Scientific Rationale for a Change in the Composition of Oral Rehydration Solution
- Christopher Duggan, MD, MPH;
- Olivier Fontaine, MD;
- Nathaniel F. Pierce, MD;
- Roger I. Glass, MD, PhD;
- Dilip Mahalanabis, MD;
- Nur Haque Alam, MD;
- Maharaj K. Bhan, MD;
- Mathuram Santosham, MD, MPH
- Author Affiliations: Division of Gastroenterology and Nutrition, Children's Hospital Boston, Boston, Mass (Dr Duggan); Child and Adolescent Health and Development, World Health Organization, Geneva, Switzerland (Dr Fontaine); Johns Hopkins Bloomberg School of Public Health, Baltimore, Md (Drs Pierce and Santosham); Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Ga (Dr Glass); Society for Applied Studies, Kolkata, India (Dr Mahalanabis); Clinical Sciences Division, ICDDR, B Centre for Health and Population Research, Dhaka, Bangladesh (Dr Alam); and Department of Pediatrics, All India Institute of Medical Sciences, New Delhi (Dr Bhan).
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Corresponding Author: Christopher Duggan, MD, MPH, Division of Gastroenterology and Nutrition, Children's Hospital Boston, 300 Longwood Ave, Boston, MA 02115 (christopher.duggan@childrens.harvard.edu).
Diarrheal diseases remain important causes of death and morbidity in developing countries, with an estimated 1.5 billion episodes and 1.5 million to 2.5 million deaths each year among children younger than 5 years.1-4 Although the number of children currently dying from diarrhea continues to be unacceptably high, it is substantially lower than the 5 million deaths per year estimated 20 years ago.5
A critical factor in this reduction in diarrhea deaths has been the widespread adoption of oral rehydration solution (ORS) programs for the treatment and prevention of diarrhea-associated dehydration.6-7 Indeed, ORS has been hailed as one of the most important medical advances of the past century,8 at least in part because of its simplicity, low cost, and remarkable ease of use.
Oral rehydation solution works on the elegantly simple physiologic principle of solute cotransport across the gastrointestinal epithelium (Figure 1). Briefly, landmark studies published in 19689-10 among patients with Vibrio cholera infections demonstrated that although the secretory nature of the diarrhea causes massive stool losses of water and electrolytes, sodium-coupled glucose cotransport remains largely intact and continues to stimulate resorption of salt and water.11 Clinical trials documenting the efficacy of ORS soon followed in the 1970s and 1980s.12-14
Figure. Coupled Transport of Sodium and Glucose in Intestinal Epithelial Cells
Although nutrient-independent sodium absorption across the brush border membrane of intestinal epithelial cells is impaired in patients with diarrhea, coupled transport of sodium and glucose is preserved, allowing absorption of salt and water provided by oral rehydration solutions (ORSs). Sodium-glucose transporter type 1 (SGLT1) mediates the transport of glucose against its concentration gradient by coupling it to sodium transport. Sodium that enters the cell is pumped into the blood by the Na+K+ATPase (adenosine triphosphatase) pump in the basolateral membrane, maintaining the sodium electrochemical gradient that drives the sodium-glucose cotransport mechanism. Transport of glucose into the blood is facilitated by glucose transporter type 2 (GLUT2).
For nearly 3 decades, the World Health Organization (WHO) and the United Nations Children's Fund (UNICEF) have recommended a single formulation of glucose-based ORS to treat or prevent dehydration from diarrhea of any etiology and in individuals of any age.15-16 The composition of the solution, which has proven both safe and effective in worldwide use, was based on its efficacy in replacing water and electrolytes in individuals with cholera infection, since these infections were in part the impetus behind the development of ORS. Concern that the sodium concentration of 90 mEq/L was too high for the lower salt losses of viral and other causes of childhood diarrhea17 was invoked to explain its low acceptance among pediatricians in industrialized countries who were concerned about the possible occurrence of hypernatremia.18 Some authors also noted that the standard WHO ORS was occasionally associated with hypernatremia in children in developing countries.19
In the hopes of actually reducing stool output, efforts to improve the efficacy of ORS were made in the 1970s through 1990s. These included the addition of other substrates for sodium cotransport (eg, the amino acids glycine,20 alanine, and glutamine21) or substitution of complex carbohydrates for glucose (eg, cooked rice powder and other cereal powders).22 With the exception of rice-based ORS, which significantly reduces stool output in cholera patients,23 these new ORS preparations were not more effective than standard ORS and are more expensive.24 Solutions with higher concentrations of cotransporters and higher osmolarity decrease rather than increase intestinal sodium and water absorption, and hypernatremia has been reported with their use.25
Recent efforts to improve the efficacy of ORS have focused on solutions of reduced osmolarity (eg, sodium ranges of 60-75 mEq/L and glucose ranges of 75-90 mmol/L), although some cereal-based ORSs may also be lower in osmolarity.26 These solutions generally preserve the 1:1 M ratio of sodium to glucose that is critical for efficient cotransport of sodium but present a lower osmolar load to the intestinal tract than does the original WHO ORS. Animal27 and human studies have indicated that such solutions may be better designed for optimal water and electrolyte transport into the bloodstream. In intestinal perfusion studies, solutions of reduced osmolarity have shown improved net water absorption and equivalent net sodium absorption compared with the standard WHO ORS.28 In clinical trials, children treated with reduced-osmolarity ORS experience less vomiting, less stool output, shorter duration of illness, and less need for supplemental intravenous fluids than do those treated with the standard WHO ORS.29-31
Advantages of Reduced-Osmolarity ORS
A number of randomized controlled trials have been conducted comparing the standard (1975 WHO) and reduced-osmolarity (2002 WHO) solutions (Table 1). In a trial of 300 adult patients with cholera,32 those who received reduced-osmolarity ORS had no differences in stool output, duration of diarrhea, or need for unscheduled intravenous therapy compared with those treated with the standard WHO ORS. Patients who received reduced-osmolarity ORS had an increased incidence of hyponatremia (serum sodium level <130 mmol/L) (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.1-4.1). The mean difference in serum sodium at 24 hours of treatment between the 2 groups was 1.2 mEq/L, and none of the patients with hyponatremia in either group was symptomatic.
Table. Composition of Standard and Reduced-Osmolarity WHO ORS
In a large multicenter trial of children with acute diarrhea not due to cholera,33 675 children aged 1 to 24 months from 5 countries were randomized to receive standard or reduced-osmolarity ORS. Although stool output and vomiting were not statistically different between the groups, the use of unscheduled intravenous fluids following initial rehydration was reduced in the group receiving reduced-osmolarity ORS (10% vs 15%) (OR, 0.6; 95% CI, 0.4-1.0). The occurrence of hyponatremia was not statistically different between the groups (11% in the reduced-osmolarity group vs 9% in the standard group) (OR, 1.3; 95% CI, 0.2-2.2).
In a meta-analysis that evaluated the effects of reduced-osmolarity ORS in 15 randomized trials of nearly 2400 children,31 use of a reduced-osmolarity ORS was associated with less frequent use of unscheduled intravenous fluids (combined OR, 0.61; 95% CI, 0.47-0.81) and less vomiting (combined OR, 0.71; 95% CI, 0.55-0.92). In addition, a statistically significant reduction in stool output was noted (standardized mean difference, –0.21; 95% CI, –0.31 to –0.12). The incidence of hyponatremia was not significantly elevated among children who received reduced-osmolarity ORS in these trials (OR, 1.45; 95% CI, 0.93-2.26).
Based on these and other relevant data, WHO and UNICEF convened a meeting in 2001 to review all published studies comparing standard and reduced-osmolarity ORS.34 The conclusions were as follows:
1. Reduced osmolarity ORS was more effective than standard ORS for acute noncholera diarrhea in children, as measured by clinically important outcomes such as reduced stool output, reduced vomiting, and reduced need for supplemental intravenous therapy. Although data were more limited, reduced-osmolarity ORS also appeared safe and effective for children with cholera;
2. Among adults with cholera, clinical outcomes were not different among those treated with reduced-osmolarity ORS compared with standard ORS, although the risk of transient asymptomatic hyponatremia was noted;
3. Given the programmatic and logistical advantages of using a single ORS composition globally, it was recommended that this be a reduced-osmolarity ORS (Table 1); and
4. Further monitoring, including postmarketing surveillance studies, were strongly encouraged to better assess any risk of symptomatic hyponatremia in cholera-endemic parts of the world.34
Concerns About Use of Reduced-Osmolarity ORS
Some concerns have been raised regarding the revised formulation of ORS.35-37 We believe, however, that the published literature does not support these concerns.
For example, concern has been raised that any reduction in the sodium concentration of ORS will increase the risk of hyponatremia, especially among cholera patients.35 Cholera stool sodium losses can be as high as 120 to 150 mEq/L, and in fact the composition of the original WHO ORS (90 mEq/L) was a compromise between those who favored a solution with 120 mEq/L of sodium and those who proposed a lower concentration better suited for children with diarrhea due to causes other than cholera. Thus, even the former formulation of standard WHO ORS contains less sodium than some thought necessary for adequate sodium repletion in cholera.
Among subsets of children with cholera in 3 published clinical trials of ORS,33, 38-39 the mean serum sodium concentration at 24 hours was 136 mEq/L in those treated with standard ORS and only 0.8 mEq/L (95% CI, 0.2-1.4 mEq/L) lower in those treated with reduced-osmolarity ORS.34 Although, as noted above, the incidence of hyponatremia was higher in adult cholera patients treated with a lower sodium solution, the clinical significance of this finding is unclear because all hyponatremic episodes in adults were transient and asymptomatic.32
Preliminary data concerning the incidence of hyponatremia in cholera-endemic areas of the world have been reassuring. A safety evaluation of reduced-osmolarity ORS was recently completed in Bangladesh among nearly 50 000 adults and children treated for diarrhea. Preliminary data analysis reveals that none of the adults had symptoms of hyponatremia during the 1-year study. Among close to 7000 children treated with reduced-osmolarity ORS, symptomatic hyponatremia was detected in only a small percentage of cases (0.2%), the majority of whom had another possible reason for hyponatremia (eg, severe pneumonia, dysentery)(N.H.A., unpublished data).
Other electrolyte abnormalities, including chronic sodium deficit and hypokalemia, have been hypothesized to occur with reduced-osmolarity ORS.35 It is likely that cholera patients, especially adults, treated with either reduced-osmolarity or standard ORS are transiently sodium depleted, and that the deficit would be somewhat greater with the reduced-osmolarity solution. There is, however, no evidence that the deficit is clinically significant with either solution. It is also likely that sodium stores would be restored in the days following resumption of a normal salt-containing diet. It has been suggested that balance studies be performed in which patients are provided only standard or reduced-osmolarity ORS for 24 to 48 hours. The practice of withholding food (and therefore additional sodium) from patients with diarrhea is not in keeping with the past 15 years of standard diarrhea management, which recommends immediate nutrition after successful rehydration.40-43 These balance studies would therefore be unethical to carry out and would have no relevance to current clinical care.
Likewise, hypokalemia has not been observed among patients treated with reduced-osmolarity ORS. In the CHOICE study,33 mean (SEM) serum potassium at 24 hours was 4.0 (0.7) mEq/L in children treated with reduced-osmolarity ORS vs 3.9 (0.8) mEq/L in those treated with the WHO ORS (O.F. unpublished data, 2001).
Concern has also been raised that reduced-osmolarity ORS may complicate the management of patients with severe protein-energy malnutrition. Children with severe protein-energy malnutrition are known to have significant alterations in fluid and electrolyte homeostasis, with an excess of extracellular fluid and resultant hyponatremia.44 However, total body sodium is increased, and indeed sodium restriction is an important aspect of clinical management. Clinical trials using reduced-osmolarity ORS among malnourished children have actually shown improved clinical outcomes. Among 64 children younger than 4 years with weight for age less than 60% of the standard, a reduced-osmolarity ORS (224 mOsm/L) was compared in a double-blind fashion with the standard WHO ORS.45 Stool output, duration of diarrhea, and intake of ORS were all significantly lower in the group receiving the reduced-osmolarity ORS compared with those given standard ORS, and mean serum sodium concentrations were normal in both groups at the end of therapy. No patient had symptoms of hyponatremia. In another trial of 180 infants with diarrhea (35 of whom had cholera infection), treatment with reduced-osmolarity ORS was associated with a significant reduction in stool frequency, an effect that was greatest in children with severe protein-energy malnutrition. Serum sodium levels in the 2 groups were not significantly different.39
Among infants with persistent diarrhea (duration >14 days), who are at risk of developing protein-energy malnutrition and early death, reduced-osmolarity ORS has also been shown to be more effective than standard ORS. In a study of 95 infants in Bangladesh hospitalized with persistent diarrhea, receipt of reduced-osmolarity ORS was associated with an approximate 40% reduction in stool output, a more prompt resolution of diarrhea, and no evidence of hyponatremia.46
Conclusions
A number of randomized controlled trials have established the superiority of reduced-osmolarity ORS over standard ORS in the management of diarrheal diseases in children. Concerns about the safety of reduced-osmolarity ORS center on its use in patients with cholera, especially adults. While the provision of 17% less sodium to patients with cholera may lead to a slightly greater negative sodium balance at the end of treatment, this deficit should be rapidly corrected when a normal diet is resumed. Experience to date provides no evidence that transient hyponatremia, which may also occur with standard ORS, has significant adverse clinical consequences for cholera patients.
The benefits of promoting the use of a single ORS solution for all patients with diarrhea, including cholera, are enormous, as has been clearly established with standard ORS. It is recognized, however, that any single ORS formulation, including standard ORS, that is promoted for use in patients of all ages and with diarrhea of any etiology must be a compromise that takes into consideration both the substantial differences in stool sodium losses that occur across the spectrum of diarrheal disease as well as substantial differences in the global burden of cholera vs noncholera diarrhea. It is estimated that acute noncholera diarrhea in children causes 1.5 million to 2.5 million deaths per year, whereas cholera causes significantly fewer deaths in all age groups (approximately 120 000 per year) (O.F., unpublished data). Reduced-osmolarity ORS has the potential to substantially reduce childhood deaths from noncholera diarrhea due to the reduced requirement for supplementary intravenous fluids. Although reduced-osmolarity ORS may not have the same benefit for cholera patients, clinical trials show it to be as effective as standard ORS. It is our view that the current evidence demonstrates the benefits of reduced-osmolarity ORS for the world's children, and that use of the revised formulation is fully justified.
