100
COMMENTS:
II. CRANIAL NERVES
pupil size - normal 0, mod
R*
abnormal 2, severely abnormal 5
L
light reflex - normal 0
R
sluggish 2, absent 5
L
eyes, resting pos. - normal 0,
R
mod. abnormal 2, severely abnormal 5
L
eyelash reflex - normal 0, sluggish 2,
R
absent 5
L
corneal reflex - normal 0,
R
sluggish 2, absent 5
L
dliospinal reflex - normal 0
R
sluggish 2, absent 5
L
oculocephalic reflex - normal 0,
R
sluggish 2, absent 5
L
auditory response - normal 0,
L
sluggish 5, absent 10
gag reflex - normal 0,
sluggish 5, absent 10
carinal cough reflex - normal 0,
sluggish 5, absent 10
COMMENTS:
III. MOTOR FUNCTION
A. Absent grasping or pathologic grasp reflex 25
B. Response to toe pinch
Quick appropriate response in all limbs
0
Sluggish appropriate response in all limbs
5
Inappropriate response in 1 or more limbs 10
C. Limb position in resting stale
Normal 0, Mod. abnormal
10
25
Severely abnormal
D. Obvious paralysis or spaslicity
25
E. Behavioral—Motor Function
1. cannot chew
15
2. cannot feed himself
15
3. cannot sit
15
4. cannot stand
15
5. cannot walk
15
6. walks with ataxia
15
7. does not clean himself
10
COMMENTS:
IV. RESPIRATION
normal
0
abnormal
50
on ventilator
100
COMMENTS:
*R = Right, L = Left.
furosemide, 1 mg/kg for oliguria; (d) lidocaine (Xylocaine,
Astra Pharmaceuticals) in 10 mg boluses in 1% solution for
cardiac irregularities; (e) regular insulin (Squibb) and 50%
dextrose-water (Travenol) at 2 units insulin/5 cc 50% dextrose in water for hyperkalemia unresponsive to furosemide
therapy; (f) peritoneal dialysis with potassium-free Dianeal
(Travenol) for hyperkalemia during oliguria unresponsive to
insulin/dextrose and furosemide therapy.
Nursing and body care included: (a) bedding change once
every 24 hours; (b) alcohol bath and rubdown once per day;
(c) saline cleansing of mouth and eyes once per day; and (d)
rotation from left to right lateral position once every two
hours.
EEG recordings and neurologic deficit (ND) scores (table
1) were obtained every 2 hours in the first 24 hours then
every 6 hours. The quantitated ND examination permitted
quantitation of ND from coma with apnea (100%) to normal
(0%). Record sheets for monitoring physiologic variables,
blood and urine composition and fluid balance were maintained.
Brain Histopathology
At 7 days PI during pentobarbital (Nembutal, Abbott
Laboratories) anesthesia (30 mg/kg body weight), the brain
was perfused with 500 cc's 4% paraformaldehyde followed
by 500 cc's 3% glutaraldehyde via the left ventricle. Two
hours later the brain and cervical spinal cord (C4) were
carefully removed and placed into 4% buffered paraformaldehyde solution for 2 weeks prior to gross and microscopic histological analysis after staining with hematoxylin
and eosin, and in some cases Nissl and Bielschowsky silver
stains. All sections were read and graded (JM and GR) according to the type and severity of histopathology and cytopathology (table 2). Three types of lesions were graded: (1)
single or multifocal infarction; (2) neuronal necrosis; and (3)
edema. The severity of these lesions was assessed on a 4point scale: minimal, 1 + ; moderate 2+; severe 3+ and maximal 4 + . The points indicating the severity of each type of
lesion were then multiplied by a weighting factor depending
upon the type of lesion (infarction 4 X, neuronal necrosis 2 X,
and edema IX) for each region of the brain examined. A
maximum score of 52 points was obtained if all three types
of lesion occurred with maximal severity. Total neuropathological scores were obtained with a maximum possible
score of 1,040 for all 20 brain areas.
Results
Of 4 monkeys subjected to 15 minutes GBI, 2 rapidly
recovered and apparently suffered no neurologic sequelae
and 2 died at 2 days PI with pulmonary edema (table 3).
MAP was not sufficiently controlled PI in monkey number
22. Barring complications in providing intensive care, 15
minutes GBI did not result in detectable ND by 7 days PI.
TABLE 2 Brain Histopathohgic Weighted Scoring System
0 = None, + - M inimal, + + - Moderate, + + + = Severe, + + + +
Weighting factor
Pathology
Brain region
Frontal cortex (F)
Parietal cortex (P)
Occipital cortex (0)
Temporal cortex (T)
Insular cortex (I)
•Total possible points = 52.
NA = Not Applicable, NE = Not Examined
X4
X2
Infarction
Ischemic neuronal changes
L
R
L
R
+ -1+ -h
+0-h
Hh
++
++
++
0
+
559
++
+++
+++
+
++
++
+++
+++
++
++
= Maximal
XI
Edema
4- +
-(-(-)+
Total pte*
26
29
29
7
17
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TABLE 3 15 Min. Global Brain Ischemia in Monkeys
Monkey no.
17
18
22
24
PI
sure.
Duration
survival
Outcome
> 7 days Rapid recovery, 9 hr PI fully awake,
placed back in cage, no apparent
neurologic sequela
49 hours 8 min rales; FIO2 = 1.0, PaO2 = 62
mm Hg, pulmonary edema, 60-80
MAP followed by cardiac arrest
48 hours No BP support, 30' PI MAP = 50
torr, hypertension during ischemia,
pulmonary edema
> 7 days 6 hours PI sitting up unsteadily 13
hours PI, ataxia, full recovery, no
apparent neurologic sequela
postUchemia, BP = blood pressure, MAP — mean arterial pres-
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Of 7 monkeys subjected to 20 minutes GBI, ischemia was
complete in 5 and incomplete in 2 as judged by EEG silence
within 15 seconds (table 4). Of the two subjected to incomplete ischemia, one survived until sacrifice at 4 days PI
with a final ND score of approximately 31%, the others survived for 60 hours PI but died after pulmonary edema. The 5
monkeys with complete ischemia for 20 minutes did not survive beyond 4 days PI. The typical sequence of events
observed after 20 minutes of GBI was a secondary rise in
ICP paralleled by a gradual rise in MAP followed by
protracted arterial hypotension unresponsive to vasopressors, secondarily isoelectric EEG, and finally cardiac
arrest. In 2 monkeys (numbers 27 and 2A) where ICP recordings were unreliable, the monkeys were hypotensive or
hypoxic prior to cardiac arrest; both of these patterns could
have resulted from a secondary increase in ICP. Twenty
minutes GBI appears to be the "upper limit" of the desirable
duration of ischemia since the monkeys invariably died
before 7 days PI with severe brain edema.
Of 19 monkeys subjected to 16 minutes GBI, 9 died before
7 days (13 to 128 hours PI) from complications in PI intensive care. In 4/9 monkeys, oliguria, hyperkalemia, and
hypotension led to cardiac arrest; 3/9 died because of intensive care "accidents" (primarily of respiratory care); 1/9
had incomplete ischemia and 1/9 died in protracted
hypotension at 24 hours PI.
Ten of the nineteen monkeys survived until sacrifice at 7
days PI with severe ND. Mean ND immediately PI was
100% (i.e., 500 points maximal deficit) and from 70% at 6
hours PI, it decreased rapidly to 50% by 24 hours PI then
remained at 50% thereafter (fig. 1). In 19 experiments EEG
TABLE 4
VOL 8, No
5, SEPTEMBER-OCTOBER
recovery time was 66 ± 39 minutes (mean ± SD) with a
range of 30 to 156 minutes. Examination of components of
ND (fig. 2) revealed severest deficits in motor function, while
cranial nerve deficit and respiration recovered rapidly
between 12 and 24 hours PI. Level of consciousness improved rapidly between 0 and 6 hours PI and was essentially
unchanged thereafter.
Respiratory variables reflected mechanical ventilation at
0 and 5 minutes PI, and at 6 hours PI, spontaneous hyperventilation (50 breaths/min) with hypocarbia. Mean Pao 2
was maintained well above 100 torr throughout.
Postischemic arterial pH was normal immediately after cuff
deflation (0 hours PI), then indicated respiratory alkalosis at
150 hours PI.
Cerebral perfusion pressure (CPP) was 53 torr at time of
cuff deflation but was subsequently maintained at about 100
torr. ICP was 8 torr preischemia, 11 torr immediately after
cuff deflation and then fluctuated within normal limits (7-16
torr), throughout the 7 days PI. Serum electrolytes were
maintained within normal limits throughout.
Histopathological analysis of 6 brains at 7 days PI
revealed a pattern of cortical and brain stem lesions (figs. 3
and 4) with severest damage in the occipital (calcarine) cortex, brainstem and especially midbrain. The lesions in hippocampus and cerebellum were mostly neuronal necrosis but
small infarcts were also present in hippocampus (1 of 6
brains) and cerebellum (1 of 6 brains). There was regional
variation in the distribution and severity of damage (fig. 5).
Neocortex was regularly damaged more severely than limbic
cortex. The parietal and the occipital cortex, especially the
calcarine area, showed the most consistent and severe
lesions. Infarction and neuronal necrosis, though frequently
present, were less severe in frontal and temporal cortex.
There was no consistent distribution of brain damage along
arterial border zones but rather the maximum damage
appeared to be in the most distal distribution of the posterior
cerebral artery. Damage to tissues in the distribution of the
anterior cerebral artery followed in severity that of the
posterior cerebral artery. The smallest number of lesions
were in the distribution of the middle cerebral artery. The
corpus striatum and thalamus contained fewer lesions than
the neocortex or midbrain. A regular site of damage (6 of 6
monkeys), in the form of circumscribed infarcts with occasional microglial proliferation and early phagocyte formation, was the oculomotor nuclei and medial longitudinal
fasciculus. Occasional infarcts were also seen in the substantia nigra in the midbrain and in the tegmentum of the pons
and medulla.
Twenty Minutes Global Brain Ischemia
Monkey no.
Duration survival
Final neurologic deficit*
25
26
> 7 days
60 hours
27
28
30 hours
24 hours
Nonisoelectric EEG
31
62
Isoelectric EEG < 16 sees
59
82
29
1A
2A
20 hours
90 hours
72 hours
90
96
100
•Maximum neurologic deficit = 100%.
1977
Cause of cardiac arrest
sacrificed
pulmonary edema
hypotension
increased ICP, hypotension
arrest
increased ICP, hypotension
increased ICP, hypotension
hypoxia
GLOBAL BRAIN ISCHEMIA MONKEY MODEL/Nemoto et al.
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MAXIMUM
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DEFICIT
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40
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20
10
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20°
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60°
80°
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HOURS
100"
120"
140°
160°
POSTISCHEMIA
FIGURE 1. Changes (in percent) in neurologic deficit score (maximum deficit = 100%) for seven days
postischemia after 16 minutes of global brain ischemia in 10 rhesus monkeys.
Discussion
Our results suggest that the ischemic "threshold" of the
brain in the rhesus monkey, is about 15 minutes. Rapid
neurologic recovery was observed after 15 minutes GBI
whereas 16 minutes GBI produced severe ND until sacrifice
at 7 days PI. These results support the findings of earlier
reports1'10> " of 14 to 15 minute "thresholds" for severe permanent brain damage after GBI without systemic circulatory arrest in rhesus monkeys.
Earlier investigators reported ischemic "thresholds" of 63,
12
8 , 11' and 813 minutes. The importance of maintaining normal PI cerebral perfusion pressures was probably not appreciated in these studies, and the limiting factor in determining the ischemic threshold or tolerance of the brain
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appeared to be the ability to provide adequate life support.
As life support techniques improved the "threshold" of
severe brain injury increased. Cantu and Ames14 reported
complete recovery without ND after 14 minutes GBI in
dogs, emphasizing the importance of maintaining adequate
cerebral perfusion pressure PI.
After 16 minutes GBI in 10 of 19 monkeys studied,
criteria of complete ischemia were obtained with survival
until sacrifice at 7 days PI. These 10 monkeys had a mean
total ND score of 50% between 24 hours and 7 days PI. Unsuccessful studies with renal "shutdown" may have been
related to excessive amounts of norepinephrine required to
maintain normal MAP or from inappropriate antidiuretic
hormone secretion." Throughout these studies we have
DEFICIT
60"
80°
100°
120°
HOURS POSTISCHEMIA
MOTOR FUNCTION
CRANIAL NERVE
RESPIRATION
CONSCIOUSNESS
140°
FIGURE 2. Changes in components of neurologic deficit examination (maximum deficit = 500 points) for
seven days postischemia after 16 minutes of global brain ischemia in 10 rhesus monkeys. Maximal deficit
points per neurologic component evaluated were: 200 for motor function and 100 points each for cranial
nerve, respiration and level of consciousness.
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FIGURE 3. Topographical distribution of cortical lesions at seven
days postischemia after 16 minutes global brain ischemia in the
rhesus monkey.
learned to appreciate the precarious state of the brain which
can be easily "pushed" to brain death by mild hypoxia or
hypotension as a result of ICU accidents. These include
"bucking" the ventilator; inadequately controlled convulsions; and pulmonary atelectasis or edema resulting from
long term spontaneous ventilation while intubated without
PEEP or sighing. If immobile, it is also important that the
monkeys be regularly rotated from one lateral position to
the other.
Monkeys subjected to 20 minutes GBI developed a
gradual increase in ICP paralleled by an increase in MAP;
secondarily leading to hypotension unresponsive to vasopressors and, eventually, cardiac arrest. The rise in ICP
suggested that after 20 minutes of GBI the volume of
edematous brain tissue had exceeded the capacity of
cerebrospinal fluid to compensate for the increase in brain
tissue H 2 O. The "critical mass" of edematous brain tissue
resulting in a generalized increase in ICP can be roughly
calculated using data on the percent increase in brain tissue
H 2 O in severe brain edema. The increase in brain tissue
volume in edematous brain ranges from 10% to as high as
18%.16- " Lofgren, et al.18 found relatively little change in
ICP with an increase in brain H 2 O of up to 5% but a rapid
and marked rise in ICP (up to 100 torr) if brain H 2 O increased by 10%. These results suggest that the critical mass
of edematous brain tissue should be approximately 25% or
20 g in the 80 g monkey brain or 300 g in the 1200 g human
brain.
On the basis of our results we speculate that the
relationship between duration of GBI and neurologic deficit
VOL
8, N o
5, SEPTEMBER-OCTOBER
1977
FIGURE 4. Distribution of lesions in the cerebral hemisphere in
coronal section (top) and cerebellum and midbrain — brain stem
(bottom) regions in the rhesus monkey at seven days postischemia
after 16 minutes global brain ischemia.
is as shown in figure 6. However, our neurologic examination is heavily biased for gross motor function and although
cranial nerve and sensory tests are conducted, they are by no
means comprehensive. Based on our ND scoring system our
16 minute model is situated at the midpoint of the steep portion of the S-shaped curve. The area between the interrupted
lines delineates ± two standard deviations. Between 10 and
15 minutes GBI there is little change in ND and 0% falls
within one standard deviation of the mean. Assuming that
the relationship between ND and duration of ischemia is
symmetrical on both sides of the midpoint of the steep portion of the curve, after 17 minutes GBI 100% ND is included
within one standard deviation. Beyond 17 minutes, ND increases to 100%. After 19 and 20 minutes of ischemia the
duration of PI survival is expected to decrease.
Our speculation on the relationship between duration of
GBI and total ND score obviously ignores earlier reports
suggesting that the tolerance of the brain to ischemic-anoxic
damage is between 4 to 8 minutes of GBI. Brierley2 concluded that the threshold of ischemic brain damage
histologically, is between 4 to 8 minutes of GBI. In 10
patients who suffered circulatory arrest for 2-15 minutes,
neurologic recovery indicated lower ischemic tolerance of
the human brain compared to monkeys.19 However,
neurologic recovery after total system circulatory arrest (as
in patients) is slower than with arrest of only brain circulation (as in our monkey model).20 In most cases of cardiac
arrest in patients neither the exact duration of ischemia nor
GLOBAL BRAIN ISCHEMIA MONKEY MODEL/Nemoto et al.
^INFARCTION
MAXIMUM POSSIBLE
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8
I
4
0
NC
H
TH
CS
I
BS
V77J
CE
FIGURE 5. Infarction and neuronal necrosis scores in the rhesus monkey brain at seven days postischemia
after 16 minutes global brain ischemia. NC = neocortex, H = hippocampus, TH = thalamus, CS = corpus striatum, BS = brain stem, CE = cerebellum.
the quality of resuscitation and PI intensive care are well
documented.
Experimental models of GBI vary in their simulation of
that found in people under diverse clinical conditions. 2023
The brain lesions in this model have regularly included
lesions in the midbrain, particularly oculomotor nuclei and
adjacent regions as reported in the model described by
Miller and Myers. 1 In our study, other cranial nerves and
brain stem nuclei were less regularly affected. The distribution of cortical lesions in our model was more caudal than
MAXIMUM NEUROLOGIC
DEFICIT
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12 13 14 15 16 17 18 19 2 0 21 2 2 23
DURATION GLOBAL BRAIN ISCHEMIA (MIN)
FIGURE 6. Hypothetical relationship between percent neurologic deficit (maximum deficit = 100%) and
duration of global brain ischemia, based upon our quanlitated neurologic deficit scoring system in monkeys
subjected to global brain ischemia without systemic circulatory arrest. The area between the interrupted
lines represents plus or minus two standard deviations according to the variability observed after 16 minutes
of global brain ischemia with seven days postischemic survival.
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that reported by Miller and Myers with maximum severity
in the medial occipital cortex (calcarine) and parietal lobes.
Major or predominant localization of lesions to the arterial
border zones as described with hypotension in the model of
Brierley, et al.24'25 could not be confirmed in our model but
differences in experimental methodology may be responsible.
In summary, we have developed a reproducible model in
the rhesus monkey of global brain ischemia resulting in
severe permanent brain damage but with survival until
sacrifice at 7 days PI. We have also developed standardized
PI monitoring, intensive care techniques and quantitated
neurologic deficit and brain histopathological scoring
systems. With this model we now have the means to evaluate
definitively the efficacy of a number of therapeutic
procedures which may be of benefit in ameliorating PI brain
damage. It is also useful to investigate pathophysiological
and biochemical mechanisms of postischemic encephalopathy.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
Acknowledgment
17.
Mr. Henry Alexander, Miss Patricia Boyle, Mr. Glenn Levy, Mr. David
Peterson and Mr. Joseph Willy provided able and dedicated technical
assistance. Miss Diane Samber assisted in the preparation of the manuscript.
Ayerst Laboratories, provided a generous supply of halothane.
18.
References
20.
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VOL 8, No 5, SEPTEMBER-OCTOBER
1977
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Stroke. 1977;8:558-564
doi: 10.1161/01.STR.8.5.558
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