Patient enrollment
This is a clinical trial that evaluated the therapeutic effect of zinc and copper supplementation added to standard oral rehydration solution (ORS) for treating acute diarrhea at the Nagpur city's Government Medical College and Hospital, India. This study was conducted in children aged 6 months to 59 months who presented to the hospital with more than three unformed stools in 24 hours and diarrheal duration of < 7 days. Any child with intractable vomiting, pre-renal or renal failure, respiratory distress, altered sensorium or any such co-morbid condition that precludes the use of oral rehydration solution (ORS) were excluded from the trial. Children with clinical signs of severe malnutrition such as kwashiorkor and marasmus were also excluded. Baseline assessment included diarrheal duration, character of the stool, degree of dehydration, age, gender, maternal education, number of children in the family, monthly parental income, diet of the child, immunization status, history of fever or vomiting, prior use of ORS, prior use of medications and the nutritional status. Children who had severe dehydration or inability to drink were temporarily excluded for 4 hours during which they received standard treatment. At the end of this time period they were reassessed for possible inclusion in the trial.
Intervention
The treatment was randomized at an individual level using a fixed randomization scheme with equal allocation of patients to the intervention and control group. The patients and the caregivers were blinded to the subject's treatment status. Two identical coded waterproof sachets of the intervention or the control were administered to the treatment and the control group only once in a day. The intervention sachet contained 40 mg of Zinc sulfate and 5 mg of Copper sulfate powder. The control sachet contained 50 mg of standard ORS powder. These sachets were dissolved in one liter of ORS by the nurse. Each day a fresh solution was prepared till the diarrheal episode lasted. The children were encouraged to take their routine feeds. Patients were also provided with other usual supportive care with antipyretics and antibiotics for bloody diarrhea. Children needing intravenous fluids were randomized after they were able to take orally. If a child was dehydrated after 6 hours of oral rehydration or if signs of severe dehydration appeared despite appropriate ORS administration then they were administered intravenous fluids and this was recorded as an "unscheduled intravenous fluid".
Measurement of clinical outcomes
The children were assessed at the same time every 24 hours till discharge. The time taken to rehydrate the child from time of admission, episodes of vomiting, use of intravenous fluids during rehydration and the use of unscheduled intravenous fluids during the maintenance of hydration was measured daily. Any complications such as pre-renal or renal failure, convulsions, electrolyte imbalance, bronchopneumonia and septicemia were recorded. The use of other medication such as antibiotics was also recorded. Weight was recorded on admission and at discharge. A child was discontinued from the study if the child experienced any of the above complications, died or if the parent withdrew consent.
The primary clinical outcome was the duration of diarrhea from the time of onset. A diarrheal day was defined as a 24-hour period with passage of at least four unformed stools and this episode was considered terminated on the last day of diarrhea followed by a 24-hour diarrheal free period. The number and proportion of patients with diarrhea > 4 days and the mean length of hospital stay was also estimated. The proportion of children with diarrhea > 4 days was estimated based on the results of the Indian community-based study of zinc supplementation, which indicated that the reduction in the duration of diarrhea was evident on the fourth day [2].
The severity of diarrhea was measured by the use of unscheduled intravenous fluids expressed as the number of subjects who received intravenous fluid at any time after randomization, weight loss at discharge, presence of complications or mortality.
Identifying and Measuring Costs
The cost data was collected to identify the direct medical, the direct non-medical and the indirect costs [3]. We used the actual financial and not economic costs and the rupee was valued in the year 1996 (1$ = Rs. 36). The price paid for a service is a good reflection of the costs of producing the service in competitive markets which prevent both excess profits and negative expected profits [4]. Average variable costs were measured as a proxy for true marginal costs.
The resources utilized for the management of acute diarrhea and their unit costs were measured in order to determine three categories of costs (direct medical costs, direct non-medical costs, and indirect costs). We enumerated every input consumed by the patient and then its unit cost. This is known as "micro-costing"[5]. The direct medical costs were calculated from the patient's and the government (provider's) perspective. The measurement of the resources utilized was from the time of onset of diarrhea and during the study period. The direct medical cost to the patient included any out of pocket expenditures for medicines or the fees paid to the physician prior to seeking treatment at the government hospital. The direct medical cost to the ministry of health was the expenditure incurred by the hospital administration after randomization. The direct non-medical and the indirect costs were from the patient's perspective. The protocol-driven costs were deducted from the total costs. The resource utilization was measured in a standard case-report form.
The direct medical costs included the services provided by the medical personnel, the medications, the type of service provided (general or intensive care) and the laboratory investigations. In the United States hospital cost accounting systems (data base for Disease related groups or DRGs, cost to charge ratios, etc) reimbursement systems for managed care and insurance allow assignment of costs to resources used, a process known as "gross accounting" [6]. In India, there is no established database of costs of medical services, investigations and the cost of hospital stay. These costs vary with respect to the type of medical services and hospital category. The government hospitals are subsidized, the charges at private and corporate hospitals overestimate costs whereas charges to the patients in non-for-profit hospitals are most likely to resemble the true costs. The unit charges account for the unit costs of the medical service rendered, the overhead and the administrative costs of that medical service and that of the supporting units. We calculated the unit costs of each patient visit at the outpatient clinic from the salaries of the staff working at this clinic times the proportion of their time spent rendering out-patient services, divided by the average number of attending patients. The cost was 1.5 times the amount actually charged to the patient by the government and resembled the cost structure of the non-for-profit-hospitals. We therefore verified the other direct medical costs calculated by us by comparing it to the charges of non-profit hospitals. Similarly the cost of a day's stay for a patient, at the diarrhea treatment and training center or at the hospital ward, was calculated by summing the average per diem cost of stay in with the daily average per-patient labor charges of the doctors, the nurses and ward attendants. The per diem cost included the cost of subsidized meals. We estimated laboratory investigations in consultation with the laboratory administrators based on average labor costs of technicians, the costs of supplies, overheads and administration. The costs of drugs were the manufacture's wholesale price.
The direct non-medical cost of traveling to the physician or the hospital for the patient and the family, cost of food to the family and patient (only if it were not included in the per-diem hospital stay cost) during hospitalization and other incidental cost to the family but attributed to the illness were measured.
The indirect costs were measured by the wages lost of employed parents or guardians attending to the child with diarrhea. This is a conservative estimation, as monetary value is not assigned for the loss time of unemployed parents. We did not estimate intangible costs like pain, suffering and lost of leisure time.
Economic analysis
The mean (± SD) of the direct medical costs and its cost components such as the visit fees, costs of antibiotics, of intravenous fluids, of laboratory tests, of ORS, of length of stay in the hospital, of out-patient visits were estimated. We also calculated the mean (± SD) of the direct non-medical and indirect costs in the study groups. The mean (± SD) of the total costs in the study groups was determined and the univariate and multivariate linear regression was used to determine the impact of the interventions, the pre and post randomization variables in predicting the total mean costs.
The cost-effectiveness of trace minerals was determined by 1) the total cost (Rs) per case of diarrhea > 4 days averted, 2) the total cost per death averted, and 3) the incremental cost effectiveness ratio (ICER), which is the ratio of difference (of the intervention and the control group) in total mean of costs in the numerator and the difference in the proportion of patients of diarrhea less than four days in the denominator. We constructed the 95% confidence intervals for the incremental cost effectiveness ratio. We used the non-parametric boot-strap method to assess the normality of this ratio and then constructed the confidence intervals [6].
We also calculated the ratio of the total mean cost and the mean number of patients with diarrhea less than 4 days (CE) for the intervention and the control group for the boot strap sample. This measured the mean cost per patient cured less that 4 days in each group. We then measured the relative cost-effectiveness (RCE) of the treatment group relative to that of the control with its 95% confidence intervals (CEtreatment / CEcontrol). STATA Version 5 was used for these statistical analyses.
Disability adjusted life years (DALYs) are an indicator of the time lived with a disability and the time lost due to premature mortality [7]. This was calculated for all children in the study using their actual age, the number of days spent with diarrhea, and disability weights ranging from 0.4 to 0.6 (based on the severity of illness) with death weighted as 1. The discount rate was 5 %. We then calculated the mean (± SD) of DALYs lost in the two study groups.