Introduction

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Diarrhoea remains a leading cause of childhood death in developing countries. The main complication is dehydration, which until the early 1960s was treated with intravenous infusion. Solutions of oral rehydration salts are now the main treatment and are particularly useful when intravenous fluids are in short supply, health services are basic, and there is a shortage of skilled staff.¹ The combination of salt and sugar probably enhances absorption of fluid because sodium and glucose transport in the small intestine are coupled; glucose promotes absorption of both sodium ions and water.² Oral rehydration salts have proved both safe and effective worldwide in hospital settings and are now widely used in the home to prevent dehydration. ^{3 4}

For more than two decades, the World Health Organization has recommended a standard formulation of glucose based oral rehydration solution with 90 mmol/l of sodium and 111 mmol/l of glucose and a total osmolarity of 311 mmol/l. It remains unclear however, whether this is the optimum sodium concentration. Some studies have found patients with blood sodium concentrations above the normal level of 150 mmol/l.⁵ Laboratory work suggests that lower concentrations of sodium and glucose enhance solute induced water absorption. ^{6 7}

We conducted a systematic review of all relevant randomised controlled trials comparing the effects of reduced osmolarity and standard WHO oral rehydration solutions. We confined the review to children, as they are most vulnerable to dehydration and electrolyte imbalance from diarrhoea.

	Methods

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Study inclusion and characteristics
We included only randomised controlled trials, defined as a trial in which the subjects were assigned prospectively to one of two or more interventions by random allocation. This excludes quasirandomised designs. Patients included were children with acute diarrhoea for less than 5 days who were treated either by reduced osmolarity oral rehydration solution (total osmolarity 250 mmol/l with reduced sodium) or by standard WHO oral rehydration solution (sodium 90 mmol/l, glucose 111mmol/l, total osmolarity 311 mmol/l).

Search strategy
We searched the following databases for published clinical trials: Medline (1966 to June 2001); Embase (1988 to May 2001); Cochrane controlled trials register in the Cochrane Library (Issue 2, 2001); and Current Contents (June 2001). We used child, diarrhoea, fluid therapy, oral rehydration, osmolar, and rehydration solutions as search terms. We also checked the citations of existing reviews and trial reports. For unpublished data and ongoing trials, we contacted current researchers and key agencies, including the WHO, the Centers for Disease Control, Atlanta, and the International Centre for Diarrhoeal Disease Research, Bangladesh.

Data extraction and synthesis
We used the standard methods of the Cochrane infectious diseases group to prepare the protocol, apply inclusion criteria, assess quality, and extract data. We assessed quality by adequacy of concealment of allocation, generation of allocation sequence, blinding, and follow up of patients. The first two authors independently extracted data on relevant outcome measures using a standardised data abstraction form, and any disagreements were resolved by discussion.

	Results

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Profile of studies
Of 41 identified studies, six were not randomised trials, eight had not used glucose based reduced osmolarity rehydration solution, six had not used standard WHO rehydration solution, two were in adults, and two did not report on any of the relevant outcomes. Seventeen studies in 16 published reports met the inclusion criteria.^11-26 One paper reported on two trials,²⁴ one in the United States and one in Panama, and we present these as separate studies. We contacted the authors of three papers, ^{22 25 26} as we judged these were three reports of the same trial. As we have not received a response, we included only the paper with the largest number of patients.²²

Description and quality of studies
Details of the 15 trials included in the analysis and their patient characteristics are available on the BMJ's website. Included studies were from Egypt (three studies), Bangladesh (three), Mexico (one), Colombia (one), India (three), Panama (one), and the United States (one). Two other studies were multicentre trials; one was conducted in Brazil, India, Mexico, and Peru and the other in Bangladesh, Brazil, India, Peru, and Vietnam.

View larger version (33K): [in this window] [in a new window]   Fig 1.   Meta-analysis of unscheduled intravenous infusion among children randomised to reduced osmolarity and standard WHO rehydration solutions

Quantitative data synthesis
Figures 1-4 show the meta-analyses for the four outcomes. Information on the primary outcome (unscheduled intravenous infusion) was available in 12 trials (n=2085), but in three of these no patients in either group required infusion. In the meta-analysis of nine trials, the need for intravenous infusion was significantly reduced for participants who received reduced osmolarity rehydration solution compared with those receiving WHO rehydration solution (odds ratio 0.61, 95% confidence interval 0.47 to 0.81).

View larger version (44K): [in this window] [in a new window]   Fig 2.   Meta-analysis of stool output among children randomised to reduced osmolarity and standard WHO rehydration solutions

View larger version (22K): [in this window] [in a new window]   Fig 3.   Meta-analysis of vomiting among children randomised to reduced osmolarity and standard WHO rehydration solutions

View larger version (21K): [in this window] [in a new window]   Fig 4.   Meta-analysis of hyponatraemia among children randomised to reduced osmolarity and standard WHO rehydration solutions

	Discussion

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We found that reduced osmolarity rehydration solution was more effective than standard WHO rehydration solution in first line treatment of children with diarrhoea. It reduced the need for unscheduled intravenous infusion, stool output during rehydration, and the number of patients with vomiting during oral rehydration treatment. The reduced osmolarity rehydration solution did not seem to increase the risk of developing hyponatraemia compared with the standard WHO solution, although we cannot exclude this possibility.

We examined trials of oral rehydration salts in children admitted to hospital with dehydration because of diarrhoea. The trials do not provide any direct evidence for or against use of oral rehydration solutions at home to prevent dehydration; nor do they provide any direct evidence that reduced osmolarity solutions are more effective in preventing dehydration in the home. Oral rehydration solutions are widely used to prevent dehydration, and further research is therefore needed in this area.

View larger version (7K): [in this window] [in a new window]   Fig 5.   Funnel plot for the nine trials in which unscheduled intravenous infusion was required

Choice of primary outcome
We stand by our selection of unscheduled intravenous infusion rather than volume of diarrhoea as the primary outcome.⁹ Some specialists consider that volume of diarrhoea is more appropriate, probably because it reflects the animal and human perfusion experiments that provide part of the rationale for a reduced osmolarity rehydration solution. Unscheduled intravenous infusion is pragmatic; it provides a measure of failed oral rehydration and has implications for healthcare resources. For these reasons, we preserved this as the primary outcome.

Cholera
We intended to examine treatment effects in patients with and without cholera.⁹ A Cochrane review of rice based rehydration compared with glucose oral rehydration solution showed that rice water was associated with lower stool volumes in cholera patients but not in diarrhoea from other causes.²⁷ The available data were, however, insufficient. Three studies included cholera patients, ^{12 14 21} but separate data for cholera patients were not available. We excluded two studies in patients with cholera because they were in adults. ^{28 29} Any recommendation for rehydration treatment for adults with cholera will need to take into account these and any other trials found through careful systematic searching.

Implications
Our study suggests that reduced osmolarity rehydration solution should replace the WHO solution as the standard treatment for dehydration caused by diarrhoea. Policymakers and clinicians may, however, consider that the risk of hyponatraemia in patients with cholera outweighs the advantages of a reduced osmolarity solution. One option would be to provide standard WHO rehydration solution for people with suspected cholera or in areas where cholera is prevalent. This is likely to be a logistical problem in areas where diarrhoea is common and coexists with cholera. The single formula sachet aids implementation of this lifesaving intervention. Providing different formulations complicates distribution and may impair the effective delivery of any oral rehydration solution to children. If policymakers decide not to use reduced osmolarity solution in areas where cholera is common, they must conduct a randomised controlled trial of the two treatments in children with cholera to determine whether the decision is correct.

	Acknowledgments

This review will be maintained in the Cochrane Library.

We thank Dr Olivier Fontaine (WHO) for support throughout the process; and Dr Sheila Bird, Medical Research Council, Cambridge, for her comments.

Contributors: SH and YK wrote the protocol, extracted, analysed and interpreted the data, and drafted the paper. PG advised on inclusion criteria and outcomes for the protocol, quality assessment, and analysis, and helped write the review. PG is the guarantor.

	Footnotes

Funding : The study is supported by WHO and the Cochrane Infectious Diseases Group is supported by the Department for International Development.

Competing interests: None declared.

Tables giving further details of the included trials are available on the BMJ's website

	References

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(Accepted 27 June 2001)