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254 www.thelancet.com/neurology Vol 9 March 2010

Adjunctive dexamethasone in bacterial meningitis:

a meta-analysis of individual patient dataDiederik van de Beek, Jeremy J Farrar, Jan de Gans, Nguyen Thi Hoang Mai, Elizabeth M Molyneux, Heikki Peltola, Tim E Peto, Irmeli Roine,

Mathew Scarborough, Constance Schultsz, Guy E Thwaites, Phung Quoc Tuan, A H Zwinderman

SummaryBackground Dexamethasone improves outcome for some patients with bacterial meningitis, but not others. We aimedto identify which patients are most likely to benefit from dexamethasone treatment.

Methods We did a meta-analysis of individual patient data from the randomised, double-blind, placebo-controlledtrials of dexamethasone for bacterial meningitis in patients of all ages for which raw data were available. The pre-determined outcome measures were death at the time of first follow-up, death or severe neurological sequelae at1 month follow-up, death or any neurological sequelae at first follow-up, and death or severe bilateral hearing loss at

first follow-up. Combined odds ratios (ORs) and tests for heterogeneity were calculated using conventionalMantel-Haenszel statistics. We also did exploratory analysis of hearing loss among survivors and other exploratorysubgroup analyses by use of logistic regression.

Findings Data from 2029 patients from five trials were included in the analysis (833 [410%] aged

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www.thelancet.com/neurology Vol 9 March 2010 255

patient data could not be acquired from the older

trials.

1727

The characteristics of the included studies areshown in table 1.The study from South America used a 22 design to

randomly assign children with bacterial meningitis todexamethasone plus glycerol, dexamethasone plusplacebo, glycerol plus placebo, or placebo plus placebo.12Data were available from children who were assigneddexamethasone plus placebo or placebo only but notfrom those who were given glycerol. During the study,the randomisation schedule was altered from a ratio oftwo dexamethasone per three placebo (randomisationschedule 1) to one dexamethasone per one placebo(randomisation schedule 2). Therefore, analyses fromthis study were stratified according to randomisation

schedule. The study in Malawian adults used a 22design to randomly assign patients to dexamethasone orplacebo and to intravenous or intramuscular ceftriaxone.14In all studies, patients were enrolled on the basis ofclinically suspected bacterial meningitis and CSF criteria.All the studies used computer-generated randomisationto allocate patients to dexamethasone or placebo.Treatment concealment was adequate in all studies.

Definitions and outcome measuresThe members of the study group met in October, 2006,and September, 2007, to discuss data sharing and theanalysis plan, including the definitions of subgroups,which were specified before the data were collated, thefinal database created, and the analysis started. Theprincipal investigators provided the raw data, which werechecked by a statistician (PQT). Inconsistencies andoutlying data were clarified with the principal investigatorsand resolved from their raw data before the analysis.

15 data fields for each patient were selected for theanalyses. The dataset included prognostic factors forunfavourable outcome and potential modifiers of thetreatment effect of dexamethasone, such as antibiotictreatment before admission, HIV infection, andmalnutrition.1,3 Definitions were agreed during the twostudy-group meetings. Values for continuous variableswere reassigned into categories. Exposure to antibiotics

before randomisation was defined by administration ofeffective oral or intravenous antibiotics within 48 hbefore the first dose of study drug was received.Malnutrition was defined by individual investigators:patients who were not assessed were categorisedaccording to the local prevalence of malnutrition. HIVtests were not done on every patient and an assessmentwas made of the likelihood of HIV infection based onlocal epidemiology. All untested Malawian adults weredefined as likely to be HIV positive. No assumption wasmade for untested Malawian children. All otheruntested adults or children were defined as likely to beHIV negative. Impairment of consciousness wascategorised by use of the Glasgow coma scale or theBlantyre coma score (table 2). The causative pathogen

was defined by CSF microscopy, CSF or blood culture,

PCR, or latex agglutination.The predetermined outcome measures were death at thetime of first follow-up; death or severe neurologicalsequelae (including severe bilateral hearing loss) at1 month follow-up; death or any neurological sequelae(including any degree of hearing loss) at first follow-up;and death or severe bilateral hearing loss at first follow-up.The number of studies that contributed to each outcome isshown by degrees of freedom (df=number of studiesminus 1). Additionally, as part of a post-hoc exploratoryanalysis and to analyse every possible endpoint of interest,we analysed hearing loss of any degree among survivors.The severity of neurological sequelae in the adult studieswas defined using the Glasgow outcome score or the

modified Rankin scale.28,29 In the paediatric studies, severeneurological disability was defined as blindness,quadraparesis, hydrocephalus requiring a shunt, or severepsychomotor retardation. Hearing loss was categorised asmoderate or severe according to definitions used in theindividual studies.

Statistical analysisAll analyses were stratified according to study site(including two strata from the South American study) toaccount for any possible centre effect, includingdifferences in mortality between centres. If appropriate,analyses were also stratified according to the baselinevariable of interest. Combined odds ratios (ORs) andtests for heterogeneity were calculated using conventionalMantel-Haenszel statistics. We also used exploratoryanalyses with logistic regression. The main purpose ofthe analysis was to establish whether dexamethasone hada differential effect in different subgroups of patients;hence, heterogeneity between the subgroups (I values)with significance levels were calculated for each subgroupanalysis. Tests for heterogeneity were calculated without

18 studies identified from Cochrane review

5 studies with individual patient data available(2447 patients)

2029 individual patient records in meta-analysis

418 patients from South Americawith unavailable data

4 trials published since

Cochrane review

17 trials without individualpatient data available orstudies other than trials

Figure 1: Literature search

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allowing for multiple comparisons, to increase thesensitivity of detecting any evidence of between-subgroupheterogeneity. To maximise the power of findingsignificant heterogeneity, missing values were removed,except where indicated, from the subgroup analyses. Acontinuity correction was made for zero events.Significance tests, with the appropriate degrees offreedom, were calculated to test for possible heterogeneitybetween studies for each subgroup analysis.

To calculate the combined ORs for death from studiesincluded in the Cochrane reviews but not otherwiseincluded in the present study, results available from thepublished literature were combined by use of conventionalMantel-Haenszel statistics. Calculation of combined ORsand 95% CIs, tests of heterogeneity between studies, andlogistic regression analyses were done by use of STATAversion 10.

Role of the funding sourceThe study sponsors had no role in the study design,collection, analysis, and interpretation of the data, or thedecision to submit the manuscript for publication.T E Peto had full access to all data in the study. All authors

approved and were responsible for submission of themanuscript.

ResultsThe baseline characteristics were similar in placebo anddexamethasone groups within the five studies (table 2).1019 (502%) patients received dexamethasone and 1010(498%) patients received placebo. 833 (411%) patientswere less than 15 years old, of whom 415 receiveddexamethasone and 418 received placebo. 1196 adults(aged 15 years) were included, of whom 604 (505%)received dexamethasone and 592 (495%) receivedplacebo. The ages of five patients were unknown.

HIV co-infection was confirmed in 549 (415%) of1322 patients tested, of whom 391 (714%) were adults

and 158 (288%) were children. An HIV test was notdone in 707 (348%) patients but, on the basis ofepidemiological risk, was judged likely to be positive in31 untested adults from Malawi and negative in adultsfrom Europe and children from South America. Noassumption was made about 139 untested childrenfrom Malawi. In total, 286 confirmed or likely HIV-infected patients received dexamethasone and294 received placebo.

The diagnosis of bacterial meningitis wasmicrobiologically confirmed in 1639 (808%) patientsand was most frequently caused by S pneumoniae(759 cases), H influenzae (297 cases), and Neisseriameningitidis (239 cases). The most common causativebacteria per study were as follows: Europe, N meningitis(38%);16 Malawi (children), S pneumoniae (40%);15Vietnam, Streptococcus suis (32%);13 Malawi (adults),S pneumoniae (59%);14and South America, H influenzae(47%).12 Mortality in the placebo groups differedsubstantially between studies: 15% in Europe, 31% inMalawian children, 12% in Vietnam, 53% in Malawianadults, and 16% in South America.

Dexamethasone was not associated with a significant

reduction in death, death or severe neurological sequelae(including severe bilateral hearing loss), death or anyneurological sequelae (including any hearing loss), ordeath or severe bilateral hearing loss, if all patients wereincluded in the analysis (table 3). However, hearing loss (ofany severity) in survivors was less common in thedexamethasone group (162 [241%] of 672 vs 195 [295%] of660; OR 077 [95% CI 060099], p=004).

The subgroup analyses for all outcome measures areshown in figures 2 and 3, and the webappendix. Durationof symptoms before treatment, severity of coma at startof treatment, whether dexamethasone was given beforeor after antibiotics, and HIV infection status did notsignificantly influence treatment response. Dexametha-sone was more effective in patients aged older than

Study

period

Patients

(n)

Age Inclusion criteria Dexamethasone dose Empirical antibiotic* Primary outcome

Europe16 19922001 301 >16 years Clinically suspected BMplus CSF criteria

10 mg four times dailyfor 4 days

Intravenous amoxicillin 2 g every 4 h(77% of patients)

Unfavourable outcome (defined by aGlasgow outcome score of 14) at 8 weeks

Malawi(child)15

19972001 598 2 months to13 years

Clinically suspected BMplus CSF criteria

04 mg/kg twice dailyfor 2 days

Intravenous benzylpenicillin200 000 IU/kg every 24 h plus

chloramphenicol 100 mg/kg every 24 h

Death at 1 month

Vietnam13 19962005 429 >14 years Clinically suspected BMplus CSF criteria

04 mg/kg twice dailyfor 4 days

Intravenous ceftriaxone 2 g every 12 h Death at 1 month

Malawi(adult)14

20022005 465 >15 years Clinically suspected BMplus CSF criteria

16 mg twice daily for4 days

Intravenous or intramuscularceftriaxone 2 g every 12 h

Death at 1 month

SouthAmerica12

19962003 236 2 months to16 years

Clinically suspected BMplus CSF or blood criteria

015 mg/kg four timesdaily for 2 days

Intravenous ceftriaxone80100 mg/kg every 24 h

Death, severe neurological sequelae, oraudiological sequelae at hospital discharge

BM=bacterial meningitis. *Dexamethasone was given before or with the first dose of per-protocol parenteral antibiotic in all five studies. 23% of patients received other antibiotic treatment. 22 design with

patients randomly assigned to dexamethasone or placebo and to intravenous or intramuscular ceftriaxone. 22 design with patients randomly assigned to dexamethasone plus glycerol, dexamethasone plus

placebo, placebo plus glycerol, or placebo plus placebo; patients assigned to receive glycerol with either dexamethasone or placebo were excluded from the individual patient data meta-analysis; data from this

trial were analysed as two strata according to randomisation schedule.

Table 1:Characteristics of the five studies included in the analysis

See Online for webappendix

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55 years in analyses of death (OR 041 [95% CI 020084],

p=001), death or severe neurological sequelae (OR 053[030084], p=003), and death or any neurologicalsequelae (OR 056 [031100], p=005). However, therewas no clear evidence of heterogeneity between the

different age groups (death, =69, 3 df, p=007,

I

545%; death or severe neurological sequelae, =66,3 df, p=009, I=534%; death or any neurologicalsequelae, =44, 3 df, p=023, I=303%). Furtherexploratory analyses, using age as a continuous variable,

Europe16

(n=301)

Malawi (child)15

(n=598)

Vietnam13

(n=429)

Malawi (adult)14

(n=465)

South America12 Total (n=2029) Dexamethasone

(n=1019)

Placebo

(n=1010)

Randomisationschedule 1(n=126)

Randomisationschedule 2(n=110)

Age (years)

55 102 0 106 16 0 0 224 112 112

Unknown 0 1 1 0 0 3 5 2 3

Sex

Men 169 (56%) 337 (56%) 315 (73%) 230 (50%) 73 (58%) 63 (57%) 1187 (58%) 601 (59%) 586 (58%)

Symptoms 20 122 (40%) 31 (5%) 248 (58%) 72 (16%) 53 (42%) 46 (42%) 572 (28%) 284 (28%) 288 (29%)

Unknown 10 (3%) 92 (15%) 2 (05%) 61 (13%) 9 (7%) 3 (3%) 177 (9%) 87 (8%) 90 (9%)

(Continues on next page)

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Europe16

(n=301)

Malawi (child)15

(n=598)

Vietnam13

(n=429)

Malawi (adult)14

(n=465)

South America12 Total (n=2029) Dexamethasone

(n=1019)

Placebo

(n=1010)

Randomisationschedule 1

(n=126)


(n=110)

(Continued from previous page)

CSF protein (mg/dL)

250 195 (65%) 412 (69%) 191 (45%) 341 (73%) 23 (18%) 33 (30%) 1195 (59%) 588 (58%) 607 (60%)

1000 mg/dL).

Table 2: Baseline characteristics of patients included in the analysis

Europe16 Malawi

(child)15Vietnam13 Malawi

(adult)14South America12 Overall Events/total (%) Test for heterogeneity



Dexamethasone Placebo 2 (5 df) p I

Death 044(020096,003)

096(070140,096)

082

(045151,053)

116

(080167,043)

146

(063337,037)

074

(027200,055)

097

(079119,075)

270/1019

(265%)

275/1010

(272%)

65 026 227%

Death or severe

neurological sequelae orbilateral severe deafness

060

(034111,007)

120

(087166,028)

075

(048117,020)

102

(069150,093)

074

(035155,042)

074

(033167,052)

092(076111,

039)

424/1003(423%)

439/992(443%)

65 026 232%

Death or any

neurological sequelae orany hearing loss

049

(028084,001)

102

(074142,089)

081

(055118,027)

103(067156,

091)

129(060277,

051)

084(039179,

065)

089(074107,

023)

541/999(542%)

567/988(574%)

71 022 293%

Death or severe

bilateral hearing loss

055

(031099,004)

103(073145,

086)

064(038108,

009)

108(073158,

070)

107(049232,

087)

070(029169,

043)

089(073169,

023)

343/942(364%)

363/934(389%)

62 028 198%

Any hearing loss insurvivors

075(034167,

048)

080(051128,

035)

077(049121,

026)

080(044145,

045)

059(021165,

031)

081(030214,

066)

077(060099,004)

162/672(241%)

195/660(295%)

03 100 00%

Data are OR (95% CI, p value) unless otherwise stated. OR values below 1 suggest a beneficial effect of steroids.

Table 3: Primary endpoints for each study and for all patients assigned to steroid therapy

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did not show any consistent interaction between age anda treatment effect (data not shown). There was also noeffect in a post-hoc analysis that restricted the study topatients treated with ceftriaxone (webappendix).

The data were explored to identify evidence ofheterogeneity between the studies. 23 subgroups wereexplored, each with five different endpoints. In patientswith moderate CNS impairment on admission, there

was some evidence of heterogeneity between three ofthe five endpoints. In the subgroup of patients withmoderate CNS impairment on admission, there wasevidence of benefit in death or severe neurologicalsequelae or bilateral hearing loss in the European study(OR 019 [95% CI 004082], p=001), but also evidenceof harm in the study of children in Malawi (OR 370[1361008], p=0006). However, no evidence of

Events/total (%) OR (95% CI) p Test for heterogeneity

between studies

Dexamethasone 2 df pPlacebo

Favours dexamethasone Favours placebo

1030201 05 1 2 3 4 5 10

Age (years)

55 15/112 (13%) 32/112 (29%) 041 (020084) 001 151 2 047

Subtotal (I2=545%, p=0086) 098 (079121)

Sex

Female 128/431 (30%) 134/410 (33%) 090 (066123) 052 462 5 046

Male 142/588 (24%) 141/599 (24%) 100 (075133) 098 550 5 036

Subtotal (I2=00%, p=0625) 095 (077118)

Preadmission symptoms

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heterogeneity was observed in patients with either no orlittle CNS impairment or with severe CNS impairment.Overall, there was no evidence of any difference inoutcome for any of the CNS subgroups in any of the fiveendpoints. The effect of HIV was explored by adjustment

with logistic regression analysis and also by studyingonly patients with proven HIV status. However, HIVstatus did not have an effect on dexamethasone treatmentoutcome (webappendix). We further explored the relationbetween age, HIV status, and dexamethasone treatment

Events/total (%) OR (95% CI) p Test for heterogeneity

between studies

Dexamethasone 2 df pPlacebo


1030201 05 1 2 3 4 5 10

Consciousness level

Normal 33/288 (11%) 25/305 (8%) 139 (078246) 026 276 4 060

Mild impairment 67/349 (19%) 79/350 (23%) 082 (055121) 032 192 5 086

Moderate impairment 89/239 (37%) 87/213 (41%) 093 (062138) 071 1250 5 003

Severe impairment 78/137 (57%) 84/138 (61%) 075 (045125) 027 990 5 008

Subtotal (I2=00%, p=0404) 091 (073114)

CSF white cell count (cells per L)

099 42/76 (55%) 34/64 (53%) 109 (053225) 082 200 4 074

100999 101/284 (36%) 104/280 (37%) 096 (066137) 080 331 5 065

10009999 80/450 (48%) 91/487 (19%) 092 (065130) 064 819 5 015

10 000 39/187 (21%) 41/162 (25%) 080 (047134) 039 266 5 075

Subtotal (I2=00%, p=0911) 093 (075115)

CSF glucose

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effect (table 4). In HIV-negative adults, dexamethasone

was associated with a reduction in death or severeneurological sequelae, including severe bilateral hearingloss (OR 068 [95% CI 048095], p=002), death orany neurological sequelae, including any hearing loss(OR 067 [050091], p=001), and death or severebilateral hearing loss (OR 061 [042089], p=001).However, this effect of dexamethasone was not presentin HIV-negative children, or in HIV-positive childrenand adults.

Gastrointestinal bleeding was reported in all studies:13 (13%) of 1021 patients on dexamethasone and19 (19%) of 1014 patients on placebo (p=014).Hyperglycaemia and infection by herpes simplex virusand varicella zoster virus were reported in some but not

all studies.4,13,16 Hyperglycaemia was recorded by the trialsin Malawian and European adults and was significantlyassociated with dexamethasone treatment (79 of390 [203%] on dexamethasone vs 60 of 376 [160%] onplacebo; p=002). Neither infection with herpes simplexvirus (labial infection in all) nor infection with varicellazoster virus were significantly associated withdexamethasone treatment.

Dexamethasone did not significantly affect mortalityin a combined analysis with the data from other studiesincluded in the Cochrane analysis8 (OR 088 [95% CI073104], p=014; figure 4).1727,3035 349 (180%) of1944 patients who received dexamethasone died,compared with 384 (198%) of 1939 patients whoreceived placebo. There was no evidence of significantheterogeneity between the trials.

DiscussionThe aim of this analysis was to establish whether anysubgroups of patients with acute bacterial meningitismight benefit from adjunctive dexamethasone and therebyexplain any differences between individual trial results.Extensive exploration of 15 prespecified subgroups did notshow robust evidence that a particular subgroup would

benefit. The apparent benefit in adults aged over 55 years

might have occurred by chance. However, it is unclearwhether it is more likely to have occurred by chance thanthe findings of no benefit in other subgroups.

This analysis of 2029 patients from five trials showedthat treatment with adjunctive dexamethasone did notsignificantly reduce mortality, neurological disability, orsevere hearing loss in bacterial meningitis. Combinationof these results with those from older published trials, forwhich the raw data were not obtainable, did not show anyevidence that dexamethasone was significantly effectivein reducing these outcomes overall. However, a post-hocanalysis on the incidence of deafness among survivorssuggested that adjunctive dexamethasone treatmentreduced the rate of hearing loss (OR 077 [95% CI 060

099; p=004), irrespective of whether patients hadreceived antibiotics before dexamethasone treatment.Theuse of adjunctive dexamethasone treatment was notassociated with an increased risk of adverse events.

Factors previously considered relevant to the decisionto start dexamethasone treatment in patients withsuspected or proven bacterial meningitis could notexplain differences in results between the five trials.These factors include duration of symptoms beforetreatment, severity of impaired consciousness at start oftreatment, whether dexamethasone was given before orafter antibiotics, and HIV infection status.7,3639 Becausethe results of the prespecified analysis failed to show anysignificant heterogeneity, extensive post-hoc analyseswere done with the inclusion of an additional deafnessendpoint. Such analyses are usually consideredunreliable, particularly if no statistical allowance is madefor multiple comparisons, because of the high chance ofa false-positive result. However, the extra analyses wereundertaken to allow the identification of subgroups ofinterest for further possible study. These exploratorypost-hoc analyses suggested a possible overall effect ondeafness among survivors and on death and severeneurological sequelae in the subgroup of HIV-negative

HIV negative HIV positive Overall Test for heterogeneity

Adult Child Adult Child 2

(3 df) p I

Death 066 (042102,006)

143 (096212,007)

119 (081175,036)

054 (028103,006)

099 (080123,099)

107 001 720%

Death or severe neurologicalsequelae or bilateral severedeafness

068 (048095,002)

109 (077155,062)

110 (073166,067)

077 (036166,044)

090 (073110,029)

48 019 374%

Death or any neurologicalsequelae or any hearing loss

067 (050091,001)

109 (077156,062)

115 (073182,054)

077 (035171,053)

088 (072107,018)

60 011 501%

Death or severe bilateralhearing loss

061 (042089,001)

116 (080167,043)

113 (075170,055)

062 (030129,020)

089 (072109,026)

81 004 285%

Any hearing loss in survivors 076 (052113,017)

067 (042107,009)

087 (046163,066)

109 (037319,087)

077 (059099,006)

09 083 00%

Data are OR (95% CI, p value) unless otherwise stated. Adults were defined as 15 years. HIV negative includes patients who tested negative or were likely to be negative. HIV

positive includes those who tested positive or were likely to be positive.

Table 4: Exploratory analyses of the influence of age and HIV infection on the treatment effect of dexamethasone

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adults (OR 068 [95% CI 054099], p=002). Thisapparent treatment effect ceased to be significant afteradjustment for multiple comparisons.

This meta-analysis is, as are all meta-analyses, limitedby the possibility that more heterogeneity exists betweenthe studies than has been identified. If such heterogeneitywere to exist, combining the studies would beinappropriate. Formal tests for heterogeneity betweenstudies and between subgroups failed to show anyconvincing evidence of heterogeneity. However, such testsare insensitive and could miss important effects. We havetherefore explored the data exhaustively for relevantsubgroups of patients that could reveal possible causes ofheterogeneity, although little such evidence was found.

On the basis of previous meta-analyses,9,10 theadministration of dexamethasone to children withH influenzae type b meningitis before the start ofantibiotic therapy is thought to reducethe incidence of

deafness.However, we found no evidence of a benefit ofadjunctive dexamethasone in all children or in anysubgroup of children with this infection.

In summary, these data indicate that patients withbacterial meningitis neither benefit from nor are harmedby treatment with adjunctive dexamethasone. Despite anindividual patient data meta-analysis of more than2000 patients, we have been unable to determineconclusively whether a subgroup of patients might benefit.To establish with certainty whether dexamethasone has aplace in the treatment of adult patients with bacterialmeningitis, a large multinational randomised controlledtrial would be necessary. This represents a formidablechallenge and one that is not likely to be met for many years.In the meantime, we suggest the benefit of adjunctivedexamethasone for all or any subgroup of patients withbacterial meningitis remains unproven and there is littlesupport for its routine use in the treatment of this disease.

Events/total (%) OR (95% CI)

Dexamethasone Placebo


1030201 05 1 2 3 4 5 10

Current meta-analysis

Europe16 11/157 (7%) 21/144 (15%) 044 (020095)

Malawi (child)15 92/305 (30%) 89/293 (30%) 099 (070140)

Vietnam13 22/215 (10%) 27/214 (13%) 079 (043144)

Malawi (adult)14 122/233 (52%) 113/232 (49%) 116 (080167)

South America randomisation schedule 112 14/50 (28%) 16/76 (21%) 146 (064334)

South America randomisation schedule 212 9/59 (15%) 10/51 (20%) 074 (027199)

Subtotal (I2=247%, p=0249) 270/1019 (26%) 276/1010 (27%) 096 (078119)

Other studies from 2007 Cochrane review 8

Bennett (1963)30 16/38 (42%) 22/47 (47%) 083 (035196)

DeLemos (1969)21 2/54 (4%) 1/63 (2%) 238 (0212705)

Belsey (1969)17 2/43 (5%) 1/43 (2%) 205 (0182348)

Bademosi (1979)18 11/28 (39%) 12/24 (50%) 065 (021195)

Girgis (1989)22 20/210 (10%) 42/219 (19%) 044 (025078)

Lebel (1989)32 0/31 1/31 (3%) 032 (001823)

Odio (1991)25 1/52 (2%) 1/49 (2%) 094 (0061547)

King (1994)31 0/50 1/51 (2%) 033 (001838)

Ciana (1995)20 8/34 (24%) 12/36 (33%) 062 (021176)

Wald (1995)33 1/69 (1%) 0/74 326 (0138145)

Kanra (1995)23 2/29 (7%) 1/27 (4%) 193 (0162255)

Qazi (1996)26 12/48 (25%) 5/41 (12%) 240 (077751)

Bhaumik (1998)19 1/14 (7%) 3/16 (19%) 033 (003364)

Lebel (1988)24* 0/51 1/49 (2%) 031 (001789)

Thomas (1999)27 3/31 (10%) 5/29 (17%) 051 (011238)

Lebel (1988)24 0/51 0/49

Schaad (1993)35 0/60 0/55

Kilpi (1995)34 0/32 0/26

Subtotal (I2=00%, p=0636) 79/925 (9%) 108/929 (12%) 069 (050097)

Overall (I2=49%, p=0396) 349/1944 (18%) 384/1939 (20%) 088 (073104)

Figure 4: Effect of adjunctive dexamethasone therapy on death

Trials included in the rest of this study1216 and other studies1727,3035 included in the Cochrane systematic review8 are shown. OR=odds ratio. *Study 1 in Lebel.24 Study 2

in Lebel.24

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www thelancet com/neurology Vol 9 March 2010 263

Contributors

The study was conceived by JJF. All the authors contributed to the study

design and the selection of data for analysis. The analysis was done byPQT, TEP, and AHZ. The paper was written by DvdB, JJF, TEP, MS, andGET, with review and comment from all the authors.

Conflicts of interest

We have no conflicts of interest.

Acknowledgments

This work was supported by the Wellcome Trust UK. DvdB is supportedby grants from the Netherlands Organization for Health Research andDevelopment (NWO-Veni grant 2006 [916.76.023]) and the AcademicMedical Center (AMC Fellowship 2008). TEP is supported by the UKNational Institute for Health Research, Biomedical Research Centre,Oxford, UK. We thank Sarah Walker (Medical Research Council, ClinicalTrials Unit, London, UK) for independent statistical advice.

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