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Osmotic therapies added to antibiotics for acute bacterial meningitis

  1. Emma CB Wall1,*,
  2. Katherine MB Ajdukiewicz2,
  3. Robert S Heyderman3,
  4. Paul Garner1

Editorial Group: Cochrane Acute Respiratory Infections Group

Published Online: 28 MAR 2013

Assessed as up-to-date: 30 NOV 2012

DOI: 10.1002/14651858.CD008806.pub2


How to Cite

Wall ECB, Ajdukiewicz KMB, Heyderman RS, Garner P. Osmotic therapies added to antibiotics for acute bacterial meningitis. Cochrane Database of Systematic Reviews 2013, Issue 3. Art. No.: CD008806. DOI: 10.1002/14651858.CD008806.pub2.

Author Information

  1. 1

    Liverpool School of Tropical Medicine, International Health Group, Liverpool, UK

  2. 2

    Pennine Acute Hospitals NHS Trust, Department of Infectious Diseases, Manchester, UK

  3. 3

    University of Malawi College of Medicine, Malawi-Liverpool-Wellcome Clinical Research Programme, Blantyre, Chichiri, Malawi

*Emma CB Wall, International Health Group, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK. emma.wall@liv.ac.uk. emma.wall@doctors.org.uk.

Publication History

  1. Publication Status: New
  2. Published Online: 28 MAR 2013

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Characteristics of included studies [ordered by study ID]
Ajdukiewicz 2011

MethodsRandomised controlled trial


ParticipantsAdults with bacterial meningitis (clinical suspicion of meningitis plus CSF evidence of infection: > 100 white cells/mm3, predominately neutrophils, a positive gram stain or cloudy CSF)


InterventionsOral glycerol 75 mg in 135 ml

Oral glucose 50% solution 135 ml


OutcomesPrimary outcome: mortality

Secondary outcomes: epilepsy, deafness, residual neurological deficit


NotesPlacebo is not potentially completely inactive and 50% glucose may exert a neurological effect in meningitis


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"A randomisation number list in blocks of 12 was produced by an independent statistician using Stata version 9.0"

Allocation concealment (selection bias)Low risk"Numbers and allocation were placed into sealed envelopes. Envelopes were opened sequentially by an independent person not involved in the clinical care or assessment of trial participants"

Blinding (performance bias and detection bias)
All outcomes
Low risk"Triple blinded"

Incomplete outcome data (attrition bias)
All outcomes
Low riskIntention-to-treat analysis, all patients included in the analysis

Selective reporting (reporting bias)Low riskNone apparent

Other biasLow riskNo other biases apparent

Kilpi 1995

MethodsRandomised controlled trial with 4 arms


ParticipantsChildren from 3 months to 15 years of age with bacterial meningitis (CSF culture positive; CSF leucocytes > 100/mm2; positive blood culture in a patient with signs and symptoms of bacterial meningitis)


InterventionsGlycerol 4.5 g/kg to a maximum 180 g/day divided into 3 doses/24 hours. Increased by 50% for dose 1 and decreased by 50% for dose 2. No details of placebo given. 3 days treatment given

Dexamethasone 1.5 mg/kg od IV divided into 3 doses/24 hours. 50% dose adjustments as per glycerol also used. 3 days treatment given

4 groups used, glycerol, glycerol + dexamethasone, dexamethasone and 'neither'


OutcomesPrimary outcome: mortality

Secondary outcomes: epilepsy, deafness, residual neurological deficit


NotesNo details given if any placebo agent was used


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"A computer generated list of random therapy assignments was kept at the children's hospital"

Allocation concealment (selection bias)Low risk"The next adjunctive treatment regimen was obtainable by telephone 24 hours a day"

It is not clear if this person giving the assignments was part of the study team or independent

Blinding (performance bias and detection bias)
All outcomes
High riskNo details of blinding are given, so we assumed that the study was unblinded

Incomplete outcome data (attrition bias)
All outcomes
High risk134 children enrolled, 12 excluded, 122 in the final series but 120 only analysed. Details of the missing data are not present in the text

Selective reporting (reporting bias)High riskNo details of the missing data given, so it is not clear if selective cases only are presented

Other biasUnclear riskGroups not completely matched, increased females in the dexamethasone group and increased meningitis due to S. pneumoniae in the control group

Peltola 2007

MethodsRandomised controlled trial with 4 arms, multicentre in South America


ParticipantsChildren aged 2 months to 16 years with bacterial meningitis (CSF culture positive, "characteristic CSF findings" with a positive blood culture or CSF positive with latex antigen test; symptoms and signs of bacterial meningitis with at least 3 of the following: CSF white cell count > 1000 cells/mm3, CSF glucose < 40 mg/dL, CSF protein > 40 mg/dL, blood white cell count >15000 cells/mm3


InterventionsGlycerol 1.5 g/kg in an 85% solution divided into 3 doses/24 hours. 2 days treatment given. Placebo saline plus carboxy methylcellulose. Doses and volumes of placebo not given in the paper

Dexamethasone 0.15 mg/kg od IV divided into 3 doses/24 hours. 2 days treatment given

4 groups used, GLY + placebo, GLY + Dex, Dex + placebo and placebo + placebo


OutcomesPrimary mortality. No secondary mortality at the end of follow up given

Secondary outcomes: epilepsy, deafness and residual neurological deficit


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Stratified block randomisation took place in blocks of 20"

Allocation concealment (selection bias)Low risk"All treatment kits were packaged according to the randomisation lists in Santiago, Chile. Saline and carboxymethylcellulose were the placebo preparations for dexamethasone and glycerol, respectively
The agents were provided in identical ampoules or bottles and were labelled only with a study code"

Blinding (performance bias and detection bias)
All outcomes
Low riskThe placebos and blinding are described above

Incomplete outcome data (attrition bias)
All outcomes
Low riskNone identified

Selective reporting (reporting bias)Low riskNo missing data identified

Other biasUnclear riskDrugs were supplied by GlaxoSmithKline and Famacia Ahumada. GSK partially funded the study

Sankar 2007

MethodsRandomised controlled trial. Single centre


ParticipantsChildren aged 2 months to 12 years with bacterial meningitis (positive CSF culture or CSF latex agglutination positive, or CSF cytology with a suggestive biochemical profile with fever and signs of CNS involvement)


InterventionsGlycerol 1.5 g/kg IV or PO 6-hourly. Placebo carboxymethyl cellulose 2% solution IV. Total dose of placebo not given just documented "matched". Dexamethasone 0.15 mg/kg 6-hourly. Duration of treatment not given in the text


OutcomesPrimary mortality. No secondary mortality at the end of follow-up given

Secondary outcomes: epilepsy, deafness and residual neurological deficit


NotesThis study was published twice, with a preliminary analysis of the osmotic effects published as Singhi 2008. Study funding, the source of drugs or co-infection documented


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomisation list prepared with simple random numbers table

Allocation concealment (selection bias)Low riskSerially numbered, sealed packets prepared, kept readily available

Blinding (performance bias and detection bias)
All outcomes
Low riskClinicians and patients blinded. It is not clear from the text if the investigators were fully blinded but the packets were prepared by a separate person from the investigating team

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Alimarante 1995Case series of mannitol used for bacterial meningitis. No randomisation or placebo use documented

Herson 1977Not a randomised controlled trial. Glycerol use discussed

Pecco 1991Literature review and documented personal experience of the use of mannitol in meningitis

Pelegrin 2012Retrospective cohort study examining patients with bacterial meningitis 1987 to 2009 who were treated with dexamethasone, mannitol and phenytoin. No data were collected prospectively and participants were not randomised to receive any of the interventions

Peltola 2010This is not a new trial, but is a specific analysis of Peltola 2007 trial looking at deafness in more detail

Singhi 2004Review article not randomised controlled trial

Singhi 2007Letter in response to the journal editorial summary of the trial Peltola 2007

Singhi 2008Duplicated trial of Sankar 2007. This was a subset of the data published in Sankar 2007, an included study. Singhi 2008 reports osmolality effects of glycerol rather than mortality outcome

Urciuoli 1963Mannitol tested for neurosurgical infections and not acute bacterial meningitis. Not a randomised controlled trial

 
Characteristics of ongoing studies [ordered by study ID]
Molyneux 2012

Trial name or titleGlycerol and high dose paracetamol for paediatric meningitis

MethodsRandomised controlled trial with 4 arms

ParticipantsChildren under 12 years with acute bacterial meningitis

InterventionsOral glycerol and oral paracetamol

OutcomesDeath, hearing loss, neurological disability, cognitive ability

Starting date2010

Contact informationProfessor Elizabeth Molyneux, Queen Elizabeth Central Hospital, Blantyre, Malawi

NotesTrial due to complete 2012

 
Comparison 1. Glycerol versus no osmotic diuretic

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Death41091Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.89, 1.33]

    1.1 No steroids
4672Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.89, 1.36]

    1.2 With steroids
3419Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.60, 1.74]

 2 Death and neurological disability41091Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.86, 1.25]

    2.1 No steroids
4672Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.87, 1.31]

    2.2 With steroids
3419Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.62, 1.46]

 3 Seizures3909Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.90, 1.30]

    3.1 No steroids
3574Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.91, 1.43]

    3.2 With steroids
2335Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.70, 1.33]

 4 Hearing loss4741Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.38, 0.93]

    4.1 No steroids
3391Risk Ratio (M-H, Fixed, 95% CI)0.56 [0.32, 0.98]

    4.2 With steroids
3350Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.32, 1.35]

 
Summary of findings for the main comparison. Glycerol for acute bacterial meningitis

Glycerol for acute bacterial meningitis

Patient or population: acute bacterial meningitis
Settings:Finland, India, South America, Malawi
Intervention: glycerol

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
Number of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlGlycerol

Death201 per 1000220 per 1000
(179 to 268)
RR 1.09
(0.89 to 1.33)
1091
(4 studies)
⊕⊕⊝⊝
low1,2,3,4

Neurological disability70 per 100056 per 1000
(32 to 97)
RR 0.8
(0.46 to 1.38)
732
(3 studies)
⊕⊝⊝⊝
very low1,5,6

Seizures324 per 1000350 per 1000
(291 to 421)
RR 1.08
(0.9 to 1.3)
909
(3 studies)
⊕⊕⊝⊝
low1,2,3,4

Hearing loss130 per 100078 per 1000
(49 to 121)
RR 0.6
(0.38 to 0.93)
741
(3 studies)
⊕⊕⊝⊝
low1,7

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval (CI)) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval
RR: risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate
Very low quality: We are very uncertain about the estimate

 1 No serious risk of bias: allocation concealment was adequate in all trials.
2Downgraded by 1 for inconsistency: one trial found a statistically significant harm with glycerol but this trial used 50% glucose as the placebo which is not an inert substance and could plausibly have exerted a positive benefit.
3The four trials were conducted in Finland, Malawi, India and South America. Three were in children and one in adults. All included patients with suspected meningitis and CSF changes suggestive of bacterial infection.
4Downgraded by 1 for imprecision: the 95% CI includes what might be a clinically important harm and no effect with glycerol.
5Downgraded by 1 for indirectness: there was significant heterogeneity in the reporting of neurological disability across the studies and formal scoring systems were not used.
6Downgraded by 2 for imprecision: the number of neurological disabilities in these studies was very low, and consequently the 95% CI is very wide. Larger trials would be necessary to have confidence in this result.
7Downgraded by 2 for imprecision: the number of patients with reported hearing loss was low in these studies. Even though the result is statistically significant, larger studies would be necessary to have full confidence in this effect.
 
Table 1. Available osmotic therapies

DrugClassMechanism of actionDose range and routeStudied/used in

GlycerolSugar alcoholProbably osmosis plus possible vascular and metabolic benefitIV 5% to 10% solution or 50 g

PO 1.5 g/kg
Meningitis (Peltola 2007), stroke (Righetti 2005)

MannitolSugar alcoholOsmotic diureticIV 20% solution

1 ml/kg to 10 ml/kg or 1 g/kg
Brain trauma (Wakai 2008), cerebral malaria (Namutangula 2007), stroke (Bereczki 2010)

 

SorbitolSugar alcoholOsmotic diuretic (weak)PO, IVExperimental brain perfusion, stroke

Hypertonic

saline
Hypertonic solutionsOsmosisIVBrain trauma (Choi 2005), stroke (Schwarz 2002)

Sodium

lactate
Hydroxy acidsOsmosis (weak)IVBrain trauma (Ichai 2009)

 IV: intravenous
PO: per oral
 
Table 2. Comparison of included study interventions

Name of studyPopulationIntervention and doseControl usedTreatment durationStudy arms

Kilpi 1995Children in FinlandGlycerol (gly) PO 4.5 g/kg max 180 g/24 hrs in 3 divided doses

 

Dexamethasone (dex) 1.5 mg/kg max 60 mg/day
No oral placebo

IV saline
3 days4 arms IV dex + gly, PO gly, IV dex, and neither treatment

Sankar 2007Children in IndiaGlycerol PO 1.5 g/kg 3 x daily

 

Dex 0.15 mg/kg 3 x daily
Oral carboxymethylcellulose 2%

IV saline
Not detailed4 arms placebo PO and IV, IV dex + PO gly, IV placebo + PO gly, IV dex + PO placebo

Peltola 2007Children in South AmericaGlycerol PO 1.5 g/kg 3 x daily

 

Dex 0.15 mg/kg 3 x daily
Oral carboxymethylcellulose 2%

IV saline
2 days4 arms placebo PO and IV, IV dex + PO gly, IV placebo + PO gly, IV dex + PO placebo

Ajdukiewicz 2011Adults in Malawi, Southern AfricaGlycerol PO 75 mg 4 x daily diluted in water or 50% dextrose solutionOral 50% dextrose solution4 daysPO gly versus PO 50% dextrose

 IV: intravenous
PO: per oral
gly: glycerol
dex: dexamethasone