JANUARY-FEBRUARY
VOL. 5
Stroke
A Journal of Cerebral Circulation
1974
NO. 1
Barbiturate Protection in Acute Focal
Cerebral Ischemia
BY ALLAN L. SMITH, M.D.,* JULIAN T. HOFF, M.D., SURL L. NIELSEN, M.D., AND C. PHILIP LARSON, M.D.
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Abstract!
Barbiturate
Protection
in Acute
Focal Cerebral
Ischemia
• We have found that anesthetic technique modifies the neurological and pathological sequelae of unilateral middle cerebral artery and internal carotid artery occlusion in dogs. Occlusion was performed in seven groups of six dogs during each of the following anesthetic
regimens: light (0.8%) halothane, "awake," deep (1.9%) halothane, deep halothane with mean
arterial pressure reduced to 55 torr, pentobarbital (56 mg per kilogram), light halothane plus 40
mg per kilogram thiopental begun just before cerebral artery occlusion, and light halothane plus
40 mg per kilogram thiopental begun 15 minutes after occlusion. Body temperature, arterial
Pco,. Po,, pH, and blood pressure (except as noted above) were maintained normal.
Neurological examinations were performed daily. On the seventh day the dogs were killed and
their brains removed for pathological study. Hemiparesis occurred infiveof six dogs under light
halothane and five of six awake dogs; a mean of 10.8% and 9.6%, respectively, of their right
hemispheres were infarcted. In the deep halothane groups, all of the normotensive and five of
the six hypotensive dogs became severely hemiplegic; mean infarction size was 28.2% and
34.1 %, respectively. Only one of the 18 dogs who received a barbiturate sustained a neurological
deficit — a transient unilateral weakness. Means of 1.4%, 2.7%, and 0.1% of the right
hemisphere were infarcted in the barbiturate animals. The protective action of barbiturates in
canine acute focal cerebral ischemia suggests that they should be considered for anesthesia in
surgery requiring cerebral vessel occlusion and perhaps even for treatment of acute stroke.
Additional Key Words
pentobarbital
stroke
Introduction
• Increasing numbers of patients with cerebrovascular disease are subjected to corrective
surgical procedures such as carotid artery thromboendarterectomy, cerebral aneurysm ligation, and
cerebral artery bypass. The temporary or permanent
occlusion of cerebral vessels required by these
procedures incurs a high risk of brain damage. It is of
From the Departments of Anesthesia, Neurosurgery and
Pathology, University of California, San Francisco, California
94143, and the Department of Anesthesia, Stanford University,
Stanford, California.
Dr. HofT is the recipient of Teacher-Investigator Award
NSI105I.
Supported in part by USPHS Grants 5PO1-GMI5571 and
GMI8740.
'Received the Irving S. Wright award for young investigators
in the field of stroke (1973) for this paper.
Strok*, Vol. 5, Jaiwary-Ftbrvary 1974
halothane
cerebral infarction
thiopental
middle cerebral artery
manifest importance to discover those factors which
might lessen the short-term and long-term hazards of
cerebral vessel occlusion. Although the effects of
arterial P COl (Paco,) and blood pressure have been
reported,1"4 there has been no direct inquiry into influence of anesthetic technique on the occurrence of
neurological damage. Accordingly, we compared the
pathological and neurological sequelae of experimental cerebral artery occlusion in animals, produced during each of seven anesthetic techniques. We have
found that anesthesia which includes barbiturate may
significantly decrease the incidence of cerebral infarction.
Methods
The right internal carotid and middle cerebral arteries were
permanently clipped through a temporal burr hole in each of
42 dogs. These dogs were divided into seven groups of six
SMITH, HOFF, NIELSEN, LARSON
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animals. Each group differed in anesthetic management as
follows:
Group 1: Light halothane* (0.8% end-tidal).
Group 2: "Awake." Halothane, given for initial surgery,
was discontinued three minutes before vessel
occlusion.
Group 3: Deep halothane (1.9% end-tidal).
Group 4: Deep halothane-hypotension. Five minutes
before cerebral vessel clipping, halothane was
increased to reduce mean arterial blood
pressure to 50 to 60 torr and pressure was held
at that level for one hour. Halothane then was
decreased to 0.8% end-tidal and blood pressure
restored to a mean of at least 110 torr.
Group 5: Pentobarbital. Anesthesia was induced with 25
mg per kilogram pentobarbital intravenously.
Just before vessel clipping, sufficient additional
drug was given to reduce EEG frequency to less
than 1 Hz.
Group 6: Light halothane plus thiopental pretreatment.
Halothane (0.8%) was maintained throughout
the study. Twenty milligrams per kilogram
thiopental were given rapidly intravenously immediately before vessel clipping and an additional 20 mg per kilogram were given slowly
over the ensuing two hours.
Group 7: Light halothane plus thiopental posttreatment.
A constant background of 0.8% halothane was
maintained. Fifteen minutes after vessel clipping, we gave 20 mg per kilogram thiopental
rapidly intravenously. An additional 20 mg per
kilogram were administered slowly over the
next two hours.
Anesthesia was induced with halothane, except in pentobarbital animals. The trachea of each dog was intubated
and the animals were ventilated with 30% O2-70% N,. An intravenous infusion was begun in a peripheral vein and a
plastic cannula was placed percutaneously into a femoral
artery for pressure measurements and blood sampling. Endtidal P c o , was continuously monitored with an infrared
analyzer and maintained at 36 to 41 torr throughout the
study. Arterial P c 0 ,, P<v and pH were measured hourly and
base deficits greater than 5 mEq per liter were corrected by
slow intravenous administration of NaHCO 3 . Arterial blood
pressure was continuously transduced and recorded on a
polygraph together with the end-tidal P C ( V Phenylephrine
was infused as needed to maintain mean arterial blood
pressure above 110 torr in all except Group 4 animals.
Inspired and end-tidal halothane concentrations were
measured by infrared analysis. The electroencephalogram
was recorded from a pair of left fronto-occipital leads. Rectal temperatures were maintained at 38°C by surface
warming.
We began surgery only after blood pressure and endtidal halothane and CO 2 concentrations had been stable for
at least 15 minutes. A 15 mm right temporal burr hole was
made and the dura opened. The internal carotid artery was
permanently occluded with a Scoville clip placed between
the origins of the posterior communicating and anterior
cerebral arteries. The middle cerebral artery was clipped just
distal to the origin of the anterior communicating artery.
The dura was not closed, but the overlying muscles and skin
*Halothane was supplied by Ayerst Laboratories.
were approximated. Mechanical ventilation and anesthesia
were maintained for six hours after vessel ligation in all dogs
but those of the "awake" group, and they were then permitted to awaken. If spontaneous ventilation did not maintain arterial POl above 60 torr and P c 0 , below 50 torr when
breathing air, ventilator therapy was continued.
On the day of surgery, 500 ml 5% dextrose and 1,000 ml
saline were given intravenously. Animals unable to drink
postoperatively were given 500 ml Ringer's lactate daily. All
dogs were treated postoperatively with intramuscular
penicillin, 10" units, and streptomycin, 0.75 gm, daily.
We scored motor function (table 1) daily for seven days
in each animal. The dogs were then killed with pentobarbital. The brain was removed and clip placement verified.
Pathological evaluation was performed by one of us (SLN),
who did not know which anesthetic had been given. The
fixed brain was cut into 3-mm thick coronal sections. A grid
with 2-mm squares, placed over each section, was used to estimate percent of infarcted and normal tissue. Representative areas of normal and abnormal tissue were stained with
hematoxylin-eosin and the abnormalities confirmed
microscopically. Criteria for infarction included loss of normal cellular elements, infiltration with macrophages, and
early vessel proliferation. The pathologist also attempted to
predict the presence or absence of hemiparesis.
Infarction data were analyzed by the Wilcoxon rank
test5 and neurological scores and experimental conditions
with analysis of variance (P < 0.05).
Results
Blood gases, arterial pressure, body temperature, and
ventilator time (table 2) differed among groups only as
follows. Blood pressure in the halothane-hypotension
group differed from that of all other groups; the 9 torr
difference between Groups 6 and 7 just reached
significance. Pentobarbital dogs had the longest ventilator time and awake dogs had the shortest ventilator
time.
The neurological scores obtained daily for seven
days were averaged and the means for the six overall
scores for each treatment group were computed (table
3, fig. 1). Most animals with deficits improved one
grade over the postoperative week. Thus, a score of
2.4 implies a dog that could not stand until the fourth
day after vessel clipping. A score of greater than 3.0
indicates an animal that died. Five of six dogs whose
cerebral vessels were clipped during light halothane
anesthesia developed obvious neurological deficits.
Equivalent deficits appeared in the "awake" animals.
TABLE 1
Neurological Evaluation Scores
Neurological signs
Score
No neurological deficit
Walks with limp or circles to side of lesion
Walks poorly; stands, but cannot support body
with right limbs held off ground
Cannot stand without support
Dead
0
1
2
3
4
Stroke, Vol. 5, January-February 1974
BARBITURATES I N CEREBRAL ISCHEMIA
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Deep halothane was significantly worse than light
halothane. All animals given deep halothane
anesthesia became hemiparetic. Neurological signs
also were severe in dogs made hypotensive with
halothane. No neurological abnormalities occurred
following deep pentobarbital anesthesia. Among the
12 animals given thiopental before or after vessel
occlusion, only one had a neurological deficit. Barbiturates, compared with light halothane or "awake,"
significantly reduced or eliminated the neurological
sequelae of middle cerebral artery and internal carotid
artery clipping.
A mean of about 10% of the right hemisphere was
infarcted in light halothane or awake dogs (table 4, fig.
2). Infarctions were three times more extensive in
deeply anesthetized halothane animals, with either
normal or decreased blood pressure. Infarctions were
small or absent in the three barbiturate groups, except
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Stroke, Vol. 5, January-February 1974
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FIGURE 2
Mean percents of right hemisphere infarcted following
artery occlusion.
cerebral
SMITH, HOFF, NIELSEN, LARSON
TABLE 3
Neurological Sequelae of Cerebral Artery Occlusion
Anesthetic
Mean neurological scores*
Light halothane
"AwakeDeep halothane
Deep halothane-hypotension
Pentobarbital
Light halothane + thiopental. preocclusion
Light halothane + thiopental. postocclusion
1.1
1.0
2.4
2.2
dt
db
db
db
0.4
0.3
0.3
0.6
0
0.05 =<= 0.05
0
Individual scores
2.6, 2.4, 0.6, 0.7, 0.4, 0
0.1, 1.7, 1.0, 1.0,2.1,0
2.0,2.9, 1.7, 1.6,3.7,2.6
1.3, 2.9, 1.4, 3.9, 0, 3.7
0, 0, 0, 0, 0, 0
0, 0, 0, 0, 0.3, 0
0, 0, 0, 0, 0, 0
*±SE analysis of variance shows F = 9.6 (P < 0.005) and least significant difference = 0.91 at the
P<0.05 level.
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neurological lesions,6 it is not surprising that thiopental was protective even when begun 15 minutes after
arterial occlusion. The duration of the postocclusion
period in which barbiturates may protect remains to
be established.
Previous studies of brain halothane uptake7
suggest that brain tissue halothane content in the
"awake" dogs fell to less than 0.2% of an atmosphere
by five minutes after vessel clipping. Thus, our
"awake" group would seem to be a reasonable approximation to "true" awake. The effect of light
halothane did not differ from "awake," but deep
halothane anesthesia resulted in a higher incidence of
hemiparesis and infarction than either light or no
halothane. The deleterious effect of deep halothane
may be a threshold phenomenon, which does not
appear during light anesthesia. Alternatively, the
adverse effects of light halothane may have been
obscured by the large variability of the results.
As might have been anticipated, deep halothane
with hypotension was no better, and perhaps worse,
than deep halothane without hypotension. Pressures
of 50 to 60 torr are below the autoregulatory range of
dog cerebral vasculature. 8 Thus, despite the
vasodilatory effect of halothane, we would expect
cerebral blood flow (CBF) to be subnormal even in
regions with intact vasculature. CBF in borderline
perfused areas would be further reduced and must
have been lower than flows consistent with survival for
the infarction data, the differences between the three
barbiturate groups and light halothane and "awake"
were significant (P < 0.05) by the Wilcoxon rank test;
differences between the latter groups and the two deep
halothane groups also were significant (P < 0.05).
Predictions by the neuropathologist (SLN) of the
extent of neurological deficit, based on size and location of infarction, were correct in 75% of cases. Incorrect predictions were not in error by more than one
unit. Figure 3 shows a coronal section of a brain with a
large infarction and figure 4 shows a brain with a
smaller infarction involving the internal capsule. Both
animals were placed in neurological Class 2 on the
first postoperative day.
Discussion
The data indicate that barbiturates reduce the injury
produced by acute arterial occlusion. Either profound
pentobarbital anesthesia or addition of a moderate
dose of thiopental to halothane anesthesia protected
against neurological deficit and/or cerebral infarction.
The fact that halothane to deep levels did not prevent
injury — but rather caused its increase — suggests
that deep anesthesia per se is not protective. The lack
of protection with light halothane anesthesia also
suggests that anesthesia, by itself, is not the means by
which the barbiturates act.
Since other workers have found that removing
the clips several hours after placement prevents
TABLE 4
Pathological Sequelae of Cerebral Artery Occlusion
Anesthetic
Light halothane
"Awake"
Deep halothane
Deep halothane-hypotension
Pentobarbital
Light halothane + thiopental, preocclusion
Light halothane + thiopental, postocclusion
Mean percent of right
hemisphere infarcfed*
10.8
9.6
28.2
34.1
1.4
2.7
0.1
d=
±
±
±
5.2
7.4
9.9
77
d= 0.8
d= 2.5
d= 0.1
Individual percents of right
hemisphere Infarcted
22.6,30.0,0.5, 1.9, 10.0,0.5
0, 1.0, 10.4,0.5,46,0
1.9,51.0,0.5,22.3,58.1,35.4
25.1, 47.0, 38.0, 53.1, 1.0, 41.1
3.4, 0, 4.9, 0, 0, 0
0, 0.5, 0.5, 15, 0, 0
0.5, 0, 0, 0, 0, 0
*±SE
Stroke, Vol. 5, January-February 1974
BARBITURATES I N CEREBRAL ISCHEMJA
an hour. Return to normal perfusion pressure would
not save these areas of brain.
Protection against cerebral hypoxia has been
suggested previously for both barbiturates and
halothane.""12 In these studies, survival was recorded
after either the entire brain or the whole animal was
subjected to severe ischemia and/or anoxia. Severe
ischemia or anoxia should produce major cardiorespiratory alterations, which may modify the
likelihood of an insult. Since anesthetics alter cardiorespiratory responses to anoxia, it is difficult to
know whether the previously reported "protection"
resulted from salutary effects of anesthetics on the
brain or on other organ systems. In the present study,
we controlled variables which affect cerebral
hemodynamics (arterial P COl , Po,, pH, blood pressure,
and body temperature). Thus, we studied specific
brain protection of anesthetics, rather than some indirect manifestation of anesthetic action. This may explain why we found halothane not to be salutary. The
protective effect of barbiturates that we observed is
consistent with earlier studies.
The mechanism of barbiturate protection may be
on a macroscopic (flow to large regions) or
microscopic (capillary, cell) level. First consider the
macroscopic level. Differences in sequelae following
the seven anesthetic techniques may relate to regional
cerebral blood flow (rCBF) alterations. Cerebral
vasodilators, which act only on normal brain blood
vessels, may divert ("steal") blood flow from ischemic
tissue. 13 ' u In contrast, cerebral vasoconstrictors,
which again act on normal vessels, may increase rCBF
to ischemic areas ("inverse steal"). 1 ' Hypocapnia is an
example of the latter phenomenon. In a canine
preparation similar to ours, smaller infarctions
followed middle cerebral artery occlusion during
hypocapnia than during normocapnia.1 Excluding the
hypotensive group, the severity of neurological sequelae (tables 3 and 4) was directly related to the expected CBF. Thiopental plus halothane (doses similar
to ours) halves CBF.1" Pentobarbital probably reduces
CBF by at least this much.17 Light halothane increases
CBF about 10% and 2.1% halothane more than
doubles CBF. 18 ' 19 Although the flow data are consistent with the steal-inverse steal hypothesis, all data are
not. Other workers have not found steals or inverse
steals with carbon dioxide.*' "• 2 1 Hypocarbia is
associated with greater lactate production in ischemic
brain than normocarbia." Furthermore, our
laboratory was not able to document the steal
phenomenon during either light or deep halothane
anesthesia in the dog middle cerebral artery occlusion
preparation.19 Using the Xenon washout technique, we
found that rCBF to the ischemic region was always increased by deep halothane anesthesia.
Coronal section of a dog brain with a 1% infarction located in the
internal capsule.
Although we could not document steals, rCBF in
intact brain areas still may affect ischemia in occluded
areas, because CBF alters intracranial pressure (ICP)
through its effect on intracranial blood volume.17 Increases in CBF raise ICP; halothane increases ICP M
and barbiturates decrease ICP." Perhaps the raised
ICP of halothane decreased effective cerebral perfusion pressure (arterial-ICP) or predisposed to cerebral
edema. Barbiturates would have the opposite effect,
i.e., a reduction in ICP.
Depression of cerebral oxygen consumption
(CMROi) may have a role in barbiturate protection
but cannot be the only factor. Both halothane18 and
barbiturates decrease CMRO 2 . U Furthermore, there
is evidence to suggest that the reduction in CMRO 2
during anesthesia reflects decreased cerebral activity
rather than a decrease in oxygen required to maintain
cellular integrity."
Several theories of the pathogenesis of irreversible
anoxic-ischemic brain damage at the microscopic level
FIOURI 3
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Coronal section of a dog brain showing 35% infarction of the right
hemisphere
Stroke, Vol. 5, January-February 1974
SMITH, HOFF, NIELSEN, LARSON
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have been advanced. We shall review some of these
ideas very briefly and then speculate on their role in
the protective action of barbiturates. While appearing
to be competitive theories, each emphasizes different
aspects of the same phenomenon, seen darkly through
the glass of differing experimental preparations.
Ames26 has suggested that the initial injury is at the
capillary. The capillary injury, together with
pericapillary swelling, is responsible for the "noreflow" phenomenon, i.e., the failure of perfusion to
reestablish itself after a period of temporary vascular
occlusion. Once the capillary damage is advanced, cell
death is inevitable. Others have emphasized the importance of CNS ultrastructure changes. Severe
hypoxia causes microvacuolization of neurons, corresponding to mitochondrial swelling, before increased tissue water appears and swelling of astrocytic
processes can obstruct capillaries.27-28 The role of both
local pericapillary edema and intracellular edema in
the irreversibility of ischemic damage also has been
stressed by Meyer29 and Sundt;6 the latter failed to
observe "no-reflow." Biochemical alterations of
severe hypoxia include a progressive fall in neuronal
high energy phosphates (ATP, phosphocreatine) and
an increase in lactate concentration.30*31 Thus, cells
are doomed because they run out of energy and are
poisoned by accumulation of acid metabolites. Finally, release of a toxic metabolite, such as serotonin,
might contribute to a self-induced and selfperpetuated worsening of the hypoxic state.6-32
Any hypothesis on the protective action of barbiturates must answer this question: How do barbiturates, which are given once and are thus a temporary measure, protect against brain infarction in
permanent arterial occlusion? Permanent survival of
the focal ischemic area implies that either a new
source of perfusion must have become established
within 6 to 24 hours of the occlusion or that remaining
vasculature was sufficient once a temporary impairment to perfusion was reversed. Since such a rapid
growth of vessels seems unlikely, we should look for a
temporary impairment to perfusions that barbiturates
could affect. It seems unlikely that barbiturates exert
their salutary effects on the biochemical abnormalities
of brain hypoxia. Although the drug decreases the rate
of fall in brain ATP content during hypotension,33 it
does not alter ATP depletion in arterial hypoxemia34
or asphyxia.33 Furthermore, the validity of ATP and
lactate levels as quantifiers of brain cell viability has
come to be questioned.34-36
We believe that barbiturates protect principally
by decreasing CBF and ICP. The lowered ICP would
minimize pressure in cerebral capillaries and venules,
thus maximizing perfusion pressure in ischemic areas.
Cerebral vasodilators like CO 2 have been found to
aggravate cerebral edema.29 In contrast, the low CBF
of barbiturate anesthesia would minimize cerebral
edema, and might reduce capillary stasis and/or
capillary damage. Cerebral edema could be the temporary factor, which contributes to irreversibility of
hypoxic cell damage, but which is prevented by barbiturates. Decreased CMRO 2 may be a secondary factor in barbiturate protection.
We compared neurological scores by computing
means and using analysis of variance, because these
techniques are more powerful for detecting differences
among small groups (N = 6) than Chi square or the
usual nonparametric measures. Treating an ordered
scale as a continuous variable for purposes of
statistical analysis is valid and appropriate in the case
of the present data;36 actually the ordered scale approximates a continuous phenomenon. Since infarctions tended to be either very small or very large, the
infarction data were not normally distributed. Kurtosis was always less than the normal value of 3, ranging from 1.0 to 2.9. Variances can be somewhat misleading in this situation and have been omitted from
figure 2. We used the nonparametric Wilcoxon test6
for group comparison, since the / test or analysis of
variance requires normally distributed data.
The severity of neurological signs in most
animals was consistent with the extent of infarction,
but a few animals suffered hemiparesis with small infarctions. Figure 4 shows the brain of one such dog.
The infarction, though small, is located in the vital internal capsule. The excellent agreement of observed
neurological signs with those predicted from autopsy
data suggests that subjectivity did not affect the
clinical evaluations.
We believe that barbiturates such as thiopental
deserve a clinical trial as anesthetics or anesthetic
supplements for surgical operations having a high risk
of brain infarction, such as carotid artery thromboendarterectomy and cerebral artery aneurysm ligation.
Thiopental is a commonly used anesthetic supplement
and only modest doses would be required. Based on a
canine induction dose for thiopental of 11 mg per
kilogram37 and a human dose of 3 mg per kilogram,
the dog dose for thiopental is three to four times the
human dose. Our 40 mg per kilogram dog dose is thus
equivalent to less than 1,000 mg thiopental in a 70 kg
man. This dose could be started just before vessel ligation in surgical operations. A common way to provide
good operating conditions for cerebral artery
aneurysm ligation is to lower the blood pressure with
deep halothane anesthesia. Results from the halothane
plus hypotension group suggest that this may not be
desirable. An equivalent degree of brain "shrinkage"
and lowering of CBF might be obtained more safely
with barbiturates.
Acknowledgments
We appreciate the excellent technical assistance of Mr. Jeffrey
Joshua Marque. Dr. E. I. Eger, II, offered helpful suggestions for
the preparation of the manuscript.
Stroke, Vol. 5, January-February 1974
BARBITURATES I N CEREBRAL ISCHEMIA
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Barbiturate Protection in Acute Focal Cerebral Ischemia
ALLAN L. SMITH, JULIAN T. HOFF, SURL L. NIELSEN and C. PHILIP LARSON
Stroke. 1974;5:1-7
doi: 10.1161/01.STR.5.1.1
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