Acute diarrheal disease continues to claim the lives of an estimated half a million children annually in India and of nearly two million children worldwide.(1) The global reduction in mortality from approximately 5 million diarrheal deaths annually twenty years ago, (2) is attributed to the widespread utilization of oral rehydration solution (ORS). The introduction of ORS, hailed as one of the most significant medical advances of the twentieth century, allowed correction of dehydration and prevention of mortality. (3) ORS use was based on the fact that cyclic AMP and other diarrhea mediators inhibited sodium chloride absorption, but not glucose-linked sodium absorption. However, conventional glucose-based ORS did not reduce duration or severity of diarrhea and paradoxically increased diarrhea in some children. (4) This led to attempts to identify solutes that would stimulate sodium absorption and at the same time reduce diarrhea. Though amino acid-linked sodium absorption was another potential target for ORS development, a number of studies that compared amino acid-based ORS with glucose-based ORS did not reveal any superiority of the former. In the 1980s, cereal-based ORS was also widely tested as an alternative to the glucose-based ORS. Cereal-based ORS was very effective, and of these only rice-based ORS survived over time. Though rice-based formulations were identified for home preparation and use, there is at least one commercially available formulation that uses rice as the glucose donor. An early meta-analysis of 13 clinical trials suggested that, compared to glucose-ORS, rice-ORS reduced stool output by about 18% in children with non-cholera diarrhea. (5) This meta-analysis also suggested that most of the effectiveness of rice- or other cereal-based ORS was due to the low osmolarity of the ORS used. Hypo-osmolar ORS was particularly effective in the subgroup without rotavirus. Following customary practice in many parts of the world, food intake was generally withheld during diarrhea for fear of aggravating symptoms. However, in the 1980s, work primarily led by pediatricians in Bangladesh showed that early refeeding was effective in reducing diarrhea in children and this became a cornerstone of therapy. Bhan et al in 1994 compiled a summary of several attempts to improve ORS for diarrhea in children and concluded that rice-based ORS, maltodextrin-containing and amino acid-containing ORS were not superior to glucose-based ORS for acute non-cholera diarrhea, provided that feeding was promptly resumed after initial rehydration of the child. (6) Several trials of rice-based ORS continued to be published, and the most recent meta-analysis concluded that rice-based ORS reduced mean stool output by 51-67% in adults and children with cholera, but was not significantly better than glucose ORS in children with non-cholera diarrhea, where mean stool output was only 4 ml/kg lower than glucose ORS. (7)

Following the introduction of ORS in the late 1960s by various groups in the Philippines, in Dhaka and in Kolkata, (8,9) the ORS formulation that was approved by the World Health Organization in 1975 is shown in Table 1. This ORS was developed following studies of fecal electrolyte composition in cholera, a disease that causes extreme dehydration and affects adults more often than children. Common cause of diarrhea in children such as rotavirus infection is characterized by lesser degree of fecal sodium loss. Pediatricians in Europe using the original glucose-ORS for children with diarrhea quickly recognized that use of this ORS sometimes caused hypernatremia. This may have been due to the fact that the children were given only ORS and not allowed supplemental water, whereas the standard practice elsewhere was to allow free intake of water in addition to ORS.

By the 1980s, European pediatricians began to use an ORS that had a lower content of sodium (usually 60 mmol/l) and lower osmolarity, and this was endorsed by the European associations. (10) At around this time, a scientific basis for reducing the osmolarity of ORS also began to emerge. Since the 1960s, it was known that reducing the osmolarity of a solution that was ingested increased the absorption of water from that solution. (11) In the 1980s, attempts were made to study the physiological effects of reduced osmolarity in the secreting intestine. Rolston and others showed that reducing the osmolarity improved small intestinal water absorption from ORS in animals with experimentally induced diarrhea. (12,13) Subsequently, Rolston also showed that reducing the sodium concentration of ORS led to better water absorption in human volunteers in south India and would be appropriate in countries with a high prevalence of tropical enteropathy. (14)