A review of cerebral vasospasm in

aneurysmal subarachnoid haemorrhage

Part I: Incidence and effects

N. W. C. Dorsch FRCSFRACS

M. T. King BSc(Hons)
Departments of Neurosm-gery and Community Medicine,
Westmead Hospital. Sydney.

Delayed ischaemia due to cerebral ‘vasospasm’ is a significant cause of morbidity and mortality after aneurysm
haemorrhage. In a literature review more than 30 000 cases were found where vasospasm after subarachnoid
haemorrhage @AH) was discussed. The incidence of angiographicvasospasm was 43.3% overall, and 67.3% where
angiographywas done at a time of maximum expected spasm. Symptomaticvasospasm or delayed ischaemic deficit
(DID) occurredin 32.5%. There wasno difference in incidenceand time coursebetweenpreoperativeand postoperative
cases. 30% of those with DID died, and permanent neurologicaldeficits occurred in 34%. A fatal outcome was much
more likelyin the presence of vasospasm, and a satisfactoryoutcome one thirdless likely.Vasospasmis thus the cause
of death in about lo%, and of disabilityin slightlymore cases of aneurysmalSAH. The extent of the problem has not
changed significantlyover three decades.

Journal of Clinical Neuroscience 1994, 1:19-26 0 Longman Group UK Ltd

Keywords: Aneurysm, Subarachnoid haemorrhage, Vasospasm

Introduction
It is known that in many cases of aneurysmal subarachnoid
haemorrhage (SAH) narrowing develops in intracranial
arteries several days later. The mechanism is basically
unknown, though it is almost certainly due to some
chemical fzzctor or combination of factors from the
extravasated blood. In a smaller proportion of patients
the narrowing is severe enough to cause ischaemic
symptoms (delayed ischaemic deficit, DID). Many with
DID dir or become permanently disabled.
A review of over 1000 reports has been done to clarify
the trur incidence and effects of vasospasm, by physically
reviewing all the literature since 1960 on cerebral
aneurysms. In many references vasospasm was not
mentioned as a keyword or noted in the abstract, but was
described in the text; computer-based reference searches
would have missed these. Many other references were
obtained from conference abstracts or proceedings, or by
attendance at meetings which did not have published
proceedings.
A number of reports were excluded because of unclear
definitions, such as uncertainty whether a topic was
angiographic or symptomatic vasospasm. There were very
few reports with fewer than 10 patients, but none were
excluded because of this. A tendency was noted towards a
higher incidence of both angiogrdphic spasm and DID in
smaller groups. For example, symptomatic spasm was
reported in 40% of patients from groups of fewer than
50, and in 31% from groups of more than 100. This may
reflect reduced accuracy when smaller numbers are
reported, or a genuine publication bias when a high
incidence is seen in a small group. No such tendency was
seen in the reporting of outcome.
Occasionally there is controversy over terminology,
particularly the word ‘vasospasm’ itself. That will not be
entered into here; ‘vasospasm’ unqualified refers to the
narrowing of arteries seen after SAH: ‘symptomatic
vasospasm’ and ‘delayed ischaemic deficit’ are treated as
synonymous, referring to the clinical syndrome where
ischaemic problems arise because of vasospasm.
Incidence of vasospasm
Angiographic vasospasm
There was much variation in the reported incidence of
angiographic vasospasm (Fig. 1)) with estimates ranging
from 19 to 97%. This variation was due largely to
inconsistency in definition of both vasospasm and SAH,

1. Clin. Neuroscience Volume 1 Number 1 January 1994 19

Review articles Cerebral vasospasm

16 is at around the end of the first weeks-T,and peak frequency

14-1 I and severity in the second week, especially days 8 to 11 .s12
The spasm usually lasts two or three weeks.5,s, l3
38 studies looked at angiography in the second week
after SAH. In 2738 cases, angiographic spasm occurred in
1842, giving an average incidence of 67.3%. When these
studies are considered separately, incidence ranges from
40% to 97% (Fig. 1). This suggests that the lower incidences
are a result of under-estimation where angiography was
carried out early after SAH. It seems likely that the higher
incidence estimates are closer to the ‘true’ incidence of
vasospasm, and it may be that if angiograms could be done
0 10 20 30 40 50 60 7b
PERCENT INCIDENCE daily, the incidence would approach 1OO%.14
In Figure 1 the number of reports in each band of 5% of
Fig. 1 Histogram showing relative frequency of reports of
incidence of angiographic vasospasm.
incidence are compared. It should be noted that in this and
Percent of reports: percentage of the total number of reports in each
in subsequent figures, very similar appearances were
category. For shaded bars, of all reports of angiographic spasm (N = 223); obtained when either the total number of patients, or the
for solid bars, of reports only from the second week after SAH (N = 38).
average number per report, were analysed in this way.
Percent incidence: bars within each 5% range of incidence represent the
proportion of reports included in that range, e.g. 9.9% of all reports and
15.8% of second week reports fell between 70 and 75%. Delayed ischaemic deficit
(symptomatic vasospasm)
This occurs, of course, much less often than angiographic
20 I
spasm. Vasospasm alone is not sufficient to cause ischaemia’s
18
unless it is very severe, or other influences such as high
p 16 intracranial pressure, low blood pressure, increased blood
0z
g 14 viscosity 14, hypoxia or hyponatraemiatss17 are involved.
ii 12 Predisposing factors such as hypertension, advanced age,
k 10 smoking, or even surgery, may also be importantl”
ii 8 The average incidence of DID, from 297 references,
iti 6 was 10 445 cases among 32 188 patients, i.e. 32.45%.
However, as with angiographic spasm, there were large
k! 4 variations between reports, which ranged from 5% to 90%
2
(Fig. 2). This was probably due to several factors, including
0
0 10 20 30 40 50 60 70 80 90 1 differences in definition. In only a few reports were strict
PERCENT INCIDENCE criteria applied to define DID, ie exclusion of other causes
Fig. 2 Histogram of relative frequency of reports of DID. of deterioration plus angiographic proof of appropriate
Percent of reports: proportion of total reports in each category. spasm. At the other extreme, in many the diagnosis of
Shaded bars: all reports of DID (N = 297); DID was made largely on clinical grounds. It was often
solid bars: strictly defined reports (N = 132).
not clear whether SAH due to causes other than aneurysms
was included. In other reports only patients who
underwent surgery were included; this will undoubtedly
and in timing of angiography, which was often not
tend to underestimate the incidence of DID.lsJs Finally,
mentioned. Often the terms were not defined, or were
in some series only patients in certain Hunt and Hess?0
defined with varying strictness. In some an estimation was
grades, either good or poor, were included; still others
based on one study, and in others only comparison with
specified a single group such as the aged.zlsz
other angiograms was accepted. Some reports did not
The extent of variation in incidence was reduced by
make clear whether they were referring only to aneurysmal
considering separately those studies which specified a
SAH, which leads to much more vasospasm than other
reasonably strict definition of DID, and were studying
causes.tl 2
vasospasm primarily. Among these 132 studies, the incidence
Accepting these limitations, the incidence of angio-
ranged from 12% to 57% (Fig. 2). The average incidence
graphic spasm was mentioned in 223 references, and
mentioned above is in fact very close to the average from
totalled 13 490 out of 31 168 cases, that is, 43.28%.
these ‘strict’ studies, which was 4068/12 449, or 32.68%.
Several points arise from Figure 2. The initial very wide
Incidence according to time
scatter of incidence estimates was reduced only by
Reports discussing timing agreed broadly that vasospasm tightening up definitional criteria (other criteria, eg
is rare in the first two days after one SAH, and increases restriction of clinical grade, pre- or post-operative status,
steadily from the fourth day. In 530 cases3 the highest were also checked to exclude possibly questionable studies,
incidence was between 10 and 17 days, peaking on day 13 but all failed to exclude further the extreme values of
at 60%. In another series4, incidence was one-third in the incidence). We suggest that much of the remaining
first week and two-thirds in the second. The mean onset variation is due to residual definitional inconsistency. The

20 J. Clin. Neuroscience Volume 1 Number 1 January 1994

Cerebral vasospasm Review articles

majority of studies fell in an incidence range of 20% to review of 25 papers on this therapyi’ concluded that
50%. Moreover, larger studies, which should give more although there was less rebleeding, there was no real
reliable estimates, tended to fall within that range. The evidence of any change in the ilatural historv of SAH.
extreme values, both large and small, may be due to other In two controlled trials of tranexamic acid there W;~S
influences such as publication bias and small, highly more DID in the treated group; Hitchcock et al”” had 1 I
selected patient groups. cases in 50 control patients, .md 22 in 50
L on 1ranexaniic
acid (~2 = 4.5, P = 0.03). In the study of Vermeulen et al:“’
Timing of DID there were 19 cases of DID in 1.55 on placebo, compared
with 37/130 on tranexamic acid (x2 = 10.X. 1’ = 0.001 ).
Whew this was discussed in detail (27 references). the
Similar effects were seen in the cooperative study on the
onset of ischaemic symptoms is usually, as would be
timing of surgervj;. with 242 cases of‘ DID (34%) in 703
expected, a day or more after that of angiographic spasm.
patients on antifibrinolytics, and 92 DID (26%) in 352
Most f’elt that DID rarely starts less than three or four days
others; this was not a controlled trial, but the difference is
after a single SAH, and the earliest onset ranged from two
considerable. Other groups, comparing 1reatrd patients
(one report) to seven days, with a mean of 4.2 days.s,l’l,““-“l
and historical controls, also showed an increase in DID.:3”-1”
From 12 rc.ferences giving mean day of onset and patient
The incidence from these plus the abovc~ ws 407 out of‘
numbers, the mean time of onset for 481 patients was
1307 (31.1%, range 13% to 43% ) in treated patients;. ;mtl
calculated to be 7.T days post SAH. For 66 cases individually
153/799 (19.1%, range 4% to 22’# ) ill ‘controls’.
notedL’i.2H.::n-:12the mean was 7.9 days (SD 3.8, 95%CI 7.0-
8.6 days). The peak of deficit was reached usually one to
Year of publication
four days after onset. In studies that mentioned
preoperative and postoperative cases separately”‘,“,:~:~, Since the first reports in the late 1970s on the importance
there was no difference in time course between these two of circulating blood volume and state of hydration of SAH
groups. patientsJ’.Jz, many groups have taken up the use of
‘hypervolaemic’ treatment as soon as possible after SAH.
Confirmation of vasospasm i.e. for prophylaxis of delayed ischaemia. Studies which
specified the use of this management are summarised in
In 110 studies angiographic confirmation of spasm was
Part ‘1 of this review, but it is possible that fluid
obtained. In these reports the incidence of DID was 3781/
management of SAH patients has improved generallv in
12 246. or 30.88%. This is probably more accurate in a
recent years. If this were the case, one might expect to SW
sense since it provides a more rigorous definition of DID,
a fall in reported incidence of DID even where it was not
hut it fails to include spasm in small, angiographically
stated that hypervolaemic propllvlasis was used. To assess
unseen perforating arteries. For that reason, we feel the
this. incidence was plotted against rhe last vcar of
overall figure of 32.5% is more acceptable.
publication of reports (Fig. 3).
Thr only clear pattern to emerge was a tvidening range
Antifibrinolytic treatment
of reported incidence, along with an increase in numbers
In recent years, several publications have referred to an of cases. From the mid 1980s on. the majoritv (particularl>~
increased risk of DID if antifibrinolytic drugs are used. A those with a strict definition) have rendrd IO congregate
in the 25%;1-50’<, range, but at the same rime. extremr
values ha\rc continued to extend outwards. That ma\ be
partly ;I function of’ the larger numhrr of reports al;d a
more \w-ied case-mix (e.g. more rcporrs from dif’ferent
80 countries), hut also suggests 2 lack of’ c.oiisistenc.\~ iI1
definition and/or methods of’id~,rltifi<~ltiol1 01’ DID. ’

Influence of vasospasm on patient outcome

Some publications mentioned thr ef‘fthct of’vasospasm on
o\.erall outcome in SAH patients. Thic has been analysetl
0
in terms of mortalitv and good rccovcr\.
10000 1 j

Effect on death rate

Table 1 shows the results of 25 studies which gave death
rates in groups of patients with ~~sospasn~ versus those
without. In all but three, the proportion of. patients with
Fig. 3 Incidence of DID according to time of publication. spasm who subsequently died was higher than in those
Upper section: individual reports, open symbols for non-strict and solid without spasm.
symbols for strict reports. Average incidence for each year also shown: This is reflected in the odds ratios (the ratio of‘ (he
dotted line for non-strict and continuous line for strict reports.
odds ot‘dying when spasm is present to the odds of death
Lower section: total number of patients reported each year. Dotted line for
numbers from non-strict and solid line for those from strict reports. in the absence of spasm). which in all hut three reports

J. din. Neuroscience Volume 1 Number 1 January 1994 21

Review articles Cerebral vasospasm

Table 1 Influence of vasospasm on death rate

Ref Spasm Dead Percent No spasm Dead Percent Odds ratio

31 10 3 30 15 2 13 2.9
43 19 6 32 17 0 0 46.6
44 55 13 24 33 2 6 4.9
45 18 5 28 34 7 21 1.5
46 26 13 50 37 6 16 5.3
47 30 7 23 42 2 5 5.7
48 30 8 27 43 3 7 4.9
49 121 32 26 49 4 8 4.0
50 36 9 25 64 6 9 3.4
51 42 11 26 65 12 18 1.6
33 17 3 18 69 3 4 5.3
52 25 7 28 81 16 20 1.6
53 41 17 41 82 12 15 3.9
54 82 48 59 111 58 52 1.3
55 74 26 35 144 23 16 2.8
56 62 7 11 147 8 5 2.3
57 82 10 12 149 3 2 6.7
58 202 49 24 165 23 14 1.9
59 672 330 49 276 101 37 1.6
13 204 10 5 296 22 7 0.7
60 324 55 17 784 68 9 2.1
61 993 362 36 2528 555 22 6.3
62 35 9 26 56 16 29 0.9
63 81 18 22 117 28 24 0.9
64 201 9 4 694 35 4 1.0
Total 3482 1067 30.6 6098 1015 16.6
Common odds ratio(95%Cl)=3.28(2.94-3.66)
Ref= reference

Table 2 Influence of vasospasm on good outcomes

Ref Spasm Good Percent No spasm Good Percent Odds ratio

65 20 8 40 24 12 50 1.5
66 19 11 58 26 21 81 3.1
44 55 16 29 33 22 67 5.0
67 86 50 58 42 30 71 1.8
48 30 10 33 43 30 70 4.7
50 36 17 47 64 44 69 2.5
51 42 29 69 65 53 82 2.0
33 17 8 47 69 38 55 1.4
52 25 7 28 81 56 69 5.7
53 41 21 51 82 67 82 4.4
68 70 28 40 105 60 57 2.0
55 74 21 28 144 66 46 2.2
56 62 29 47 147 126 86 6.9
57 82 56 68 149 135 91 4.8
58 202 69 34 165 84 51 2.0
13 204 148 73 296 227 77 1.2
61 993 339 34 2528 1688 67 3.9
63 81 30 37 117 48 41 2.7
69 19 2 11 107 71 66 1.2
70 9 5 56 38 29 76 15.7
64 201 147 73 694 608 88 2.5
Total 2368 1051 44.4 5019 3515 70.0
Common oddsratio
(95% Cl)= 3.05(2.73-3.40)
Ref= reference

22 1. Clin. Neuroscience Volume 1 Number 1 January 1994

Cerebral vasospasm
was more than 1, and in over half exceeded 3. The results
are summarised by a common odds ratio71 of 3.28 (95%
CI 2.94 to 3.66), indicating a consistent and significant
increased risk of death for a patient with vasospasm.
Effect on good outcomes
Results of 21 studies that mentioned outcome in terms of
good recovery, i.e. 1 on the Glasgow Outcome Scale
(GOS) iz where it was possible to assess this, are shown in
Table 2. In every report, a higher proportion of patients
in the groups without vasospasm recovered than in the
groups with spasm. Odds ratios here are all more than 1.
The common odds ratio71 of 3.05 (95% CI 2.73 to 3.40)
indicates much better odds for a good recovery for a
patient without vasospasm.
Outcome of delayed ischaemicdeficit
In studies of outcome of DID the level of definition and
reporting was very variable. Often, it was not stated
whether a particular outcome was a direct or indirect effect
of vasospasm or from another cause. Another difference
was that the time of ‘final’ outcome assessment, if
mentioned, varied markedly. Terms such as ‘good
outcome’ or ‘continuing deficit’ were used often but
defined rarely. Only occasionally was the GOS used.
Because many reports had only three outcome levels, cases
have been grouped here into categories of good outcome,
permanent deficit, and death.
Outcome of DID was mentioned in 197 reports, in 106
ofwhich the analysis was complete enough for these three
categories. Deaths and permanent deficits were from all
causes including vasospasm. This is still applicable to the
clinical situation, as the figures are the actual outcomes
for patients with DID. These reports showed a death rate
of 1009/3327 (30.3%). permanent deficits in 1132
(34.0%), and good outcome in 1186 (35.7%).
Incomplete figures
In the other 91 references, outcome was not completely
specified as above. 51 mentioned only the death rate, with
504 deaths in 1455 cases, i.e. 34.6%. 40 other reports
categorised outcomes only as good or not good. There
were 406 good outcomes in 1074 cases, or 37.8%. Both
these figures are similar to those above for complete
reports.
Time of publication
The results from the 106 studies with complete outcome
reports were analysed for change across time (Fig. 4). to
assess whether there was any improvement in later years
as a result of improved fluid management. Studies were
grouped by latest year of publication, and numbers in each
outcome category pooled within each time group. A
confidence interval was calculated for the proportion of
patients in each category, based on a multinomial
probability distribution in which death, disability and good
recovery were the only possible (mutually exclusive)
outcomes.7J As Figure 4 suggests, there was no obvious
1. din.
Review articles
L 4
<75 76-60 81-3 84-5 86 87 86 89 90 91 92
YEAR OF PUBLICATION
Fig. 4 Outcome of established DID according to time of
publication, with 95% confidence bars.
Squares:death rates. Diamonds: permanent deficit
Triangles: good outcome.
change in outcome with time, although a trend towards a
fall in mortality is hinted at (there were only three reports
in 1992). The only definite message from these figures is
that of all patients with DID, untreated, about 30% will
die, a third will recover well, and the rest will have a
permanent neurological deficit.
Discussion
As noted, considerable difficulty was experienced in
preparing this review, in being certain in many reports of
numbers, of type of spasm, of definitions of outcome, and
of treatment. This was not necessarily the fault of the
authors of those reports, since many were not primarily
on vasospasm, but dealt more with other aspects of SAH
or aneurysms, mentioning spasm or ischaemia only in
passing.
As with complications of disease generally, reported
incidence will be higher the more the complication is
sought. Similarly, ischaemia is more likely to be noted if
that is the main topic of the publication concerned. Factors
such as these could contribute to the wide variation
reported both in the incidence and, to a lesser extent, in
the effects of vasospasm. On the other hand, there was a
smaller scatter in reported incidence of DID if the strictly
defined reports were looked at alone.
Because of problems comparing the various descriptive
systems for outcome, only three outcome categories have
been used here. These are obviously very broad, and for
differentiation of minor degrees of disability even the
Glasgow Outcome Scales are coarse.74 In this context the
only really satisfactory outcome for cerebral aneurysm
patients is that of GOS 1, i.e. able to return to work, with
no or only minor neurological deficits. A GOS of 2, even
though the patient may be independent, should not be
considered satisfactory in people who before were mostly
fit and productive. For this reason, the category of ‘good
outcome’ above includes, where possible, only those
recovering to GOS 1.
Despite the wide variations, the averages obtained are
in agreement with what most neurosurgeons have felt is
the actual scope of the problem of vasospasm. They
-- ___-
Neuroscience Volume 1 Number 1 January 1994 23
Review articles Cerebral vasospasm

confirm that vasospasm is a large contributor to the still high 8. Kim H, Mizukami M, Kawase T, Takemae T, Araki G.
morbidity and mortality seen after aneurysm haemorrhage. Time course of vasospasm: its clinical significance.
Neurol Med Chir 1979; 19:95-102.
It causes clinically evident deterioration in almost one-third
9. Pasqualin A, Rosta L, Da Pian R, Cavazzani P, Scienza R.
of cases. Of those affected, about one-third die because of Role of computed tomography in the management of
it, and a similar proportion are left with a permanent deficit. vasospasm after subarachnoid hemorrhage.
Thus, in any group of patients with aneurysmal SAH, about Neurosurgery 1984; 15:344-53.
10% will die and 10% have a permanent disability resulting 10. Saito I, San0 K. Vasospasm after aneurysm rupture:
incidence, onset, and course. In: Wilkins RH (ed):
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Cerebral arterial spasm. Baltimore: Williams and Wilkins,
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decade on the need for adequate fluids in SAH patients, 11. Ahyai A, Rittmeyer K, Spoerri 0.
there is no real evidence of a recent overall reduction in Differentialdiagnostische ervigungen beim bild des
the incidence of vasospasm, and although outcome may angiospasmus. In: Voth D, Glees P (eds) : Der zerebrale
Angiospasmus. Berlin: Walter de Gruyter, 1984:293-7.
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12. Miller CA, Hunt CD, Hunt WE. Course of vasospasm
It was felt that treating staff may unconsciously have following subarachnoid haemorrhage. Serial
corrected the previous tendency to keep these patients angiography, its relation to timing and perioperative
dehydrated, even if the administration of increased fluids care. In: Auer L M (ed): Timing of aneurysm surgery.
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Berlin: Springer-Verlag, 1986:269-81.
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Volume 1 Number 1 January 1994 25
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January 1994