Initial Loss of Consciousness and Risk of Delayed Cerebral Ischemia Af... blob:https://www.ahajournals.

org/eb6e0368-1e9a-476d-9053-9926ae4b3241

Stroke
Volume 30, Issue 11, November 1999; Pages 2268-2271
https://doi.org/10.1161/01.STR.30.11.2268

ORIGINAL CONTRIBUTIONS

Initial Loss of Consciousness and Risk of Delayed Cerebral

Ischemia After Aneurysmal Subarachnoid Hemorrhage
J. W. Hop, G. J. E. Rinkel, A. Algra, and J. van Gijn

ABSTRACT: Background and Purpose—Delayed cerebral ischemia (DCI) is a major cause of

death and disability in patients with aneurysmal subarachnoid hemorrhage. We studied the
prognostic value for DCI of 2 factors: the duration of unconsciousness after the hemorrhage and
the presence of risk factors for atherosclerosis.Methods—In 125 consecutive patients admitted
within 4 days after hemorrhage, we assessed the presence and duration of unconsciousness after
the hemorrhage, the neurological condition on admission, the amount of subarachnoid blood, the
size of the ventricles, and a history of smoking, hypertension, stroke, or myocardial infarction. The
relationship between these variables and the development of DCI was analyzed by means of the
Cox proportional hazards model.Results—The univariate hazard ratio (HR) for the development of
DCI in patients who had lost consciousness for >1 hour was 6.0 (95% CI 3.0 to 12.0) compared
with patients who had no loss or a <1-hour loss of consciousness. The presence of any risk factor
for atherosclerosis yielded an HR of 1.4 (95% CI 0.6 to 3.5). The HR for unconsciousness
remained essentially the same after adjustment for other risk factors for DCI. The HR for a poor
World Federation of Neurological Surgeons score (grade IV or V) on admission was 2.9 (95% CI
1.5 to 5.5); that for a large amount of subarachnoid blood on CT was 3.4 (95% CI 1.6 to
7.3).Conclusions—The duration of unconsciousness after subarachnoid hemorrhage is a strong
predictor for the occurrence of DCI. This observation may contribute to a better understanding of
the pathogenesis of DCI and increased attention for patients at risk.

Key Words: aneurysm ■ atherosclerosis ■ cerebral ischemia ■ risk factors ■ subarachnoid

hemorrhage

Copyright © 1999 by American Heart Association

D
elayed cerebral ischemia (DCI) occurs in approximately 20% to 30% of patients with
aneurysmal subarachnoid hemorrhage (SAH) and is a major cause of death and disability in
these patients.1 2 3 4 5 Despite many years of research, the pathogenesis of DCI is still not
clarified.6 Identification of risk factors may contribute to a better understanding of the pathogenesis
of DCI and may improve prevention and treatment. Several studies7 8 9 10 11 12 have shown that a

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poor clinical condition on admission and a large amount of extravasated blood increase the risk of
DCI. We studied 2 additional baseline characteristics to assess their prognostic value for the
development of DCI after SAH: first, the duration of initial loss of consciousness after the
hemorrhage, because this might reflect the severity of the initial ischemia caused by a reduced
perfusion pressure during aneurysmal rupture,13 which could be related to later development of
DCI; and second, the presence of 3 main risk factors for atherosclerotic disease (smoking,
hypertension, and previous history of stroke or myocardial infarction), because preexistent
atherosclerotic lesions might explain the often multifocal localizations of DCI. To adjust our data for
the known risk factors, we incorporated the clinical condition on admission and the amount of
extravasated blood in our analyses.

SUBJECTS AND METHODS

We prospectively studied a consecutive series of 125 patients with SAH who were admitted to the
University Hospital Utrecht between January 1995 and July 1996. Only patients who were
admitted within 4 days after the hemorrhage were included in the study. The diagnosis of SAH was
made by the presence of extravasated blood in the basal cisterns on CT, or if CT was negative, by
xanthochromia of the cerebrospinal fluid.14 Patients with nonaneurysmal perimesencephalic
hemorrhage15 were excluded, as were patients with other nonaneurysmal causes for the SAH.
Conventional and/or CT angiography was performed in 107 patients; the remaining 18 patients
died before angiography could be performed. We included these patients because the distribution
of hemorrhage on the CT scan strongly suggested an aneurysmal origin; in 6 of these the
aneurysm was confirmed by postmortem examination.
The clinical condition on admission was assessed by means of the World Federation of
Neurological Surgeons (WFNS) scale, a 5-point scale based on the Glasgow Coma Scale and the
presence or absence of focal deficits.16 A dichotomy was made between good (WFNS I, II, and III)
and poor (WFNS IV and V) neurological condition on admission.
All patients were kept under continuous observation for at least 2 weeks of their hospitalization
and were treated according to a standardized protocol, which consisted of absolute bedrest, oral
nimodipine treatment, refraining from antihypertensive medication, and intravenous administration
of fluid until a positive fluid balance of at least 750 cc was achieved. Early surgery (within 4 days
after the hemorrhage) was performed in 45 patients who were either in a very good condition on
admission (WFNS score I or II) or required acute surgical intervention because of an early rebleed,
presence of a large hematoma, or severe hydrocephalus. In 46 other patients, clipping of the
aneurysm was postponed until at least 10 days after the hemorrhage; 34 patients did not undergo
surgery. All patients received standard hypervolemic normotensive treatment when DCI was
suspected.
One of the authors (J.W.H.) personally interviewed the patients during the initial days of
hospitalization, always in the presence of a proxy or other eyewitness of the event. In patients
whose condition did not allow a personal interview (n=40), data about the duration of
unconsciousness and previous history were obtained from a proxy only, with verification from the
medical records. Data from patients who died soon after admission (n=18) were obtained from the

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medical records only.

In all patients we recorded the duration of loss of consciousness for the SAH leading to hospital
admission and for any subsequent rebleed. Loss of consciousness out of hospital was considered
present if the eyewitness reported in the interview that “no purposeful response to verbal or
physical stimulation” had occurred. Because an exact assessment of duration of unconsciousness
may not always be reliable, we applied easily distinguishable categories: (1) no loss of
consciousness, (2) <1 hour, (3) between 1 and 24 hours, and (4) >24 hours. For the analyses we
dichotomized the duration of unconsciousness at 1 hour to discriminate between less-severe and
more-severe impact of the hemorrhage. An additional analysis on any duration of
unconsciousness versus no loss of consciousness was performed. In 2 patients the duration of
unconsciousness could not be assessed because they were alone at the time of the hemorrhage;
both were found in a confused state by others. These 2 patients were excluded from all analyses.
For every patient we recorded the following additional items: history of hypertension (diastolic
blood pressure >95 mm Hg on at least 2 occasions, or medical treatment), history of myocardial
infarction or stroke, and former or current smoking. Additionally, we asked whether patients had
used any salicylates within 2 weeks before the bleed, because this might possibly protect against
DCI.17
We assessed the amount of cisternal blood on the initial CT scan according to the method
described by Hijdra et al.18 Patients in whom the initial CT was performed more than 2 days after
the hemorrhage (n=11) or whose initial CT scan could not be retrieved from the referring hospital
(n=6) were excluded from this part of the assessment. The sum scores of blood in the
subarachnoid space were dichotomized at their median value (23). We quantified the size of the
frontal horns by means of the bicaudate index (BCI). To calculate age-adjusted relative sizes, the
BCIs were divided by the corresponding upper limit per age group.19 Hydrocephalus was defined
as an age-adjusted relative BCI of >1.
The primary outcome event was the occurrence of DCI, which was divided into probable and
definite DCI. Probable ischemia was defined as a gradual decline in the level of consciousness or
a gradual development of new focal deficits or both, with no evidence for a rebleed or
hydrocephalus on CT, and exclusion of other medical causes, but without hypodensity on CT scan.
Definite ischemia was defined as probable ischemia, but with confirmation of infarction on CT or at
autopsy. In all analyses, the proportion of patients with DCI includes both definite and probable
ischemia. Other outcome events were rebleeding, defined as a sudden clinical deterioration with
evidence of new blood on CT in comparison with a previous scan, and death from all causes. The
recording of outcome events ended 3 months after admission.

Data Analyses
Because many patients die in the first days after the hemorrhage, the proportion of patients at risk
for DCI differs per day. Moreover, the risk of dying might be related to the variables of interest. To
exclude the patients who die early in the analyses, we used survival analysis techniques in which
we censored deaths: we compared the occurrence of the primary outcome event (DCI) for all
selected baseline characteristics by means of the Cox proportional hazards model, which yielded a
crude hazard ratio (HR). In subsequent multivariate analyses we assessed to which extent

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adjusted HRs in patients with short or no unconsciousness compared with patients who were
unconscious for >1 hour differed from the crude HR. HRs may be interpreted as relative risks20 ;
they were considered statistically significant (P<0.05) if the 95% CI did not include 1.
Because rebleeding generally induces a new episode of loss of consciousness, with a
subsequently altered risk of DCI, we performed 2 analyses: in the first analysis, the occurrence of
DCI was related to the duration of unconsciousness from the hemorrhage leading to hospital
admission. A time window of 24 hours was applied in the assessment of the duration of loss of
consciousness; eg, in a patient who deteriorated within the first 24 hours after the hemorrhage, the
longest episode of loss of consciousness was recorded. Any deterioration after 24 hours was
considered a separate outcome event. Patients were censored in case of rebleeding or death from
all causes. In the second analysis, which incorporated rebleeding, the longest episode of loss of
consciousness was recorded and set at t=0 (left truncation), with the occurrence of DCI as primary
outcome event and with censoring only for death from all causes.

RESULTS
Forty of the 125 (32%) patients who fulfilled the inclusion criteria died during their clinical course,
14 within the first day after admission. Thirty-nine patients (31%) developed DCI, 34 definite and 5
probable. In 20 of these patients the ischemic symptoms developed after operation.
The Table shows the occurrence of DCI, based on the hemorrhage on admission, in relation to
the baseline characteristics. A poor WFNS grade on admission, duration of unconsciousness of >1
hour, and a large amount of blood in the subarachnoid space were significantly related to the
presence of DCI in the univariate analysis. The crude HR associated with unconsciousness >1
hour was 6.0 (95% CI 3.0 to 12.0) in the first analysis (based on the hemorrhage on admission)
and 5.7 (95% CI 2.8 to 11.6) in the second (based on the hemorrhage with the longest duration of
unconsciousness in case of a rebleed). Because both analyses yielded similar results, all data
refer to the first type of analysis. We found no significant influence of sex, age, smoking,
hypertension, history of stroke or myocardial infarction, or recent use of aspirin. The HR for the
presence of any risk factor for atherosclerotic disease (smoking or history of hypertension, stroke,
or myocardial infarction) versus none of these risk factors was 1.4 (95% CI 0.6 to 3.5); the HR for
any duration of unconsciousness versus no loss of consciousness was 3.3 (95% CI 1.3 to 8.5).
The HR for duration of unconsciousness remained essentially the same after adjustment for
sex, age, WFNS grade on admission, amount of blood in the subarachnoid space, timing of
surgery, presence of risk factors for atherosclerosis, and recent use of aspirin. Stepwise
introduction of the univariately significant variables into the multivariate model resulted in statistical
significance for the duration of unconsciousness and the sum score of subarachnoid blood only.
The Figure shows the Kaplan-Meier curves for the occurrence of DCI according to duration of
unconsciousness.

DISCUSSION

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The duration of unconsciousness after the very moment of a SAH proved to be a strong predictor
for the occurrence of DCI. Patients who lose consciousness for >1 hour at the time of the
hemorrhage have a 6-fold increased risk for the development of DCI compared with those who
lose consciousness for <1 hour or who remain fully awake at the time of the hemorrhage. This
increased risk is of the same magnitude when episodes of rebleeding are taken into account. The
prognostic value of the duration of unconsciousness for the development of DCI is stronger than
that of previously identified risk factors, such as the neurological condition on admission and the
amount of cisternal blood on CT. This might be explained by the fact that both neurological
condition and amount of blood in the subarachnoid space change over time and thus depend on
the time interval between onset of SAH and admission, whereas the duration of unconsciousness
after the SAH is an unchanging characteristic. Because the duration of loss of consciousness on
the one hand and neurological grade on admission and amount of subarachnoid blood on the
other are related, adjustment for these risk factors did not essentially alter the results.
The loss of consciousness at the time of the hemorrhage is caused by global ischemia,
resulting from a lack of perfusion pressure during aneurysmal rupture.13 The duration of loss of
consciousness might reflect the severity of this perfusion deficits and global ischemia. Our data
suggest that the severity of the initial ischemia is an important pathogenetic factor in the
development of DCI. Elucidation of the underlying pathophysiological mechanism requires further
study.
We did not find an increased risk for DCI in the presence of risk factors for atherosclerosis. In a
recent study,21 cigarette smoking was found to increase the risk of symptomatic vasospasm after
aneurysmal SAH. Our study could not support this finding to a significant degree.
The use of salicylates in the 2-week period before admission did not alter the risk for DCI.
Increased platelet aggregability might play a role in the pathogenesis of DCI.22 23 24 An
observational study has shown that patients who had taken aspirin prior to their hemorrhage had a
relatively low risk for ischemic symptoms and ischemic lesions on CT.17 That study was based on
the presence of salicylates in urine samples on admission, whereas in our study the use of
salicylates was not well documented in the medical records and the information obtained from
relatives on use of salicylates may have been unreliable.
We did not investigate other factors that might be related to the occurrence of DCI, such as
factors related to the surgical procedure, because these are difficult to quantify.
One might question the reliability of the assessment of duration of unconsciousness by patients
and proxies. Indeed an assessment of the exact duration may be difficult to make. During the
personal interview, most patients and all proxies remembered in detail the circumstances under
which the SAH occurred, the presenting symptoms, and the subsequent activities. A distinction
between the presence or absence of unconsciousness and between the duration of
unconsciousness for less than or more than 1 hour was never difficult to make.
Another limitation of our study is that for 18 patients who died soon after admission, we did not
personally interview a proxy or eyewitness. Data on possible risk factors in these patients were
often lacking in the medical records; a dichotomy in duration of unconsciousness at 1 hour could
reliably be made.
The duration of unconsciousness is a very important risk factor for the development of DCI.

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This finding may provide new insights into the pathogenesis of DCI and may lead to increased
attention for patients at high risk of delayed ischemia.

Figure 1. Kaplan-Meier curve for the composite outcome event of death or DCI, according to the duration of
unconsciousness. The height under the curves refers to the proportion of patients who are still alive and did
not develop DCI.

Table 1. Occurrence of DCI in Relation to Selected Baseline Characteristics, by Univariate Analysis (Table
view)

Characteristic Total, n DCI Present, n (%) HR 95% CI

Demographic characteristics
Female 87 26 (29.9)
Male 36 13 (36.1) 1.2 0.6 to 2.3
Age ≤52 y 64 19 (29.7)
Age >52 y 59 20 (33.9) 1.1 0.6 to 2.5
Condition on admission
WFNS I, II, or III 78 21 (26.9)
WFNS IV or V 45 18 (40.0) 2.9 1.5 to 5.5
Unconscious ≤1 h 69 12 (17.4)
Unconscious >1 h 54 27 (50.0) 6.0 3.0 to 12.0
Findings on initial CT
Sum score SAH ≤23 49 9 (18.4)
Sum score SAH >23 57 25 (43.9) 3.4 1.6 to 7.3
Relative BCI ≤1 76 24 (31.6)
Relative BCI >1 27 10 (37.0) 1.2 0.5 to 2.4

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Characteristic Total, n DCI Present, n (%) HR 95% CI

Risk factors
Nonsmoker1 39 12 (30.8)
Current smoker 52 20 (38.5) 1.2 0.6 to 2.4
No hypertension 85 27 (31.8)
Hypertension 30 11 (36.7) 1.3 0.7 to 2.7
No history of stroke or MI 107 36 (33.6)
History of stroke or MI 11 3 (27.3) 1.1 0.3 to 3.6
No recent use of aspirin 89 30 (33.7)
Recent use of aspirin 14 5 (35.7) 1.1 0.4 to 2.8

MI indicates myocardial infarction.

1 Two former smokers are included.

ARTICLE INFORMATION
Received March 15, 1999; accepted July 19, 1999; published online November 1, 1999.

Correspondence
Correspondence to J.W. Hop, MD, University Department of Neurology, PO Box 85500, 3508 GA Utrecht,
Netherlands. E-mail j.w.hop@neuro.azu.nl

Affiliations
From the University Department of Neurology (J.W.H., G.J.E.R., A.A., J. v G.) and Julius Center for Patient
Oriented Research (A.A.), Utrecht, the Netherlands. .

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