Dr Swati Mulye
Associate Professor, Department of Pediatrics,
Shree Aurobindo Institute Medical Sciences, Indore

Introduction
Diarrhea is associated with 18% mortality among children aged <5 years, accounting for 1.9 million deaths ¹, primarily in developing countries. Despite advances in the use of oral rehydration therapy (ORT), diarrhea-associated mortality has not declined significantly in the past few years. The continued high mortality underscores a need for further improvements in case management and primary prevention. Dietary deficiency of some micronutrients has been shown to increase the susceptibility of infants and children to gastrointestinal infections and to have direct adverse effects on gastrointestinal tract structure and function. ^2-7

ORT and ORS
Oral rehydration solutions (ORS) are now widely used to treat diarrhea and have greatly reduced mortality from dehydration. A major limitation, so far only partially overcome, is that oral rehydration therapy (ORT) is effective at rehydration and correcting electrolyte imbalance, but generally is less impressive at reducing the purging rate. ORS is a cost effective medication in the world.

Despite the advent of a number of antidiarrheal drugs, none has found a place in the routine management of acute diarrhea. This is particularly relevant to developing nations, where the financial burden of public health results in a poor distribution of meager resources. Mortality due to dehydration and hyponatremia, especially in infancy accounts for several millions each year. ^{8, 9} If properly administrated by caregivers, ORS can not only reduce mortality but also diminish the need for hospitalization and intravenous rehydration. This shortcoming lessens the acceptance of ORT by primary caregivers and increases the risk of an early interruption of the rehydration process, the introduction of inappropriate feedings and reinfection causing the perpetuation of a vicious cycle.

The physiologic characteristics of the small intestine present challenges and opportunities to achieve a successful therapeutic intervention. Improving the efficacy of ORS has been a persistent effort involving clinicians, field workers and researchers.

The most important factors influencing the success of an ORS are: electrolyte and base content, carbohydrate type and concentration and osmolality.

Table 1 - Schematic History and Possible Trends in the Formulation  of ORS¹⁰

Early Formulas	Attempted Modifi cations	Current Formulas	Future Develop ments
High carbohydrate     Low sodium	Better Glucose/     Sodium Balance	Sodium <75 mM	Sodium: Glucose ratio      > 0.5
Iso or Hypertonic     ORS	Amino Acids (Gly, Ala, Gln)	Glucose < 111 mM (or rice extract     powders; local or     commercial)	Rice (wheat) extracts     (glucose polymers)
	Iso or Hypertonic ORS	Iso or Hypotonic ORS	Live or killed Lactobacilli
			Soluble Fibers or non-absorbable carbohydrates
			Zinc salts

New reduced osmolarity ORS
In spite of the success of the ORS, there remained criticism from health workers and mothers that the original ORS solution did not stop diarrhea or reduce the duration of the episode. Hence, during the past 20 years, research has been undertaken to develop an improved ORS that would be safe and effective for treating or preventing dehydration in all types of diarrhea, and would also have other clinical benefits when compared with the standard ORS.

Studies have shown that the efficacy of ORS for treatment of children with acute diarrhea is improved by reducing its sodium concentration to 75 mEq/l, its glucose concentration to 75 mmol/l, and its total osmolarity to 245 mOsm/l. 11 This compares to the original solution which contained 90 mEq/l of sodium with a total osmolarity of 311 mOsm/l. There has been a concern that the original solution, which is slightly hyperosmolar when compared with plasma, may risk hypernatremia or an increase in stool output, especially in infants and young children.

The study results clearly describe the advantages of this new reduced osmolarity ORS solution in treating children with acute diarrhea:

	It reduces stool output or stool volume by about 25% when compared to the original WHO UNICEF ORS solution,
	It reduces vomiting by almost 30%.
	It reduces the need for unscheduled IV therapy by more than 30%.

Because of the improved effectiveness of reduced osmolarity ORS solution, especially for children with acute, non-cholera diarrhoea, WHO and UNICEF are recommending that countries manufacture and use the following formulation in place of the previously recommended ORS solution. ¹¹

COMPOSITION OF REDUCED OSMOLARITY ORS

Reduced osmolarity ORS	grams/litre
Sodium chloride	2.6
Glucose, anhydrous	13.5
Potassium chloride	1.5
Trisodium citrate, dihydrate	2.9
Total weight	20.5

Reduced osmolarity ORS	grams/litre
Sodium	75
Chloride	65
Glucose, anhydrous	75
Potassium	20
Citrate	10
Total osmolarity	245

Recommendations of the IAP National Task Force for use of ORS in diarrhea, August 18-19, 2003 ¹²

	All doctors should prescribe ORS for all ages in all types of diarrhea.
	The group noted that the new improved universal ORS recommended by the WHO containing sodium 75 mmol/L and glucose 75 mmol/L, osmolarity 245 mOsmol/L is acceptable for all ages and may be made freely available by the Government.
	The current formulations ORS A and ORS citrate allowed in the Indian Pharmacopia, 1996 should no longer be used and only the above recommended formulations be in the market.
	The powder packet to make 1 liter of solution should be continued. Since mothers tend to use ORS a glass at a time, a measuring device should be included inside to measure the required amount of powder accurately for 200 ml of fluid.
	The group was deeply concerned that ORS was not available free of cost at public institutions. It recommended that measures should be taken by the Government to improve its availability and reduce its cost.
	The group did not currently recommend marketing of ORS with additives (probiotics, minerals). They should only be permitted after demonstrating benefit in studies carried out in Indian patients as breastfeeding rates, dietary habits and intestinal flora varies from European and North American children.

 Zinc as an Adjuvant in the Rehabilitation of Patients with Diarrhea
The link between malnutrition and chronic diarrhea is particularly strong early in life. ^13,14 It has been shown that intestinal permeability is exacerbated by zinc deficiency. A 5mg/day zinc supplement suffices to improve that condition,¹⁵ although protein losses cannot be fully controlled, even with a higher dose.¹⁶ More recently it has been shown that zinc supplements improve the speed of recovery and diminish week long diarrhea episodes.⁵ Zinc supplements (20 mg/day) with multivitamins reduced 33% illness duration in Bangladeshi children ⁶ Equally encouraging results were obtained in Pakistan with doses of 3mg/kg/day ¹⁷ and in Peru, with 20 mg/day ⁷ Of even greater significance appears to be the fact that zinc supplementation, even in modest doses, not only reduced diarrheal disease duration and prevalence, but also diminished the incidence of pneumonia. ¹⁸

A general feature of these trials is that infants and children who were growth retarded and malnourished improved better than others with zinc supplementation. Two mechanisms have been proposed to account for the interaction between zinc deficiency and diarrhea. The expression of nitric oxide synthase, the enzyme involved in the formation of nitric oxide from L-arginine, is greater in the intestine of zinc deficient rats, especially after induction of the enzyme by interleukin (IL-1a). ¹⁹ Alternatively, it has been reported that in zinc deficiency there is over expression or uroguanylin, a peptide related to the cellular receptor of thermostable E. coli toxin. ²⁰ This would present a greater number of receptor sites for toxin attachment and thus trigger the chain of reactions leading to diarrhea. ²¹ A potential benefit of the presence of zinc salts in the intestinal lumen may be that they could act as nitric oxide scavengers and reduce its intracellular biologic effects.²²

A number of randomized controlled trials carried out in developing countries explored the efficacy of zinc in preventing intestinal infections. The incidence and duration of acute and persistent diarrhea were significantly lower in zinc supplemented children versus placebo-treated counterparts ^23,24 Moreover, in children younger than 5 years, zinc treatment during acute diarrhea illness resulted in fewer subsequent diarrhea episodes and in a concomitant reduction in the use of antibiotics .25,26 The preventive and therapeutic effects of zinc in reducing diarrhea morbidity have relevant economic implications in terms of hospitalization and antibiotic use .²⁷

Recommendations
Given the benefits of zinc supplementation in a large number of studies, in May 2004, the United Nations Children's Fund (UNICEF) and the WHO issued a statement recommending that all children with diarrhea in developing countries be treated with zinc. ²⁷ The new WHO/UNICEF recommendation to incorporate zinc supplementation into diarrhea management is based on a substantial body of scientific evidence of benefits emerging from 17 efficacy studies - 12 on acute and 5 on persistent diarrhea.28,29 Together these studies have demonstrated that zinc in addition to ORS reduces both the duration and severity of acute diarrhea relative to treatment with ORS alone^28,29 .These benefits are significant both statistically and clinically. Treatment of diarrhea for 10-14 days with zinc supplements also reduces the incidence of diarrhea and pneumonia in the 2-3 months after the treatment with zinc supplements .30A large community-based study in Bangladesh demonstrated the feasibility of incorporating zinc into diarrhea treatment with ORS into a program setting .26 This effectiveness study recorded a reduction in duration of diarrhea in those given zinc that was comparable to the efficacy studies. The study also noted significant reductions in hospitalizations from diarrhea and overall mortality among children living in villages where zinc in addition to ORS was available relative to those living in areas where only ORS was available. Additionally, the use of zinc was associated with important indirect benefits. For example, inappropriate use of antibiotics and other medicines was reduced, visits to pharmacies and village drug sellers were also reduced, and the use of ORS was increased .²⁶ Available evidence also indicates that zinc for diarrhea treatment is highly cost-effective.

Recommendations of the IAP National Task Force for use of Zinc in Diarrhea, August 18-19, 2003

	Based on studies in India and other developing countries there is sufficient evidence to recommend zinc in the treatment of acute diarrhea as adjunct to oral rehydration. However, ORS remains the mainstay of therapy during acute diarrhea and zinc has an additional modest benefit in the reduction of stool volume and duration of diarrhea as an adjunct to ORS. Under all circumstances, oral rehydration therapy must remain the main stay of treatment.
	Treatment of acute diarrhea with zinc may have benefits on morbidity and mortality from other childhood infections and these should be further investigated.
	A uniform dose of 20 mg of elemental zinc should be given during the period of diarrhea and for 7 days after cessation of diarrhea to children older than 3 months. Recommendations for below 3 months must await further research.
	Based on all the studies the group proposed that zinc salts e.g., sulphate, gluconate or acetate may be recommended. The industry should be encouraged to prepare a zinc formulation, which contains only zinc. Until these are available, the group proposed that formulations providing vitamins together with zinc may be used provided doses of former are within 1 RDA .Iron containing formulations should not be used with zinc as iron interferes with zinc absorption. 10

Conclusion
Thus, there is abundant evidence to justify the widespread inclusion of zinc supplements for diarrhea treatment. The world must face the challenges to enable this to happen. The changes in the programme are simple and incorporating these into diarrhea control programs will have a lasting impact on child health. National and local level health decision makers are needed to contribute local knowledge to successfully design programs that will ensure the highest coverage possible. The world cannot afford to ignore that revitalizing diarrhea control programs to include zinc supplementation and reinforcement of the importance of ORS use is a child health goal. Urgent action is needed from governments, international aid agencies, and donors to accept this challenge and decrease childhood diarrhea deaths.

References

	1.		Bryce J, Boschi-Pinto C, Shibuya K, Black RE. WHO estimates of the causes of death in children. Lancet 2005;365:1147-52.
	2.		Gebhord RI, Karonani R, Priggle WF, McClain CJ: Effect of severe zinc deficiency on activity of intestinal disaccharidases and 3-OH-3-methyl glutaryl coenzyme A reductase in the rat. J Nutr 113:855-859, 1983.
	3.		Golden BE, Golden MHN: Zinc, sodium and potassium losses in the diarrheas of malnutrition and zinc deficiency. In Mills CF, Brenner I, Chesters JF (eds): -Trace Elements in Man and Animals-TEMA 5.- Aberdeen, UK: Rowett Research Institute, pp228-232, 1985.
	4.		Bhan MK, Bhandari N: The role of zinc and vitamin A in persistent diarrhea among infants and young children. J Pediar Gastro Nutr 26:446-453, 1998
	5.		Sazawal S, Black RE, Bhan MK, Bhandari N, Sinha A, Jalla S:Zinc supplementation in young children with acute diarrhea in India. New Engl J Med 1995; 333:839-844, 1995.
	6.		Roy SK, Tomkins AM, Mahalanabis D, Akramuzzaman SM,Haider R, Behrens RH, Fuchs G: Impact of zinc supplementation on persistent diarrhea in malnourished Bangladeshi children. Acta Paediatr 1998;87:1235-1239,
	7.		Penny ME, Peerson JM, Marin RM, Duran A, Lanara CF, Lo¨nnerdal B, Black RE, Brown RH: Randomized, community-based trial of the effect of zinc supplementation, with and without other micronutrients, on the duration of persistent childhood diarrhea in Lima, Peru. J Pediatr 1999;135:208-217,
	8.		Roberto Berni Canani and Serena Ruotolo. The Dawning of the Zinc Era in the Treatment of Pediatric Acute Gastroenteritis Worldwide Editorial. Journal of Pediatric Gastroenterology and Nutrition 42:253-255
	9.		Bern C, Martines J, de Zoysa I, Glass RI. The magnitude of the global problem of diarrhoeal disease: a ten-year update. BullWHO. 1992;70:705-714.
	10.		Wapnir RA. Zinc deficiency, malnutrition and the gastrointestinal tract. J Nutr. 2000;130: 1388-1392
	11.		Implementing the new recommendations on the clinical management of diarrhea: guidelines for policy makers and programme managers. World Health Organization, 2006 , chapter 2 , Page 4

Further Reading
https://www.pediatriconcall.com/fordoctor/diseasesand
condition/Gastrointestinal_disorders/Zn_ORS.asp