Efficacy of a New Hypotonic Oral Rehydration Solution Containing Zinc and Prebiotics in the Treatment of Children With Acute Diarrhea

Study Design and Funding Prospective, randomized controlled trial in collaboration with family pediatricians, who care for children up to 14 years of age in the Italian Public Health System. The study protocol was illustrated and discussed during 3 meetings. The research is not funded by any pharmaceutical company and all the authors declared no conflict of interest. The study protocol was reviewed and approved by the Ethics Committee of the University Federico II of Naples.

Participants Children 3-36 months old seen in the pediatrician offices from November 2007 to March 2008 presenting acute diarrhea lasting less than 48 h are considered eligible for the study. Exclusion criteria are: diarrhea lasting more than 48 h, malnutrition as judged by a body weight/height ratio below the 5th percentile, clinical signs of severe dehydration, clinical signs of a coexisting severe acute systemic illness (meningitis, sepsis, pneumonia), immunodeficiency, underlying severe chronic disease, malnutrition, cystic fibrosis, food allergy or other chronic gastrointestinal diseases, use of pre/probiotics in the previous 3 weeks, use of antibiotics or any antidiarrheal medication in the previous 3 weeks.

Acute diarrhea is defined as a decrease in the consistency of stools (loose or liquid) and/or an increase of frequency of evacuations (3 or >3 in 24 h), with or without fever or vomiting. Informed consent is obtained from the parents of all enrolled children. Microbiologic and other laboratory investigations performed only if required for specific clinical reasons.

Intervention Enrolled patients are randomly allocated to standard hypotonic ORS (group 1) or to super-hypotonic ORS containing zinc and prebiotics (group 2). We used two commercial ORS ORS preparations available on the market as sachets with similar cost and packaging. The composition of the two ORSs is reported in Table 1.

Randomization and Blinding Patients are allocated to each group according to a computer-generated randomization list. The researchers responsible for enrolling patients allocate the next available number upon entry into the trial. The parents are instructed to rehydrate orally their children with 30-50 ml/kg of ORS in 3-4 h for mild dehydration and with 50-100 ml/kg of ORS in 3-4 h for moderate dehydration, and to administer 10 ml/kg/die of ORS in a graduated glass or bottle for dehydration prevention until cessation of symptoms. Three to four hours after, children are fed with a normal appropriate-for-age diet including full strength lactose-containing formula or cow's milk.Treatment allocation is concealed to maintain the single-blind status. Upon enrolment, the patient's parent receive the envelope containing a written prescription of the name of the ORS product and instructions about how it should be administered. To circumvent the problems in performing a double-blind study on commercially available products in a large population, we use the third-part blind observer method to assess the efficacy of the ORS preparations. To ensure unbiased efficacy assessment, the investigators collecting the reporting forms completed by the parent are blind to the patient's treatment assignment, whereas the family pediatricians in charge of treatment allocation are excluded from efficacy assessment. The reporting forms are sent to the coordinating centre at the Department of Pediatrics for analysis. We previously used this procedure in a study of 5 probiotic preparations in children affected by acute diarrhea (Berni Canani R et al. BMJ 2007;335-340). Upon enrollment, patients undergo a physical examination and clinical history taking to identify the patient, to determine the duration and severity of diarrhea, to assess associated clinical features (fever, vomiting and dehydration) and to establish nutritional status and previous therapy. The parents of enrolled children are instructed to record daily on a specific form: i) the number of fecal outputs and their consistency; ii) the amount of daily ORS assumed by the child; and iii) possible adverse events. We also record the number of the parent's missed work days, the number of hospital admissions in each group, the use of other medications.