Br.J. Anaesth. (1985), 57, 82-95
BARBITURATES IN BRAIN ISCHAEMIA
H. M. SHAPIRO
The role of barbiturates as the prototypical pharmacological neuroprotective drugs has emerged
over the past three decades from demonstrations
that they extend rudimentary neurological function
during severe hypoxia, limit the area of infarction
following cerebral vascular occlusion, and reduce
intracranial pressure under a variety of circumstances. Most studies indicate that very high
doses of barbiturates are required to elicit a protective effect. This can result in severe depression of
brain function and other excitable tissues throughout the body, in addition to cardiovascular instability and respiratory depression. While the search for
non-anaesthetic drugs with neuroprotective actions
is actively pursued, evaluation of barbiturates continues, for protection against different forms of cerebral ischaemia. Within this context, this paper
reviews the relevant pharmacology of barbiturates
used in high doses to prevent neuropathology in
brain ischaemia. Also discussed are laboratory and
clinical trials of barbiturates during hypoxia, focal
and global ischaemia and intracranial hypertension.
A closing section indicates the guidelines involved in
applying continuous high-dose barbiturate therapy
in management of patients.
Cerebral effects of barbiturates
The most obvious central nervous system effect of
barbiturates is a dose-dependent reversible depression of neurological function (Harvey, 1980). While
the precise mechanism(s) of this effect remains
unknown, it clearly involves interference with
synaptic transmission and multineuronal networks
and to a lesser extent a direct local anaesthetic influence upon membrane structures (Harvey, 1980).
Some evidence also points towards an indirect effect
HARVEY M. SHAPIRO, M.D., Neuroanesthesia Research, M-029,
Department of Anesthesiology, University of California at San
Diego, La Jolla, California 92093, U.S.A.
of barbiturates on neurotransmission. They may
enhance presynaptic inhibition by facilitating the
binding of gamma-aminobutyric acid (GABA) to
GABA-specific sites regulating neuronal ionic conductance (Higashi and Nishi, 1982; MacDonald and
MacLean, 1982). It is also recognized that different
structurally specific brain target sites are involved in
the anaesthetic and anticonvulsant activities of barbiturates which display both these activities (Andrews and Mark, 1982). This may explain the ability
of phenobarbitone to exert a strong anticonvulsant
action with minimal sedation, while thiopentone
and pentobarbitone exhibit anticonvulsant properties at doses associated with a high degree of sedation
(Harvey, 1980; MacDonald and McLean, 1982).
Associated with barbiturate brain function depression is a parallel dose-dependent reduction in cerebral metabolic rate (CMR) and blood flow (CBF).
These CBR and CMR effects plateau at the point
where electroencephalographic (EEG) activity
becomes isoelectric. This suppression of synaptic
activity is associated with maximal reductions in
CMR (for oxygen) and CBF of approximately 50%
(Pierce et al., 1962; Michenfelder, 1974). Barbiturate-induced reductions in CBF are accompanied by
increases in cerebral vascular resistance and reductions in cerebral blood volume, and this presumably
explains their action in reducing intracranial pressure (ICP) (Shapiro, 1975). The cerebrovascular
resistance increase from barbiturates is associated
with metabolically mediated direct or indirect
(neurogenic) vascular events, or both, since direct
application of pentobarbitone to isolated cerebral
vessels reduces their contractile response (Edvinsson and McCulloch, 1981; Marin, Loboto and
Rico, 1981). Cerebral blood flow and metabolic rates
are distributed heterogeneously throughout the
brain and barbiturates cause non-uniform alterations in local flow and metabolism in different struc-
B A R B I T U R A T E S I N B R A I N ISCHAEMIA
tures (Shapiro et al., 1975).
A popular explanation for the cerebral protective
action of barbiturates relates to their ability to depress
brain metabolism during periods of critically low
C B F . As noted above, C M R depression by barbiturates has a baseline effect when the E E G is already
isoelectric and synaptic activity has ceased (Michenfelder, 1974). Reductions in cerebral metabolism
below the isoelectric threshold may be obtained with
techniques acting not only on synaptic activity: for
example lignocaine (impedes membrane ionic flux),
ouabain (blocks ionic p u m p s ) , and hypothermia
(slows chemical reactions) (Astrup, Sorensen and
Sorensen 1981a, b). Combinations of barbiturates
with lignocaine or hypothermia, or both, are additive with regard to C M R depression (Lafferty et al.,
1978; Hagerdal et al., 1979; A s t r u p , Sorensen and
Sorensen, 1981b). However, when the EEG is already
isoelectric from extreme hypothermia (18 °C), the
addition of barbiturates-does not reduce metabolism
further (Steen et al., 1983).
Subcellular biochemical events which characterize barbiturate anaesthesia include a reduction in
glycolytic flux accompanied by increased tissue concentrations of glucose, glucogen and phosphocreatine (Strang and Bacheland, 1973; Carlsson,
Harp and Siesjo, 1975; Siesjo, 1978; Benzi, Agnoli
and Dagani, 1979; Harvey, 1980). Maintenance of a
normal energy charge potential (of adenine phosphate compounds) indicates that barbiturate anaesthesia does not result from energy deprivation, but
rather from blockade of neuronal transmission
(Siesjo, 1978). W h e n C M R oxygen is reduced by
50% with thiopentone, glycolytic flux is retarded at
the phosphofructokinase step (Carlsson, Harp and
Siesjo, 1975). While confirming phosphofructokinase inhibition during beta frequency EEG discharges, other studies indicate a shift toward
reduced hexokinase activity at deeper levels of
anaesthesia (Krieglstein and Sperling, 1981).
Hexokinase inhibition is postulated to result from
barbiturate solubilization of membrane binding of
the enzyme (Krieglstein and Sperling, 1981). Other
metabolic changes include reduced flux and pool
size in the citric acid cycle and alterations in amino
acid ratios secondary presumably to reduced delivery
of pyruvate (Carlsson, H a r p and Siesjo, 1975).
BARBITURATES AND PROTECTION AGAINST CEREBRAL
ISCHAEMIA: PREVENTION AND TREATMENT
For the purposes of the following discussion prevention is defined as therapy administered before an
83
anticipated ischaemic episode that limits subsequent
neuronal loss or infarction. Treatment consists of
therapy begun after or during brain ischaemia which
limits the pathological consequence of the ischaemic
insult. Ischaemia occurs whenever metabolic
demands are not coupled with blood flow sufficient
to prevent a shift to anaerobic metabolism. Within
this context, relative ischaemia occurs whenever an
increase in metabolism outstrips compensatory
blood flow increases and there is a resultant loss of
aerobic metabolic capacity. Prolonged generalized
seizure activity is an extreme example of this situation.
N u m e r o u s theories have emerged to explain the
ability of barbiturates to prevent or treat brain
ischaemia under a variety of circumstances. Definitive proof has not emerged for a single protective
mechanism of barbiturates, and it is possible that a
combination of actions may prevent or reduce the
effects of cerebral ischaemia in specific disease
states. Presently, most therapeutic approaches to
treatment.of ischaemic brain are based upon the
principle of improving the ratio of oxygen supply to
oxygen demand (Steen and Michenfelder, 1980).
Barbiturate therapy for acute ischaemic brain disease can improve this ratio via its anticonvulsant,
metabolic and cerebral vascular effects. Reduction
of C M R is probably responsible for prolonged survival of animals under lethal hypoxic conditions
(Wilhjelm and Arnfred, 1965; Steen and Michenfelder, 1979; Artru and Michenfelder, 1981). Similarly, suppression of normal or hypermetabolic conditions, or both, in the border zone ischaemic tissues
(penumbra) surrounding a brain infarct produced
by occlusive vascular disease improves the oxygen
supply:demand relationship. Barbiturate-related
increases in vascular resistance in non-diseased areas
of the brain may shunt flow into regions of critically
reduced C B F in focal cerebral vascular disease. T h e
same vascular action in situations of intracranial
hypertension can decrease ICP, increase the overall
cerebral perfusion pressure (CPP = AP - ICP),
and shunt blood into flow-compromised areas.
Seizures related to ischaemia are potentially
dangerous, since flow is already compromised and
the metabolic demand is extremely high. In this situation, the anticonvulsant action of barbiturates is
probably the paramount protective mechanism
(Michenfelder, 1982; T o d d et al., 1982).
Molecular mechanisms of barbiturate protection
are more controversial, as a result partly of incomplete understanding of the critical molecular events
leading to ischaemic tissue death. They include
84
BRITISH JOURNAL OF ANAESTHESIA
stabilization of lysosomal membranes, quenching of
free radical reactions, and reduction of intracellular
calcium concentrations and modified amino acid or
neurotransmitter release (Steen and Michenfelder,
1980). Among barbiturates, only thiopentone has
significant free radical scavenging properties
(Smith, Rehncrona and Siesjo, 1980).
and cardiovascular actions of the drugs tested. The
model is also critically dependent upon temperature
and the degree of hypoxia. Too much oxygen and all
survive; too little oxygen and all die, without regard
to the drug being evaluated. Extrapolation of any
protective action in this model to clinical cerebral
ischaemia should be tempered by recognition of its
evanescent protective actions over an extremely narrow range of tissue ischaemia.
Specific Applications of Barbiturate Protection
Hypoxia
Laboratory. Twenty years ago, several anaesthetic
agents were found to have a protective action in mice
breathing 5% oxygen in nitrogen (Arnfred and Secher, 1962; Wilhjelm and Arnfred, 1965). In this
model, protection consisted of prolonged survival as
determined by observation of last gasp activity.
Although several anaesthetics conveyed protection
in this model, barbiturates emerged as conferring
significantly greater protection (Wilhjelm and
Arnfred, 1965). More recent studies with the
hypoxic mouse model indicate that it is the anaesthetic action of barbiturates rather than brain barbiturate concentration that is associated with protection
(Steen and Michenfelder, 1979). In mice rendered
tolerant to barbiturates, the hypoxic survival curve
was shifted to the right; that is, higher doses were
required to obtain the same protection (Steen and
Michenfelder, 1979). Hypothermia alone also
increases survival times, and the addition of either
pentobarbitone or phenytoin to moderate hypothermia further improves survival (Steen and Michenfelder, 1980; Artru and Michenfelder, 1981). Further
support for this concept is that barbiturate suppression of functional brain activity, rather than a direct
molecular action is protective and is drawn from tissue culture studies of hypoxic neurones. Anoxic
exposures of mature hippocampal cell cultures
resulted in neuronal death, unless synaptic transmission was inhibited by magnesium (Rothman,
1983). It appears that any manoeuvre impairing normal or excess neurotransmission should have a role
in protecting ischaemic brain.
Focal ischaemia
The ability of barbiturates to reduce the expected
area of cerebral infarction has been documented
repeatedly under a variety of experimental conditions associated with focal brain ischaemia. The
number of variables influencing the outcome of individual studies are many and include the dose, timing
and duration of administration of the barbiturate, in
addition to the permanent or transient nature of the
cerebral vascular occlusion, species selected for
study, vascular anatomical variables, incidence of
seizures, and cardiovascular responses. Procedures
calling for permanent vascular occlusion relate to the
clinical stroke syndrome, while those associated
with transient occlusive periods may provide
anaesthetic management guidelines during cerebral
vascular reconstructive surgery.
Acute focal ischaemia results in unpredictable
heterogenous changes in local CBF and time-dependent neuronal injury (Garcia, 1984). Survival of foeally ischaemic tissue appears to depend upon maintaining a critical balance between blood flow and
metabolism. In focal ischaemia, barbiturates are
believed to accomplish this by reducing metabolism
and improving collateral flow. Other drugs (calcium
blocking agents, lignocaine, etc.) which reduce
metabolism and techniques aimed at improving collateral flow to ischaemic tissue are available (Shapiro, 1984; Gisvold and Steen, 1985). These may
share some common mechanisms with barbiturates
and include decreasing ischaemic vasospasm, reducing cerebral oedema, improving CBF rheology,
decreasing ICP, and antiprostaglandin and antiplatelet activities (Garcia, 1984). Increasing local
cerebral perfusion pressure by increasing arterial
While the hypoxic mouse model provides a pressure and shunt devices remain the mainstay of
screening procedure in recognition of drugs with a intraoperative brain protection.
very specialized protective action, it gives us little
Laboratory. During acute middle cerebral artery
more information than recognizing an anaesthetic
effect (with related CMR depression) and has no occlusion, measurement of cerebral oxygen availadirect clinical application. Retention of last gasp bility revealed an increase in the flow:metabolism
activity is a complex event. Besides relating to a cere- ratio in ischaemic cortex produced by barbiturates
bral protective effect it may also reflect respiratory (Feustel, Ingvar and Severinghaus, 1981). Local
BARBITURATES IN BRAIN ISCHAEMIA
cerebral blood flow studies under similar experimental conditions suggest that the increase in oxygen availability relates to a homogenizing influence
of barbiturates on CBF distribution in ischaemic
cortex (Branston, Hope and Symon, 1979). Brain
intracellular pH during focal ischaemia decreases
less in barbiturate-anaesthetized monkeys than in
those given halothane (Anderson and Sundt, 1983).
While this may represent barbiturate protection, it
could also result from a direct toxic or CBF effect of
halothane (Michenfelder and Theye, 1975). Barbiturates prolong the duration of evoked potential
activity in ischaemic primate cortex, but have no
effect on the ischaemic threshold for intracellular
potassium efflux (Branston, Hope and Symon, 1979;
Astrup, Siesjo and Symon, 1981). Prolongation of
evoked potentials represents protection of brain
function as it relates to CMR, while potassium efflux
is considered a sign that cellular homeostasis is
threatened.
Barbiturates given before or following permanent
cerebral vascular occlusion have been shown to
reduce significantly the area of infarction in a
number of species (Smith et al., 1974; Moseley, Laurent and Molimari, 1975; Michenfelder, Milde and
Sundt, 1976; Selman et al., 1981b). A few reports
suggest that the use of barbiturates may increase the
area of infarction when the vascular occlusion is permanent and barbiturates cause hypotension, which
limits development of collateral flow (Rockoff, Marshall and Shapiro, 1979; Selman et al., 1981b).
In primates subjected to permanent middle cerebral artery occlusion, the reduction in infarct size was
proportional to the dose of barbiturate and effective
treatment could be demonstrated when institution
(Levy and Brierley, 1979; Hoff et al., 1975) of
therapy was delayed from 30 min to 2 h (Smith et
al., 1974; Moseley, Laurent and Molimari, 1975;
Michenfelder, Milde and Sundt, 1976; Tamura et
al., 1979; Selman et al., 1981b; Spetzler et al.,
1982). Several studies in animals with permanent
cerebral vascular occlusions indicate that protective
mechanisms other than CMR reduction may contribute to reduction in infarct size. In comparative
studies in cats, the same degree of cerebral protection was obtained during MCA occlusion with pentobarbitone and imidazole derivative (Tamura et al.,
1979; Ochiai et al., 1982). Equal degrees of infarct
reduction in these experiments were obtained
despite considerably less CMR depression by the
imidazole, and in the absence of a barbiturateinduced flow increase in the ischaemic cortex. When
pentobarbitone and hypothermia are compared at
85
concentrations resulting in similar CBF and CMR
effects, only the barbiturate significantly reduced
ischaemic cerebral oedema in monkeys with MCA
occlusion (Simeone, Frazer and Lawner, 1979).
Thus protective mechanisms probably exist in
addition to the cerebral haemodynamic and
metabolic influences upon focally ischaemic brain
tissue.
Barbiturates also have protective effects in
models of focal cerebral ischaemia in which a transient period of vascular occlusion is followed by recirculation (Levy and Brierley, 1979; Selman et al.,
1981b). While it seems reasonable to expect that barbiturate protection conferred during permanent
cerebral vascular occlusion would also extend to
transient occlusion, the additional factor of reperfusion into zones of previously severely ischaemic tissue needs consideration. In situations of relatively
short occlusion, such as those associated with vascular reconstructive surgery, no additional problems
should be expected. However, when flow is restored
to an area that has begun the process of infarction,
recirculation may enhance oedema and haemorrhagic infarction (Selman et al., 1981 b). In a series of
baboons subjected to either permanent or transient
MCA occlusion, reperfusion after 6 h of cerebral
ischaemia was more detrimental in the absence of
protective measures than continued occlusion (Selman et al., 1981b). In these experiments, when the
same period of occlusion was followed by reperfusion, barbiturate-induced coma maintained (started
30 min after occlusion) for 96 h, provided nearly
complete protection. Barbiturate dose was adjusted
to maintain the EEG potential at less than 2 /JLV and
with arterial pressure maintained within 15% of control. Intracranial hypertension was prevented only
in the group treated with this procedure. In a similar
series of laboratory therapeutic trials, high dose barbiturate anaesthesia, begun 30 min following MCA
occlusion and maintained during an extracranial to
intracranial vascular shunting procedure, appeared
to confer protection (Spetzler et al., 1982).
Clinical. While the concept of brain protection by
barbiturates during focal cerebral ischaemia seems
established by laboratory studies, clinical experience has been very limited and anecdotal. A compelling reason for slow translation of positive animal
findings into clinical practice relates to the reluctance of clinicians to subject the older population,
prone to stroke, to the dangerous side effects and
intensive supportive care required with high-dose
barbiturate therapy. Also, many occlusive stroke
patients remain conscious despite severe focal
86
BRITISH JOURNAL OF ANAESTHESIA
neurological deficits. In a series of four patients with
inadvertent permanent intraoperative MCA
occlusion treatment promptly with 5 days of highdose barbiturate therapy, all died of intracranial
hypertension which developed when the barbiturates were discontinued (Rockoff, Marshall and
Shapiro, 1979). In untreated patients with the same
lesion, increased intracranial pressure developed
approximately 2 days earlier and was the cause of
death. Thus, it appears that barbiturate therapy
retarded processes relating to formation of cerebral
oedema or loss of cerebral vasomotor control, or
both. This mechanism may be important in naturally occurring clinical stroke with a great potential for
development of collateral blood flow and dissolution
of embolic occlusion. In the four patients in the
study described above, reperfusion and collateralization potential was absent because the occlusive
agent was intravascular embolization of a polymer
material (Rockoff, Marshall and Shapiro, 1979).
More recently, a patient with severe eclampsia complicated by hemiplegia and intracranial hypertension made an excellent neurological recovery after 12
days of high-dose barbiturate treatment (Caseby,
1983).
The most frequent potential clinical application of
barbiturate therapy for protection during focal
ischaemia occurs during extra- and intracranial
revascularization procedures. In this instance,
anaesthesia is usually required, thereby reducing the
additional risk to the patient. Most procedures
suggest maintenance of high concentrations of barbiturate for periods less than the duration of the total
surgical procedure and this further limits the risk.
While reduced risk may be inherent in the
intraoperative use of barbiturate therapy, determination of the risk:benefit ratio may be very difficult. This problem is compounded by the existing
low incidence of neurological morbidity and mortality in correctly selected patients operated upon by
experienced and skilled surgeons. Further com-
plicating the problem of evaluating the efficacy of
intraoperative barbiturate therapy, is that the
suggested dose schedules are very different from
those found necessary in the laboratory and without
substantiation of their clinical effect. Table I lists
various objectives and dose ranges associated with
intraoperative use of barbiturates. For example,
many centres use thiopentone 4-5 mg kg"',
administered just before internal carotid artery
occlusion during carotid endarterectomy. This
results in an average period of 5 min of EEG burstsuppression, while the carotid occlusion period is up
to five times longer in duration (Moffat et al., 1983).
It is possible that local CMR depression by barbiturate retention within poorly perfused brain areas
persists and is not detected by the surface EEG electrodes. This might result in locally reduced
metabolism which could result from either
uncleared barbiturate or ischaemia, or both. In addition, preferential shunting of blood from barbiturate-induced cerebral vasoconstriction in well perfused tissue is not possible for prolonged periods as
a result of almost immediate washout of the drug. In
this milieu, it appears that an extraordinarily large
prospective study will be required to establish the
intraoperative efficacy of barbiturate protection.
When intracranial microvascular procedures are
performed, more sustained blood barbiturate concentrations are usually suggested since the occlusion
periods are longer and the potential for sufficient
collateral circulation less than with carotid endarterectomy. There are isolated reports of barbiturate
protection during temporary intracranial vascular
occlusion for aneurysm surgery, in addition to
extracranial-intracranial shunting procedures (Hoff,
Pitts and Spetzler, 1977; Spetzler et al., 1982). In one
of these patients operated on under thiopentone
anaesthesia (46 mg kg~'/5 h) a marked hemiparesis
developed 48 h after operation as a result of a clotted
shunt (Spetzler et al., 1982). Removal of the clot,
again under barbiturate protection, resulted in
TABLE I. Intraoperative use of thiopentone therapy
Load
(mgkg" 1 )
Time
(min)
2-2.5
4
3
Maintenance
(mgkg" I min~ 1 )
Peak
OigmT1)
1-1.5
38-42
—
20
10
10
—
—
75
60
0.1-0.2
80
Indication
Anaesthesia
Burst-suppression
Vascular surgery
Vascular surgery
Author
Becker and others (1977)
Moffat and others (1983)
Spetzler and others (1982)
Todd and others (1982)
87
BARBITURATES IN BRAIN ISCHAEMIA
resolution of the hemiparesis. While resolution of
the deficit may have been unlikely without re-operation, the role of barbiturates in this process cannot
be established without further systematic clinical
studies.
At present, it is difficult to suggest specific
guidelines for the intraoperative use of high doses of
barbiturates for brain protection during revascularization. However, at least two different approaches
are possible, based on different rationales. The first
approach (favoured by this author) consists of identifying high risk patients by trial vascular occlusion
(of at least 5 min) with EEG monitoring. If this
occlusion results in EEG abnormalities that cannot
be corrected by a temporary shunt or if a shunt is not
technically feasible, or both, then barbiturates may
be administered. They should be given after the
temporary test occlusion has been released and the
EEG returns to its normal baseline. If the EEG does
not recover, the occurrence of an embolic event is
presumed and high dose thiopentone should be sustained for a longer period than described below. Protection for temporary vascular occlusion should be
achieved with thiopentone given in doses sufficient
to achieve an isoelectric EEG or burst suppression
patterns, or both. Drug administration continues for
the duration of occlusion and then ceases. A grossly
asymmetric EEG pattern on emergence in a previously normal patient suggests intraoperative brain
ischaemia and barbiturates should be recommenced
as diagnostic studies or reoperation, or both, is
initiated. Administration of fluids i.v. and vasopressors are used to maintain arterial pressure, to within
30% of the highest baseline ranges obtained before
operation.
The second approach to the use of barbiturates for
prevention of brain ischaemia during revascularization surgery assumes that these drugs always provide a greater margin of safety than the risks
involved in their use. In this instance they are used
routinely before clamping with or without a test
occlusion period or plans to use a shunt device. The
guidelines for the administration schedule remain
the same as noted above. This author does not know
of any laboratory trial indicating that a single dose of
thiopentone given to achieve a very short (5-10 min)
EEG burst suppression period is sufficient to provide protection against brain ischaemia of significantly longer duration (Moffat et al., 1983). In the
absence of such studies, it is premature for
generalized clinical application of high dose barbiturate therapy for brain protection for permanent or
transient focal ischaemia (Yatsu, 1982).
Global brain ischaemia
Before discussing the available data describing
application of barbiturates in the treatment of global
cerebral-anoxic-ischaemic insults, it is important to
define the relationship of the timing of therapy to the
aims of treatment. Presumably, when barbiturates
are given immediately following a cardiac arrest,
they are administered to block pathophysiological
events leading to neuronal death. Following
neuronal death, brain swelling may occur and barbiturates could be administered to reduce intracranial pressure, and block further compromises of
cerebral perfusion pressure. However, intracranial
hypertension following cardiac arrest is a late
occurrence and denotes widespread neuropathology
and usually does not result in brainstem compression (Graham, 1985). This circumstance will be
reviewed under intracranial hypertension control,
while the data discussed here relate to the immediate
prevention of neuronal death.
Laboratory. An important study on barbiturate
protection during global brain ischaemia, published
in 1966, indicated that pentobarbitone anaesthesia
before the insult was protective (Goldstein, Wells
and Keats, 1966), but these results could not be
reproduced by another laboratory using the same
model with brain ischaemia produced by aorto—vena
caval clamping (Steen, Milde and Michenfelder,
1979).
In 1978 a report was published indicating that
massive doses of barbiturate administered after 16
min of selective cerebral circulatory arrest ameliorated brain damage (Bleyaert et al., 1978). This
study obtained selective cerebral circulatory arrest
by using a high pressure neck tourniquet, deep
halothane anaesthesia, ganglionic blockade and
positive airway pressure. Assessment of CBF was
not peformed in individual animals and the chance
of partial reperfusion during the arrest period could
not be excluded. In addition, different programmes
of supportive care were used for the control and
treatment groups (Bleyaert et al., 1978; Rockoff and
Shapiro, 1978). When the study was repeated in the
same laboratory with control of these factors, no
benefit from thiopentone was found (Gisvold et al.,
1984). Another group used ventricular fibrillation
followed by resuscitation and a prolonged period of
intensive care (Todd et al., 1982). They found
increased survivors among the thiopentone treated
animals and this was attributed to suppression of seizures. However, the surviving treated animals had
the same degree of neurological impairment as the
88
untreated controls. While this study supports the concept that postcardiac arrest therapy may influence
neurological outcome, it does "not necessarily indicate that barbiturates are required. Other anticonvulsants, with less profound brain depressant and
circulatory effects, may accomplish the same goal at
reduced risk.
The conclusion emerging from most global cerebral ischaemia resuscitation studies is that immediate
post-resuscitation supportive care (including rapid
restoration and maintenance of cerebral perfusion
pressure and normal arterial blood-gas tensions) can
influence neurological outcome (Gisvold et al.,
1984). Other therapeutic approaches aimed at limiting post-arrest brain pathophysiology include correction of late perfusion abnormalities and blocking
biochemical pathways leading to autolysis or formation of toxic metabolites (Shapiro, 1984).
Only one prospective randomized clinical trial of
thiopentone loading following cardiopulmonary
arrest has been accomplished (Abramson et al.,
1983). This international co-operative study
examined 281 patients and found no difference between the thiopentone-treated patients and those
receiving standard post-arrest care. Thus, the clinical findings are in agreement with the laboratory
data and do not support the use of barbiturates after
resuscitation from cardiac arrest.
Intracranial hypertension
Uncontrolled intracranial hypertension causes
focal or global reductions in cerebral perfusion pressure resulting in localized or generalized cerebral
ischaemia, or both. Severely increased ICP is
encountered most commonly in head injured
patients. When ICP persistently exceeds
25 mm Hg in this group of patients, mortality ranges
from 80% to 100% (Marshall, Smith and Shapiro,
1979a; Miller, 1979; Saul and Ducker, 1982). Successful attempts to reduce severely increased ICP
correlate with improved outcome (Becker et al.,
1977). The ability of barbiturates to reduce
increased ICP probably represents the major
protective mechanism in intracranial hypertension.
In addition, the protective mechanisms outlined for
focal ischaemia may also apply when the ICP is high,
since scattered regions of low CBF also exist.
Laboratory. Precise laboratory models for intracranial hypertension complicating head injury or
infectious disease are not available. However,
laboratory models resulting in one or more of the
pathological processes recognized in clinical cases of
BRITISH JOURNAL OF ANAESTHESIA
intracranial hypertension have been developed.
These pathophysiological conditions include cerebral vasomotor paralysis, cerebral oedema and acute
hydrocephalus. When cerebral vasomotor paralysis
is present, swelling of the intravascular blood compartment occurs (Langfitt, 1968). This can develop
suddenly, with stimulation of certain brain areas, or
more gradually during expansion and deflation of an
extradural balloon. Barbiturates have been found to
be effective in reducing increased ICP secondary to
vasoparalysis or cerebral oedema, or both (Langfitt,
1968; Ischii, 1976; Smith and Marque, 1976). This
therapeutic action is presumed to result from
increase in cerebral vascular resistance which
reduces cerebral blood volume and may also reduce
vasogenic cerebral oedema by increasing proximal
arteriolar resistance or reducing systemic arterial
pressure, or both. The timing of administration of
barbiturates may be important in relation to the
pathophysiological phase of the intracranial hypertension. When barbiturates are administered before
deflation of an extradural balloon, cerebral perfusion pressure decreases without a reduction in ICP
(Bricolo and Glick, 1981). Thus if therapy is
initiated at a stage when the cerebral vasculature is
compressed by an extradural haematoma, arterial
hypotension caused by the drug may increase the tendency to develop cerebral ischaemia.
Clinical. In the 1930's, several reports indicated
that administration of barbiturates to patients
resulted in either a reduction or no increase in cerebrospinal fluid (CSF) pressure (Butler, 1936;
Horsley, 1937; Gurdjian, Webster and Sprank,
1939). This effect was dose-dependent and did not
occur with sub-hypnotic doses (Horsley, 1937).
Thirty years later, these results were confirmed
when either a thiopentone or pentobarbitone induction of anaesthesia was noted to be accompanied by
a reduction of increased ICP in a small series of
neurosurgical patients (Sondergard, 1961). In 1973,
thiopentone was reported to reduce an increased
ICP, while improving the overall CPP during induction of anaesthesia (Shapiro, Galindo and Wyte,
1973). This report clearly indicated that ICP reduction was not an event dependent upon reduction of
arterial pressure, but resulted directly from an
intracranial effect of the drug. The principle of
inducing anaesthesia with a drug possessing potent
cerebrovasoconstrictive properties was established,
and thiopentone remains one of the most commonly
used drugs for inducing anaesthesia in patients with
intracranial hypertension. Use of barbiturates to control intraoperative episodes of increased ICP pro-
BARBITURATES IN BRAIN ISCHAEMIA
89
duced by noxious stimuli is generally accepted age 15-50 yr, a recent computerized tomographic
(Shapiro, 1975; Bedford et al., 1980). Barbiturates brain scan, removal of operable haematoma, and faihave also been used successfully as part of a multi- lure of conventional aggressive therapy to control
modal therapy to control acute malignant ICP (less than 25 mm Hg for 30 min, less than
intraoperative brain swelling (Day et al., 1982).
30 mm Hg for 15 min, or less than 40 mm Hg for 1
There have been several non-randomized clinical min or longer). Conventional therapy for ICP contrials of high dose barbiturate therapy to reduce trol as defined in this study includes steroids,
muscle
intracranial hypertension complicating cranio- anticonvulsants, adequate sedation,
cerebral trauma. The first clinical application of this paralysis, recent administration of mannitol, PaCO7
approach was in 1974 and utilized a combination of less than 4 kPa (30 mm Hg), PaOi greater than 9.3
coma-inducing doses of pentobarbitone and kPa (70 mm Hg) and, when possible, drainage
hypothermia to control persistently increased ICP of CSF. Guidelines for the care of patients in this
(Shapiro, Wyte and Loser, 1974). Following this study include avoidance of hyperthermia and
initial report, other clinical studies indicated that maintenance of cardiovascular stability, using a
ICP control could be obtained without inducing Swan-Ganz catheter to guide fluid and circulatory
hypothermia (Marshall, Smith and Shapiro, 1979b; drug administration. Preliminary results describing
Frost et al., 1981; Hoppe, Christensen and Christ- the experience with the first 40 patients randomized
ensen, 1981; Sidi et al., 1983). This decreased the into the study should have become available in late
logistical requirements for the therapy, and also 1984.
improved the margin of safety by avoiding
High-dose barbiturate therapy has also been
hypothermia-induced cardiac arrhythmias.
utilized for control of ICP in a variety of nonIn comparing clinical experience with high-dose traumatic conditions associated with intracranial
barbiturate therapy for ICP control in different hypertension. These include near-drowning
institutions, several factors become clear. The first encephalopathy, Reye's syndrome and subconcerns the fact that this is a major undertaking arachnoid haemorrhage (Marshall et al., 1978;
requiring continuous intensive care support for days Belopavlovic and Buchthal, 1980; Conn et al., 1980;
or weeks. A majority of the patients respond initially Woodcock, Ropper and Kennedy, 1982). No conto barbiturate administration with reductions in trolled studies exist in these situations, and although
ICP, often accompanied by increased CPP. How- initial reduction in ICP may often be obtained in
ever, ICP control may only be transient, and the cases of non-traumatic intracranial hypertension,
relationship of barbiturate-related reductions in ICP later in the course, increased ICP is often associated
to functional neurological outcome remains unclear. with brain death. This may be the case in this categCurrently, a multicentre trial is in progress of ory of patient, because brain swelling is likely to be
high-dose barbiturate therapy for ICP control in the result of neuronal death, rather than its cause (as
head injured patients (L. F. Marshall, 1985, per- is often the case in head trauma). Table II lists the
sonal communication). The study has strict entry indications and dose ranges for high-dose barbitucriteria which include: Glasgow Coma Score of 3-7, rate therapy as applied in the intensive care unit.
TABLE II. The use of barbiturate therapy in the ICU
Load
(mgkg"1)
Maintenance
(nig kg"'min" 1 )
Range
Thiopentone
2
2
15
Sedation
Thiopentone
—
2-A
54
Increased ICP
Increased ICP
Increased ICP
Increased ICP
Pentobarbitone
Pentobarbitone
Pentobarbitone
Indication
4-7
\-A
—
15-35
0.5-1.3
2-3.5
20-40
25-36
—
Author
Carlton, Karl and
Goldiner(1978)
Lundar, Ganes and
Lindegaard(1983)
Traeger and others (1983)
Schaibleandothers(1982)
Marshall and others (1978)
90
BRITISH JOURNAL OF ANAESTHESIA
Technique of High Dose Barbiturate Therapy
Whilst not endorsing the general application of this
therapy at the present time, the author recognizes
that, in some individual and compelling clinical situations, barbiturates may be the only remaining
therapeutic tool. This management outline is presented in the hope of improving patient safety as we
await the results of studies which will clearly establish the indications and procedures for high-dose
barbiturate therapy.
The following guidelines for the management of
continuous high-dose barbiturate therapy for intracranial hypertension focus on the intensive care unit
phase of therapy.
While directed mainly toward control ot persistently increased ICP, these guidelines are applicable, with modifications, to patients with ischaemic
cerebral vascular disease. In patients with severe
intracranial hypertension, coma already exists and it
may or may not be present in individuals with occlusive stroke. Patients with large cerebral hemisphere
infarctions are prone to develop increased ICP as the
terminal event (Ng and Nimmannita, 1970).
Side effects
Dose-dependent cardiovascular and ventilatory
depression are the major side effects of large doses of
barbiturates. In the ICU, the lungs of patients with
increased ICP who are candidates for this treatment
will already be mechanically ventilated. Much of the
antecedent therapy reducing or preventing the
development of intracranial hypertension involves
diuretics and fluid restriction. This results in systemic dehydration and intravascular volume depletion. In this situation, the cardiovascular depressant
effects of barbiturates are potentiated and severe
hypotension with or without cardiac decompensation can occur (Shubin and Weil, 1965; Skovsted,
Price and Price, 1970;Traegeretal., 1983). Barbiturates increase the capacitance of the venous bed by
central and peripherial sympatholytic effects (Skovsted, Price and Price, 1970; MacKenzie, McGrath
and Tetrault, 1976). In the absence of intravascular
volume depletion, the direct cardiac effects of relatively high doses of barbiturates are minimal
(Becker and Tonnesen, 1978; Chamberlain, Seed
and Chung, 1977). Direct myocardial depression
and, to a lesser extent, direct vasodilatation from
barbiturates are likely to occur only when large
bolus doses are administered rapidly (Altura and
Altura, 1975; Chamberlain, Seed and Chung, 1977).
These dangerous side effects can be obviated by slow
administration of the loading dose and by adequate
prior restoration of circulating blood volume. Fluid
replacement should be accomplished with isotonic
electrolyte or colloidal solutions under right atrial or
pulmonary capillary wedge pressure monitoring
(Traeger, et al., 1983) Rapid reductions in serum
osmolality and overexpansion of vascular volume
should be avoided, as they increase the propensity
for development of cerebral oedema.
High doses of barbiturates interfere with thermoregulation and render the patients poikilothermic (Dominguez de Vilotta et al., 1981). Active
warming or cooling may be required to maintain
core temperature at 33-39 °C. As gastrointestinal
motility is inhibited by high-dose barbiturate
therapy, gastrointestinal feeding is contraindicated
and nasogastric decompression required. Urinary
output decreases in proportion to reductions in cardiac output and tubular reabsorption of glucose and
sodium (Harvey, 1980). Barbiturates can increase
hepatic microsomal activity, leading to alterations in
biotransformation of barbiturates in addition to
other drugs and hormones. While clinical experience indicates that infections complicating the management of prolonged coma are frequent, they are
more likely to result from immobility and invasive
monitoring than from a direct influence of barbiturates on bacterial clearance (Archer et al., 1981).
Skilled nursing is a major requirement for the successful application of high-dose barbiturate therapy.
Monitoring
The selection of monitoring devices is based upon
the need to assess direct cerebral effects of treatment, and to control deleterious cardiovascular-pulmonary side effects. Specialized monitoring for
intracranial events related to the disease process or
its response to treatment, or both, includes
neurological examination, ICP measurement, EEG
recording and, occasionally, computerized tomography (L. F. Marshall, 1985, personal communication).
Neurological examination during barbiturate
coma is limited. Occasionally, deep tendon reflexes
may be preserved, while brainstem signs (such as the
oculo-cephalic and corneal reflexes and spontaneous ventilation) are abolished (L. F. Marshall, 1985,
personal communication). Pupil size and configuratin remain useful determinants of brain deterioration even in the presence of high blood barbiturate
concentrations. In this situation, they are usually
constricted and non-reactive to light, but rapidly
91
BARBITURATES IN BRAIN ISCHAEMIA
become dilated in response to brain herniation,
hypoxia or reductions in CPP. Pupil alterations or
abrupt persistent increases in ICP, or both, are indications for computerized tomography.
ICP monitoring is an absolute requirement for
application of high-dose barbiturate therapy in head
injured patients. It is probably also indicated when
this therapy is applied to stroke patients, especially
when the area of infarction is expected to be large.
The preferred route for ICP monitoring is the ventricular catheter, as it provides a route for rapid volume decompression of the intracranial space. The
subarachnoid bolt may be used when ventricular
shift or collapse prevents easy access to the ventricular CSF space. ICP monitoring should be continued
for 24-48 h following clearance of barbiturates from
the, blood after cessation of therapy.
Recording of EEG is a useful adjunct to monitoring high-dose barbiturate therapy in head injured
patients. In stroke patients, continuous recording of
the EEG is mandatory as it provides a major guide to
barbiturate dose.
A number of investigators have questioned the
validity of EEG monitoring (Kassell et al., 1980; Selman et al., 1981a). When ICP is high, cerebrovascular and cerebral blood volume responses to barbiturates may be unpredictable and bear little relationship to the EEG effect of the drug. Also, when the
EEG is already abnormal or severely depressed, its
effectiveness in determining the optimal dose of barbiturates may be questioned. In most instances of
occlusive stroke, the opposite hemisphere EEG is
usually intact and useful for guiding therapy. In certain situations where EEG activity is isoelectric,
either from barbiturates or the disease process, measurement of auditory evoked potentials may be helpful. This measurement is useful in determining
brainstem viability (Starr, 1976; Lundar, Ganes and
Lindegaard, 1983). This type of monitoring of certain
brainstem functions is possible because the auditory
response potentials are resistant to very high doses of
barbiturates (Prior, 1985).
During the loading and acute maintenance phase
of barbiturate therapy, the (weight) pre-determined
dose, rate of administration, and blood concentrations correlate poorly with the cerebral metabolic
and haemodynamic responses (Kassell et al., 1980;
Selman et al., 1981a). In this situation, the EEG correlates best with the CBF and CMR changes until
the EEG plateaus at an isoelectric or burst suppression pattern. In the more chronic phases of maintenance of barbiturate coma, there is evidence to
suggest that the relatively coupled relationship of
the EEG to CBF and CMR may be broken (Gronert et
al., 1981). This may be a manifestation of development of cerebral metabolic tolerance to barbiturates.
Continuous measurement of systemic arterial
pressure is required when high dose barbiturate
therapy is used. Since arterial and cerebral perfusion
pressures are important determinants of barbiturate
dosing, continuous monitoring of arterial pressure is
required during induced barbiturate coma. The
arterial catheter also provides access for obtaining
arterial blood for determination of blood-gas status.
A Swan-Ganz catheter completes the required invasive monitoring and is extremely useful in guiding
replacement of fluid and the use of vasopressors.
More generalized requirements include an i.v. cannula, nasogastric tube, ECG monitor, temperature
determination, urinary bladder catheter and access
to a laboratory which can rapidly perform blood
barbiturate concentration determinations on a daily
basis.
Induction and maintenance of high dose
barbiturate therapy
In the ICU, pentobarbitone is the most widely
used barbiturate for control of ICP and reduction of
infarct size. Pharmacokinetic factors favouring the
rapid central nervous system uptake and redistribution of thiopentone are unimportant when therapy is
applied for several days. Pentobarbitone is
associated with a more gradual onset of cardiovascular side effects and may therefore be safer. While no
strict guidelines have been developed for induction
and maintenance of high-dose barbiturate therapy,
there is general agreement with regard to diseasespecific therapeutic objectives. With intracranial
hypertension the objective is reduced ICP with
increased CPP. In focal cerebrovascular disease, the
objective is induction of an EEG burst-suppression
or isoelectric pattern and prevention of an ICP
increase. These objectives should be achieved with
minimal reduction in arterial systemic pressure.
The multicentre barbiturate trial for head injured
patients can be used to provide reasonable
guidelines for high dose barbiturate therapy (L. F.
Marshall, 1985, personal communication). The initial portion of the loading dose of pentobarbitone is
10 mg kg - 1 administered over 30 min with
administration rate determined by the cardiovascular response. The objective is to maintain a mean
arterial pressure in excess of 70 mm Hg, and cardiac
filling pressures sufficient to maintain a cardiac
index of 2 litre min"1 m~2. Following this, pentobarbitone 5 mg kg"1 is given each hour for the
92
BRITISH JOURNAL OF ANAESTHESIA
next 3 h. Over the first 4 h of treatment, 2025 mg k g ^ m a y be administered and this should
result in a blood barbiturate concentration of greater
than 2.0 mg dl" 1 . A maintenance dose of
2.5 mg kg"1 h"1 should be given to achieve a stable
blood barbiturate concentration of 3-4 mg dl" 1 ,
and pentobarbitone concentrations should be determined at 4, 12 and 24 h after initiating therapy. If
ICP control or EEG burst suppression, or both, are
achieved before achieving the higher stable blood
barbiturate concentrations, dosage is reduced
accordingly. If hypotension below 70 mm Hg or a
reduction in CPP below 50 mm Hg, or both, ensues,
volume expansion or dopamine, or both, may be
used to correct these conditions.
Following achievement of stable pentobarbitone
concentrations and the desired therapeutic effect,
blood barbiturate concentrations should be monitored daily with appropriate intensive care support
(which includes continuing anticonvulsants—usually phenytoin). If escape of the ICP to values
exceeding 20 mm Hg occurs and the barbiturate
concentration is less than 3.0 m g d l " 1 , additional
pentobarbitone 5 mg kg""1 doses may be used to
regain control of ICP. When ICP has been maintained at less than 20 mm Hg for 48 h, or the
therapy period for stroke has elapsed (96 or more h),
gradual reduction in therapy over 2-4 days may be
attempted. Standard measures to control ICP intermittently, for example hyperventilation or osmotic
diuretics, may be required during the tapering
phase.
High blood barbiturate concentrations preclude
determination of cerebral death using EEG
methods. Cerebral death can be presumed when the
ICP and arterial pressure are equal and no intracranial blood flow can be demonstrated with angiographic techniques.
SUMMARY
This review has indicated that barbiturates are useful in controlling ICP during anaesthesia in patients
with intracranial hypertension. While laboratory
data indicate that intraoperative administration of
barbiturates during episodes of transient cerebral
ischaemia, associated with surgical revascularization
procedures, should be efficacious, current
intraoperative results claiming benefit are anecdotal. Continuous high-dose barbiturate therapy
(induced barbiturate coma) for occlusive stroke and
persistently increased intracranial pressure is currently undergoing clinical trials. While it is clear that
this therapy can often reduce increased ICP in head
injured patients, its influence on neurological outcome remains to be determined by a multicentre trial
at present in progress. Despite evidence that highdose barbiturate therapy can reduce the area of
infarction in occlusive stroke in the laboratory,
organized clinical trials have not yet commenced.
Until more definitive knowledge is available concerning the influence of high-dose barbiturate
therapy in treating different forms of cerebral
ischaemia, its application should be viewed sceptically and limited to centres willing to create an
organized data base for inter-institutional evaluation
of this form of treatment. If barbiturate therapy
proves successful and the mechanisms involved are
better understood, drugs with fewer side-effects and
risks may become available to combat cerebral
ischaemia.
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