Effect of Pa^Oo
on
Hyperemia and
Ischemia in Experimental Cerebra
Infarction
BY TAKENORI YAMAGUCHI, M.D., FRANCO REGLI, M.D.,
AND ARTHUR G. WALTZ, M.D.
Abitract:
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Effect of PaCOi
on Hyperemia
and Ischemia in
Experimental
Cerebral
Infarction
• To assess the effects of Pa^.^ on cerebral ischemia and reactive hyperemia,
the right middle cerebral artery was occluded in 18 cats. Four to six hours later,
PaCOo was adjusted by mechanical ventilation, with or without CO.,, to less than
20 torr in four cats, 31 to 38 torr in six, and 46 to 68 torr in eight. Regional
cerebral blood flow (CBF) then was measured at multiple sites in each
hemisphere by autoradiography. In regions of brain tissue outside the
distribution of the occluded middle cerebral artery, log10 CBF correlated
positively with Paco,,. In ischemic regions, CBF was higher in normocapnic
cats. Reactive hyperemia occurred in two cats of the hypocapnic group, in four
cats of the normocapnic group, but in only one hypercapnic cat (PaCOo = 46
torr). Hyperemia also was found outside potentially ischemic regions in five
cats. Multiple hyperemic foci developed in six cats. Neither hypocapnia nor
hypercapnia was associated with a smaller size or higher CBF of regions of
cerebral ischemia produced by occlusion of a middle cerebral artery, although
hypercapnia inhibited the development of hyperemia.
ADDITIONAL KEY WORDS
carbon-14 antipyrine
• Numerous studies of humans1^4 and animals6"8 have shown that an increase of arterial
carbon dioxide tension (Paco 2 ) causes an
increase of cerebral blood flow (CBF) in
normal brain tissue, and that a decrease of
Pac 0;! causes a decrease of CBF. Studies of the
From the Cerebrovascular Clinical Research Center,
Department of Neurology, Mayo Clinic and Mayo
Foundation, and the Mayo Graduate School of
Medicine (University of Minnesota), Rochester,
Minnesota.
A preliminary report of these data was read at
the International Symposium on Cerebral Blood Flow,
London, September 17 to 19, 1970; an abstract was
published in the Transactions of the Symposium.
This investigation was supported in part by
Research Grant NB-6663 from the National Institutes
of Health, Public Health Service. Dr. Regli is the
recipient of a Medical-Biological Scholar's Stipend
from the Schweizer Akademie der Medizinischen
Wissenschaften.
Stroke, Vol. 2, March-April
7971
arterial occlusion
autoradiography
autoregulation
cerebral blood flow
effects of changes of Paco2 on the vasculature
of ischemic brain tissue, however, have
provided varied results and interpretations.
When ischemia is severe and acute, there
appears to be an impairment or loss of
reactivity of the cerebral vasculature to
changes of Pacoo-8"19 If only a small amount of
brain tissue is ischemic, or if measurements are
made days to weeks after the onset of
ischemia, the impairment of cerebral vascular
reactivity may be less. 8 ' 11 " 18
Hyperemia, or "luxury perfusion,"19 may
develop in or near a region of cerebral
ischemia or infarction.11-15' 20~23 The significance of hyperemia to the process of cerebral
infarction remains obscure. When hyperemia
develops in regions of brain with preexisting
ischemia (reactive hyperemia) 23 or is confined
to the territory normally supplied by an
139
YAMAGUCHI, REGLI, WALTZ
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occluded artery, it may be beneficial if it occurs
early enough and lasts long enough to provide
sufficient oxygen and glucose for preservation
of neuronal function. However, if hyperemia
leads to an increase of cerebral edema or to
hemorrhagic infarction, it may be harmful.
Moreover, if hyperemia develops outside
regions of brain that are ischemic, CBF of
regions already ischemic may decrease further,
a situation analogous to the paradoxical
response of CBF to increases of Pa^,., that
occurs in ischemic brain tissue.8"10' 12~14
The present study was designed to
investigate the reactivity of the vasculature of
various ischemic and nonischemic cerebral
structures to Pa^o,, and to assess the influence
of Pa ro ., on the development of hyperemia, on
the degree of ischemia, and on the sizes of
ischemic regions after occlusion of a middle
cerebral artery in cats.
Methods
Eighteen adult cats ranging in weight from 2.05 to
4.25 kg were anesthetized lightly with pentobarbital (25 mg/kg) injected intrapleurally, and the
right middle cerebral artery of each was occluded
with a miniature Mayfield clip via the extradural
approach.24 Approximately four to six hours after
occlusion, a tracheostomy was put in place. A
short arterial catheter was passed transfemorally
to the abdominal aorta for monitoring blood
pressure with a strain gauge and for drawing
blood samples for measurement of Pa^.,-,,,, Pao0>
pH, and hematocrit. A venous catheter was passed
transfemorally to the inferior vena cava for the
injection of drugs and a diffusible radioactive
indicator. Rectal temperature was monitored
continuously. Each cat was then paralyzed with a
minimal dose of d-tubocurarine injected intravenously, and ventilated artificially with a respirator.
Four cats (hypocapnic group) were given air
mixed only with oxygen at a rate of about 36
respirations per minute for at least 20 minutes,
until Pa c0 ^ was less than 20 torr. Six cats
(normocapnic group) were ventilated at normal
respiratory rates (approximately 24/min) with a
mixture of air, small amounts of CO2, and
oxygen, so that PaCOo was within the normal
range for cats (31 to 38 torr). Larger amounts of
COj were given to eight cats (hypercapnic
group); Ps^oo w a s higher than 58 torr for all of
these but one, for which P a ^ was 46 torr.
Less than two minutes after PaCOo was
140
determined, 14C-antipyrine was injected for the
measurement of regional CBF by the autoradiographical method of Landau and associates,25 as
modified by Reivich and associates.22- 2H- 20 Approximately 375 fid of the indicator, dissolved in
5 ml of isotonic saline, were injected into the
inferior vena cava at a constant rate for one
minute by an automatic infusion pump. During
the injection, 0.2 ml of arterial blood was
withdrawn every ten seconds for measurement of
the increasing arterial concentration of the
indicator. The circulation of blood then was
stopped by a rapid intravenous injection of a
saturated solution of potassium chloride. The
brain was removed quickly (within ten minutes)
and frozen instantaneously at —100 to —150 C in
2-methyl butane cooled with liquid nitrogen. The
frozen brain, warmed to —20 C in a freezer for
two to four days, was cut coronally into five
slices. Two serial sections, 20/x thick, were made
from each slice in a cryostat, one for autoradiography and the other for histopathological study.
The remainders of the slices were fixed in 10%
formalin, sectioned, and used also for histopathological study.
The sections of brain used for autoradiography
were placed on glass slides and dried on a hot
plate. The slides then were put in a cassette with
the sections of brain facing the emulsion of x-ray
film. Plastic disks containing known concentrations
of 14C-antipyrine also were put in the cassette. The
film was developed after ten weeks, and the optical
densities of the autoradiographical images were
measured with a densitometer. The concentrations
of 14C-antipyrine in various regions of brain were
determined from a curve plotted using values for
the densities and the concentrations of the plastic
disks. Values for regional CBF were calculated by
digital computer from the equation20
Ct,(T) = \ k , l Ca,e
in which Ct,(T) was the concentration of 14C-antipyrine in tissue at time T (one minute), X was the
blood-tissue partition coefficient (A = 1 for antipyrine), Ca, was the arterial concentration of the
indicator, and k, (with A. = 1) was the blood flow
value in milliliters per gram of tissue per minute
(ml/gm/min).
Measurements of regional CBF were made
for at least three sites in the gray matter of each
cortical gyrus and three sites in each caudate
nucleus. Measurements from cortical gray matter
were separated into four groups: those from
regions normally supplied by the middle cerebral
artery and those from regions normally supplied
by the anterior cerebral artery, both in the
ischemic and in the nonischemic hemisphere. The
Stroke, Vol. 2, March-April 7971
EFFECT OF Pa c0 ,, ON HYPEREMIA AND ISCHEMIA
o Nonischemic hemisphere
• lschemic hemisphere
*Hyperemia in cortex
supplied by MCA
•S 30
o
o
each region was considered to represent CBF of
white matter of that anatomical region, without
intermixed gray matter. Additional measurements
of CBF were made for other regions of the
ischemic hemisphere if there was visible evidence
of high or low optical density.
o o
o ^^
,-'r=0
|
"
e 1.0
Results
CORRELATION OF REGIONAL CBF WITH fa
r
"OOj
Nonlschemic Hemisphere
<o 05
40
60
80
FIGURE 1
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Relationship between PaCQ and regional cerebral
blood flow (CBF) of cerebral cortex after unilateral
occlusion of middle cerebral artery (MCA). Correlation coefficient (r=0.87) of iog10 CBF of nonischemic cortex and Paco was statistically significant
(P < 0.001).
border between the middle cerebral artery territory and the anterior cerebral artery territory was
taken as the center of the lateral gyrus. The means
of the measurements for each group and for each
caudate nucleus were considered to represent CBF
of those anatomical regions. For white matter,
measurements were made from the centrum
semiovale, the internal capsule, and white matter
supplied by the anterior cerebral artery in each
hemisphere. The minimal value obtained from
10
o Nonischemic hemisphere
• lschemic hemisphere
CBF of each of six regions of the gray and the
white matter of the nonischemic hemispheres
showed a positive correlation with Pa<;o2
(table 1, figs. 1-3). The correlation coefficients
for loglft CBF and Paco2 ranged from 0.77 to
0.90 for the different regions; all coefficients
were significantly different from zero.
Itchemlc Hemisphere
In regions of brain normally supplied by the
occluded middle cerebral artery, there was no
correlation between CBF and Pac 0o (figs. 13 ) . Mean CBF values for each of these regions
were highest in the normocapnic group of cats.
Values for CBF were lower with both
hypocapnia and hypercapnia, and the differences generally were statistically significant
(table 1).
In regions of gray matter normally
.5 30
\ 20
o°
,-%' r=086
oNonischemic hemisphere
• Ischemic hemisphere
*Hyperemia in cortex
supplied by ACA
r»0 67
io
|
05
0
0.1 r
20
40
60
80
™co 2 -torr
FIGURE 2
Relationship between Pa00 and regional cerebral
blood flow (CBF) of white matter after unilateral occlusion of middle cerebral artery. Internal capsule is
normally supplied by middle cerebral artery. Correlation coefficient (r = 0.86) of log10 CBF of nonischemic
was statistically significant
capsule and Paco
(P < 0.001).
Stroke, Vol. 2, March-April 7971
20
40
60
80
Pa^-torr
FIGURE 3
Relationship between Pa00 and regional cerebral
blood flow (CBF) of cerebral cortex outside the territory supplied by occluded middle cerebral artery.
ACA, anterior cerebral artery. Correlation coefficients
(r = 0.87 and r — 0.67) of log10 CBF and Pa00 were
statistically significant (nonischemic hemisphere:
P < 0.001; ischemic hemisphere: P < 0.01). Difference between slopes of regression lines (least-squares
analysis) was not statistically significant.
141
YAMAGUCHI, REGLI, WALTZ
TABLE 1
P°col and Regional Cerebral Blood Flow After Occlusion of a Middle Cerebral Artery in Cats
Sit*
Cortex supplied
by middle cerebral
artery
torr
<20
31-38
46-<S8
Cartbrol blood flow, ml/gm/mln
Nonischemic
llchemic
hMmisph*r*
hemisphere
Mean
SD
SD
Mean
0.82*t
1.34t
2.77
0.20
0.39
0.92
0.22
<20
0.82 # t
0.38
31-38
1.33t
2.77
0.88
46-68
0.31
<20
1.12
Caudate nucleus
0.20
31-38
(supplied by middle cerebral
1.51
2.18
46-68
artery)
2.96
0.05
0.25*8
Internal capsule
<20
0.10
(supplied by middle cerebral
0.42t
31-38
0.21
0.75
artery)
46-68
0.06
0.23§U
Centrum semiovale
<20
0.42t
0.07
31-38
(supplied by middle cerebral
0.69
0.15
46-68
artery)
0.28OT
0.08
White matter
<20
0.528
0.09
supplied by anterior cerebral
31-38
0.91
0.20
artery
46-68
Significantly different from normocapnia (*P < 0.05, IP < 0.01); from hypercapnia
P < 0.001).
Cortex supplied
by anterior cerebral
artery
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supplied by the anterior cerebral artery of a
hemisphere to which the middle cerebral artery
was occluded, there was a positive correlation
between logi0 CBF and Paco2 (fig. 3).
Although the correlation coefficient was somewhat lower than that for the opposite hemispheres, the difference between the slopes of
the regression lines was not statistically
significant. However, in the hypercapnic group
of cats, CBF of both the gray and the white
matter normally supplied by an anterior
cerebral artery was lower in the ischemic
hemisphere (table 1), and the differences were
statistically significant (gray matter: P < 0.05;
white matter: P < 0.001).
HYPEREMIA
Reactive hyperemia (CBF greater than 115%
of that of analogous regions of the nonischemic
hemisphere) was found in parts of the brain
normally supplied by the occluded middle
cerebral artery in seven cats (table 2). Two of
these cats were from the hypocapnic group,
four from the normocapnic group, and only
142
0.72
0.98+
0.64
0.24
0.31
0.17
0.85+
1.27
1.89
0.29
0.45
0.70
0.32*
0.81t
0.33
0.41
0.20
0.25
0.181T
0.35+
0.21
0.07
0.05
0.10
0.19fl
0.34t
0.21
0.03
0.05
0.08
0.261T
0.46
0.44
0.06
0.11
0.16
< 0.05,
< 0.01,
one from the hypercapnic group. The hypercapnic cat that had hyperemia was the one with
the lowest Pac0o of the group, 46 torr (fig. 4).
Multiple hyperemic foci were found in the
territory normally supplied by the occluded
middle cerebral artery in both cats of the
hypocapnic group and in two of the four cats
of the normocapnic group that had hyperemia.
One cat, with Pac0o of 19 torr, had six
hyperemic foci (fig. 5). Because of regional
hyperemia, mean CBF values for the ischemic
hemispheres occasionally were nearly as high
as those of the nonischemic hemispheres.
Regional hyperemia was found outside
the usual area of distribution of the occluded
middle cerebral artery, in brain tissue normally
supplied by an anterior cerebral artery in five
cats (table 2, fig. 4). Two of these cats were
from the hypocapnic group, two from the
normocapnic group, and one from the hypercapnic group. Each of these five cats also had
hyperemia in regions normally supplied by the
occluded middle cerebral artery, except one of
the two cats from the hypocapnic group.
Strok; Vol. 2, March-April 1971
EFFECT OF Pa c o
ON HYPEREMIA AND ISCHEMIA
TABLE 2
P°oot ai id Hyperemia After Occlusion of a Middle Cerebral Artery in Cats
Pathological
change
C«r«braJ blood flow, ml/gm/mln
Nonfccrtemic
Itchemk
hemisphere
hemiipriere
Ischemic to
nonlichcmic
flow, %
Cat
torr
Siu
1
18
Gray matter,
middle cerebral artery
White matter,
middle cerebral artery
Gray matter,
anterior cerebral artery
Yes
0.83
1.27
153
No
0.20
0.27
135
No
0.67
0.83
124
Gray matter,
middle cerebral
Gray matter,
middle cerebral
Gray matter,
middle cerebral
Gray matter,
middle cerebral
Caudate nucleus
White matter,
middle cerebral
Yes
0.73
2.15
295
Yes
0.74
1.90
257
Yes
0.55
1.39
253
Yes
0.79
1.31
166
No
No
0.61
0.18
0.89
0.47
146
261
2
19
artery
artery
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artery
artery
artery
3
20
Gray matter,
anterior cerebral artery
No
0.74
1.08
146
4
5
31
36
Caudate nucleus
Gray matter,
middle cerebral artery
White matter,
middle cerebral artery
Gray matter,
anterior cerebral artery
No
Yes
1.39
1.25
1.79
1.61
129
129
No
0.28
0.44
157
No
1.38
1.59
115
Gray matter,
middle cerebral artery
Gray matter,
middle cerebral artery
No
1.15
1.77
154
No
0.91
1.15
126
Gray matter,
middle cerebral artery
Gray matter,
anterior cerebral artery
No
2.06
2.62
127
No
2.39
3.41
143
No
0.41
0.87
212
No
1.96
3.35
171
6
7
8
38
38
46
White matter,
middle cerebral artery
Gray matter,
anterior cerebral artery
MISCELLANEOUS
There were no evident differences in the total
volumes of the ischemic regions produced by
occlusion of a middle cerebral artery in the
different cats despite the differences of Paro.,Although there was only a short time
between occlusion of a middle cerebral artery
and measurement of CBF, histopathological
studies showed early ischemic changes in the
Strok; Vol. 2, March-April 1971
neurons in regions of brain normally supplied
by the occluded artery in 17 of the 18 cats.
Reactive hyperemia was found in some regions
with early ischemic neuronal degeneration23
(table 2 ) .
Blood pressure at the time of measurement of CBF did not influence the development
of hyperemia. There was no evident relationship between reactive hyperemia and the
143
YAMAGUCHI, REGLI, WALTZ
198
68
24
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Peo, 4 6
FIGURE 4
Autoradiograph of ischemic cerebral hemisphere of
hypercapnic cat (Pa00 = 46 torr). Optical density o]
autoradiographical image is directly related to cerebral
blood flow: darker regions are those with higher flow.
Cerebral blood flow values are indicated in
ml/gm/min X 100. Asterisks (*) indicate regions of
hyperemia in white matter normally supplied by occluded middle cerebral artery and in gray matter
normally supplied by anterior cerebral artery. A large
ischemic zone can be seen.
development of edema. No hemorrhagic infarcts were noted. CBF of ischemic regions was
not lower in animals with regions of hyperemia
than in those without hyperemia.
Discussion
Pa co ., AND REGIONAL CBF
A positive correlation between Paco., and CBF
of nonischemic, relatively normal brain tissue
has again been demonstrated. From analysis of
the present data, particularly calculations of
correlation coefficients, it is apparent that
regulatory arterioles deep in brain substance
react to Pacoo to the same degree as those of
cortex. Moreover, the exponential nature of the
144
response of CBF to Paco2 has been
confirmed.8
The ineffectiveness of hypercapnia in
producing increased CBF in ischemic brain
tissue, found previously for cortex,8"10 has been
demonstrated for deeper cerebral structures by
the present study. A paradoxical reaction of
decreased CBF with increased Pacoo8""15 ("intracerebral steal") can be inferred from the
significantly lower CBF values found for
certain ischemic cerebral structures, notably
the caudate nucleus and internal capsule, in the
hypercapnic group of cats. Such a paradoxical
reaction presumably is related to vasodilatation
and increases of CBF in nonischemic regions,
with diversion of the flow of blood from
ischemic regions. Failure of others10"18 to find
paradoxical reactions may be related to less
severe ischemia, smaller ischemic regions, or a
less acute process in the cerebral hemispheres
studied. The available evidence shows unequivocally that increases of Paco,, can cause
decreases of CBF of acutely ischemic brain
tissue, such that the use of CO 2 inhalation for
treatment of acute ischemic strokes in humans
seems unjustified.
Hyperventilation has been suggested for
the treatment of cerebral ischemia, 10 ' 27 - 28 with
the hope that a paradoxical reaction may cause
increases of CBF in ischemic regions from
vascular constriction in nonischemic regions
("inverse cerebral steal") or from decreases of
cerebral edema and intracranial pressure. In
animal studies, however, hypocapnia has not
been shown to cause increases of CBF of
ischemic cortex 8 or to cause decreases of the
sizes of infarcts or ischemic regions that
result from occlusion of a middle cerebral
artery (unless Pacoo is decreased before
occlusion). 2 ^ 81 Results of preliminary studies
in humans are conflicting.82-86 The present
data confirm the results of earlier controlled
studies in animals, and cast further doubt on
the possibility of a beneficial effect of
hypocapnia for humans with acute ischemic
strokes.
HYPEREMIA
Three distinct types of hyperemia (increased
CBF, or "luxury perfusion") have been
described in relation to cerebral ischemia: 23
Stroke, Vol. 2, March-April 1971
EFFECT OF Pocc,2 ON HYPEREMIA AND ISCHEMIA
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FIGURE 5
Autoradiographs of nonischemic (left) and ischemic cerebral hemispheres of hypocapnic cat
(Paco = 19 torr). Note multiple hyperemic foci in gray matter normally supplied by occluded middle cerebral artery. Two additional hyperemic foci were found in other sections
of this brain.
(1) reactive hyperemia in regions previously
ischemic, (2) hyperemia due to increased flow
through anastomotic or collateral vessels in
nonischemic regions, and (3) hypervascularity
developing late after infarction. Reactive
hyperemia, in regions normally supplied by an
occluded middle cerebral artery, developed in
seven of the 18 cats ( 3 9 % ) , and histological
evidence of preexisting ischemia was seen in
three of these. This incidence is much lower
than that of a previous study,23 in which six of
seven cats studied shortly after occlusion of a
middle cerebral artery had foci of reactive
hyperemia. The different incidence is explained
by differences of Paco2. In the present study,
hyperemic regions were not found in seven of
eight hypercapnic cats.
The absence of reactive hyperemia with
hypercapnia may be due in part to the
definition used for hyperemia (CBF greater
than 115% of that of analogous regions of the
opposite, nonischemic hemisphere) in that
CBF of ischemic regions cannot match that of
Stroke, Vol. 2, March-April 1971
nonischemic regions when Pacoo is increased.
However, visual inspection of the autoradiographical images of the brains of the hypercapnic cats failed to reveal any areas of increased
optical density in potentially ischemic regions.
Thus, hypercapnia inhibits reactive hyperemia
in relation to ischemia, perhaps because of
vasodilatation in nonischemic regions, a situation analogous to the paradoxical reaction of
CBF to increases of Pace,., that occurs in
ischemic brain tissue. Unfortunately, the significance of reactive hyperemia to the process
of cerebral infarction is not clarified by this
finding.
Previously, hyperemia outside potentially
ischemic zones was seen only late after
occlusion of a middle cerebral artery, 23 and
was attributed to increased blood flow through
anastomotic vessels to supply regions formerly
served by the occluded artery. Because anastomotic vessels can develop only with time,
other mechanisms must be used to explain
hyperemia found in regions supplied by an
anterior cerebral artery in this study, in which
145
YAMAGUCHI, REGLI, WALTZ
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CBF was determined soon after occlusion of a
middle cerebral artery. Most likely such
hyperemia is a reaction to manipulation of the
anterior cerebral artery at the base of the brain
or to extradural retraction of the brain during
the surgical procedure for occlusion of the right
middle cerebral artery. Surgical trauma would
modify the reactivity of regulatory vessels as
well, and explain the relatively low mean CBF
value found for regions supplied by the
anterior cerebral arteries of the ischemic
hemispheres in hypercapnic animals. Less
likely causes of impaired reactivity and
hyperemia in territory supplied by an anterior
cerebral artery are: (1) spread of acidic
metabolites from ischemic regions, either by
direct diffusion through brain tissue or by
countercurrent diffusion from veins draining
ischemic tissue and passing through nonischemic tissue, (2) autonomic reflex activity,
mediated by axon reflexes or through brain
stem pathways, (3) reaction to venous stasis in
ischemic tissue, or (4) reaction to cerebral
edema and intracranial hypertension. Regardless of cause, hyperemia in territory supplied
by an anterior cerebral artery does not seem to
influence the ischemia or reactive hyperemia
that develops after occlusion of a middle
cerebral artery.
5.
6.
7.
8.
9.
10.
11.
12.
Acknowledgment
Dr. H. Okazaki assisted in the histopathological
studies. Technical, instrumentation, and analytical
assistance were provided by Robert E. Anderson,
Robert D. Ostrom, and the Mayo Clinic Medical
Sciences Computer Facility.
13.
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Effect of PaCOCO2 on Hyperemia and Ischemia in Experimental Cerebral Infarction
TAKENORI YAMAGUCHI, FRANCO REGLI and ARTHUR G. WALTZ
Stroke. 1971;2:139-147
doi: 10.1161/01.STR.2.2.139
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