From the Departments of Neurology (F.H.V., D.H.) and Neurosurgery
(H.W.C.B., C.J.J.A.), Academisch Ziekenhuis Rotterdam Dijkzigt, the
Netherlands.
Correspondence to Djo Hasan, MD, PhD, Intensive Care Neurology and Neurosurgery, 40 Dr Molewaterplein, 3015 GD Rotterdam, Netherlands. E-mail hasan{at}mediaport.org
Methods—We studied 348 patients admitted within 72 hours after
aneurysmal SAH. Patients with negative angiography results and
those in whom death appeared imminent on admission were excluded. The
first group (group A) consisted of 176 consecutive patients admitted
from 1977 through 1982. Maximum daily fluid intake was 1.5 to 2 L.
Hyponatremia was treated with fluid restriction (<1
L/24 h). Antihypertensive treatment with diuretic agents was
given if diastolic blood pressure was >110 mm Hg.
Patients in the second group (172 consecutive patients; group B) were
admitted from 1989 through 1992. Daily fluid intake was at least 3 L,
unless cardiac failure occurred. Diuretic agents and
antihypertensive medications were avoided. Cerebral ischemia
was treated with vigorous plasma volume expansion under intermittent
monitoring of pulmonary wedge pressure, cardiac output, and
arterial blood pressure, aiming for a hematocrit of 0.29 to
0.33. Aneurysm surgery was planned for day 12.
Results—Patients admitted in group B had less favorable
characteristics for the development of cerebral ischemia and
for good outcome when compared with patients in group A. Despite this,
we found a significant decrease in the frequency of delayed cerebral
ischemia in patients of group B treated with tranexamic acid
(P=0.00005 by log rank test) and significantly improved
outcomes among patients with delayed cerebral ischemia
(P=0.006 by
Conclusions—We conclude that the outcome in our patients with
aneurysmal SAH was improved but that rebleeding remains a major
cause of death. Patient outcome can be further improved if we can
increase the efficacy of preventive measures against rebleeding by
performing early aneurysm surgery.
CT scanning was performed on admission (initial CT scan). The amount of
blood in each of the 10 cisterns was graded, on a scale of 0 to 3,
separately for each of the 10 cisterns (maximum sum score of
30).22 A sum score of 18 or higher was regarded
as a "high cisternal blood score." Similarly,
intraventricular blood was graded separately for
each of the four ventricles (maximum sum score of 12). Because a
ventricular score of 1 reflects sedimentation of red blood
cells in the ventricle, we considered relevant only a score of >1 for
at least one of the four ventricles, and we referred only to this as
"presence of intraventricular blood."
All patients were kept in the ICU during the first 28 days or until
death or aneurysm surgery. The level of consciousness was
assessed by means of the 14-point GCS.23 When
deterioration of the patient's clinical condition occurred, physical
examination (and CT scan if possible) was repeated. Hydrocephalus
detected by CT on admission was referred to as "hydrocephalus on the
initial CT." Hydrocephalus is defined as the bicaudate index (width
of the frontal horns at the level of the foramina of Monro, divided by
the corresponding diameter of the brain) on the CT exceeding the 95th
percentile for age. The upper limits were as follows: <36 years of
age, 0.16; 36 to 45 years, 0.17; 46 to 55 years, 0.18; 56 to 65 years,
0.19; 66 to 75 years, 0.20; and 76 to 85 years,
0.21.24 25 Clinical events occurring during the
observation period were defined as follows: (1) deterioration from
hydrocephalus was defined as deterioration of the level of
consciousness with no detectable cause other than hydrocephalus
confirmed by a repeat CT; (2) probable delayed ischemia was
gradual development of focal neurological signs with or without
deterioration of the level of consciousness, without confirmation by CT
or autopsy; (3) definite cerebral ischemia was defined as
development of focal neurological signs or deterioration of the level
of consciousness, or both, with CT or autopsy evidence of cerebral
infarction; (4) probable rebleeding was sudden deterioration of the
level of consciousness and death, without CT confirmation or if autopsy
was refused; and (5) definite rebleeding was defined as sudden
deterioration of the level of consciousness, with or without focal
signs, with an increase in the amount of blood on a repeat CT or at
autopsy when compared with a previous CT scan. In the analysis
we counted definite and probable cerebral ischemia as cerebral
ischemia and definite and probable rebleeding as rebleeding.
In the first period (November 1977 through December 1982, group A), the
patients (n=176) were enrolled in a multicenter trial (centers in the
United Kingdom and the Netherlands were involved) on the effect of
tranexamic acid.26 These patients were randomized
for tranexamic acid: 89 patients received placebo treatment (group
A1) and 87 patients were treated with tranexamic
acid for 28 days or until aneurysm surgery (6 g/d
intravenously in the first week and 4 g/d
intravenously or 6 g/d orally in the next 3 weeks, group
A2). Maximum daily fluid intake was between 1.5
and 2 L. Hyponatremia was treated with fluid
restriction (<1 L/24 h) under the assumption, now proved incorrect,
that hyponatremia was caused by the syndrome of
inappropriate secretion of antidiuretic
hormone.27 28 29 30 We did not apply preventive
measures against cerebral ischemia or hypervolemic
hemodilution. Antihypertensive treatment with diuretic agents
was given if diastolic blood pressure was >110
mm Hg. External ventricular drainage was performed when
the patient deteriorated from hydrocephalus, we were reluctant to
insert a ventricular catheter when the clinical condition
of the patient deteriorated mildly. We preferred external drainage to
internal shunt in the first 2 weeks after SAH.
From 1989 through 1992 all 172 patients (group B) were treated with
tranexamic acid and nimodipine (6x60 mg/d orally or 2 mg/h
intravenously) during the first 21 days or until their
operations.1 2 As preventive measure for cerebral
ischemia, daily fluid intake was at least 3 L unless cardiac
failure occurred.27 28 29 30 Fludrocortisone (2x0.2
mg/d) was administered as a preventive measure against
hyponatremia. When hyponatremia did
occur, sodium chloride was administered. Diuretic agents were
avoided. Antihypertensive medication was not given unless the patient
was on this medication on admission. In the absence of a hematoma with
mass effect and if blood did not completely fill the third and fourth
ventricles, we treated hydrocephalus by means of serial lumbar puncture
or external lumbar CSF drainage. If hydrocephalus persisted or if a
contraindication for lumbar puncture existed, an external
ventricular catheter was inserted. We preferred external
CSF drainage to internal shunt during the first 2 weeks after the bleed
for obvious reasons. When cerebral ischemia occurred, it was
treated with vigorous plasma volume expansion under intermittent
monitoring of pulmonary wedge pressure, cardiac output,
pulmonary arterial pressure, systemic vascular
resistance (by means of a Swan-Ganz catheter), and systemic
arterial blood pressure, aiming at a hematocrit of 0.29 to
0.33.13 14 15 16 17 18 19 20 21
Angiography was performed depending on the patients' clinical
condition. An aneurysm was confirmed either by angiography or
by autopsy in 130 of 176 (74%) patients in group A and in 142 of 172
(83%) patients in group B (Table 1
Differences in frequency of entry characteristics, outcome, and
cause of death between groups were assessed with the two-sided
Figure 3
In group A, both cerebral ischemia and rebleeding are
major causes of death (Table 2
The high frequency of hydrocephalus demonstrated on the
admission CT scan and the high frequency of deterioration from
hydrocephalus in group B compared with those in group A are probably
the result of the higher frequency of patients with high amounts of
cisternal blood and a higher frequency of the presence of
ventricular blood in group B (Figure 1
Daily fluid intake in group B was much higher than that in group
A, and fluid restriction in hyponatremic patients was omitted in group
B in contrast to group A. In addition, cerebral ischemia in
group B was treated with hypervolemic hemodilution (aiming for a
hematocrit of about 0.30) under invasive monitoring of cardiac output,
pulmonary wedge pressure, pulmonary
arterial pressure, and systemic blood pressure. The idea
was to optimize the low shear-rate viscosity of the whole blood and to
ensure adequate cerebral perfusion pressure in order to restore the
regional cerebral blood flow in perfusion areas beyond the vasospastic
vessels.13 14 15 16 17 18 19 20 21 Although patients in group B were
treated with tranexamic acid, and despite the fact that this treatment
may precipitate cerebral ischemia in patients with
aneurysmal SAH, the occurrence of cerebral ischemia in
group B was significantly lower than that in group
A2 (P=0.00005 by log rank test) and
slightly lower than that of group A1 (Figure 2
Although the characteristics of the patients in group B were
worse than those of group A patients with regard to the prognostic
factors for the occurrence of cerebral ischemia and bad
outcome,39 40 41 42 43 44 the decrease in the frequency and
mortality rate of cerebral ischemia and the improved results of
hydrocephalus treatment led to an increase in the proportion of
patients fit for aneurysm surgery at the end of the second week
after the initial bleed. As a result, overall outcome improved
significantly (Figure 3
An article on a study performed from 1977 through 1981 reported
good outcome in patients with SAH (46%), similar to that in group
A.45 Other studies, performed after 1985, have
reported a similar proportion (56%) of good outcome when compared with
group B.5 Others have reported a better result
(71% to 87% good outcome) than that in group
B.43 46 47 48 49 50 Patients included in the latter study
were those admitted to a neurosurgical unit. Consequently, most of
these patients were in a fair clinical condition, fit for surgery. This
probably explains the difference in outcome when compared with group B.
Improved outcome, when corrected for prognostic factors for bad
outcome,39 40 42 43 is probably the result of
improved management: operative technique, timing of aneurysm
surgery, or improved medical treatment. In a retrospective study, it
was reported that outcome improved after treatment with hypervolemic
hemodilution was initiated.48 On the other hand,
nonrandomized trials on the timing of aneurysm surgery failed
to show a significant difference between early and delayed surgery.
Although early surgery lowered the rebleeding rate significantly, this
beneficial effect was negated by a substantial increase in
postoperative cerebral ischemia.5 6 7 8 9 10 11 12 In
contrast, a prospectively performed randomized
study3 reported an improved outcome after early
surgery (0 to 3 days) compared with that after delayed surgery (>8
days after SAH) (96% [25 of 26 patients] versus 77% [22 of 28
patients]). However, the difference did not reach statistical
significance because of the small numbers of patients included.
We conclude that outcome in our patients with aneurysmal
SAH was improved in the course of time as the result of a change in the
medical treatment strategy of these patients, which led to an improved
outcome in patients with cerebral ischemia and those with
deterioration from hydrocephalus. On the other hand, rebleeding remains
a major cause of death. A further improvement in the outcome of these
patients is possible if we can increase the efficacy of preventive
measures against rebleeding by performing early aneurysm
surgery.
Received August 20, 1997;
revision received January 19, 1998;
accepted February 5, 1998.
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© 1998 American Heart Association, Inc.
Original Contributions
Impact of Medical Treatment on the Outcome of Patients After Aneurysmal Subarachnoid Hemorrhage
Abstract
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Background and Purpose—The rationale
behind early aneurysm surgery in patients with
subarachnoid hemorrhage (SAH) is the prevention of
rebleeding as early as possible after SAH. In addition, by clipping the
aneurysm as early as possible, one can apply treatment for
cerebral ischemia more vigorously (induced hypertension)
without the risk of rebleeding. Hypervolemic hemodilution is now a
well-accepted treatment for delayed cerebral ischemia. We
compared the prospectively collected clinical data and outcome of
patients admitted to the intensive care unit in the period 1977 to 1982
with those of patients admitted in the period 1989 to 1992 to measure
the effect of the change in medical management procedures on patients
admitted in our hospital with SAH. 
2 test) and among patients
with deterioration from hydrocephalus (P=0.001 by
2 test). This resulted in a significant improvement of
the overall outcome of patients in group B when compared with those in
group A (P=0.006 by 2 test). The major
cause of death in group B was rebleeding (P=0.011 by
2 test).
Key Words: hemodilution • intracranial aneurysm • outcome • subarachnoid hemorrhage
Introduction
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Treatment of SAH is
aimed at prevention of rebleeding through clipping of the
aneurysm and at prevention and treatment of cerebral
ischemia and hydrocephalus. Many articles have been published
on the management of patients after SAH from a ruptured intracranial
aneurysm, and almost all reported either results of a study
concerning drug efficacy1 2 or results of studies
concerning early versus delayed aneurysm surgery. More and more
neurosurgeons rely on early aneurysm surgery rather than
delayed surgery for the prevention of rebleeding after
aneurysmal SAH.3 4 5 6 7 8 9 10 11 12 The rationale behind
early aneurysm surgery is that by clipping the aneurysm
as early as possible, one can apply treatment for cerebral
ischemia more vigorously (for example, induced hypertension)
without the risk of a rebleed. However, in most studies early
aneurysm surgery failed to improve outcome when compared with
delayed surgery, probably because of an increase in the frequency of
cerebral ischemia.5 6 7 8 9 10 11 12 However, two
studies reported a beneficial effect of early
surgery.3 4 In contrast to the previous
studies,5 6 7 8 9 10 11 12 in these two
studies3 4 prophylactic hypervolemic
therapy was applied during the postoperative period. In addition, the
favorable effects of hypervolemic hemodilution on cerebral perfusion
have been reported in experimental studies13 14
and on cerebral ischemia in patients with
SAH.15 16 17 18 19 20 21 Until recently, early aneurysm
surgery was not performed in our center. On the other hand, medical
treatment of patients with SAH was gradually changing: increase in
daily fluid intake, immediate treatment of hydrocephalus and high CSF
pressure, introduction of treatment of cerebral ischemia with
hypervolemic hemodilution, and prescription of nimodipine. Therefore,
we have the opportunity to compare the prospectively collected clinical
data and outcome of patients admitted to the ICU in the period 1977 to
1982 with those of patients admitted in the period 1989 to 1992. We did
not restrict our study to patients who were fit enough to undergo
aneurysm surgery, and our objective was to measure the effect
of the change in the whole package of medical management in all
patients admitted to our hospital with SAH.
Subjects and Methods
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
From November 1977 through December 1992 we studied 779
consecutive patients with SAH who were admitted to the ICU. All
patients had clinical features of SAH and were admitted within 72 hours
after the bleed. SAH was confirmed by CT, revealing distribution of
subarachnoid blood compatible with aneurysmal
hemorrhage, or when the CT scan revealed no blood, by
spectrophotometric analysis of the CSF. If the patient had a
motor score of 3 on the GCS and negative pupillary reflexes on
admission, or if the motor score on admission was 
2 and the level of
consciousness did not improve within 72 hours after admission, the
patient was excluded from the study (80 patients). In addition,
patients with negative angiograms (39 patients) were not entered in the
study. Between 1977 and 1982, medical treatment remained unchanged.
From 1983 until 1989, medical treatment of patients with SAH was
gradually changing (for example, increase in daily fluid intake,
immediate treatment of hydrocephalus, treatment of cerebral
ischemia with hypervolemic hemodilution, and prescription of
nimodipine). From 1989 onward, medical treatment remained grossly
unchanged. Therefore, from the remaining 660 patients, we included
those admitted between 1977 and 1982 (n=176) and between 1989 and 1992
(n=172). 
). In
the remaining 76 of the 348 (22%) patients aneurysm rupture
was considered highly probable because of the extravasation of blood in
the frontal interhemispheric, suprasellar, or Sylvian cisterns without
evidence of other causes of SAH. Aneurysm clipping was planned
for day 12 in all groups. All surviving patients had a follow-up for at
least 3 months after SAH. They visited the outpatient clinic or were
interviewed by means of a written questionnaire. Outcome was assessed
by means of the 5-point GOS.31 We reduced the GOS
to three categories: dead (GOS score of 1), dependent (GOS score of 2
or 3), and independent (GOS score of 4 or 5).
View this table:
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Table 1. Characteristics of 348 Patients With
Aneurysmal SAH 2 test. Because patients with a GCS score of
13 (14-point GCS) were either drowsy or disorientated without a
decrease in the motor score, we chose a GCS score of 12 as the
breakpoint for the analysis (Figure 1). Differences in first-occurring
cerebral events (deterioration from hydrocephalus, delayed cerebral
ischemia, and rebleeding) and differences in time-dependent
medical treatments (aneurysm surgery, external CSF drainage,
internal CSF shunt) between groups were analyzed by plotting
Kaplan-Meier survivor function estimates against time.
Univariate analysis, stratified by one variable
at a time, was performed with the log rank
test.32 33 We stress that in the analysis
of outcome at 3 months (as presented in Figure 3), calculations
of the proportion of patients with first-occurring cerebral
complication were done with simple arithmetic. On the other hand, in
the Kaplan-Meier plots as presented in Figure 1, calculations
of the proportion of patients with first-occurring cerebral
complication were performed by means of the estimation of the survivor
function.32 One must bear in mind that there is a
difference in the results of the calculated proportion of patients
between these two methods due to, among others, the censoring mechanism
of survival analysis.34
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Figure 1. Plots of Kaplan-Meier survival function estimates
against time on the first-occurring cerebral complication after the
initial SAH and on aneurysm surgery in 348 patients.
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Figure 3. Bar graph showing the outcome at 3 months in 348
patients with SAH, stratified by first-occurring cerebral complication
after SAH.
Results
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Characteristics of all patients are presented in
Table 1
. Patients in group A exhibited less cisternal
(P<0.000001 by 2 test) and less
ventricular blood on the initial CT scan compared with
patients in group B. The proportion of patients with an
aneurysm of the posterior circulation was significantly higher
in group B than in group A. Hydrocephalus on the initial CT was found
in a significantly greater proportion in patients of group B than in
group A. The proportion of patients free from deterioration from
hydrocephalus was lower in group B than in group
A1 (P<0.000001 by log rank test) and
group A2 (P=0.00003 by log rank test;
Figure 1). In addition, the proportion of patients free from
deterioration from hydrocephalus was lower in group
A2 than group A1
(P=0.0044 by log rank test; Figure 1). In patients treated
with tranexamic acid, cerebral ischemia developed less often in
group B compared with group A2
(P=0.00005 by log rank test; Figure 1). The difference in
the development of cerebral ischemia between group
A1 and group A2 was not
statistically significant. The proportion of patients free from
rebleeding was lower in group A2
(P=0.0009 by log rank test) and group B (P=0.0049
by log rank test) than in group A1 (Figure 1).
Aneurysm surgery was performed more frequently in group B than
in group A1 (P=0.0290 by log rank
test) and group A2 (P=0.000005 by log
rank test; Figure 1). The proportion of patients free from
aneurysm surgery in group A1 was lower
than that in group A2 (P=0.0341 by log
rank test; Figure 1). The proportions of patients who received CSF
drainage and internal ventricular shunting are summarized
in Figure 2. External CSF drainage was
performed more frequently in group B than group
A1 (P=0.0016 by log rank test) and
group A2 (P=0.0006 by log rank test).
No differences in the frequency of internal ventricular
shunts between groups were seen.
View larger version (16K):
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Figure 2. Plots of Kaplan-Meier survival function estimates
against time on CSF drainage after the initial SAH in 348
patients. shows the outcome at 3
months of all 348 patients. In patients without complications, outcome
between group A and group B was not significantly different. Mortality
in patients in whom rebleeding occurred as a first cerebral
complication was slightly higher in group B than group A, but the
difference was not statistically significant. Outcome in patients with
deterioration from hydrocephalus in group B was significantly better
when compared with that of patients in group A (P=0.001 by
2 test). This difference is caused by a
decrease in the proportion of patients with dependent outcome and a
decrease in the mortality of patients with deterioration from
hydrocephalus in group B. Among patients with cerebral
ischemia, outcome was also significantly better in group B than
in group A (P=0.006 by 2 test).
This change was caused by a decrease in the mortality of patients with
cerebral ischemia in group B. As a consequence, overall outcome
in group B was significantly better than that in group A
(P=0.006 by 2 test). ). In group
B, cerebral ischemia as cause of death occurred significantly
less often than in group A (P=0.033 by
2 test). In contrast, rebleeding as cause of
death occurred significantly more often in group B than in group A
(P=0.011 by 2 test).
View this table:
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Table 2. Cause of Death in 144 Patients With
Aneurysmal SAH
Discussion
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Patients in group B had more unfavorable prognostic factors for
cerebral ischemia (such as amount of cisternal blood on the
initial CT scan and the presence of ventricular blood) and
for good outcome (amount of cisternal blood and aneurysm of the
posterior circulation) than patients in group A (Table 1). This is
probably the result of a change in the referral behavior of
consultants in the region of our hospital. Apparently, more
patients with severe bleeding were referred to our hospital from 1989
through 1992 (group B). ). Both are
prognostic factors for the development of deterioration from
hydrocephalus.35 36 Improvement of outcome in
patients with hydrocephalus is obviously the result of a change in the
treatment of hydrocephalus. In group A patients, we were reluctant to
insert a ventricular catheter when the clinical condition
of the patient deteriorated mildly. In contrast, we switched to lumbar
puncture and lumbar external drainage in group B, and we initiated
external CSF drainage more frequently than in group A (Figure 3).
Despite this, the need for permanent internal shunting was not
different between group A2 and group B; both
groups were treated with tranexamic acid (Figure 3), a risk factor for
deterioration from hydrocephalus.35 36 It is
known that external CSF drainage may precipitate
rebleeding.37 38 Despite this, there was a
significant decrease in the proportion of death and dependent patients
in those patients with deterioration from hydrocephalus in group B
compared with similar patients in group A, which resulted from our
change in strategy (P=0.006 by 2
test; Figure 3). ).
Moreover, outcome at 3 months for patients in group B was significantly
better than that of group A (Figure 3). The decrease in the occurrence
of cerebral ischemia in group B can probably be attributed to
the high daily fluid intake and the well-accepted beneficial effect of
hypervolemic hemodilution.13 14 15 16 17 18 19 20 21 ). However, rebleeding became a more frequent
cause of death in group B when compared with group A (Table 2).
Selected Abbreviations and Acronyms
CSF
=
cerebrospinal fluid
GCS
=
Glasgow Coma Scale
GOS
=
Glasgow Outcome Scale
SAH
=
subarachnoid hemorrhage
Acknowledgments
We thank Betty Mast for excellent research assistance and
secretarial help and Dr D.W.J. Dippel for advice concerning the
statistics.
References
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
1.
Pickard JD, Murray GD, Illingworth R, Shaw MDM,
Teasdale GM, Foy PM, Humphrey PRD, Lang DA, Nelson R, Richards P, Sinar
J, Bailey S, Skene A. Effect of oral nimodipine on cerebral infarction
and outcome after subarachnoid hemorrhage: British
aneurysm nimodipine trial. BMJ. 1989;298:636–642.
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