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Uso de terapias osmóticas mais antibióticos para meningite bacteriana aguda

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Referencias

References to studies included in this review

Ajdukiewicz 2011 {published data only}

Ajdukiewicz KM. Glycerol adjuvant therapy in adult bacterial meningitis in Malawi [MD thesis]. Liverpool (UK): University of Liverpool, 2012. CENTRAL
Ajdukiewicz KM, Cartwright KE, Scarborough M, Mwambene JB, Goodson P, Molyneux ME, et al. Glycerol adjuvant therapy in adults with bacterial meningitis in a high HIV seroprevalence setting in Malawi: a double‐blind, randomised controlled trial. Lancet Infectious Diseases 2011;11(4):293‐300. CENTRAL

Kilpi 1995 {published data only}

Kilpi T, Peltola H, Jauhiainen T, Kallio MJ. Oral glycerol and intravenous dexamethasone in preventing neurologic and audiologic sequelae of childhood bacterial meningitis. The Finnish Study Group. Pediatric Infectious Disease Journal 1995;14(4):270‐8. CENTRAL

Molyneux 2014 {published data only}

Molyneux EM, Kawaza K, Phiri A, Chimalizeni Y, Mankhambo L, Schwalbe E, et al. Glycerol and acetaminophen as adjuvant therapy did not affect the outcome of bacterial meningitis in Malawian children. Pediatric Infectious Disease Journal 2014;33(2):214‐6. CENTRAL

Peltola 2007 {published data only}

Peltola H, Roine I, Fernandez J, Gonzlez MA, Zavala I, Gonzalez A, et al. Hearing impairment in childhood bacterial meningitis is little relieved by dexamethasone or glycerol. Paediatrics 2010;125(1):e1‐8. CENTRAL
Peltola H, Roine I, Fernandez J, Zavala I, Ayala SG, Mata AG, et al. Adjuvant glycerol and/or dexamethasone to improve the outcomes of childhood bacterial meningitis: a prospective, randomized, double‐blind, placebo‐controlled trial. Clinical Infectious Diseases 2007;45(10):1277‐86. CENTRAL

Sankar 2007 {published data only}

Sankar J, Singhi P, Bansal A, Ray P, Singhi S. Role of dexamethasone and oral glycerol in reducing hearing and neurological sequelae in children with bacterial meningitis. Indian Pediatrics 2007;44(9):649‐56. CENTRAL
Singhi S, Järvinen A, Peltola H. Increase in serum osmolality is possible mechanism for the beneficial effects of glycerol in childhood bacterial meningitis. Pediatric Infectious Diseases Journal 2008;27(10):892‐6. CENTRAL

References to studies excluded from this review

Almirante 1995 {published data only}

Almirante B, Cortés E, Pigrau C, Gasser I, del Valle O, Campos L, et al. Therapy and outcome of pneumococcal meningitis in adults. A recent series of 70 episodes. Medicina Clinica 1995;105(18):681‐6. CENTRAL

CTRI/2015/04/005668 {published data only}

CTRI/2015/04/005668. Oral glycerol in newborn brain infections [Randomized comparison of oral glycerol and standard treatment versus standard treatment alone in management of neonatal bacterial meningitis]. ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=11180 (first received 7 April 2015). CENTRAL

Glimåker 2014 {published data only}

Glimåker M, Johansson B, Halldorsdottir H, Wanecek M, Elmi‐Terander A, Ghatan PH, et al. Neuro‐intensive treatment targeting intracranial hypertension improves outcome in severe bacterial meningitis: an intervention‐control study. PloS One 2014;9(3):e91976. CENTRAL

Herson 1977 {published data only}

Herson VC, Todd JK. Prediction of morbidity in Hemophilus influenzae meningitis. Pediatrics 1977;59(1):35‐9. CENTRAL

Kumar 2014 {published data only}

CTRI/2012/05/002650. The effects of cerebral perfusion pressure and intracranial pressure targeted therapy in children with raised intracranial pressure and acute central nervous system infections [A pilot study to compare the outcome of CPP targeted therapy versus ICP targeted therapy in children with acute meningitis]. ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=4595 (first received 14 May 2012). CENTRAL
Kumar R, Singhi S, Singhi P, Jayashree M, Bansal A, Bhatti A. Randomized controlled trial comparing cerebral perfusion pressure‐targeted therapy versus intracranial pressure‐targeted therapy for raised intracranial pressure due to acute CNS infections in children. Critical Care Medicine 2014;42(8):1775‐87. CENTRAL

Molyneux 2015 {published data only}

Molyneux E, Njiram'madzi J. Prevention and treatment of bacterial meningitis in resource poor settings. Pediatric Infectious Disease Journal 2015;34(4):441‐3. CENTRAL

Pecco 1991 {published data only}

Pecco P, Pavesio D, Peisino MG. Rational basis of modern therapy of bacterial meningitis. Review of the literature and our clinical experience of 122 pediatric cases. Panminerva Medica 1991;33(4):185‐90. CENTRAL

Pelegrin 2012 {published data only}

Pelegrin I, Verdaguer R, Ariza J, Viladrich PF, Cabellos C. Effect of adjuvant therapy in pneumococcal meningitis: seizures and mortality. Clinical Microbiology and Infection 2012;19(Suppl):834. CENTRAL

Peltola 2013 {published data only}

Peltola H, Leib SL. Performance of adjunctive therapy in bacterial meningitis depends on circumstances. Pediatric Infectious Disease Journal 2013;32(12):1381‐2. CENTRAL

Singhi 2004 {published data only}

Singhi S, Khetarpal R, Baranwal AK, Singhi PD. Intensive care needs of children with acute bacterial meningitis: a developing country perspective. Annals of Tropical Paediatrics 2004;24(2):133‐40. CENTRAL

Singhi 2007 {published data only}

Singhi S, Singhi P. Glycerol and dexamethasone in bacterial meningitis in low‐income countries: response to the editorial commentary. Clinical Infectious Diseases 2007;47(5):732‐3. CENTRAL

Urciuoli 1963 {published data only}

Urciuoli R. A new osmotic drug: hypertonic solution of mannitol. Advantages as compared with urea. Use in the treatment of aseptic serous meningitis and postoperative cerebrospinal fluid fistulas. Gazzetta Medica Italiana 1963;122:234‐6. CENTRAL

Vaziri 2016 {published data only}

Vaziri S, Mansouri F, Sayad B, Ghadiri K, Torkashvand E, Rezaei M, et al. Meta‐analysis of studies comparing adjuvant dexamethasone to glycerol to improve clinical outcome of bacterial meningitis. Journal of Research in Medical Sciences 2016;21(2):8. CENTRAL

Atkins 2004

Atkins D, Best D, Briss PA, Eccles M, Falck‐Ytter Y, Flottorp S, et al. GRADE Working Group. Grading quality of evidence and strength of recommendations. BMJ 2004;328(7454):1490.

Bereczki 2007

Bereczki D, Liu M, Fernandes do Prado G, Fekete I. Mannitol for acute stroke. Cochrane Database of Systematic Reviews 2007, Issue 3. [DOI: 10.1002/14651858.CD001153.pub2]

Blaser 2010

Blaser C, Klein M, Grandgirard D, Wittwer M, Peltola H, Weigand M, et al. Adjuvant glycerol is not beneficial in experimental pneumococcal meningitis. BMC Infectious Diseases 2010;10:84.

Brouwer 2011

Brouwer M, van de Beek D. Glycerol in bacterial meningitis: one strike and out?. Lancet Infectious Diseases 2011;11(4):257‐8.

Brouwer 2015

Brouwer MC, McIntyre P, de Gans J, Prasad K, van de Beek D. Corticosteroids for acute bacterial meningitis. Cochrane Database of Systematic Reviews 2015, Issue 9. [DOI: 10.1002/14651858.CD004405.pub5]

BTF 2000

Brain Trauma Foundation. The American Association of Neurological Surgeons. The Joint Section on Neurotrauma and Critical Care. Initial management. Journal of Neurotrauma 2000;17(6‐7):463‐9.

Choi 2005

Choi CW, Hwang JH, Chang JS, Park WS, Kim BI, Choi JH, et al. Effects of hypertonic (7%) saline on brain injury in experimental Escherichia coli meningitis. Journal of Korean Medical Science 2005;20(5):870‐6.

de Gans 2002

de Gans J, van de Beek D. Dexamethasone in adults with bacterial meningitis. New England Journal of Medicine 2002;347(20):1549‐56.

Domingo 2009

Domingo P, Suarez‐Lozano I, Torres F, Pomar V, Ribera E, Galindo MJ, et al. Bacterial meningitis in HIV‐1‐infected patients in the era of highly active antiretroviral therapy. Journal of Acquired Immune Deficiency Syndromes 2009;51(5):582‐7.

GRADEpro GDT 2014 [Computer program]

GRADE Working Group, McMaster University. GRADEpro GDT. Version accessed prior to 6 September 2017. Hamilton (ON): GRADE Working Group, McMaster University, 2014.

Harnden 2006

Harnden A, Ninis N, Thompson M, Perera R, Levin M, Mant D, et al. Parenteral penicillin for children with meningococcal disease before hospital admission: case‐control study. BMJ (Clinical Research ed.) 2006;332(7553):1295‐8.

Higgins 2011

Higgins JP, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.

Ichai 2009

Ichai C, Armando G, Orban JC, Berthier F, Rami L, Samat‐Long C, et al. Sodium lactate versus mannitol in the treatment of intracranial hypertensive episodes in severe traumatic brain‐injured patients. Intensive Care Medicine 2009;35(3):471‐9.

Lefebvre 2011

Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searching for studies. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0 (updated March 2011). The Cochrane Collaboration. Available from www.handbook.cochrane.org2011.

Maconochie 2016

Maconochie IK, Baumer JH. Fluid therapy for acute bacterial meningitis. Cochrane Database of Systematic Reviews 2016, Issue 11. [DOI: 10.1002/14651858.CD004786.pub5]

Mahdi 2012

Mahdi LK, Wang H, Van der Hoek M, Paton JC, Ogunniyi AD. Identification of a novel pneumococcal vaccine antigen preferentially expressed during meningitis in mice. Journal of Clinical Investigation 2012;122(6):2208‐20.

Mathew 1972

Mathew NT, Rivera VM, Meyer JS, Charney JZ, Hartmann A. Double‐blind evaluation of glycerol therapy in acute cerebral infarction. Lancet 1972;2(7791):1327‐9.

McCormick 2012

McCormick DW, Wilson ML, Mankhambo L, Phiri A, Chimalizeni Y, Kawaza K, et al. Risk factors for death and severe sequelae in Malawian children with bacterial meningitis, 1997‐2010. Pediatric Infectious Diseases Journal 2012;32(2):e54‐61.

Meyer 1972

Meyer JS, Teraura T, Marx P, Hashi K, Sakamoto K. Brain swelling due to experimental cerebral infarction. Changes in vasomotor capacitance and effects of intravenous glycerol. Brain 1972;95(4):833‐52.

Molyneux 2002

Molyneux EM, Walsh AL, Forsyth H, Tembo M, Mwenechanya J, Kayira K, et al. Dexamethasone treatment in childhood bacterial meningitis in Malawi: a randomised controlled trial. Lancet 2002;360(9328):211‐8.

Molyneux 2006

Molyneux E, Riordan FA, Walsh A. Acute bacterial meningitis in children presenting to the Royal Liverpool Children's Hospital, Liverpool, UK and the Queen Elizabeth Central Hospital in Blantyre, Malawi: a world of difference. Annals of Tropical Paediatrics 2006;26(1):29‐37.

Namutangula 2007

Namutangula B, Ndeezi G, Byarugaba JS, Tumwine JK. Mannitol as adjunct therapy for childhood cerebral malaria in Uganda: a randomized clinical trial. Malaria Journal 2007;6:138.

Nguyen 2007

Nguyen TH, Tran TH, Thwaites G, Ly VC, Dinh XS, Ho Dang TN, et al. Dexamethasone in Vietnamese adolescents and adults with bacterial meningitis. New England Journal of Medicine 2007;357(24):2431‐40.

Okoromah 2011

Okoromah CAN, Afolabi BB, Wall ECB. Mannitol and other osmotic diuretics as adjuncts for treating cerebral malaria. Cochrane Database of Systematic Reviews 2011, Issue 4. [DOI: 10.1002/14651858.CD004615.pub3]

Pelkonen 2009

Pelkonen T, Roine I, Monteiro L, Correia M, Pitkaranta A, Bernardino L, et al. Risk factors for death and severe neurological sequelae in childhood bacterial meningitis in sub‐Saharan Africa. Clinical Infectious Diseases 2009;48(8):1107‐10.

Peltola 2009

Peltola H, Roine I. Improving the outcomes in children with bacterial meningitis. Current Opinion in Infectious Diseases 2009;22(3):250‐5.

Review Manager 2014 [Computer program]

Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager 5 (RevMan). Version 5.3. Copenhagen: Nordic Cochrane Centre, The Cochrane Collaboration, 2014.

Righetti 2004

Righetti E, Celani MG, Cantisani TA, Sterzi R, Boysen G, Ricci S. Glycerol for acute stroke. Cochrane Database of Systematic Reviews 2004, Issue 2. [DOI: 10.1002/14651858.CD000096.pub2]

Roine 2009

Roine I, Saukkoriipi A, Leinonen M, Peltola H. Microbial genome count in cerebrospinal fluid compared with clinical characteristics in pneumococcal and Haemophilus influenzae type B meningitis in children. Diagnostic Microbiology Infectious Diseases 2009;63(1):16‐23.

Saez‐Llorens 2007

Saez‐Llorens X, McCracken GH. Glycerol and bacterial meningitis. Clinical Infectious Diseases 2007;45(10):1287‐9.

Scarborough 2007

Scarborough M, Gordon SB, Whitty CJ, French N, Njalale Y, Chitani A, et al. Corticosteroids for bacterial meningitis in adults in sub‐Saharan Africa. New England Journal of Medicine 2007;357(24):2441‐50.

Schmidt 1998

Schmidt H, Stuertz K, Chen V, Stringaris AK, Bruck W, Nau R. Glycerol does not reduce neuronal damage in experimental Streptococcus pneumoniae meningitis in rabbits. Inflammopharmacology 1998;6(1):19‐26.

Schwarz 2002

Schwarz S, Georgiadis D, Aschoff A, Schwab S. Effects of hypertonic (10%) saline in patients with raised intracranial pressure after stroke. Stroke 2002;33(1):136‐40.

Singhi 2008

Singhi S, Järvinen A, Peltola H. Increase in serum osmolality is possible mechanism for the beneficial effects of glycerol in childhood bacterial meningitis. Pediatric Infectious Diseases Journal 2008;27(10):892‐6.

Stoll 1998

Stoll J, Hagen M, Bartylla T, Weber K, Jost M, Treib V. Changes of cerebral perfusion after osmotherapy in acute cerebral edema assessed with perfusion weighted MRI. Neurological Research 1998;20(6):474‐8.

Sudarsanam 2017

Sudarsanam TD, Rupali P, Tharyan P, Abraham OC, Thomas K. Pre‐admission antibiotics for suspected cases of meningococcal disease. Cochrane Database of Systematic Reviews 2017, Issue 6. [DOI: 10.1002/14651858.CD005437.pub4]

UNDP 2016

United Nations Development Programme. Human Development Report. hdr.undp.org/en/reports/global/hdr2009/ (accessed prior to 13 September 2017).

van de Beek 2009

van de Beek D. Corticosteroids for acute adult bacterial meningitis. Medical Maladies Infectieuse 2009;39(7‐8):531‐8.

van de Beek 2010

van de Beek D, Farrar JJ, de Gans J, Mai NT, Molyneux EM, Peltola H, et al. Adjunctive dexamethasone in bacterial meningitis: a meta‐analysis of individual patient data. Lancet Neurology 2010;9(3):254‐63.

van Well 2012

van Well GT, Sanders MS, Ouburg S, van Furth AM, Morré SA. Polymorphisms in toll‐like receptors 2, 4, and 9 are highly associated with hearing loss in survivors of bacterial meningitis. PLoS One 2012;7(5):e35837.

Wakai 2013

Wakai A, McCabe A, Roberts I, Schierhout G. Mannitol for acute traumatic brain injury. Cochrane Database of Systematic Reviews 2013, Issue 8. [DOI: 10.1002/14651858.CD001049.pub5]

Wall 2017

Wall EC, Mukaka M, Scarborough M, Ajdukiewicz KMA, Cartwright KE, Nyirenda M, et al. Prediction of outcome from adult bacterial meningitis in a high‐HIV‐seroprevalence, resource‐poor setting using the Malawi Adult Meningitis Score (MAMS). Clinical Infectious Diseases 2017;64(4):413‐9.

Yu 1992

Yu YL, Kumana CR, Lauder IJ, Cheung YK, Chan FL, Kou M, et al. Treatment of acute cerebral hemorrhage with intravenous glycerol. A double‐blind, placebo‐controlled, randomized trial. Stroke 1992;23(7):967‐71.

Yu 1993

Yu YL, Kumana CR, Lauder IJ, Cheung YK, Chan FL, Kou M, et al. Treatment of acute cortical infarct with intravenous glycerol. A double‐blind, placebo‐controlled randomized trial. Stroke 1993;24(8):1119‐24.

References to other published versions of this review

Wall 2010

Wall ECB, Ajdukiewicz KMB, Heyderman RS, Garner P. Osmotic therapies as adjuncts to antibiotics for acute bacterial meningitis. Cochrane Database of Systematic Reviews 2010, Issue 11. [DOI: 10.1002/14651858.CD008806]

Wall 2013

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. [DOI: 10.1002/14651858.CD008806.pub2]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Ajdukiewicz 2011

Methods

Randomised controlled trial

Participants

Adults 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)

Interventions

Oral glycerol 75 mg in 135 mL

Oral glucose 50% solution 135 mL

Outcomes

Primary outcome: mortality

Secondary outcomes: epilepsy, deafness, residual neurological deficit at day 40

Notes

Source of funding: the Meningitis Research Foundation

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

Risk of bias

Bias

Authors' judgement

Support 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 risk

Intention‐to‐treat analysis; all participants included in the analysis

Selective reporting (reporting bias)

Low risk

None apparent

Other bias

Low risk

No other biases apparent

Kilpi 1995

Methods

Randomised controlled trial with 4 arms

Participants

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

Interventions

Glycerol 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. Treatment given for 3 days

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

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

Outcomes

Primary outcome: mortality

Secondary outcomes: epilepsy, deafness, residual neurological deficit

Notes

Source of funding: the Arvo and Lea Ylppö Foundation, Helsinki, Finland, and Roche Oy, Helsinki, Finland

No details given of whether any placebo agent was used

Risk of bias

Bias

Authors' judgement

Support 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 was 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 risk

No details of blinding were given, so we assumed the study was unblinded

Incomplete outcome data (attrition bias)
All outcomes

High risk

134 children enrolled, 12 excluded, 122 in the final series but only 120 analysed. Details of the missing data were not present in the text

Selective reporting (reporting bias)

High risk

No details of the missing data given, so it is not clear if selective cases are presented

Other bias

Unclear risk

Groups not completely matched: more females in the dexamethasone group and increased meningitis due to S pneumoniae in the control group

Molyneux 2014

Methods

Randomised controlled trial with 4 arms

Participants

Children aged 2 months or older with bacterial meningitis (CSF culture positive; CSF leucocytes ≥ 100/mm² with positive blood culture; CSF ≥ 100 leukocytes with signs and symptoms of bacterial meningitis)

Interventions

1. Glycerol + paracetamol

2. Glycerol

3. Paracetamol

4. Placebo

All placebo‐controlled: carboxymethylcellulose (placebo for glycerol) and cocoa butter base suppository (placebo for paracetamol)

Doses: glycerol 6 g/kg/day in 4 daily doses (maximum 2.5 mg/dose) for 2 days

Acetaminophen rectal suppository 35 mg/kg first dose followed by 20 mg/kg 6‐hourly for 42 hours

Outcomes

Primary outcome:

  • Survival to 6 months post discharge with no sequelae

Secondary outcomes:

  • Sequelae that affect daily life (e.g. hemiplegia, deafness, blindness, seizures, global developmental delay) at 6 months

  • Severe incapacitating sequelae

  • Death

Notes

Source of funding: the Academy of Finland

In the trial registration from 2008, the primary outcomes were: death, severe neurological sequelae and hearing loss; secondary outcomes were: audiological or neurological sequelae

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"...randomisation was computer generated in permuted blocks of 12"

Allocation concealment (selection bias)

Unclear risk

No information

Blinding (performance bias and detection bias)
All outcomes

Low risk

No report in trial. Email from author that the trial was "double blind"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Intention‐to‐treat analysis; all participants included in the analysis

Selective reporting (reporting bias)

Unclear risk

None apparent. Some differences between trial report and trial registration

Other bias

Unclear risk

No detailed baseline characteristics: "baseline data for the 4 groups were similar except more children had received antibiotics in the paracetamol + glycerol group"

Peltola 2007

Methods

Randomised controlled trial with 4 arms, multicentre in South America

Participants

Children 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 >15,000 cells/mm³

Interventions

Glycerol 1.5 g/kg in an 85% solution divided into 3 doses/24 hours. Treatment given for 2 days

Placebo: saline plus carboxy methylcellulose. Doses and volumes of placebo not given in the paper

Dexamethasone 0.15 mg/kg once daily IV divided into 3 doses/24 hours. Treatment given for 2 days

4 groups: glycerol + placebo, glycerol + dexamethasone, dexamethasone + placebo and placebo + placebo

Outcomes

Primary mortality. No secondary mortality at the end of follow‐up given

Secondary outcomes: epilepsy, deafness and residual neurological deficit

Notes

Source of funding: GlaxoSmithKline, Alfred Kordelin, Päivikki and Sakari Sohlberg, and Sigfrid Jusélius Funds. Farmacia Ahumada donated glycerol and both placebo preparations. Laboratorio de Chile partly donated ceftriaxone.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear 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 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"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

None identified

Selective reporting (reporting bias)

Low risk

No missing data identified

Other bias

Unclear risk

Drugs were supplied by GlaxoSmithKline (GSK) and Farmacia Ahumada. GSK partially funded the study

Sankar 2007

Methods

Randomised controlled trial. Single centre

Participants

Children 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)

Interventions

Glycerol 1.5 g/kg IV or orally 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 reported

Outcomes

Primary mortality. No secondary mortality at the end of follow‐up given

Secondary outcomes: epilepsy, deafness and residual neurological deficit

Notes

Source of funding: reported as "Nil"

This study was published twice, with a preliminary analysis of the osmotic effects published as Singhi 2008

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation list prepared with a simple random numbers table

Allocation concealment (selection bias)

Low risk

Serially numbered, sealed packets prepared, kept readily available

Blinding (performance bias and detection bias)
All outcomes

Low risk

Clinicians and participants blinded. It was not clear from the text if the investigators were fully blinded but the packets were prepared by a separate person from the investigating team

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Outcome data were complete

Selective reporting (reporting bias)

Unclear risk

No data were reported for important outcomes: adverse events and time for stopping treatment

Other bias

Low risk

No other biases apparent

CNS ‐ central nervous system; CSF ‐ cerebrospinal fluid; IV ‐ intravenous

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Almirante 1995

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

CTRI/2015/04/005668

RCT of newborns with bacterial meningitis receiving oral glycerol versus standard treatment. Eligible for inclusion, but the trial was suspended. This was confirmed by the trialists

Glimåker 2014

Not a RCT: retrospectively identified controls. Osmotherapy (hypertonic saline) was one of the interventions

Herson 1977

Not a RCT. Glycerol use discussed

Kumar 2014

Open‐label RCT of children with raised intracranial pressure due to acute CNS infections, including meningitis receiving fluid and vasoactive therapy to maintain cerebral perfusion pressure above 60 mm Hg versus hyperventilation and osmotherapy to maintain intercranial pressure below 20 mm Hg

Molyneux 2015

Review article. Glycerol use discussed

Pecco 1991

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

Pelegrin 2012

Retrospective 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 2013

Review article. Glycerol use discussed

Singhi 2004

Review article. Not a RCT

Singhi 2007

Letter in response to the journal editorial summary of Peltola 2007

Urciuoli 1963

Mannitol tested for neurosurgical infections and not acute bacterial meningitis. Not a RCT

Vaziri 2016

Systematic review. Glycerol use discussed

CNS ‐ central nervous system; RCT ‐ randomised controlled trial

Data and analyses

Open in table viewer
Comparison 1. Glycerol versus no osmotic diuretic

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

5

1272

Risk Ratio (M‐H, Fixed, 95% CI)

1.08 [0.90, 1.30]

Analysis 1.1

Comparison 1 Glycerol versus no osmotic diuretic, Outcome 1 Death.

Comparison 1 Glycerol versus no osmotic diuretic, Outcome 1 Death.

1.1 No steroids

5

853

Risk Ratio (M‐H, Fixed, 95% CI)

1.10 [0.90, 1.33]

1.2 With steroids

3

419

Risk Ratio (M‐H, Fixed, 95% CI)

1.02 [0.60, 1.74]

2 Neurological disability Show forest plot

5

1270

Risk Ratio (M‐H, Fixed, 95% CI)

0.73 [0.53, 1.00]

Analysis 1.2

Comparison 1 Glycerol versus no osmotic diuretic, Outcome 2 Neurological disability.

Comparison 1 Glycerol versus no osmotic diuretic, Outcome 2 Neurological disability.

2.1 No steroids

5

851

Risk Ratio (M‐H, Fixed, 95% CI)

0.71 [0.49, 1.01]

2.2 With steroids

3

419

Risk Ratio (M‐H, Fixed, 95% CI)

0.82 [0.38, 1.77]

3 Seizures Show forest plot

4

1090

Risk Ratio (M‐H, Fixed, 95% CI)

1.08 [0.90, 1.30]

Analysis 1.3

Comparison 1 Glycerol versus no osmotic diuretic, Outcome 3 Seizures.

Comparison 1 Glycerol versus no osmotic diuretic, Outcome 3 Seizures.

3.1 No steroids

4

755

Risk Ratio (M‐H, Fixed, 95% CI)

1.15 [0.92, 1.44]

3.2 With steroids

2

335

Risk Ratio (M‐H, Fixed, 95% CI)

0.96 [0.70, 1.33]

4 Hearing loss Show forest plot

5

922

Risk Ratio (M‐H, Fixed, 95% CI)

0.64 [0.44, 0.93]

Analysis 1.4

Comparison 1 Glycerol versus no osmotic diuretic, Outcome 4 Hearing loss.

Comparison 1 Glycerol versus no osmotic diuretic, Outcome 4 Hearing loss.

4.1 No steroids

4

572

Risk Ratio (M‐H, Fixed, 95% CI)

0.63 [0.41, 0.99]

4.2 With steroids

3

350

Risk Ratio (M‐H, Fixed, 95% CI)

0.66 [0.32, 1.35]

5 Adverse effects: nausea, vomiting, diarrhoea Show forest plot

2

851

Risk Ratio (M‐H, Random, 95% CI)

1.09 [0.81, 1.47]

Analysis 1.5

Comparison 1 Glycerol versus no osmotic diuretic, Outcome 5 Adverse effects: nausea, vomiting, diarrhoea.

Comparison 1 Glycerol versus no osmotic diuretic, Outcome 5 Adverse effects: nausea, vomiting, diarrhoea.

5.1 No steroids

2

546

Risk Ratio (M‐H, Random, 95% CI)

1.22 [0.81, 1.83]

5.2 With steroids

1

305

Risk Ratio (M‐H, Random, 95% CI)

0.86 [0.66, 1.13]

6 Adverse effects: gastrointestinal bleeding Show forest plot

3

607

Risk Ratio (M‐H, Random, 95% CI)

0.93 [0.39, 2.19]

Analysis 1.6

Comparison 1 Glycerol versus no osmotic diuretic, Outcome 6 Adverse effects: gastrointestinal bleeding.

Comparison 1 Glycerol versus no osmotic diuretic, Outcome 6 Adverse effects: gastrointestinal bleeding.

6.1 No steroids

3

296

Risk Ratio (M‐H, Random, 95% CI)

0.39 [0.06, 2.60]

6.2 With steroids

3

311

Risk Ratio (M‐H, Random, 95% CI)

1.16 [0.44, 3.04]

Study screening flow diagram
Figuras y tablas -
Figure 1

Study screening flow diagram

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
Figuras y tablas -
Figure 2

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study
Figuras y tablas -
Figure 3

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study

Comparison 1 Glycerol versus no osmotic diuretic, Outcome 1 Death.
Figuras y tablas -
Analysis 1.1

Comparison 1 Glycerol versus no osmotic diuretic, Outcome 1 Death.

Comparison 1 Glycerol versus no osmotic diuretic, Outcome 2 Neurological disability.
Figuras y tablas -
Analysis 1.2

Comparison 1 Glycerol versus no osmotic diuretic, Outcome 2 Neurological disability.

Comparison 1 Glycerol versus no osmotic diuretic, Outcome 3 Seizures.
Figuras y tablas -
Analysis 1.3

Comparison 1 Glycerol versus no osmotic diuretic, Outcome 3 Seizures.

Comparison 1 Glycerol versus no osmotic diuretic, Outcome 4 Hearing loss.
Figuras y tablas -
Analysis 1.4

Comparison 1 Glycerol versus no osmotic diuretic, Outcome 4 Hearing loss.

Comparison 1 Glycerol versus no osmotic diuretic, Outcome 5 Adverse effects: nausea, vomiting, diarrhoea.
Figuras y tablas -
Analysis 1.5

Comparison 1 Glycerol versus no osmotic diuretic, Outcome 5 Adverse effects: nausea, vomiting, diarrhoea.

Comparison 1 Glycerol versus no osmotic diuretic, Outcome 6 Adverse effects: gastrointestinal bleeding.
Figuras y tablas -
Analysis 1.6

Comparison 1 Glycerol versus no osmotic diuretic, Outcome 6 Adverse effects: gastrointestinal bleeding.

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

Glycerol for acute bacterial meningitis

Patient or population: children and adults with acute bacterial meningitis
Settings: Finland, India, South America, Malawi
Intervention: glycerol with or without steroids compared with placebo. All participants received broad‐spectrum antibiotics

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

Number of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Glycerol

Death

19 per 100

21 per 100
(17 to 25)

RR 1.08
(0.90 to 1.30)

1272
(5 studies)

⊕⊕⊕⊝
Moderate1,2,3,4

Downgraded for imprecision.

Glycerol probably has little or no effect on death

Neurological disability

9 per 100

6 per 100

(5 to 9)

RR 0.73

(0.53 to 1.00)

1270

(5 studies)

⊕⊕⊝⊝

Low1,3,4,5

Downgraded for imprecision and inconsistency.

Glycerol may reduce disability

Seizures

32 per 100

35 per 100
(29 to 42)

RR 1.08
(0.90 to 1.30)

1090
(4 studies)

⊕⊕⊝⊝
Low1,3,4,6

Downgraded for inconsistency and imprecision.

Glycerol may have little or no effect on seizures

Hearing loss

16 per 100

10 per 100
(7 to 15)

RR 0.64
(0.44 to 0.93)

922
(5 studies)

⊕⊕⊕⊝
Moderate1,2,3,7

Downgraded for imprecision.

Glycerol probably reduces hearing loss

Adverse effects: nausea, vomiting, diarrhoea

47 per 100

51 per 100

(38 to 69)

RR 1.09

(0.81 to 1.47)

851
(2 studies)

⊕⊝⊝⊝
Very low1,3,4,8,9

Downgraded for serious inconsistency and imprecision.

The effect of glycerol on adverse events: nausea, vomiting and diarrhoea is uncertain

Adverse effects: gastrointestinal bleeding

3 per 100

3 per 100

(13 to 8)

RR 0.93

(0.39 to 2.19)

607
(3 studies)

⊕⊕⊕⊝
Moderate1,2,3,4

Downgraded for imprecision.

Glycerol probably has little or no effect on adverse events: gastrointestinal bleeding

*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

1No serious risk of bias: allocation concealment was adequate in four trials and unclear (not reported) in one trial.
2Not downgraded for inconsistency.

3Not downgraded for indirectness. The five trials were conducted in Finland, Malawi, India and South America. Four were in children and one in adults. All included patients with suspected meningitis and cerebrospinal fluid (CSF) changes suggestive of bacterial infection.
4Downgraded by one level for imprecision: the 95% CI includes what might be a clinically important harm and no effect with glycerol.

5Downgraded by one level for inconsistency: in the Finnish trial the risk of neurological sequelae was reduced with glycerol (RR 0.50, 95% CI 0.32 to 0.78, N = 329), but this was not found in the other studies and the meta‐analysis did not detect a difference (I² = 59%).

6Downgraded by one level for inconsistency: in the trial with adults the risk of seizures was higher with glycerol (RR 1.62, 95% CI 1.18 to 2.23, N = 250), but this was not found in the other studies and the meta‐analysis did not detect a difference (I² = 62%).
7Downgraded by one level for imprecision: the number of patients with reported hearing loss was low in these studies and the 95% CI includes both no effect and what might be a clinically important benefit with glycerol. Larger studies would be necessary to have full confidence in this effect.

8Another two trials reported on this outcome but the results could not be added to the meta‐analysis; one reported more cases of vomiting with glycerol and the other that the incidence of vomiting was "similar" in the treatment groups.

9Downgraded by two levels for inconsistency: in the South American and Finnish trials the risk of adverse effects was increased with glycerol, but this was not found in the Malawi and India trials, and the meta‐analysis did not detect a difference (I² = 79%).

Figuras y tablas -
Summary of findings for the main comparison. Glycerol for acute bacterial meningitis
Table 1. Available osmotic therapies

Drug

Class

Mechanism of action

Dose range and route

Studied/used in

Glycerol

Sugar alcohol

Probably osmosis plus possible vascular and metabolic benefit

IV 5% to 10% solution or 50 g

Oral 1.5 g/kg

Meningitis (Peltola 2007), stroke (Righetti 2004)

Mannitol

Sugar alcohol

Osmotic diuretic

IV 20% solution

1 mL/kg to 10 mL/kg or 1 g/kg

Brain trauma (Wakai 2013), cerebral malaria (Namutangula 2007), stroke (Bereczki 2007)

 

Sorbitol

Sugar alcohol

Osmotic diuretic (weak)

Oral, IV

Experimental brain perfusion, stroke

Hypertonic

saline

Hypertonic solutions

Osmosis

IV

Brain trauma (Choi 2005), stroke (Schwarz 2002)

Sodium

lactate

Hydroxy acids

Osmosis (weak)

IV

Brain trauma (Ichai 2009)

IV: intravenous

Figuras y tablas -
Table 1. Available osmotic therapies
Table 2. Comparison of included study interventions

Name of study

Population

Intervention and dose

Control used

Treatment duration

Study arms

Kilpi 1995

Children in Finland

Oral glycerol 4.5 g/kg max 180 g/24 h in 3 divided doses

Dexamethasone (dex) 1.5 mg/kg max 60 mg/day

No oral placebo

IV saline

3 days

4 arms: IV dexamethasone + glycerol, oral glycerol, IV dexamethasone, neither treatment

Sankar 2007

Children in India

Oral glycerol 1.5 g/kg 3 x daily

Dexamethasone 0.15 mg/kg 3 x daily

Oral carboxymethylcellulose 2%

IV saline

Not detailed

4 arms: placebo oral and IV, IV dexamethasone + oral glycerol, IV placebo + oral glycerol, IV dexamethasone + oral placebo

Peltola 2007

Children in South America

Oral glycerol 1.5 g/kg 3 x daily

Dexamethasone 0.15 mg/kg 3 x daily

Oral carboxymethylcellulose 2%

IV saline

2 days

4 arms: oral and IV placebo, IV dexamethasone + oral glycerol, IV placebo + oral glycerol, IV dexamethasone + oral placebo

Ajdukiewicz 2011

Adults in Malawi, Southern Africa

Oral glycerol 75 mg 4 x daily diluted in water or 50% dextrose solution

Oral 50% dextrose solution

4 days

Oral glycerol versus oral 50% dextrose

Molyneux 2014

Children in Malawi, Southern Africa

Oral glycerol 25 mL/dose (maximum dose) = 100 mL/24 hours.

Acetaminophen 35 mg/kg 6‐hourly

Oral carboxymethylcellulose 2%

2 days

3 arms: oral glycerol and oral acetaminophen, oral placebo and glycerol, oral acetaminophen and oral placebo

IV: intravenous

Figuras y tablas -
Table 2. Comparison of included study interventions
Comparison 1. Glycerol versus no osmotic diuretic

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Death Show forest plot

5

1272

Risk Ratio (M‐H, Fixed, 95% CI)

1.08 [0.90, 1.30]

1.1 No steroids

5

853

Risk Ratio (M‐H, Fixed, 95% CI)

1.10 [0.90, 1.33]

1.2 With steroids

3

419

Risk Ratio (M‐H, Fixed, 95% CI)

1.02 [0.60, 1.74]

2 Neurological disability Show forest plot

5

1270

Risk Ratio (M‐H, Fixed, 95% CI)

0.73 [0.53, 1.00]

2.1 No steroids

5

851

Risk Ratio (M‐H, Fixed, 95% CI)

0.71 [0.49, 1.01]

2.2 With steroids

3

419

Risk Ratio (M‐H, Fixed, 95% CI)

0.82 [0.38, 1.77]

3 Seizures Show forest plot

4

1090

Risk Ratio (M‐H, Fixed, 95% CI)

1.08 [0.90, 1.30]

3.1 No steroids

4

755

Risk Ratio (M‐H, Fixed, 95% CI)

1.15 [0.92, 1.44]

3.2 With steroids

2

335

Risk Ratio (M‐H, Fixed, 95% CI)

0.96 [0.70, 1.33]

4 Hearing loss Show forest plot

5

922

Risk Ratio (M‐H, Fixed, 95% CI)

0.64 [0.44, 0.93]

4.1 No steroids

4

572

Risk Ratio (M‐H, Fixed, 95% CI)

0.63 [0.41, 0.99]

4.2 With steroids

3

350

Risk Ratio (M‐H, Fixed, 95% CI)

0.66 [0.32, 1.35]

5 Adverse effects: nausea, vomiting, diarrhoea Show forest plot

2

851

Risk Ratio (M‐H, Random, 95% CI)

1.09 [0.81, 1.47]

5.1 No steroids

2

546

Risk Ratio (M‐H, Random, 95% CI)

1.22 [0.81, 1.83]

5.2 With steroids

1

305

Risk Ratio (M‐H, Random, 95% CI)

0.86 [0.66, 1.13]

6 Adverse effects: gastrointestinal bleeding Show forest plot

3

607

Risk Ratio (M‐H, Random, 95% CI)

0.93 [0.39, 2.19]

6.1 No steroids

3

296

Risk Ratio (M‐H, Random, 95% CI)

0.39 [0.06, 2.60]

6.2 With steroids

3

311

Risk Ratio (M‐H, Random, 95% CI)

1.16 [0.44, 3.04]

Figuras y tablas -
Comparison 1. Glycerol versus no osmotic diuretic