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Osmotic therapies added to antibiotics for acute bacterial meningitis

Appendices

Appendix 1. MEDLINE (Ovid) search strategy

1 exp Meningitis/
2 meningit*.tw.
3 1 or 2
4 Osmosis/
5 Osmotic Pressure/
6 exp Diuretics, Osmotic/
7 (osmos* or osmot* or osmol*).tw.
8 exp Sugar Alcohols/
9 glycer*.tw,nm.
10 1,2,3‐propanetrio*.tw,nm.
11 mannitol*.tw,nm.
12 sorbit*.tw,nm.
13 Sodium Lactate/
14 (sodium adj2 lactat*).tw,nm.
15 Saline Solution, Hypertonic/
16 (hypertonic adj2 saline*).tw,nm.
17 or/4‐16
18 3 and 17

Appendix 2. Embase (Elsevier) search strategy

#20 #16 AND #19
#19 #17 OR #18
#18 random*:ab,ti OR placebo*:ab,ti OR factorial*:ab,ti OR crossover*:ab,ti OR 'cross over':ab,ti OR 'cross‐over':ab,ti OR assign*:ab,ti OR allocat*:ab,ti OR volunteer*:ab,ti OR ((doubl* OR singl*) NEAR/2 (blind* OR mask*)):ab,ti
#17 'randomized controlled trial'/exp OR 'single blind procedure'/exp OR 'double blind procedure'/exp OR 'crossover procedure'/exp
#16 #3 AND #15
#15 #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14
#14 (hypertonic NEAR/2 saline):ab,ti
#13 'sodium chloride'/de
#12 (lactat* NEAR/2 sodium):ab,ti
#11 'lactate sodium'/de
#10 sorbit*:ab,ti
#9 mannitol*:ab,ti
#8 '1,2,3‐propanetriol':ab,ti OR propanetrio*:ab,ti
#7 glycer*:ab,ti
#6 'sugar alcohol'/exp
#5 osmotic*:ab,ti
#4 'osmotic diuretic agent'/exp
#3 #1 OR #2
#2 meningit*:ab,ti
#1 'meningitis'/exp

Appendix 3. CINAHL (Ebsco) search strategy

S12 S3 and S11
S11 S4 or S5 or S6 or S7 or S8 or S9 or S10
S10 TI hypertonic N2 saline or AB hypertonic N2 saline
S9 (MH "Saline Solution, Hypertonic")
S8 TI sodium N2 lactat* or AB sodium N2 lactat*
S7 TI ( glycerol* or 1,2,3‐propanetriol or propanetriol* or mannitol* or sorbit* ) or AB ( glycerol* or 1,2,3‐propanetriol or propanetriol* or mannitol* or sorbit* )
S6 AB sugar alcohol* or TI sugar alcohol*
S5 (MH "Sugar Alcohols+")
S4 TI osmotic* or AB osmotic*
S3 S1 or S2
S2 TI meningit* or AB meningit*
S1 (MH "Meningitis+")

Appendix 4. LILACS (BIREME) search strategy

> Search > (MH:Meningitis OR Meningite OR MH:C10.228.228.507$ OR C10.228.566$ OR MH:C01 252.200$ OR C10.228.228.180.500$ OR meningit$) AND (MH:"Diuretics, Osmotic" OR "Diuréticos Osmóticos" OR "Diuréticos Osmóticos" OR "Osmotic Diuretics" OR MH:D27.505.696.560.500.453$ OR osmot$ OR osmos$ OR osmol$ OR MH:"Sugar Alcohols" OR "Alcoholes del Azúcar" OR "Álcoois de Açúcar" OR MH:D02.033.800$ OR MH:D09.853$ OR "sugar alcohols" OR glycer$ OR "1,2,3‐propanetriol" OR mannitol$ OR sorbit$ OR MH:"Sodium Lactate" OR "Lactato de Sodio" OR "Lactato de Sódio" OR MH:D02.241.511.459.500$ OR "sodium lactate" OR MH:"Saline Solution, Hypertonic" OR "Solución Salina Hipertónica" OR "Solução Salina Hipertônica" OR "Hypertonic Saline Solution" OR "Sodium Chloride Solution, Hypertonic" OR "Hypertonic Solution, Saline" OR "Solución Hipertónica de Cloruro de Sodio" OR "Solução Hipertônica de Cloreto de Sódio" OR "hypertonic saline") > clinical_trials

Appendix 5. ClinicalTrials.gov search strategy

Search terms: (meningitis OR meningitides) AND (osmosis or osmoses or osmotic or osmolarity or glycerol OR glycerine OR glycerin OR or 1,2,3‐propanetriol or propanetriol or mannitol or sorbitol or sodium lactate or (hypertonic AND saline))

Appendix 6. WHO ICTRP search strategy

Search terms: meningit* AND osmos* or meningit* AND osmot* OR meningit* AND osmol* or meningit* AND glycer* OR meningit* AND 1,2,3‐propanetrio* or meningit* AND mannitol* or meningit* AND sorbit* or meningit* AND sodium lactate or meningit* AND hypertonic AND saline*

Study screening flow diagram
Figures and Tables -
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
Figures and Tables -
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
Figures and Tables -
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.
Figures and Tables -
Analysis 1.1

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

Comparison 1 Glycerol versus no osmotic diuretic, Outcome 2 Neurological disability.
Figures and Tables -
Analysis 1.2

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

Comparison 1 Glycerol versus no osmotic diuretic, Outcome 3 Seizures.
Figures and Tables -
Analysis 1.3

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

Comparison 1 Glycerol versus no osmotic diuretic, Outcome 4 Hearing loss.
Figures and Tables -
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.
Figures and Tables -
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.
Figures and Tables -
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%).

Figures and Tables -
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

Figures and Tables -
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

Figures and Tables -
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]

Figures and Tables -
Comparison 1. Glycerol versus no osmotic diuretic