Osmotic therapies added to antibiotics for acute bacterial meningitis

Emma CB Wall; Katherine MB Ajdukiewicz; Hanna Bergman; Robert S Heyderman; Paul Garner

doi:10.1002/14651858.CD008806.pub3

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Figure 1

Study screening flow diagram

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Figure 2

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

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Figure 3

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

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Analysis 1.1

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

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Analysis 1.2

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

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Analysis 1.3

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

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Analysis 1.4

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

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Analysis 1.5

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

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Analysis 1.6

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

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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)	⊕⊕⊕⊝ Moderate^1,2,3,4	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)	⊕⊕⊝⊝ Low^1,3,4,5	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)	⊕⊕⊝⊝ Low^1,3,4,6	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)	⊕⊕⊕⊝ Moderate^1,2,3,7	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 low^1,3,4,8,9	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)	⊕⊕⊕⊝ Moderate^1,2,3,4	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%).

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

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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

Table 1. Available osmotic therapies

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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

Table 2. Comparison of included study interventions

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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]

Comparison 1. Glycerol versus no osmotic diuretic

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