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Cerebral vasospasm after subarachnoid hemorrhage An update.

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Cerebral Vasospasm after Subarachnoid
Roberto C . Heros, MD, Nicholas T. Zervas, MD, and Vassilios Varsos, MD
Symptomatic vasospasm, or delayed cerebral ischemia associated with arteriographic evidence of arterial consrriction,
is currently the most important cause of morbidity after acute subarachnoid hemorrhage. The development of vasospasm is directly correlated with the presence of thick blood clots in the basal subarachnoid cisterns, which can be
detected by an early computed tomographic scan. Symptomatic vasospasm usually develops between 4 and 12 days after
subarachnoid hemorrhage. The onset is gradual, occurring over hours or days. There is typically a gradual deterioration of the level of consciousness, accompanied by focal neurological deficits that are determined by the arterial
territories involved. Hyponatremia frequently occurs and may exacerbate the symptoms. The patients are usually
volume depleted, and therefore many authorities now treat them with replenishment and expansion of their intravascular volume with colloid and blood. Volume expansion, together with elevation of the systemic blood pressure and
reduction of the intracranial pressure when elevated, constitute the only currently available effective therapy for
symptomatic vasospasm. The cause of vasospasm remains obscure. Mechanisms of smooth muscle cell contraction and
relaxation and experimental efforts to elucidate the nature of vasospasm are reviewed.
Heros RC, Zervas NT, Varsos V: Cerebral vasospasm after subarachnoid hemorrhage: an update.
Ann Neurol 14:599-608, 1983
Delayed neurological deficits develop frequently as a
result of cerebral ischemia after subarachnoid hemorrhage (SAH) from ruptured aneurysms. When a patient deteriorates neurologically a few days after SAH
and obvious causes of deterioration, such as rebleeding, hydrocephalus, sepsis, and electrolyte imbalances,
are ruled out, cerebral ischemia is left as the almost
certain cause. The following observations suggest that
the neurological decline is ischemic: (1) clinically, the
deficits usually correspond to the known territories of
one or more major cerebral vessels 119, 731; (2) studies
of regional cerebral blood flow have demonstrated focally decreased flow over the clinically affected arterial
territories 13I, 351; (3) the presence of ischemic infarctions in the arterial territories involved clinically has
been confirmed both by computed tomographic (CT)
scan [68] and postmortem examination 1733; (4)the
clinical deficits have frequently responded favorably to
improvement of cerebral perfusion pressure, which
would be expected to ameliorate the effects of ischemia
[40, 44, 661;and ( 5 ) severe arterial constriction in the
arterial territories clinically involved has been detected
almost uniformly in arteriograms performed at the onset of neurological deterioration {3, 28, 73, 98). This
predictable arterial constriction seen arteriographically
has led to the widespread use of the term vasospasm.
We use the term symptomatic vasospasm to denote the
clinical syndrome of delayed cerebral ischemia associated with arteriographic arterial constriction. The latter
is referred to as arteriographic vasospasm or simply as
From the Neurosurgical Service, Massachusetts General Hospital
and Harvard Medical School, Boston, MA 02 114.
Received Mar 79, 1083, and in revised form May 23, 1983. Accepted for publication May 23, 1983.
Depending on the criteria used to define it, vasospasm
can be detected on 30 to 70% of arteriograms performed 4 to 12 days after SAH from a ruptured aneurysm [3, 23, 28, 901. However, only about 20 to 30%
of patients with SAH from a ruptured aneurysm suffer
delayed clinical deterioration from cerebral ischemia
(symptomatic vasospasm). Almost invariably, these are
the patients whose arteriograms show severe regional
or generalized vasospasm. Of these patients, about
one-half either die or are left with a serious neurological deficit {19, 33, 56, 761. At present, rebleeding
occurs in 8 to 129%of patients after aneurysmal hemorrhage 132, 671, so that vasospasm is at least as important as rebleeding as a cause of morbidity and mortality
after aneurysmal hemorrhage.
The incidence of postoperative vasospasm correlates
with the clinical grade of the patient, the degree of
preoperative angiographic vasospasm, and particularly
the timing of operation. When operation is performed
Address reprint requests to Dr Heros, Director of Cerebrovascular
Surgery, Massachusetts General Hospital, Boston, MA 02 114.
within the first week after SAH, symptomatic vasospasm develops in almost 50% of patients and about
10% sustain a severe permanent neurological deficit
[48]. Even when operation is performed after the first
week in patients in good condition, postoperative ischemia with serious clinical consequences frequently
develops in those patients whose preoperative arteriograms showed vasospasm [111. As would be expected,
the degree and severity of postoperative vasospasm
correlates highly with the surgical outcome. In one
series postoperative vasospasm was detected angiographically in about 70%, of patients with a poor outcome, but in only 14% of patients with a good outcome [3].
Cerebral vasospasm is almost never seen after SAH
from other causes, such as arteriovenous malformations or tumors. It is seen occasionally following
traumatic SAH but then is almost always associated
with severe traumatic injury to the brain. Vasospasm is
seen occasionally in the absence of SAH, usually accompanying an inflammatory process such as meningitis [33f.
Clinical and Radiographic Prediction
It is important to know which patients are likely to
develop symptomatic vasospasm after SAH. This
knowledge may influence the timing of angiography
and operation, the preoperative and postoperative
management of the patient, and the operative and anesthetic management. No correlation has been found between the occurrence or severity of vasospasm and the
age or sex of the patient, the size of the aneurysm, or
the presence of hypertension, generalized arteriosclerosis, or diabetes 13, 23, 981. The incidence of symptomatic vasospasm is slightly higher in patients with
aneurysms of the medial circle of Willis, such as an
aneurysm on the internal carotid artery, than in patients with more peripheral aneurysms, such as those
on the middle cerebral bifurcation 1281.
The most important clinical predictor of vasospasm
is the clinical grade of the patient on admission to the
hospital. For example, in a cooperative study significant
angiographic vasospasm was seen in 22% of grade I
patients and in 53% and 74% of grade IV and V patients, respectively [28). In addition, certain laboratory
data, such as peripheral blood leukocytosis and increased levels of catecholamines in blood and urine,
and electrocardiographic abnormalities such as Q
waves, elevated ST segments, peaked T waves, short
PR intervals, large U waves, and long QT segments are
predictive of vasospasm [12, 53, 621. In general, these
abnormalities reflect the degree of hypothalamic dysfunction, which correlates highly with the severity of
the SAH {95, 971.More sophisticated ancillary laboratory studies, such as regional cerebral blood flow determinations [3 1, 351 and positron emission tomography
600 Annals of Neurology
Vol 14
[29), can show a regional correlation between vasospasm and depressed blood flow and metabolism as
well as increased local blood volume.
Although the clinical and laboratory clues described
are of value, the most important and reliable way to
predict the occurrence, severity, and distribution of vasospasm is the careful study of a plain CT scan performed within 3 days of SAH [ 1 4 , 19, 5 1 ) . A strong
correlation has been found between the presence of
thick clots in the subarachnoid cisterns and the future
development of severe vasospasm in the corresponding
arterial territory. Fisher and collaborators [19], for example, found that 23 of 24 patients who had subarachnoid blood clots larger than 5 x 3 mm (measured on
reproduced CT scan images) developed serious symptomatic vasospasm in the corresponding arterial territory. Conversely, when subarachnoid blood was not
detected or was distributed diffusely in a thin layer,
symptomatic vasospasm occurred in only 1 of 18 patients. The presence of blood clots in the ventricles or
in the brain parenchyma did not affect the incidence of
vasospasm. Mizukami and colleagues [ 5 11, working independently, reported almost identical findings. Our
experience with more than 100 cases over the last rwo
P. Kistler and R. C. Heros, unpublished data,
1983) confirms a direct but imperfect correlation between thick clots seen in an early CT scan and the
subsequent development of symptomatic vasospasm.
Almost one-third of patients with SAH from a ruptured cerebral aneurysm die before reaching medical
attention. Another 20%, never recover from the initial
hemorrhage and either die or remain incapacitated
from the immediate effects of the hemorrhage [3.21.
Only about one-half of patients, therefore, recover
from the initial effects of the SAH. Even when cared
for under optimal conditions in specialized centers,
about one-third of this group suffer delayed deterioration as a result of rebleeding, vasospasm, hydrocephalus, operation, or a number of other problems. Many of
these patients, probably one-half to two-thirds, will recover completely if treated appropriately, but the rest
will either die or remain with a serious neurological
deficit 132). Little can be done for patients who never
recover from the initial SAH. Our current chalienge is
to prevent SAH by improving our efficiency in detecting and treating aneurysms before they rupture and,
once SAH has occurred, to decrease the subsequent
morbidity in patients who recover from the initial cffects of the hemorrhage. Toward the latter end, proper
diagnosis of the cause of delayed deterioration is essential, because management varies considerably depending on the cause.
The clinical syndrome of vasospasm has some salient
features [20, 32f. The onset is usually between 4 arid
No 6 December 1983
12 days after SAH; it almost never occurs earlier than
48 hours, and only rarely later than 2 weeks, after
SAH, and usually is not cataclysmic. It is frequently,
but by no means invariably, preceded by a slight increase in headache, sometimes accompanied by meningism as well as low-grade fever. Hyponatremia is frequently noted for a day or two before vasospasm
develops. Most commonly there is an early disturbance
of consciousness, such as confusion, disorientation, and
drowsiness. Focal syvptoms, corresponding to the
arterial territories involved, usually develop after a
change in sensorium, but sometimes subtle focal signs
such as a pronator drift or a visual hemineglect are the
first signs noted. The syndrome may progress no further and, after some fluctuations, resolve within a few
days; it can progress gradually to a major focal deficit;
or it can progress relentlessly, resulting in deep coma
and decerebration within hours. When the anterior cerebral territory is affected, disturbances of sensorium
are prominent. Frontal release signs, incontinence, and
akinesia are observed early and may progress to mutism. Middle cerebral arterial spasm in the dominant
hemisphere leads to hemiparesis and aphasia; in the
nondominant hemisphere, it results in hemiparesis and
anosognosia. When both middle cerebral territories or
the anterior cerebral and at least a portion of the middle cerebral territory are involved, disturbances of consciousness are prominent. This is also the case when
the posterior circulation is involved extensively [20}.
We have seen the development of a complete homonymous hemianopia unaccompanied by any other
neurological sign in a patient with focal spasm of the
right posterior cerebral artery.
Vasospasm is not the only cause of delayed deterioration. Peerless [60]presents an excellent discussion of
the differential diagnosis of delayed deterioration in
patients with SAH. In his series of 420 patients, vasospasm accounted for 30% of the cases of delayed deterioration. Rebleeding was responsible for only 6%.
Hydrocephalus accounted for 14%, and hyponatremia
secondary to volume depletion and/or inappropriate
antidiuretic hormone (ADH) secretion was found in
18% of the patients. Many other causes of deterioration were identified, such as arterial thromboembolism,
seizures, sepsis, respiratory complications, pulmonary
embolism, cardiac problems, and drug reactions. It
seems clear, then, that considerable effort should be
spent in establishing the correct diagnosis in a patient
with deterioration after SAH.
Rebleeding usually develops abruptly, with loss of
consciousness if severe, or sudden increase in headache
and meningism if less severe. Major focal deficits can
be observed immediately if the bleeding is intraparenchymal. The C T scan is usually diagnostic. Hydrocephalus may develop rather abruptly and result in stupor
and coma in cases of intraventricular hemorrhage.
More frequently, hydrocephalus develops gradually
and results first in increased headache and then in
gradual deterioration of consciousness and in incontinence. It can be difficult to distinguish hydrocephalus
from symptomatic vasospasm of the anterior cerebral
arteries on clinical grounds, but serial C T scans showing progressive ventriculomegaly are diagnostic. The
conditions can coexist.
Hyponatremia is the most common electrolyte imbalance seen after SAH [8l}. It is usually associated
with excessive loss of salt in the urine, serum hypoosmolarity, and increased levels of circulating ADH. In
contrast to the syndrome of inappropriate ADH secretion, however, the total blood and plasma volume
usually are decreased in the condition. Therefore, it has
been postulated that the hyponatremia seen after SAH
is caused primarily by excessive natriuresis with appropriate increased secretion of A D H 15 5 ) . Hyponatremia frequently accompanies vasospasm, as indicated
earlier, but occasionally it is the sole cause of neurological deterioration; one may see patients develop not
only disturbances of sensorium, but also subtle focal
neurological deficits that resolve with correction of the
electrolyte balance.
As noted earlier, vasospasm after SAH correlates directly with the amount of blood in the subarachnoid
space. Furthermore, the fact that vasospasm usually develops in vessels surrounded by thick layers of blood
indicates that the blood may be directly responsible for
the spasm and is not just an epiphenomenon indicating
the severity of the hemorrhage. If the latter were the
case, patients with severe parenchymal or ventricular
hemorrhages from ruptured aneurysms would develop
severe vasospasm; they d o not, however, unless there is
a subarachnoid clot around the blood vessels at the
base [17, 50, 51). How blood around these vessels
leads to vasospasm is not known. A very brief review
of the physiology of smooth muscle contraction may be
helpful at this point.
Muscle contraction develops as a result of thick myosin filaments and thin actin filaments sliding over each
other, with a resultant shortening of the muscle fiber.
This shortening occurs when the globular head of myosin binds with actin, which can occur only when a
specific myosin light chain is phosphorylated. Phosphorylation is brought about by a myosin light chain
kinase that is dependent on calcium binding by
calmodulin, a ubiquitous calcium-binding regulatory
protein. Calmodulin binds calcium at calcium concentrations of lo-’ to
M; hence, when calcium
concentrations in the sarcoplasm are greater than 10
M, the cell is fully contracted, and when calcium concentrations are below lo-.’ M, the cell is relaxed. The
sarcoplasmic calcium concentration is determined by
Neurological Progress: Heros et al: Cerebral Vasospasm after SAH
the relative rates of calcium influx and efflux both
across the cell membrane and from cellular organelles
such as the sarcoplasmic reticulum. The activity of the
phosphorylating myosin light chain kinase responsible
for allowing smooth muscle contraction is regulated
not only by the degree of calcium binding by calmodulin, but also by a cyclic adenosine monophosphate
(AMP)-dependent protein kinase that, in turn, can be
stimulated by the activation of P-adrenergic receptors
in the cellular membrane. In this manner, increased
availability of cyclic AMP in the sarcoplasm, which can
be brought about by p stimulation, reduces the affinity
of the myosin light chain kinase for Ca++/calmodulin,
thus effectively reducing its ability to induce smooth
muscle contraction. Relaxation is not simply a passive
process but, rather, an energy-dependent process
brought about by an active extrusion of calcium from
the sarcoplasm both across the cell membrane and into
cellular organelles. This decrease in the sarcoplasmic
calcium concentration is necessary for active enzymatic
dissolution of the myosin and actin cross-bridges responsible for contraction. An adequate supply of highenergy phosphate bonds from adenosine triphosphate
and phosphocreatine is necessary for these reactions
[9, 13, 52, 74, 7 7 , 92f. This oversimplified review may
help explain how a number of physiological and pathological processes, such as neurotransmitter stimulation,
extracellular electrolyte concentration, and energy supply, can affect the sarcoplasmic concentration of calcium, cyclic AMP, and other factors responsible for the
degree of contraction of the smooth muscle cell.
Numerous experimental designs have been developed to study vasospasm since Echlin’s pioneering
demonstration that blood can cause cerebral arterial
constriction { 161. These methods have been reviewed
in detail 133, 87, 1041. In general, vasospasm has been
studied in vitro by analyzing the response of systemic
or cerebral arteries from animals and human cadavers
to different vasoconstrictor and vasodilator substances.
In vivo studies generally involve the introduction of
blood into the subarachnoid space of animals by injection or by arterial puncture and the analysis of the
resulting degree of spasm and its prevention or amelioration by different substances.
The results of studies designed to clarify the causes
of vasospasm have been reviewed in detail by several
investigators 133, 61, 79, 1041. Endogenous substances
that have been thought to operate in the genesis of
vasospasm include serotonin [6, 17, 65, 93, 1061, catecholamines 12, 381, prostaglandins 145, 64, 93, 1021,
angiotensin 17, 251, histamine [6, 93J, and hemoglobin
derivatives, particularly oxyhemoglobin [ 59, 85, 86,
91, 1091. These substances become available for interaction with the blood vessels in the subarachnoid
space through neurotransmitter release (either locally
or into the bloodstream), local platelet and mast cell
Annals of Neurology
Vol 14
No 6
activation and release, or red blood cell lysis and hemoglobin degradation. In addition to chemical factors,
some mechanical factors, such as distortion of arachnoidal strands and displacement and compression of
the vessels within the distended arachnoidal cisterns,
are believed to contribute [8, 361. No single substance
or mechanical factor acting in isolation is currently
thought to be the one causative agent of vasospasm.
This conclusion is based on the fact that, both c1inic:ally
and experimentally, the neutralization of each of these
factors has failed to prevent or ameliorate vasospasm
consistently 133, 87, 94, 96, 104, 1091. Vasospasm
must be the product of a complicated interaction of
several factors, as will be discussed.
Neurogenic factors, although not thought to be important in the normal physiological regulation of cerebral arteries, may become important under pathological conditions such as acute SAH. The presence of
a rich plexus of adrenergic fibers within the adventitial
layer of the pial vasculature has been amply documented 118, 54, 57, 631. These nerves appear to originate in the cervical sympathetic ganglia and, perhaps,
the locus ceruleus, and terminate in a series of
varicosities in the smooth muscle cells. The dense-core
vesicles located in these varicosities are responsible not
only for the synthesis and release of norepinephr.ine,
but also for the re-uptake of this neurotransmitter and
thus for the regulation of its effect on the smooth muscle cell [ l o l l . After SAH these dense-core vesicles
disappear 124, 631; thus, the cerebral blood vessels are
rendered abnormally susceptible to the effect of circulating catecholamines. In addition, the level of circulating catecholamines usually increases after SAH as
a result of hypothalamic dysfunction [12, 5 3 , 62, 95,
973. It is possible, then, that this increase in circulating
catecholamines, associated with abnormal sensitivity of
the cerebral vessels to catecholamines, is a factor in the
complex genesis of vasospasm.
It has become increasingly clear that,
whether induced experimentally or occurring after
spontaneous SAH, can be associated with morphological changes in the affected blood vessels. Studieii of
human vessels that have been in spasm show that considerable necrosis of the smooth muscle cells can be
seen several days to several weeks after SAH. In addition, there is infiltration of the media with macrophages
and swelling of the intima, which can lead eventually to
subendothelial fibrosis and further narrowing of the
lumen 110, 341. Many of these changes have been reproduced by experimental injection of high doses of
vasoconstrictive substances or blood into the subarachnoid space 12, 82, 84, 1031. In our laboratory an experimental model of two sequential intracisternal in jections of blood in dogs has resulted consistently in
smooth cell necrosis and intimal changes such, as
vacuolization of endothelial cells and adventitid
December 1983
infiltration by erythrocytes, leukocytes, and mast cells
[46, 87). The latter effect is of particular interest, because it is possible that this adventitial infiltration interferes with the normal nourishment of cerebral blood
vessels by obstructing an adventitial circulatory matrix
1108). Despite the clinical and experimental evidence
that morphological changes can be observed in vessels
in spasm, it is difficult to accept myonecrosis as the final
common denominator of severe vasospasrn, because, in
patients who survive, vasospasm always subsides after a
period of several days to weeks, and chronic angiographic changes have not been described.
Thus, the cause of vasospasm is unknown. Any
plausible theory must account for the following facts:
(1) vasospasm correlates directly with the quantity of
blood around the involved vessels in the subarachnoid
space; (2) vasospasm usually takes 3 to 4 days, or
longer, to develop and invariably subsides within a few
weeks; and (3) clinically established vasospasm is not
reversed by vasodilators or by pharmacological inhibitors of specific vasoactive substances. It is possible
that vasoactive substances such as serotonin, prostaglandins, and catecholamines released from platelets
within the clot in the subarachnoid space in some way
sensitize the arterial wall to the effects of certain
by-products of hemoglobin degradation. These byproducts take several days to appear, because the lysis
of red blood cells in the subarachnoid space is gradual.
Another factor may be the abnormal sensitivity of
these blood vessels to catecholamines, which may be
circulating at abnormally high levels, as discussed earlier. These factors may lead to a derangement of the
energy processes within the membrane of the cell and
intracellular organelles that permits abnormally high
accumulations of sarcoplasmic calcium and thus results
in sustained contraction. This contraction, which may
begin as a reversible physiological response, may be
sufficiently protracted and severe to cause structural
damage to the vessel wall, perhaps by interfering with
its normal nutrition. These intrinsic structural changes,
as well as extrinsic infiltration of the vessel wall by
inflammatory cells and red blood cells, lead to temporarily irreversible constriction of the vessel lumen. If
the patient survives, the vessels regain a normal appearance, if not function, within a few weeks.
The ideal management of vasospasm is prevention.
Some general measures in the preoperative care of the
patient with a ruptured aneurysm bear on this problem.
Control of blood pressure is still controversial, but
more and more clinicians are abandoning the practice
of inducing hypotension as a prophylactic routine. As
will be discussed later, increased cerebral perfusion
pressure is of value once clinical vasospasm develops,
and it seems counterproductive to induce hypotension,
which may precipitate clinical symptoms in a patient
who otherwise might have had asymptomatic vasospasm [32). Our policy has been to maintain normotensive levels. Patients are treated with relatively
short-acting drugs, such as nitroprusside, when the
pressure is markedly elevated, and propanolol or hydralazine when hypertension is only moderate. These
drugs allow rapid elevation of the blood pressure if
clinical vasospasm supervenes.
The same considerations apply to fluid restriction.
Intravascular volume decreases gradually in most patients with SAH because of a decrease in both total red
blood cell mass and plasma volume 149, 55). Further
iatrogenic volume depletion can only exacerbate this
problem and render the patient more susceptible to the
ischemic effects of vasospasm. We treat patients whose
CT scans indicate that they may be at risk of developing symptomatic vasospasm with daily infusions of
colloid, i.e., albumin, even when they are clinically
asymptomatic. We have no proof of the effectiveness
of this regimen, however. Careful attention to electrolyte balance is important. As pointed out, hyponatremia frequently develops for a day or two before the
onset of clinical symptoms of vasospasm. Significant
hyponatremia can only worsen these symptoms. Usually the hyponatremia is caused by excessive loss of
sodium in the urine with secondary volume depletion
and excessive secretion of ADH. The logical therapy
for this syndrome is water restriction and replenishment of intravascular volume [ 5 5 ) . Sodium replenishment alone will not correct the problem, because as
long as intravascular volume remains depleted, excessive A D H will be secreted and the kidneys will simply
continue to excrete sodium and retain the water, which
exacerbates the problem.
Antifibrinolytic agents have been thought to increase the severity of vasospasm [37, 72). The evidence for this effect, however, is not conclusive [ l ,
32). The controversy regarding the efficacy and safety
of antifibrinolytic agents continues to rage [l, 67).
Nevertheless, we still use these agents, because the
rebleeding rate on our service has decreased considerably with this therapy [32}.
In general, the results of pharmacological attempts to
prevent vasospasm have been disappointing 194, 967.
Zervas and collaborators [106, 107) found that low
doses of reserpine and oral kanamycin, which reduce
blood levels of serotonin and other catecholamines
without substantially reducing the systemic blood pressure, were effective in preventing experimental vasospasm. A subsequent clinical study suggested that this
regimen is of some value in preventing symptomatic
vasospasm [105). Our current clinical impression is
that reserpine and kanamycin, when given to patients
in good condition for several days preoperatively, help
prevent postoperative vasospasm. We have not been
Neurological Progress: Heros et al: Cerebral Vasospasm after SAH
able to demonstrate a clear benefit from this regimen in
the prevention of preoperative vasospasm. Knuckey
and Stokes 1431 recently reported similar findings in a
controlled study. A preliminary report on the prophylactic use of both a- and p-adrenergic blockers indicated that these agents might benefit female, but not
male, patients during the preoperative period [89]. Experimental studies in our laboratory by l s t l e r and coworkers {42] and Von Essen and co-workers [88]
showed satisfactory prevention of vasospasm by nitroglycerin. On the basis of these results, we are studying
in a controlled trial the prophylactic use of nitroglycerin in patients at high risk of developing vasospasm.
The results of the recently completed study by Allen
[ S ] on nimodipine, a calcium-channel blocker that appears to cross the blood-brain barrier relatively well,
are promising. In a well-designed double-blind controlled study involving 125 patients, they found no
substantial difference in overall outcome between patients given nimodipine and control subjects. When the
causes of deterioration were analyzed in a blinded fashion, however, they found that in the control group 16
patients developed ischemic symptoms, 8 of whom had
a poor outcome or died. In contrast, in the group
treated with nimodipine, 13 patients developed ischemic symptoms but only 1 had a permanent poor outcome. The difference between the number of patients
in the control and treated groups who had a poor outcome from delayed ischemia was statistically significant
(p < 0.05). There were no serious side effects from
nimodipine treatment. Nimodipine is not yet available
for general clinical use in the United States, and the
value of other calcium-channel blockers in cerebral vasospasm has not been established. In addition, recent
experimental evidence has suggested that treatment
with nimodipine may alter autoregulation and may increase the susceptibility to ischemic damage by interfering with cellular energy metabolism C301. Therefore, caution is in order until the value of these drugs is
proved in studies with larger numbers of patients. One
such study is currently being organized (G. S. Allen,
personal communication, 1983).
It has been suggested by several neurosurgeons, particularly in Japan, that early operation with removal of
as much blood as possible from the subarachnoid cisterns may prevent vasospasm. Early operation was
abandoned years ago by most neurosurgeons, because
operation while the brain was acutely swollen and friable led to unacceptable morbidity and mortality [ 151.
Selected recent series from neurosurgical centers, however, have shown that operations within 72 hours of
SAH in patients who are in good condition can yield
acceptable surgical results [26, 39, 47, S O , 69-71, 78,
831. There has been a suggestion, but no proof, that
vasospasm can be prevented by thorough removal of
the clot during these early operations C50, 831. In spite
604 Annals of Neurology
Vol 14
of these selected reports, it is sobering to learn that a
recent cooperative study conducted by 133 experienced Japanese neurosurgeons found the mortality after early operations in patients in good preoperative
neurological condition to be 26% [l5]. It remains to
be proved that by decreasing the morbidity associated
with rebleeding and, perhaps, by decreasing the incidence of vasospasm, early operation will improve the
overall morbidity associated with aneurysmal SAH.
The results of a study of this question currently being
conducted at the University of Iowa are awaited with
Once clinical symptoms of delayed ischemia have
developed, pharmacological therapies designed to reverse vasospasm generally yield disappointing results
[961. P-adrenergic drugs, in combination with lidocaine
to prevent arrhythmias [ 7 5 ] or in association with
phosphodiesterase inhibitors such as aminophylline
121, 221, have been of some benefit. It has been suggested, however, that the benefit of these regimens
relates to their ability to increase cardiac output 1751.
Vasodilators, such as nitroprusside, used in conjunction with vasopressors have also been reported to be of
some value 141; in our experience, however, this regimen has resulted in exacerbation of preexisting increased intracranial pressure, with disastrous consequence.
Increasing the cerebral perfusion pressure is the only
therapeutic measure currently thought to be of value in
relieving the ischemic symptoms associated with vasospasm 115, 32, 40, 76, 361. This increase can be effected by decreasing intracranial pressure or by raising
systemic pressure. The former should be the first step
when the patient appears to be symptomatic from documented intracranial hypertension. Caution should be
exercised, however, and abrupt reduction of intracranial pressure should be avoided, because it can be associated with rebleeding {58]. Systemic pressure can be
increased either by increasing peripheral resistance
with vasopressor drugs or by increasing cardiac ourput
by intravascular volume expansion and cardiotonic
drugs. The reversal of ischemic neurological deficits
from vasospasm by the cautious use of vasopressors
and by expansion of blood volume with blood and colloid was documented by Kosnik and Hunt [44:/
1976. This regimen is based on the assumption that
autoregulation is impaired early in ischemic brain 114 1,
SO]. If this is the case, an increase in cerebral perfusion pressure should increase blood flow to ischemic
regions of the brain. Recent clinical evidence has
confirmed the value of volume expansion, with or without the associated use of vasopressors, in reversing
ischemic neurological deficits after SAH 115, 27, 32,
40,66, 763. Because the greatest danger of this therapy
is the production of rebleeding in patients with untreated aneurysms by increasing the systemic pressure,
No 6 December 1083
it would be ideal if the same effects could be accomplished without a concomitant increase in systemic
pressure. Indeed, at least one group claims that an increase in systemic pressure is not necessary and that the
increase in cardiac output achieved by volume expansion is the key element in this regimen [Gb}.The effectiveness of volume expansion alone, without induced
hypertension, remains to be confirmed in larger studies.
The technique used for volume expansion and induced hypertension varies from clinic to clinic and can
be complicated. On the basis of experimental data,
Wood and co-workers 179, loo} recommend dilutional
hypervolemia with colloid infusions. They believe that
the rheological advantages, such as decreased viscosity,
achieved by hemodilution overcompensate for the very
slight decrease in oxygen-carrying capacity that is a byproduct of hemodilution. In the laboratory they found
that volume expansion by infusions of whole blood
failed to increase cortical blood flow in ischemic brain
{loo},whereas hemodilutional hypervolemia with lowmolecular-weight dextran did increase regional blood
flow in ischemic areas, although not to a statistically
significant degree [991. Other clinicians believe that
infusions of blood are an important part of the program
of volume expansion 140, 60, 761.
Kassell and co-workers [40) present an excellent review of their experience with a regimen of volume
expansion and induced hypertension in patients with
symptomatic vasospasm. In a group of 58 patients with
progressive neurological deterioration, they achieved
permanent improvement in 43. They used crystalloid
and colloid (whole blood, packed cells, and albumin to
keep the hematocrit at about 40%) to expand intravascular volume. Low-molecular-weight dextran was used
early in their series and then abandoned because of
adverse hematological reactions. For vasopressors they
used levarterenol, metaraminol, and isoproterenol but
came to prefer dopamine and dobutamine because they
seemed easiest to regulate. Digitalis was used in patients with evidence of pulmonary vascular congestion
or deteriorating cardiac output. Fludrocortisone or desoxycorticosterone acetate was used in certain cases to
assist in maintaining hypervolemia and hypertension.
Atropine was used as necessary to keep the pulse rate
between 80 and 120 beats per minute. Vasopressin was
used in patients with excessive urine output. These
workers monitored volume expansion with a central
venous pressure line or a Swan-Ganz catheter and
aimed at raising the central venous pressure to a level
of about 10 mm Hg or the pulmonary wedge pressure
to a level of 18 to 20 mm Hg. The mean systemic
blood pressure was raised to levels 20 to 100 mm Hg
higher than pretreatment levels, but the pressure was
not allowed to rise above 240 mm Hg in patients with
obliterated aneurysms or above 160 mm Hg in patients
with untreated aneurysms. The blood pressure elevation was maintained for as long as 8 days in some patients. The complications with this regimen included
pulmonary edema in 17% of the patients and rebleeding from untreated aneurysms in 19%. Other complications were significant hyponatremia in 2 patients,
hemothorax from the central line in 1 patient, and
myocardial infarction in another patient [401.
We use a similar regimen but have been reluctant to
raise the systolic pressure much above 200 mm Hg
under any circumstance. In addition, we have not used
mineralocorticoids to achieve salt retention, although
their use may make good clinical sense in selected patients. We caution against the widespread use of vasopressin, because most of these patients already have
elevated levels of ADH and hyponatremia could be
induced or exacerbated under these circumstances
After many years of intensive research, the only
therapy of substantial value currently available for vasospasm is symptomatic-namely, improvement of cerebral perfusion pressure. New avenues of research must
be explored to determine whether specific remedies
for vasospasm can be found. Better understanding of
both the normal physiology of smooth muscle contraction and relaxation and the pathophysiology of vasospasm are necessary to direct these research efforts.
Supported in part by Grants HL28152 and HL22573 from the National Institutes of Health.
The authors wish to acknowledge the invaluable help of Dr Philip
Ktstler in the care of patients with subarachnoid hemorrhage at the
Massachusetts General Hospital. H e has stimulated many of the
clinical observations noted in this paper.
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