Sandercock 2011

Cochrane Database of Systematic Reviews
Corticosteroids for acute ischaemic stroke (Review)
Sandercock PAG, Soane T
Sandercock PAG, Soane T.

Corticosteroids for acute ischaemic stroke.
Cochrane Database of Systematic Reviews 2011, Issue 9. Art. No.: CD000064.
DOI: 10.1002/14651858.CD000064.pub2.
www.cochranelibrary.com
Corticosteroids for acute ischaemic stroke (Review)

Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Analysis 1.1. Comparison 1 Corticosteroids versus placebo, Outcome 1 All deaths. . . . . . . . . . . . . 18
Analysis 1.2. Comparison 1 Corticosteroids versus placebo, Outcome 2 Deaths within one month. . . . . . . 19
FEEDBACK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Corticosteroids for acute ischaemic stroke (Review) i

[Intervention Review]
Corticosteroids for acute ischaemic stroke
Peter AG Sandercock1 , Tim Soane2
1 Division
of Clinical Neurosciences, University of Edinburgh, Edinburgh, UK. 2 Department of Clinical Neurosciences, Western
General Hospital, Edinburgh, UK
Contact address: Peter AG Sandercock, Division of Clinical Neurosciences, University of Edinburgh, Neurosciences Trials Unit,
Bramwell Dott Building, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK. [email protected].
Editorial group: Cochrane Stroke Group.

Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 9, 2011.
Review content assessed as up-to-date: 8 March 2011.
Citation: Sandercock PAG, Soane T. Corticosteroids for acute ischaemic stroke. Cochrane Database of Systematic Reviews 2011, Issue
9. Art. No.: CD000064. DOI: 10.1002/14651858.CD000064.pub2.
ABSTRACT
Background
The majority of strokes are due to cerebral infarction. Ischaemic cerebral tissue tends to develop cytotoxic oedema which, if the blood-
brain barrier is disrupted, may be followed by vasogenic oedema. Large infarcts can develop life-threatening massive oedema. Early
treatment with corticosteroids could theoretically help reduce both cytotoxic and vasogenic oedema and so improve the clinical outcome
after a stroke.
Objectives
To assess the effect of corticosteroids in acute presumed ischaemic stroke.
Search methods
We searched the Cochrane Stroke Group Trials Register (last searched: 17 February 2011).
Selection criteria
Published randomised trials comparing corticosteroids with placebo or a control group in people with acute (presumed or definite)
ischaemic stroke. Trials were included if treatment began within 48 hours of stroke onset and if clinical outcomes were assessed.
Data collection and analysis
Two review authors independently applied the inclusion criteria, assessed trial quality and extracted the data.
Main results
Eight trials involving 466 people were included. Details of trial quality that may relate to bias were not available for most trials. No
difference was shown in the odds of death within one year (odds ratio (OR) 0.87, 95% confidence interval (CI) 0.57 to 1.34). Treatment
did not appear to improve functional outcome in survivors. Seven trials reported neurological impairment but pooling the data was
impossible because no common scale or time interval was used. The results were inconsistent between individual trials. The only adverse
effects reported were small numbers of gastrointestinal bleeds, infections and deterioration of hyperglycaemia across both groups. The
results are unchanged since the previous update.
Corticosteroids for acute ischaemic stroke (Review) 1
Authors’ conclusions
There is not enough evidence to evaluate corticosteroid treatment for people with acute presumed ischaemic stroke. The conclusions
are unchanged since the previous update.
PLAIN LANGUAGE SUMMARY
Corticosteroids for acute ischaemic stroke
There is no evidence of benefit from corticosteroids for acute ischaemic stroke. Stroke from blockage of an artery to a part of the brain
causes swelling of that part of the brain. The swelling produces pressure effects, may cause additional brain cells to die, or delays the
recovery of damaged but recoverable brain cells. Reduction of this swelling may relieve pressure on adjacent parts of the brain, reduce
the number of brain cells that are killed and allow better recovery of damaged brain cells. Corticosteroids have been used to reduce
this brain swelling in order to help limit damage and speed recovery. However, from the small and inadequate amount of evidence
available from eight trials involving 466 participants, this review found no benefit of corticosteroids on reducing the number of deaths
or improving functional outcome in survivors.
OBJECTIVES
BACKGROUND
To determine whether the administration of intravenous corticos-
Cerebral oedema can cause clinical deterioration and death after teroids in patients with acute presumed ischaemic stroke is a safe
ischaemic stroke by producing direct pressure and vascular oc- and effective treatment.
clusive effects, as well as indirect effects through vasospasm and
necrosis (Battistini 1981; Gomes 2005). Massive cerebral oedema
following a large hemispheric infarction can lead to transtentorial METHODS
herniation and death, but in appropriately selected younger pa-
tients decompressive hemicraniectomy can be life-saving (Staykov
2011). Oedema complicating ischaemic stroke therefore remains Criteria for considering studies for this review
of considerable potential relevance to acute stroke care. Cerebral
oedema may be classified into cytotoxic and vasogenic types where
cytotoxic oedema is related to cell membrane dysfunction while Types of studies
vasogenic oedema is related to the breakdown of the function All attempts were made to identify all unconfounded, definitely or
of the blood-brain barrier. Vasogenic cerebral oedema associated possibly truly randomised trials in which treatment with corticos-
with intracranial tumours often responds well to corticosteroids teroid therapy was compared with control in patients following an
(Shapiro 1975; Gomes 2005), and though most of the oedema as- acute (presumed) ischaemic stroke. We excluded trials in which
sociated with large cerebral infarcts is vasogenic, some of the brain allocation to a treatment or control group was not definitely truly
swelling in cerebral infarcts is due to cytotoxic oedema. It is not random or in which treatment allocation was not concealed since
clear if corticosteroids reduce cytotoxic oedema (Battistini 1981). prior knowledge of treatment allocation may have led to biased
Although studies of their use in acute stroke have been disappoint- treatment allocation (Schulz 1995).
ing, some physicians continue to treat stroke with corticosteroids.
For example, some 20% of patients with acute ischaemic stroke
in the USA in the 1980s, who were involved in the Stroke Data Types of participants
Bank study, were treated with corticosteroids (Faulkes 1988). In a We included patients with acute (presumed or definite) ischaemic
survey in China, 19% of physicians reported that they used cor- stroke where attempts were made to exclude intracerebral haemor-
ticosteroids routinely and 61% said that they used them at times rhage. Definite ischaemic stroke implies patients in whom a com-
for certain patients (Chen 1997). However, there are potentially puterised tomography (CT) scan was performed before randomi-
serious side-effects from the use of corticosteroids. sation. Presumed ischaemic stroke means patients who did not
have a CT scan and, therefore, where haemorrhage could not be whether or not CT scanning was performed prior to randomisa-
reliably excluded. tion.
For the original review, if any of the above data were not avail-
able in the publications, the review authors requested further in-
Types of interventions formation through correspondence with the trialists. Where no
Corticosteroid (intravenous, intra-muscular or oral) versus con- further information was obtained, the results from the ’on-treat-
trol. ment’ analysis were used, based on the data extractable from the
publication. Due to the age of many of the studies, data regarding
disability were difficult to obtain. Where data were not available
Types of outcome measures about the type of stroke and cause of death, these were sought by
The main outcomes of interest were: the original review authors from the trialists. For this update, we
1. the number of patients who died from any cause during the did not seek to contact any of the trialists.
scheduled follow-up period; For the original review both proportional and absolute risk reduc-
2. functional outcome among survivors; tions were calculated for each outcome. A test for heterogeneity
3. adverse effects of treatment, where documented. of treatment effect between the trials was made using a standard
Wherever possible, we analysed results on an intention-to-treat Chi2 statistic. The typical treatment effect across trials, the ’typical
basis. odds ratio (OR)’ (that is the odds of an unfavourable outcome
amongst treatment-allocated patients to the corresponding odds
amongst controls), was calculated using the Peto OR method.
Search methods for identification of studies
See the ’Specialized register’ section in the Cochrane Stroke Group
module.
We identified trials in the Cochrane Stroke Group Trials Register, RESULTS
which was last searched by the Managing Editor on 17 February
2011.
For the original review, the review authors contacted numerous
researchers in an effort to identify unpublished and ongoing stud- Description of studies
ies, and also asked investigators of published trials to provide ad-
ditional information on cause of death. We have not repeated this See: Characteristics of included studies; Characteristics of excluded
exercise for this update. studies.
One new trial meeting the inclusion criteria has been identified See Characteristics of included studies. We identified 24 trials
for this update. from the search of the Cochrane Stroke Group Trials Register of
which eight fulfilled the entry criteria. We did not identify any
ongoing trials. All included trials used dexamethasone except two,
which used betamethasone. Four trials compared dexamethasone
Data collection and analysis with an unspecified placebo, two trials compared dexamethasone
For the original review, two review authors (NQ, SL - see with placebo water, one trial compared betamethasone with vita-
Acknowledgements) independently selected the trials for inclu- min C and one trial compared betamethasone with an unspecified
sion. placebo.
For this update, we independently agreed that one additional study The mean age of the patients in the trials, where it was quoted,
was eligible for inclusion. We re-assessed the methodological qual- ranged from 66 years to 75 years. Approximately half the patients
ity of each study for this update. We did not use a scoring system were male. Only one trial (Norris 1986) used CT scanning to ex-
to assess quality but noted the following details: randomisation clude haemorrhage. The severity of stroke as judged by overall case
method, blinding, whether intention-to-treat (ITT) analyses were fatality ranged from 7% to 79%, though this assessment is con-
documented and possible from the published data, and the num- founded with duration of follow-up. Only three trials had follow-
ber of patients lost to follow-up. We independently extracted and up beyond one month: three months for McQueen 1978, and 12
cross-checked the data, and discussed discrepancies. We sought months for Mulley 1978 and Ogun 2001. The timing of treatment
data on the number of patients with each outcome measure (where from onset of stroke was within 24 hours for four trials, 48 hours
available) by allocated treatment group. To allow an ITT analy- for three trials and not specified for one trial (McQueen 1978).
sis, we sought the data irrespective of compliance, and whether or Only two trials used a measure of functional disability (Mulley
not the patient was subsequently deemed ineligible or otherwise 1978; Ogun 2001), the remainder used neurological impairment
excluded from treatment or follow-up. We also sought data on scales.

Risk of bias in included studies Infection was more frequent in the treatment group in two trials (4
versus 0) but less frequent in one trial (0 versus 4). Gastrointestinal
Eight trials met our inclusion criteria and have been included in
bleeding was reported as being more frequent in the treatment
the analysis and are summarised in the Characteristics of included
group in three trials (7 versus 4) but less frequent in one trial (0
studies table. The reasons for excluding the 15 trials from the
versus 3). Norris 1986 reported withdrawals from adverse events
analysis are summarised in the Characteristics of excluded studies
as follows (treatment versus control): gastrointestinal bleeding (3
table. Information about trial quality that may relate to bias was
versus 2), infection (0 versus 4), worsening hyperglycaemia (4
not available from many trials for:
versus 0).
1. reporting of randomisation and concealment;
2. whether concealment was adequate;
3. whether blinding was adequate;
4. assessment of the success of blinding;
5. any important imbalances in the treatment groups; DISCUSSION
6. number of patients excluded from the analysis. The results of this review do not support the hypothesis that in-
Adverse events were reported in a systematic fashion in only one travenous or intramuscular corticosteroids reduce all-cause case
trial, so the adverse event data have not been pooled but merely fatality following stroke. However, the small number of patients
described. and events in the trials mean that there is great imprecision and
that this treatment could increase the odds of death by as much as
34%, or reduce it by as much as 43% (95% CI). Few patients had
the diagnosis of ischaemic stroke confirmed by a CT scan, and
Effects of interventions
it is conceivable that the results were influenced by the inclusion
The total number of individuals included in the eight trials was of haemorrhagic strokes. It is possible that the relative treatment
466. There was no evidence of statistical heterogeneity. The eight effects of corticosteroids may vary between patients with differ-
trials showed a non-significant decrease in the odds of death ing levels of absolute risk. Although the evidence is limited, the
(within one year) of 0.87 (95% CI 0.57 to 1.34). Only one small present review would be compatible with the notion that corti-
trial reported a marginal statistically significant hazard in the odds costeroids are beneficial in high-risk patients with large infarcts
of death and all other trials were statistically non-significant. There and much vasogenic oedema (Mulley 1978), and either ineffective
was no evidence that the effect on deaths within one month (OR or harmful among low-risk patients with smaller infarcts and less
0.97; 95% CI 0.63 to 1.47) was substantially different from the vasogenic oedema. Two trials with higher case-fatality rates in the
effect on deaths within one year. The results of the trials that used control groups (Mulley 1978; Norris 1986) both reported trends
betamethasone did not substantially differ from those using dex- (statistically non-significant) in favour of treatment. However, one
amethasone. other trial with a higher case-fatality rate did not favour treatment
We could not do analysis by cause of death since we did not receive (Ogun 2001). There was no significant heterogeneity of results
appropriate data from the trial investigators. from the different trials, nor was there any evidence to suggest bias
Six trials reported neurological impairment scales but pooling from selective reporting of trials based on the results. The point
these data was impossible because no common scale nor time in- estimates of the ORs for the different trials were evenly spread
terval was used. Four trials reported no difference in neurological around the pooled point estimate.
impairment, one reported a statistically significant benefit (Patten
In general, neither neurological nor functional outcome was any
1972) and one reported a statistically significant worsening (Norris
better in those patients who survived. Treating severe disability and
1976). The only trials to report functional disability found a non-
death as one endpoint (from the one trial that measured functional
significant difference at 12 months. Mulley et al found full inde-
outcome) made no difference to the conclusion.
pendence in 10 survivors in the dexamethasone group and eight
in the placebo group; for severe disability the figures were four in Adverse effects of treatment were few (approximately 10%). They
the dexamethasone group and three in the placebo group (Mulley were generally more frequent in the treatment group, for infection,
1978). Ogun et al found of the three survivors in the dexametha- worsening hyperglycaemia and gastrointestinal bleeding, as would
sone group two were ambulant and one was chair bound, whilst be expected from the mode of action of corticosteroids. Given the
in the placebo group the two survivors were bed bound and chair unsystematic manner of reporting adverse events in these trials,
bound (Ogun 2001). there may have been under-reporting as trials of dexamethasone
Only one of the eight trials reported non-fatal adverse effects in a using similar doses in cerebral haemorrhage report much higher
systematic manner (Norris 1986); there were generally few adverse adverse event rates in the treatment group (Poungvarin 1987). Ev-
events and these were limited to gastrointestinal bleeding, infection idence from a much larger-scale trial of high-dose corticosteroids
and hyperglycaemia. Diabetes or its worsening was reported to be in traumatic brain injury highlights the potential hazards. The
more frequent in the treatment group in three trials (12 versus 0). MRC CRASH study, a randomised controlled trial of high-dose

corticosteroids in over 10,000 patients with acute traumatic brain for this treatment to be recommended. We do not feel that the
injury, showed that allocation to corticosteroids was associated present data hold enough promise of clinically worthwhile benefits
with a significant excess of deaths from all causes, and was not to advocate a large-scale trial.
associated with any significant reduction in disability in survivors
(CRASH 2005).
ACKNOWLEDGEMENTS
AUTHORS’ CONCLUSIONS We thank the authors of the previous versions of this systematic
review: N Qizilbash, J Lopez Arrieta and S Lewington. We should
Implications for practice also like to thank those trialists who provided additional data: G
Trials of corticosteroids do not provide evidence of a beneficial Mulley, JW Norris, BM Patten. Thanks to M Murphy for helping
effect on death following acute (presumed) ischaemic stroke. Nor in the correspondence with the trialists. We would particularly like
do the data on neurological impairment or functional outcome to thank Hazel Fraser for updating the search and copy editing
suggest any benefit in survivors. There is, therefore, no evidence support.
to support the routine use of corticosteroids in the management
of acute ischaemic stroke.
Ongoing trials
Implications for research We are not aware of any ongoing trials of corticosteroids but would
Given the adverse effects of corticosteroids, the benefits on both be grateful for any information about any other relevant trials not
case fatality and functional outcome would need to be substantial included in this review.
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Indicates the major publication for the study

CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Bauer 1973
Methods Double-blind, placebo controlled

Randomised
Number of patients excluded after randomisation: 5 (including 1 lost to follow-up, none
included in analysis)
Number lost to follow-up: 1
Participants USA
54 in total (after exclusions): 30 female, 24 male
Mean age: 66 years
Time from onset of stroke to enrolment: within 48 hours
Method of diagnosis: clinical, lumbar puncture 100%
28 dexamethasone
26 placebo
Interventions Dexamethasone versus placebo

Intervention: dexamethasone 12 mg i.v. stat, 4 mg i.m. 6 hourly for 3 days, 4 mg i.m. 8
hourly for 3 days, 4 mg i.m. 12 hourly for 2 days, 4 mg i.m. 24 hourly for 2 days: total
dose: 120 mg dexamethasone
Placebo: unspecified
All patients: prophylactic ulcer diet and antacid (30 cc Maalox) 4 times a day where oral
intake possible
Duration: 10 days
Outcomes Death at 14 days

Neurological impairment in the level of consciousness, the motor system and of menta-
tion at 14 days
Notes Exclusions: more than 300 red blood cells per cc in the cerebrospinal fluid; history of
gastro-intestinal bleeding or symptomatic duodenal ulcer
Follow-up: 14 days
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection Unclear risk Not stated, but assumed computer-gener-
bias) ated by Merck, Sharp & Dohme
Allocation concealment (selection bias) Unclear risk “randomisation was performed on a con-
secutive admission basis”. Blind until last
patient assessed

Bauer 1973 (Continued)
Blinding (performance bias and detection Low risk “coded vials which contained either
bias) Decadron [dexamethasone] or a similarly
All outcomes appearing placebo”
Incomplete outcome data (attrition bias) Low risk 5 patients withdrawn (3 placebo, 2 dexam-
All outcomes ethasone). These were not included in anal-
yses
Selective reporting (reporting bias) Low risk
Gupta 1978

Randomised
Number of patients excluded after randomisation: not stated
Number of losses to follow-up: not stated
Participants India
30 patients (sex breakdown and age not stated)
Time from onset of stroke to enrolment: less than 24 hours
Method of diagnosis: clinical, lumbar puncture to exclude haemorrhage (100%)
13 Betamethasone
17 Placebo
Interventions Betamethasone versus placebo

Intervention: betamethasone 10 mg stat, 10 mg/day in divided doses for 2 days, 8 mg/
day in divided doses for 3 days, 6 mg/day in divided doses for 3 days, 4 mg/day for 3
days, 2 mg/day for 10 days: total dose: 94 mg betamethasone
Duration: 21 days
Outcomes Death at 21 days

Neurological status (self-made method) at 1, 2 and 3 days, and at 1, 2 and 3 weeks
Cerebrospinal fluid pressures
Adverse events not reported
Notes Exclusions: not stated

Follow-up: 21 days
Risk of bias
Random sequence generation (selection Unclear risk Not stated

bias)
Allocation concealment (selection bias) Unclear risk Not stated

Gupta 1978 (Continued)
Blinding (performance bias and detection Low risk “ampoules of the drug and placebo were
bias) similar in appearance”
All outcomes
Incomplete outcome data (attrition bias) Unclear risk Authors do not indicate if there were any
All outcomes patients excluded or lost to follow-up prior
to analysis
McQueen 1978

Randomised
Participants New Zealand

48 in total (sex breakdown and age not stated)
Time from onset of stroke to enrolment: not stated
Method of diagnosis: clinical diagnosis of cerebral thrombosis, lumbar puncture ?%
24 betamethasone
24 placebo
Interventions Betamethasone versus placebo

Interventions: betamethasone 12 mg i.m. stat, 4 mg i.m. 8 hourly for 1 day, 4 mg i.m.
8 hourly for 9 days, 4 mg i.m. 2 hourly for 2 days, 2 mg i.m. 2 hourly for 2 days: total
dose: 345 mg betamethasone
Placebo: vitamin C
Duration: 14 days
Outcomes Death at 12 weeks

Causes of death
Neurological scores (not available) at 14th to 15th day and week 12
Notes Exclusions: subarachnoid haemorrhage; severe diabetes; pre-existing steroid treatment;

known peptic ulceration
Follow-up: 12 weeks
Risk of bias
Random sequence generation (selection Unclear risk Not stated, but probably prepared by out-
bias) sider to study
Allocation concealment (selection bias) Unclear risk “each centre received packages of be-
tamethasone or identical placebo in ran-
domised order within blocks of six. As pa-

McQueen 1978 (Continued)
tients were entered into the trial they were

given the medication designated by the
next number in the treatment block”
Blinding (performance bias and detection Low risk “packages of betamethasone or identical
bias) placebo”
All outcomes
Incomplete outcome data (attrition bias) Unclear risk Authors do not indicate if there were any
All outcomes patients excluded or lost to follow-up prior
to analysis
Mulley 1978

Randomised
Number of patients excluded after randomisation: 16 (not included in analysis, 5 due
to alternative diagnoses (subarachnoid haemorrhage, cerebral tumour, demyelinating
disease and ethanol overdose), 5 due to history revealing previous stroke or onset over 48
hours previously, 1 due to developing tuberculosis, and 1 at the request of the admitting
physician, treatment allocations not stated)
Number lost to follow-up: 4 (2 dexamethasone, 2 placebo, not included in analysis)
Participants UK
134 in total (118 included in final analysis)
Mean age: 70 years (no breakdown by sex)
Method of diagnosis: clinical, lumbar puncture ?%
61 dexamethasone
57 placebo

Interventions: dexamethasone 4.2 mg i.m. 6 hourly for 10 days, 4.2 mg i.m. 8 hourly
for 1 day, 4.2 mg i.m. 12 hourly for 2 days, 4.2 mg i.m. once for 1 day: total dose: 201.
6 mg dexamethasone
Placebo: water
Duration: 14 days
Outcomes Death at day 10 and at 3 and 12 months

Functional disability (Adams method) at 12 months
Adverse effects of treatment
Quality of life
Duration of hospital stay
Notes Exclusions: previous stroke; considered to have intracranial tumour, injury or subarach-
noid haemorrhage; diabetes mellitus; peptic ulcer; already receiving steroids
Follow-up: 12 months

Mulley 1978 (Continued)
Risk of bias
Random sequence generation (selection Unclear risk Not stated

bias)
Allocation concealment (selection bias) Low risk “each of the four wards contained a se-
ries of sealed envelopes containing ran-
domised treatment instructions ... After en-
tering into the trial the next envelope was
opened”
Blinding (performance bias and detection Low risk “treatment ampoules identified only by a
bias) code number”, “the treatment code was
All outcomes available to [one of the trial organisers],
who did not participate in assessment”
Incomplete outcome data (attrition bias) Low risk 16 patients excluded after randomisation
All outcomes and not included in analysis. 4 patients lost
to follow-up (2 placebo, 2 treatment) not
included in analysis
Norris 1976

Randomised
Number of losses to follow-up: 1 (lost after assessment on day 22, included in analysis)
Participants Canada
53 in total (including 1 lost to follow-up): 24 female, 29 male
Mean age: 70 years
Method of diagnosis: clinical, lumbar puncture 100%, brain scan 100%, angiography ?
%
26 dexamethasone
27 placebo
Interventions Dexamethasone versus placebo.

Intervention: dexamethasone 8 mg stat bolus, 4 mg 6 hourly gradually decreased over
12 days: total dose: 140 mg dexamethasone
Duration: 12 days
Outcomes Death at day 29

Cause of death at day 29
Neurological status (self-made scale) at days 1, 8, 15, 22 and 29
Norris 1976 (Continued)
Notes Exclusions: recent peptic ulcer; concurrent infection, psychiatric disturbances

Follow-up: 29 days
Risk of bias
Random sequence generation (selection Low risk Correspondence with author suggests ran-
bias) dom number tables
Allocation concealment (selection bias) Unclear risk “patients ... were randomly allocated on ad-
mission to a placebo or steroid group in a
double-blind manner”
Blinding (performance bias and detection Low risk “each patient received either dexametha-
bias) sone or matching placebo”
All outcomes
Incomplete outcome data (attrition bias) Unclear risk 1 patient lost to follow-up but included
All outcomes in analysis, not stated if any patients were
excluded after randomisation: “53 patients
completed the study”
Norris 1986

Randomised
Number of patients excluded after randomisation: 13 (6 placebo and 7 dexamethasone
due to presumed side effects: diabetes (4 steroid, 0 placebo), infection (0 steroid, 4
placebo), gastrointestinal bleed (3 steroid, 2 placebo))
Participants Canada
113 in total: 61 female, 52 male
Mean age: 75 years
Method of diagnosis: CT used in (not stated but implied) 100% ?
54 dexamethasone
59 placebo

Intervention: dexamethasone 24 mg p.o./i.v. 6 hourly with progressive reduction of dose
until day 12: total dose: 480 mg dexamethasone
Duration: 12 days

Norris 1986 (Continued)

Cause of death at day 21
Neurological impairment (Toronto stroke method) at days 6, 12, 21
Notes Exclusions: cerebral haemorrhage by CT, mild stroke, massive previous stroke, terminal
stroke, dementia, diabetes mellitus, concurrent sepsis, gastrointestinal haemorrhage, or
cardiac embolic source
Follow-up: 21 days
Risk of bias
Random sequence generation (selection Low risk Random number tables

bias)
Allocation concealment (selection bias) Unclear risk “consecutive patients admitted to the
stroke unit were entered into the study”,
“patients were assigned to receive either
dexamethasone or placebo according to
random number”
Blinding (performance bias and detection Low risk “material was supplied in identical-appear-
bias) ing vials bearing the patients number in the
All outcomes study”
Incomplete outcome data (attrition bias) Unclear risk 13 patients excluded after randomisation
All outcomes and not included in analysis. ? patients lost
to follow-up (likely 0)
Ogun 2001

Randomised
Number of patients excluded after randomisation: 0
Number of losses to follow-up: 0
Participants Nigeria
13 in total (cannot determine age and sex breakdown)
Method of diagnosis: clinical, using Siriraj stroke score to distinguish haemorrhagic from
ischaemic stroke
5 dexamethasone
8 placebo

Ogun 2001 (Continued)

Interventions: dexamethasone 100 mg stat, 16 mg 6 hourly for 2 days: total dose: 228
mg dexamethasone
Placebo: water
Duration: 2 days
Outcomes Death at 1 and 6 months

Notes Exclusions: presentation after 24 hours; primary subarachnoid haemorrhage; symptoms

suggestive of head injury, subdural, tumour; brainstem stroke; diabetes mellitus; peptic
ulcer; sepsis; previous stroke in same hemisphere; impairment of consciousness
Follow-up: 6 months
Risk of bias
Random sequence generation (selection Unclear risk “by simple ballot”

bias)
Allocation concealment (selection bias) Unclear risk “patients were sequentially paired and ran-
domised”, “the code was broken after the
first 20 patients ... by [one author] who was
not involved in assessment of patients”
Blinding (performance bias and detection Low risk “ampoules were prepared by MCA Chem-
bias) ical, Italy and contained either dexametha-
All outcomes sone or distilled water ... these were indis-
tinguishable and kept in identically num-
bered boxes; one box for each patient”
Incomplete outcome data (attrition bias) Unclear risk Authors do not state if there were any pa-
All outcomes tients excluded subsequent to randomisa-
tion. None were lost to follow-up

Patten 1972

Randomised
Number of patients excluded after randomisation: 7 (3 placebo due to alternative di-
agnosis (subdural haematoma), alternative cause of death (ruptured abdominal aortic
aneurysm) and 1 due to concomitant administration of dextran 40; 3 dexamethasone
due to exacerbation of diabetes and stopping of steroid, alternative diagnosis (subarach-
noid haemorrhage) and 1 due to concomitant administration of anticoagulant therapy;
1 (? allocation) who had not received any treatment due to nursing error)
Participants USA
31 in total: 15 female, 16 male
Mean age: 69 years
Method of diagnosis: clinical, lumbar puncture ?%, isotope brain scan ?%, angiography
?%
17 dexamethasone
20 placebo

Intervention: dexamethasone 10 mg i.v. stat, 4 mg i.m. 6 hourly for 10 days, dose
gradually decreased to 0 over 7 days: total dose: unknown
Control: placebo
All patients: oral antacid
Duration: 17 days

Motor function (self-made scoring) at days 3, 6, 10 and 17
Mental function (self-made scoring) at days 3, 6, 10 and 17
Notes Exclusions: subarachnoid haemorrhage

Follow-up: 17 days
Risk of bias
Random sequence generation (selection Low risk Random number tables

bias)
Allocation concealment (selection bias) Low risk randomisation not broken until end of trial
Blinding (performance bias and detection Low risk “the material was supplied in identical ap-
bias) pearing vials bearing the patients number
All outcomes in the study”

Patten 1972 (Continued)
Incomplete outcome data (attrition bias) Unclear risk Number lost to follow-up not stated. The
All outcomes authors provide outcome data on those
randomised and subsequently excluded, so
that an ITT analysis can be performed
Selective reporting (reporting bias) Unclear risk Patient excluded from the analysis due to al-
ternative mechanism of death despite meet-
ing inclusion criteria and receiving treat-
ment
CT: computerised tomography

i.m.: intramuscular
ITT: intention-to-treat
i.v.: intravenous
p.o.: per os (by mouth)
stat: immediately
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Albizzati 1979 Glycerol treatment compared with dexamethasone and not placebo
Barolin 1976 Not randomised - alternate allocation
Dyken 1956 Alternate allocation
Freeman 1978 No data on deaths in each treatment group given. Contained haemorrhagic stroke. Dexamethasone plus
mannitol versus placebo
Gahlot 1982 Glycerol compared with dexamethasone and not placebo
Gilsanz 1975 Glycerol treatment compared with dexamethasone and not with placebo
Hasan 1989 Subarachnoid haemorrhage only
Hetzel 1957 No information on randomisation procedure or blinding
Kaste 1976 Dexamethasone plus dextran versus placebo
Kumar 1989 Uneven allocation between treatment (25 participants) and control (15 participants) and confounded by the
administration of antacids to the treatment group only

(Continued)
Paal 1981 Dexamethasone plus dextran plus aspirin versus placebo
Poungvarin 1987 Haemorrhagic stroke only
Rompel 1980 No data available
Rubinstein 1965 Not randomised - unequal allocation between treatment (21 participants) and placebo (6 participants)
Russek 1955 Open, uncontrolled study
Santambrogio 1978 No data provided on number of deaths
Tellez 1973 Haemorraghic stroke only
Wright 1974 No randomised allocation

DATA AND ANALYSES
Comparison 1. Corticosteroids versus placebo
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 All deaths 8 466 Peto Odds Ratio (Peto, Fixed, 95% CI) 0.87 [0.57, 1.34]
2 Deaths within one month 8 466 Peto Odds Ratio (Peto, Fixed, 95% CI) 0.97 [0.63, 1.47]
Analysis 1.1. Comparison 1 Corticosteroids versus placebo, Outcome 1 All deaths.
Review: Corticosteroids for acute ischaemic stroke
Comparison: 1 Corticosteroids versus placebo
Outcome: 1 All deaths
Peto Peto
Study or subgroup Treatment Control Odds Ratio Weight Odds Ratio
n/N n/N Peto,Fixed,95% CI Peto,Fixed,95% CI
Bauer 1973 5/28 9/26 12.4 % 0.42 [ 0.13, 1.42 ]
Gupta 1978 2/13 2/17 4.2 % 1.35 [ 0.17, 10.93 ]
McQueen 1978 12/24 5/24 13.2 % 3.49 [ 1.08, 11.24 ]
Mulley 1978 42/61 45/57 27.1 % 0.60 [ 0.26, 1.35 ]
Norris 1976 7/29 5/24 11.0 % 1.20 [ 0.33, 4.33 ]
Norris 1986 13/54 15/59 25.0 % 0.93 [ 0.40, 2.18 ]
Ogun 2001 2/5 6/8 3.7 % 0.26 [ 0.03, 2.32 ]
Patten 1972 1/17 2/20 3.3 % 0.58 [ 0.06, 6.04 ]
Total (95% CI) 231 235 100.0 % 0.87 [ 0.57, 1.34 ]

Total events: 84 (Treatment), 89 (Control)
Heterogeneity: Chi2 = 9.32, df = 7 (P = 0.23); I2 =25%
Test for overall effect: Z = 0.62 (P = 0.53)
Test for subgroup differences: Not applicable
0.02 0.1 1 10 50

Analysis 1.2. Comparison 1 Corticosteroids versus placebo, Outcome 2 Deaths within one month.
Review: Corticosteroids for acute ischaemic stroke
Comparison: 1 Corticosteroids versus placebo
Outcome: 2 Deaths within one month
Peto Peto
Study or subgroup Treatment Control Odds Ratio Weight Odds Ratio
n/N n/N Peto,Fixed,95% CI Peto,Fixed,95% CI
Bauer 1973 5/28 9/26 12.1 % 0.42 [ 0.13, 1.42 ]
Gupta 1978 2/13 2/17 4.0 % 1.35 [ 0.17, 10.93 ]
McQueen 1978 9/24 0/24 8.5 % 11.14 [ 2.65, 46.74 ]
Mulley 1978 25/61 27/57 33.5 % 0.77 [ 0.37, 1.60 ]
Norris 1976 7/29 5/24 10.7 % 1.20 [ 0.33, 4.33 ]
Norris 1986 13/54 15/59 24.3 % 0.93 [ 0.40, 2.18 ]
Ogun 2001 2/5 6/8 3.6 % 0.26 [ 0.03, 2.32 ]
Patten 1972 1/17 2/20 3.2 % 0.58 [ 0.06, 6.04 ]
Total (95% CI) 231 235 100.0 % 0.97 [ 0.63, 1.47 ]

Total events: 64 (Treatment), 66 (Control)
Heterogeneity: Chi2 = 15.10, df = 7 (P = 0.03); I2 =54%
Test for overall effect: Z = 0.17 (P = 0.87)
Test for subgroup differences: Not applicable
0.02 0.1 1 10 50
FEEDBACK
Comment
Summary
Is it possible to compare outcomes between included and certain excluded trials where the latter were excluded on the grounds that
they were confounded?
Reply
Since non-randomised studies may be biased towards a positive treatment effect (Schulz 1995), it would introduce a systematic bias
into the analysis by comparing outcomes between included studies and those excluded trials which were confounded. Larger scale
randomised evidence is required if it is still considered appropriate to further test these drugs.
Contributors
Walid Matat
WHAT’S NEW
Last assessed as up-to-date: 8 March 2011.
Date Event Description
9 March 2011 New citation required but conclusions have not changed New review team.
9 March 2011 New search has been performed We have updated the search and have included one new
study (13 patients), bringing the total number of in-
cluded trials to eight, involving 466 participants. We have
revised the text. The overall conclusions are unchanged
HISTORY
Protocol first published: Issue 3, 1997
Review first published: Issue 3, 1997
Date Event Description
5 August 2008 Amended Converted to new review format.
CONTRIBUTIONS OF AUTHORS
Peter Sandercock: article selection, data abstraction, analysis construction, co-writer of the review.
Tim Soane: article selection, data abstraction, analysis construction, co-writer of the review.
DECLARATIONS OF INTEREST
None known
SOURCES OF SUPPORT

Internal sources
• University of Oxford, UK.
External sources
• NHS Anglia and Oxford Region Research and Development Programme, England, UK.
INDEX TERMS
Medical Subject Headings (MeSH)

Anti-Inflammatory Agents [∗ therapeutic use]; Brain Edema [∗ drug therapy; etiology]; Brain Ischemia [complications; drug therapy];
Glucocorticoids [∗ therapeutic use]; Randomized Controlled Trials as Topic; Steroids; Stroke [complications; ∗ drug therapy]
MeSH check words

Humans


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Cochrane Database of Systematic Reviews

Corticosteroids for acute ischaemic stroke (Review)

Sandercock PAG, Soane T

Sandercock PAG, Soane T.

Corticosteroids for acute ischaemic stroke (Review)

Corticosteroids for acute ischaemic stroke (Review) i

Corticosteroids for acute ischaemic stroke

Peter AG Sandercock1 , Tim Soane2

Editorial group: Cochrane Stroke Group.

To assess the effect of corticosteroids in acute presumed ischaemic stroke.

Data collection and analysis

PLAIN LANGUAGE SUMMARY

Corticosteroids for acute ischaemic stroke

Corticosteroids for acute ischaemic stroke (Review) 3

Corticosteroids for acute ischaemic stroke (Review) 4

Corticosteroids for acute ischaemic stroke (Review) 6

Characteristics of included studies [ordered by study ID]

Methods Double-blind, placebo controlled

Interventions Dexamethasone versus placebo

Outcomes Death at 14 days

Bias Authors’ judgement Support for judgement

Corticosteroids for acute ischaemic stroke (Review) 7

Selective reporting (reporting bias) Low risk

Methods Double-blind, placebo controlled

Interventions Betamethasone versus placebo

Outcomes Death at 21 days

Notes Exclusions: not stated

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Not stated

Allocation concealment (selection bias) Unclear risk Not stated

Corticosteroids for acute ischaemic stroke (Review) 8

Methods Double-blind, placebo controlled

Participants New Zealand

Interventions Betamethasone versus placebo

Outcomes Death at 12 weeks

Notes Exclusions: subarachnoid haemorrhage; severe diabetes; pre-existing steroid treatment;

Bias Authors’ judgement Support for judgement

Corticosteroids for acute ischaemic stroke (Review) 9

tients were entered into the trial they were

Methods Double-blind, placebo controlled

Interventions Dexamethasone versus placebo

Outcomes Death at day 10 and at 3 and 12 months

Corticosteroids for acute ischaemic stroke (Review) 10

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Not stated

Methods Double-blind, placebo controlled

Interventions Dexamethasone versus placebo.

Outcomes Death at day 29

Adverse effects of treatment

Notes Exclusions: recent peptic ulcer; concurrent infection, psychiatric disturbances

Bias Authors’ judgement Support for judgement

Methods Double-blind, placebo controlled

Interventions Dexamethasone versus placebo

Corticosteroids for acute ischaemic stroke (Review) 12

Outcomes Death at day 21

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Random number tables

Methods Double-blind, placebo controlled

Corticosteroids for acute ischaemic stroke (Review) 13