Throw in the Zinc? Minerals and Acute Childhood Diarrhea
Abstract & Commentary
By Bridget S. Bongaard, MD, FACP. Dr. Bongaard is the Director of the Integrative Medicine Service Line at CMC-NorthEast Medical Center; she reports no financial relationship to this field of study.
Synopsis: This novel, large randomized controlled trial of 808 Indian children with acute dysentery, ranging in age from 6 to 59 months, assigned each subject to one of three arms of treatment for 14 days using a base of standard oral hydration formula for each group: placebo having no additives, zinc 20 mg/5 mL supplementation, or zinc 20 mg/5 mL plus copper 2 mg/5 mL supplementation. The authors concluded that despite prior data showing favorable response to zinc additive therapy, there was no difference in the severity, duration, or relapse of the illness between their study cohorts.
Source: Patel A, et al. Zinc and copper supplementation in acute diarrhea in children: A double-blind randomized controlled trial. BMC Med 2009,7:12.
Morbidity and mortality from acute infantile dysentery in underdeveloped countries is staggering, and represents a significant public health issue. There are 4.6 million pediatric deaths due to dysentery (25%-30% of all deaths of children younger than age 5) in underdeveloped countries, and though there are a number of potential infectious etiologies, rotavirus leads the pack (possibilities typically include rotavirus, adenovirus, astrovirus, and Norwalk-like virus).1
Diarrhea has a significant impact on intestinal absorption, nutrition, and childhood development, as well as global mortality.2 There has been a remarkable reduction in death from this malady, from 4.6 million annual deaths 20 years ago to approximately 1.6-2.1 million current deaths, largely due to the development and institution of protocols utilizing glucose-electrolyte oral re-hydration solutions.2 Severe, unrelenting diarrhea precipitates significant zinc and copper losses in the body. Zinc is a critically important mineral that regulates the transport of water and electrolytes across the intestinal mucosal, preventing villous atrophy and improving overall immunity.3 Copper is speculated to be helpful; however, it has yet to be proven clinically to be synergistic with the administration of zinc. The zinc:copper ratio is also important to maintain, as excessive amounts of copper can interfere with zinc absorption and lead to zinc deficiency, and large oral doses of zinc can interfere with copper bioavailability. It is not known, however, whether severe diarrhea can lead to total body deficiency of both mineral stores. Children with malnutrition or recurrent diarrhea may already be at high risk due to total body deficiencies of both minerals, further complicating the issue.
The authors of this community-based, controlled study note that a recently published Cochrane review reported a reduction in acute diarrhea within 12 hours with the addition of supplemental zinc to standard World Health Organization (WHO) oral dehydration therapy in affected children.4 The studies, however, were heterogeneous for method and amount of zinc, and did not control for additional supplements in the form of multivitamins or vitamin A, making it difficult to determine the effectiveness of zinc therapy alone. The study by Patel et al uniquely utilized strict protocols for supplementation with copper and zinc in the same ratio as is customarily seen in the diet to limit adverse effects.
Children were excluded if there was known HIV infection, kwashiorkor, or another chronic or severe complicating illness. Also excluded were those who required IV hydration (though if successfully rehydrated and able to take oral replacement afterward, they were included in the study). Participants were required to have acute dysentery > 72 hours and be able to take oral fluids or feedings. Patients were discontinued from the study if they developed complications such as electrolyte imbalance, azotemia, convulsions, acidosis, congestive heart failure, hemolytic uremic syndrome, septicemia, loss of consciousness or death, or if the patient left against medical advice.
An independent laboratory checked the replacement syrup solution contents for accuracy and ensured the zinc sulfate solution contained 20 mg/5 mL of elemental zinc, while the zinc with copper sulfate solution contained an additional 2 mg/5 mL of elemental copper. Any child who vomited the chosen experimental preparation was given a second dose to achieve a total of 0.5 mL/kg/d of the syrup. The doses were administered on a daily basis, and continued until the 14th day of follow- up even if the patient had been discharged from the hospital. Bottles were weighed periodically to measure treatment compliance. All patients were monitored for dehydration, and fluid balance was achieved by administering a solution of WHO standard guideline of 100 mg/kg oral rehydration solution to match oral or fecal losses on a volume-to-volume basis until diarrhea ceased. Mothers were encouraged to nurse or feed their children when tolerated. Stools were measured by volume but were not cultured for infectious agents. Venous blood samples for baseline serum zinc and copper were performed on admission and a second sample was obtained at day 14 of follow-up for comparison.
There was not a statistically significant difference between the groups' intake of the oral syrup while completing 14 days of oral therapy, whether the full treatment was rendered at home, in the hospital, or both. There was an average daily zinc intake of 14.3 mg of zinc in the zinc group, and 13.5 mg of zinc and 1.3 mg of copper in the zinc and copper group. Neither mean duration of diarrhea nor mean stool weight differed between the trial groups. Also, there was no significant cohort difference between the amounts of oral rehydration solution or IV fluids, the mean duration of diarrhea, or the proportion of patients with diarrhea for > 5 days or > 14 days. As a final note, between the three groups, there was an insignificant difference in time to cessation of diarrhea and reduction in duration of diarrhea, and neither baseline serum zinc nor serum copper levels had an effect on the duration or volume of diarrhea.
Commentary
The mean absolute difference in serum zinc from baseline to the 14th day increased significantly in the zinc-supplemented groups, indicating adherence and bioavailability of the supplements due to the study's meticulous methods ensuring that all children received similar doses, frequency, and duration of syrups (of identical appearance) for the entire 14 days. The lack of improvement despite the addition of zinc sulfate or copper sulfate to the standard oral rehydration solution protocols could be due to many reasons. The doses of zinc used in this study were lower than other studies that showed effectiveness, with the dose differing between the average intakes of 13.9 mg in this study compared to 20 mg fixed-dose administration in other studies. This difference may not be valid, however, as the other studies did not report the actual mean consumption.
This study scrupulously determined the variances in each treatment cohort, as well as calculated the baseline serum zinc compared to end of study levels, and showed a corresponding increase in the cohorts treated with zinc. Total body zinc deficiency (serum zinc level £ 60 mg/dL) could affect the outcomes despite supplementation; however, there are other studies to support that despite initial low levels of zinc, there is no difference in morbidity and mortality between placebo and supplemented groups. It certainly may be important to note that serum zinc levels do not necessarily reflect the measure of body zinc status; however, they do play a role in intestinal inflammation.5 Measurement of dietary zinc or copper intake and tissue zinc or copper status perhaps may better explain the impact of zinc supplementation on tissue function. Also, not all studies that reported a positive effect were in children with zinc deficiency. Therefore, it seems there are other critical factors involved. A potential confounding variable considered was that breastfeeding or increased zinc store acquired in utero may create a selective advantage in the younger children, although in this current study, 41% of children were between age 6 and 12 months and 56% had received breastfeeding yet achieved no improvement with supplementation of zinc or copper during their illness.
Could the difference be due to the infectious etiology of the dysentery? This is an interesting point as zinc has a positive effect on enteropathogenic Escherichia coli, but a much less significant effect on rotavirus and E. coli heat-stable enterotoxin. As stated in the introduction, rotavirus is an extremely common cause of dysentery in this population and may have accounted for the lack of response to the zinc or copper/zinc treatment arms. Unfortunately, the diarrheal pathogens were not indexed in the treated population, or correlated to age or severity of illness. Furthermore, there may have been a positive difference in the meta-analysis studies due to less rigorous measurement of diarrheal volume losses as compared to this meticulous study, which could account for a perceived difference in overall outcome of treatment.
This trial is the first to evaluate the impact of oral zinc and copper administration on the duration of acute diarrhea. The results shed light on the variance in outcomes in treatment of severe childhood dysentery (a leading cause of childhood morbidity and mortality), and a re-examination of available trial results is needed to determine how to stop this debilitating process. Zinc and copper supplementation are relatively innocuous when properly dosed, and may present advantage in some cases of childhood dysentery; however, further trials are necessary before making this a universal recommendation.
Reference
1. Nguyen TV, et al. Diarrhea caused by rotavirus in children less than 5 years of age in Hanoi, Vietnam. J Clin Microbiol 2004;42:5745-5750.
2. Petri WA, et al. Enteric infections, diarrhea, and their impact on function, and development. J Clin Investigation 2008;118:1277-1288.
3. Patel A, et al. Zinc and copper supplementation in acute diarrhea in children: A double-blind randomized controlled trial. BMC Med 2009;7:22.
4. Lazzerini M, Ronfani L. Oral zinc for treating diarrhoea in children. Cochrane Database Syst Rev 2008;(3):CD005436; doi: 10.1002/14651858. CD005436.pub2.
5. Al-Gindan Y, et al. Intestinal inflammation in rats induces metallothionein in colonic submucosal. J Clin Biochem Nutr 2009;44:131-141.
This novel, large randomized controlled trial of 808 Indian children with acute dysentery, ranging in age from 6 to 59 months, assigned each subject to one of three arms of treatment for 14 days using a base of standard oral hydration formula for each group: placebo having no additives, zinc 20 mg/5 mL supplementation, or zinc 20 mg/5 mL plus copper 2 mg/5 mL supplementation.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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