Hyperglycemia and Clinical Outcome in Aneurysmal
Subarachnoid Hemorrhage
A Meta-Analysis
Nyika D. Kruyt; Geert Jan Biessels; Rob J. de Haan; Marinus Vermeulen; Gabriel J.E. Rinkel;
Bert Coert; Yvo B.W.E.M. Roos
Downloaded from http://stroke.ahajournals.org/ by guest on July 12, 2017
Background and Purpose—Hyperglycemia may worsen outcome after aneurysmal subarachnoid hemorrhage. We
performed a systematic review to investigate the relation between admission hyperglycemia and outcome after
aneurysmal subarachnoid hemorrhage.
Methods—We included cohort studies or clinical trials of patients with aneurysmal subarachnoid hemorrhage admitted
within 72 hours that documented admission glucose levels or the rate of hyperglycemia. Outcome had to be assessed
prospectively after 3 or more months. The overall mean glucose level was calculated by weighting for the number of
patients included in each study. To calculate the effect size, we pooled the ORs and 95% 95% CIs of poor clinical
outcome in patients with or without hyperglycemia.
Results—We searched MEDLINE, EMBASE, Science Citation Index, and the bibliographies of relevant studies. We
included 17 studies totaling 4095 patients. The mean admission glucose level was 9.3 mmol/L (range, 7.4 to
10.9 mmol/L; 14 studies, 3373 patients) and the median proportion of patients with hyperglycemia was 69% (range, 29
to 100; 16 studies, 3995 patients; cutoff levels of hyperglycemia, 5.7 to 12.0 mmol/L). The pooled OR (8 studies, 2164
patients) for poor outcome associated with hyperglycemia was 3.1 (95% CI, 2.3 to 4.3). Cutoff points for defining
hyperglycemia varied across studies (6.4 to 11.1 mmol/L), but this had no clear effect on the observed OR for poor
outcome.
Conclusions—After aneurysmal subarachnoid hemorrhage, admission glucose levels are often high and hyperglycemia is
associated with an increased risk of poor clinical outcome. A randomized clinical trial is warranted to study the potential
benefit of glycemic control after aneurysmal subarachnoid hemorrhage. (Stroke. 2009;40:e424-e430.)
Key Words: clinical outcome 䡲 glucose 䡲 hyperglycemia 䡲 subarachnoid hemorrhage
A
neurysmal subarachnoid hemorrhage (SAH) is a devastating disease with a high case fatality and morbidity.1–3
Clinical outcome depends on the severity of the initial
hemorrhage, but complications such as recurrent bleeding,
secondary ischemia, hydrocephalus or general medical complications also play an important role in clinical outcome.4 –7
Analysis of risk factors for primary and secondary damage,
especially if these can be modified, is important because this
has the potential to improve treatment.
Hyperglycemia is a frequent finding in critically ill patients
admitted to the intensive care unit and is associated with poor
clinical outcome.8 Randomized clinical trials have shown that
tight glycemic control improves outcome in these patients,9,10
and today, this treatment is implemented in many intensive
care unit facilities. Also, in patients with neurological emergencies such as ischemic stroke or primary intracerebral
hemorrhage, levels of glucose are often high and hyperglycemia is associated with an increased case fatality. There are
as yet no randomized clinical trials that favor tight glycemic
control after ischemic stroke,11,12 but further trials investigating this treatment are currently in progress.13 Meanwhile,
guidelines for the management of ischemic stroke do recommend treatment of hyperglycemia.14,15
After aneurysmal SAH, hyperglycemia was reported as
early as 192516 and has also been associated with poor
clinical outcome.17–24 Despite this observation, this association was never systematically investigated. Importantly, as
can be seen from recent reviews and current guidelines, this
potentially modifiable factor is not widely considered as a
risk factor for poor outcome after aneurysmal SAH.1,3,6,25 We
therefore decided to perform a systematic review to investigate mean levels of admission glucose in patients with an
Received July 5, 2008; final revision received October 28, 2008; accepted November 3, 2008.
From the Departments of Neurology (N.D.K., M.V., Y.B.W.E.M.R.), Clinical Epidemiology and Biostatistics (R.J.d.H.), and Neurosurgery (B.C.),
Academic Medical Centre, University of Amsterdam, The Netherlands; and the Department of Neurology (N.D.K., G.J.B., G.J.E.R.), Rudolf Magnus
Institute of Neuroscience, University Medical Center Utrecht, The Netherlands.
Correspondence to Nyika D. Kruyt, Department of Neurology, H2-222, Academic Medical Centre, University of Amsterdam. PO Box 22700, 1100
DE Amsterdam, The Netherlands. E-mail [email protected]
© 2009 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.108.529974
e424
Kruyt et al
Hyperglycemia and Clinical Outcome in Aneurysmal SAH
aneurysmal SAH and to assess the strength of the association
between admission hyperglycemia and clinical outcome.
Methods
Selection of Studies
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Two reviewers (N.D.K., Y.B.W.E.M.R.) performed an independent
computerized MEDLINE and EMBASE search of published studies
(MEDLINE: 1966 to April 2008; EMBASE: 1980 to April 2008)
written in English, German, French, or Spanish. One researcher
(N.D.K.) was supported by a clinical librarian experienced in
literature searching. We searched by subject headings “blood glucose” and “subarachnoid hemorrhage” truncated text words “hyperglyc(a)emia,” “glucose,” “subarachnoid,” “SAH,” “h(a)emorrhage,”
and “bleeding.” Additionally, experts in the field were contacted to
identify any further citations. Full-text versions were obtained from
all studies that were considered to be potentially relevant by one or
both reviewers. After a first selection, the bibliographies of all
relevant studies were searched manually for additional studies and
this method of crosschecking was continued until no further publications were found. Finally, we performed a computerized search of
the Science Citation Index from 1988 to April 2008 to retrieve
studies citing any of the included studies. Any disagreement between
the reviewers on whether an article had to be included was resolved
by consensus or arbitration by a third author (M.V.).
Cohort studies were reviewed with the aid of the STrengthening
the Reporting of OBservational studies in Epidemiology (STROBE)
statement26 and had to comply with the following inclusion criteria:
(1) original data report on an inception cohort or a clinical trial; (2)
the diagnosis of SAH had to be made by the presence of extravasated
blood in the basal cisterns on a CT scan, or, if the CT scan was
negative, by xanthochromic cerebrospinal fluid. Patients with perimesencephalic or other nonaneurysmal causes for SAH had to be
excluded; (3) admission within 72 hours from ictus; and (4) data
available on the mean level of admission glucose or the proportion of
patients with hyperglycemia on admission. To be included in the
analysis on the association between hyperglycemia and clinical
outcome, outcome had to be assessed prospectively with a validated
scale such as the modified Rankin scale (mRS)27 or the Glasgow
Outcome Scale (GOS).28 We defined poor clinical outcome as a
mRS score ⱖ4 or a GOS score ⱕ3 (ie, severe disability) if possible;
otherwise, we adopted the definition from each individual study
unless poor outcome was defined as death. Outcome had to be
assessed ⱖ3 months after the ictus and in at least 90% of the
included patients.
Mean age and clinical condition on admission were extracted
because these characteristics are known to be strong predictors of
poor clinical outcome.5,6 We adapted the definition used by each
individual study to distinguish “good” and “poor ” clinical condition
on admission.
If an article complied with the inclusion criteria but lacked
information on parameters for analysis, or when outcomes were
reported but not related to hyperglycemia, we approached the authors
to obtain these data.
Because studies had to fulfill these strict inclusion criteria, no
further formal quality assessment was undertaken.
Statistical Analysis
Patient characteristics, mean glucose values, and the rates of hyperglycemia on admission were summarized using descriptive statistics.
The weighted mean admission glucose across the studies was
calculated as follows. We summed the mean glucose from each
separate study multiplied by the number of patients in that study.
This sum was then divided by the total number of patients included
across all studies.
For the assessment of the strength of the association between
admission hyperglycemia and poor clinical outcome, unadjusted
ORs were extracted from the individual studies and verified with the
raw data if provided or the ORs were calculated directly from the raw
data if this was not reported in the text. To generate a summary
e425
estimate of the unadjusted OR and the corresponding 95% CI for
poor outcome in patients with hyperglycemia compared with patients
with no hyperglycemia, the unadjusted ORs were pooled using a
random effects model (RevMan Version 4.2.10). In subanalysis, we
explored if the strength of the association between hyperglycemia
and outcome was affected by the cutoff value used to define
hyperglycemia. To this end, studies were assigned to either of 2
subgroups, one for studies with cutoff values for hyperglycemia
below the median cutoff value across all studies and one for studies
with cutoff values above this median.
Publication bias was evaluated using Egger’s bias plot and Egger’s
test.29 Heterogeneity among studies was assessed with the Cochrane’s Q test (significant probability value set at ⬍0.10). The I2
was calculated, which describes the percentage of total variation
across studies that is due to heterogeneity rather than chance. I2
values of 25%, 50%, and 75% correspond to cutoff points for low,
moderate, and high degrees of heterogeneity.30
Finally, a random effect metaregression was performed (STATA
Version 10) to estimate the extent to which study characteristics in
terms of patients’ mean age and the proportion of patients with a
poor clinical condition on admission explain heterogeneity in the size
of effect between the studies.
Results
Article Search
The MEDLINE search yielded 185 citations and the EMBASE
search 132 citations. Two additional relevant studies were
found by searching the bibliographies.22,31 Screening reference lists of major published trials on aneurysmal SAH and a
search of the Science Citation Index did not yield any
additional studies. After filtering out duplicates, 207 citations
remained. After review of the identified studies, 17 studies
were included for analyses (Figure 1).17–21,32– 43 Sixteen studies were observational cohort studies and one study was a
randomized trial.21 From the randomized trial, we could use
data from both the treatment and control group because no
association was found between treatment and outcome
(nicardipine versus placebo44).
Baseline Characteristics of Studies, Glucose
and Hyperglycemia
Patients were included within 24 hours in 5, within 48 hours
in 3, and within 72 hours in the remaining 9 studies. All
studies defined admission glucose as the first random (nonfasting) glucose assessment on admission, and these assessments were used to determine whether a patient was hyperglycemic. One study reported admission glucose to be
missing in 1% of the included patients.35 All other studies
reported that there were no missing admission glucose values;
in 6 of these studies, the absence of admission glucose was an
exclusion criterion.18 –21,32,42 For calculating the overall mean
glucose, 14 of the 17 studies totaling 3373 patients could be
included because in 3 studies, overall mean glucose levels
were not reported and the authors did not have this information available for us. The weighted mean admission glucose
was 9.3 mmol/L (range, 7.4 to 10.9 mmol/L). The median
proportion of patients with hyperglycemia was 69% (range,
29 to 100; 16 studies, 3995 patients). The cutoff values used
to define hyperglycemia varied considerably from study to
study (range, ⬎5.7 to ⬎12.0 mmol/L), but most studies used
a cutoff value between ⬎6.0 and ⬎8.0 mol/L (Table). Three
e426
Stroke
June 2009
207 potentially eligible reports identified
and screened for retrieval
166 reports excluded:
89 no aneurysmal SAH
44 retrospective studies
22 editorials or opinions
6 case reports
5 reviews
41 reports retrieved for detailed assessment
24 reports excluded
14 admittance >72 hrs.
6 described the same population as
another study
4 glucose levels or rate of
hyperglycemia not reported or not
assessed on admittance
Figure 1. Flow diagram of search strategy
and study selection. *Four reports were
included after the authors confirmed inclusion ⬍72 hours. #For 4 reports, these data
were provided by the authors⫹. †For one
report, these data were provided by the
authors.
17 reports included for analyses*
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16 reported the rate of hyperglycemia#
14 reported the mean glucose level †
8 † reports reported the rate of hyperglycemia
and outcome.
9 reports excluded:
7 outcome assessed ≤3 months
1 relation hyperglycemia and outcome
could not be assessed
1 outcome retrospectively assessed
studies reported which glucose values prompted insulin
treatment (⬎6.4, ⬎10, and ⬎12 mmol/L).
Hyperglycemia and Clinical Outcome
For the analysis of the association between hyperglycemia
and clinical outcome, 8 studies including 2164 patients were
included. Outcome was assessed after 3 months in 6 and after
6 months in 2 studies. These outcomes were assessed with the
GOS in 5 and with the mRS in 3 studies. The proportion of
patients with a history of diabetes mellitus (DM) was not
always stated (3 studies18,40,43) or patients with DM were
excluded (4 studies20,21,32,35). One study reported that 1% had
DM. Regarding patient selection, one study only included
patients with poor-grade SAH,32 and one study included
surgically treated patients only.40
Figure 2 shows the (pooled) unadjusted ORs for poor
outcome in patients with hyperglycemia compared with
patients without hyperglycemia on admission (pooled OR
3.1; 95% CI, 2.3 to 4.3; Cochrane’s Q test: P⫽0.10;
I2⫽41.4%). For studies with a definition of hyperglycemia
ⱕ7.0 mmol/L, the pooled OR was 3.0 (95% CI, 1.9 to 4.6;
Cochrane’s Q test: P⫽0.12; I2⫽45.4%), and for studies with
a definition ⬎7.0 mmol/L, the pooled OR was 3.3 (95% CI,
1.9 to 5.8; Cochrane’s Q test: P⫽0.17; I2⫽43.6%). Egger’s
plot (not presented) and Egger’s test (P⫽0.43) did not
indicate publication bias.
For metaregression analysis, we could extract the mean age
in all except one study21 (weighted mean, 53.1 years; range,
50.4 to 54.9 years). The proportion of patients with a poor
clinical condition on admission was available in all studies
(weighted mean, 42%; range, 21% to 100%).
The results did not demonstrate significant associations
between these study characteristics and the effect of hyperglycemia on outcome (P⬎0.60).
Discussion
Our meta-analysis shows that after aneurysmal SAH, high
levels of blood glucose on admission are a frequent finding
and that hyperglycemia on admission is associated with poor
clinical outcome. The point estimate of the observed effect
size of hyperglycemia on poor clinical outcome is similar to
the point estimates of the effect size of hyperglycemia on case
fatality in nondiabetic patients with myocardial infarction45 or
ischemic stroke.46
There are several potential explanations for the high
admission glucose levels and the observed association between hyperglycemia on admission and poor outcome in
patients with aneurysmal SAH. First, hyperglycemia could be
a secondary phenomenon to a transient stress reaction inflicted by the insult. Indeed, previous studies showed that the
release of catecholamines and levels of glucose relate to the
clinical magnitude of the SAH.17–23 Second, hyperglycemia
could be part of an acute (ie, not pre-existent) metabolic
response arising after the SAH that persists beyond the acute
phase. Such a persistent state has been described in other
groups of critically ill patients47–50 and has been associated
with cardiovascular complications and poor clinical outcome.50,51 For example, after ischemic stroke, persistent
hyperglycemia was associated with infarct expansion and
worse clinical outcome.52 Indeed, also after aneurysmal SAH,
(fasting) glucose values remain high during the clinical
course,18 –20 and persistent abnormalities of glucose metabolism predict the occurrence of vasospasm, secondary ischemia, and poor clinical outcome.17,20,24,33
Third, as is common in ischemic stroke,53,54 hyperglycemia
could represent pre-existent but previously unrecognized DM
or disturbances in glucose metabolism short of DM. As such,
Kruyt et al
Table.
Hyperglycemia and Clinical Outcome in Aneurysmal SAH
e427
Study Characteristics of Included Studies
Time to
Outcome
Assessment,
Months
Publication
Year
No. of
Patients
Time Ictus
to Inclusion,
Hours
Lanzino17
1993
593
⬍72
NR
NR
9.3
⬎6.7
83
NR
21
mRS ⬎3
ⱖ3
29
Alberti15§
2000
99
⬍72
50.4
32
10.7
⬎9.0
67
NR
100‡
GOS ⬍4
ⱖ6
48
Yoshimoto45
2001
103
⬍72
55.0
37
10.8
⬎11.1
66
Dorhout
Mees43§
2003
337
⬍24
52.4
36
9.5
⬎7.0
77
First Author
Mean
Age,
Years
Men,
%
Mean
Glucose,
mmol/L
Definition
HG, mmol/L
HG, %
Cutoff to
Treat
HG, mmol/L
NR
10
Poor
Admission
Condition, %
Definition
of Poor
Outcome
Poor
Outcome,
%
67
GOS ⬍4
ⱖ3
63
52
GOS ⬍4
ⱖ3
59
Claassen42
2004
467㛳
⬍72
54.0
29
NR
⬎10.0
40
NR
61
mRS ⬎3
ⱖ3
40
Sarrafzadeh43§
2004
149
⬍72
50.9
28
8.4
⬎6.7
75
NR
54
GOS ⬍4
ⱖ6
28
Juvela40§
2005
175
⬍48
51.0
50
8.2
⬎6.4
76
Kruyt36§
2008
299
⬍48
54.9
35
7.4
⬎6.9
47
53.1
34
8.9
Weighted
mean*
6.4
12
67
22
GOS ⬍4
ⱖ3
31
23
mRS ⬎3
ⱖ3
33
42
39
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Berek47
1993
69
⬍24
47.0
47
NR
⬎8.3
29
…
…
…
…
…
Lepore46
1998
52
⬍24
53.4
50
10.9
⬎11.0
44
…
…
…
…
…
Charpentier21
1999
244
⬍72
50.4
41
NR
⬎12.0
46
…
…
…
…
…
Fukui44
2003
100
⬍24
59.1
36
10.5
NR
NR
…
…
…
…
…
Satoh39§
2005
585
⬍72
55.6
47
9.1
⬎6.9
78
…
…
…
…
…
Sato38
2006
46
⬍24
61.3
37
10.9
⬎7.2
100
…
…
…
…
…
Batjatia41
2005
352
⬍48
54.6
30
9.2
⬎7.6
68
…
…
…
…
…
Kitsuta37
2006
202
⬍72
58.0
38
12.7
⬎6.7
97
…
…
…
…
…
Frontera16§
2006
281
⬍72
54.1
29
8.8
⬎5.7
87
…
…
…
…
…
51.4
34
9.3
Weighted
mean†
70
46
*For studies included in the analysis with outcome.
†For all studies.
‡Only patients with poor-grade SAH were included.
§Additional data were provided by the authors.
㛳Hyperglycemia was related to outcome in 409 patients.
HG indicates hyperglycemia; NR, not reported.
not hyperglycemia in itself, but the underlying, pre-existent
metabolic abnormality could lead to a poorer outcome. In
contrast to ischemic stroke, however, there appears to be no
association between DM and the occurrence of aneurysmal
SAH4,55,56; likewise, the number of patients with unrecognized DM will be relatively low.
Irrespective of its origin, high levels of glucose also could
be causally linked with poor clinical outcome. There are
several observations in support of this hypothesis. The
relation with poor clinical outcome persisted when studies
with a high or low median cutoff to define hyperglycemia
were combined. This indicates that glucose levels relate to
poor clinical outcome independent of the cutoff used to
define hyperglycemia. Moreover, although not consistent,18,20
multivariate analyses in previous studies have shown that the
association between hyperglycemia and poor outcome is
independent from other predictors of poor outcome such as
age or the severity of the ictus.17,21,35,37 Unfortunately, we did
not possess individual patient data to include such predictors
in our meta-analysis.
Improvement of clinical outcome as reported in randomized controlled trials57 that investigated tight glycemic control
in surgical patients admitted to an intensive care unit,58 in
medical patients admitted to an intensive care unit treated for
more that 2 days,10 in patients undergoing coronary artery
bypass grafting,59 and in patients with myocardial infarction60
provide supportive evidence for a causal role of hyperglycemia in poor outcome. However, other randomized controlled
trials that investigated the role of tight glycemic control
showed neutral results in patients undergoing coronary artery
bypass grafting,61 in patients with acute myocardial infarction,62,63 and in patients with acute stroke (non-SAH).12
Therefore, caution is warranted in extrapolating the positive
finding of, for instance, patients in the intensive care unit to
patients with aneurysmal SAH. Extrapolation of trial results
is even more difficult and dangerous because of the significant differences between the treatments used in the trials.
With regard to the trial investigating tight glycemic control in
patients with stroke (not SAH),12 for instance, it was hampered by short treatment duration (24 hours) and poor
glycemic control in the treatment group with only a small
absolute reduction in blood glucose (0.57 mmol/L).
Unfortunately, most studies included in this review did not
provide detailed data on glycemic control; therefore, we
could not investigate whether such treatment would alter the
association between hyperglycemia and outcome after aneurysmal SAH. To date, one randomized trial has been performed in which was tested whether intensive insulin therapy
improves neurological outcome after aneurysmal SAH in
patients admitted to an intensive care facility.64 Although the
results did not favor such treatment, the number of included
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June 2009
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Figure 2. Pooled analyses on poor outcome associated with admission hyperglycemia in patients with aneurysmal SAH. Included studies were subdivided according to the cutoff value used in each individual study to define hyperglycemia into studies with a definition of
hyperglycemia ⱕ7.0 mmol/L or ⬎7.0 mmol/L.
patients was too small (N⫽78) to reliably assess effects on
clinical outcome.
Our study has some limitations that need to be addressed.
First, although we used strict inclusion criteria, the quality of
the studies can vary from study to study and research
questions were retrospectively established in some studies.
Extrapolation of these data should therefore be done with
caution, although the presented results show that the relation
between hyperglycemia and poor outcome after SAH is
robust and consistent. Second, although not statistically
significant, there was moderate between-study heterogeneity.
Our metaregression, however, did not show evidence that this
heterogeneity could be explained by study characteristics
with regard to patients’ age and clinical condition at admission. However, this analysis on heterogeneity was based on a
small number of studies and a limited available set of possible
effect modifiers.
It should be emphasized that it remains unclear whether
hyperglycemia on admission is causally related to poor
clinical outcome after aneurysmal SAH. Although the current article only investigated the association between
admission hyperglycemia and clinical outcome, in previous studies, we20 and others17,19,24,33 showed already that
persistent hyperglycemia throughout the clinical course is
an even stronger predictor of poor outcome after SAH.
With this in mind, the presented results provide sufficient
support to justify a large-scale randomized controlled trials
to determine whether glucose-lowering during the acute
and subacute phases is beneficial in patients with aneurysmal SAH.
Acknowledgments
We thank Mrs H.C. Dyserinck (clinical librarian) for her assistance
in the article search.
Sources of Funding
The research of N.D.K. and G.J.B. was supported by a grant from the
Academic Medical Centre, University of Amsterdam and the University Medical Centre Utrecht, and grant 907-00-140 from the
Netherlands Organization of Scientific Research (ZonMw).
Disclosures
None.
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Hyperglycemia and Clinical Outcome in Aneurysmal Subarachnoid Hemorrhage: A
Meta-Analysis
Nyika D. Kruyt, Geert Jan Biessels, Rob J. de Haan, Marinus Vermeulen, Gabriel J.E. Rinkel,
Bert Coert and Yvo B.W.E.M. Roos
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Stroke. 2009;40:e424-e430; originally published online April 23, 2009;
doi: 10.1161/STROKEAHA.108.529974
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