A better oral rehydration solution?

Diarrhoea remains one of the leading causes of death in children below 5 years of age in developing countries, resulting in over 4 million deaths a year. Most diarrhoeal deaths are caused by dehydration, which can be treated by replacing fluid loss with oral rehydration solution in over 90% of cases. For over 20 years the World Health Organization and Unicef have recommended an oral rehydration solution containing 90 mmol/l of sodium and 111 mmol/l of glucose.¹,² This solution is of established efficacy in treating children and adults with diarrhoea regardless of its cause. Despite proved efficacy, the acceptance of oral rehydration solution by patients worldwide and particularly outside facility-based treatment centres has been less than optimal and even poor. As a result, other formulations have been developed and tested, and this week's issue carries a meta-analysis of studies comparing the standard WHO oral rehydration solution with reduced osmolarity solutions (p 81).³

One of the major constraints of the WHO oral rehydration solution is that it does not visibly reduce the severity of diarrhoea (volume of stool and duration of diarrhoea), which is often perceived by patients and parents to represent failure or lack of efficacy of oral rehydration solution. Attempts in the past decade to improve on the current WHO solution have included substituting the glucose with other substrates, including cereals such as rice, and the addition of glycine, alanine, and glutamine, among others. Despite these efforts, the standard WHO solution has held up remarkably well. None of the modified solutions studied to date have been deemed to have the right combination of efficacy, safety, and feasibility for programme implementation to warrant a change in the standard WHO formulation.

More recently, however, several studies have evaluated the effect of reducing the osmotic load of oral rehydration solution by reducing amounts of sodium or glucose, or both. Many, but not all, of these reduced osmolarity oral rehydration solutions suggest superior efficacy compared with the standard WHO solution. However, the ability to make definite conclusions about efficacy and safety of reduced osmolarity oral rehydration solution compared with the standard WHO solution has been constrained by differences in formulations of reduced osmolarity solutions and differences or limitations in study designs.

In this context the meta-analysis reported by Hahn et al in this week's issue makes an important contribution to our understanding of the potential role of reduced osmolarity oral rehydration solution.³ Their main finding that, compared with the standard WHO solution, reduced osmolarity rehydration solution resulted in fewer failures requiring the use of intravenous fluids is important because many of the most severe adverse effects related to rehydration are due to complications of intravenous fluids. Anyone who has ever witnessed the death of a young child from fluid overload via intravenous fluids in the course of treatment of dehydration can testify to the value of this finding. Yet aspects of the analysis and subsequent conclusions by the authors merit further consideration.

The use of unscheduled intravenous fluids as the sole primary outcome of efficacy rather than other key clinical diarrhoeal disease outcomes, such as stool output or duration of diarrhoea, or stay in hospital, can be questioned. Standard WHO oral rehydration solution is of proved efficacy but does little to reduce diarrhoeal stool output, which is often cited as the single greatest barrier to its acceptance. The underlying rationale for reduced osmolarity solutions is the observation of improved net water absorption in animal and human perfusion studies.⁴ Reduced stool output has therefore been the primary and perhaps most important programmatic aim for reduced osmolarity oral rehydration solution. Though the meta-analysis suggests there is a total reduction in stool output, the magnitude and the reliability of this among children in the various studies were uneven and almost certainly too small to be observed by most communities of patients or their parents.

Despite their efforts, Hahn et al were not able to examine treatment effects of reduced osmolarity and standard rehydration solutions in children with cholera—that is, those with the highest faecal sodium excretion. A major concern about reduced osmolarity solution has been that the reduced sodium content of these formulations might increase the risk of a symptomatic hyponatraemia (serum sodium below 125 mmol/l) and associated sequelae, especially in patients with cholera. More recently, reduced osmolarity oral rehydration solution in adults with cholera was observed to be associated with an increased risk of hyponatraemia, although, importantly, not symptomatic hyponatraemia.⁵ Yet similar, more definitive information for children is not available. Though the evidence to date with paediatric cholera is reassuring, to place the burden of proving equivalent safety of reduced osmolarity solution on those advocating the standard WHO solution, as proposed by the authors, is debatable.

Should reduced osmolarity solution replace the current WHO oral rehydration solution as the new “standard” or should there be two standard solutions, one for regions where cholera is endemic and another for everywhere else? The balance of evidence as highlighted by Hahn et al's study indicates that reduced osmolarity oral rehydration solution is superior to standard WHO oral rehydration solution in certain relevant aspects. Yet it probably falls short in overcoming the major obstacle of improving acceptance and compliance by sweeping away misguided perceptions of the lack of efficacy of oral rehydration solution. The benefits of reduced complications associated with intravenous infusion (not just rate of infusions) compared with an incompletely defined risk of symptomatic hyponatraemia with reduced osmolarity solution in children with cholera are not known and make it difficult to promote reduced osmolarity solution alone in areas where cholera is endemic. In this context, reduced osmolarity oral rehydration solution is an important and meaningful step but not a leap forward.

Papers p 81