Effectiveness of three commonly used transition phase diets in the inpatient management of children with severe acute malnutrition: A pilot randomized controlled trial in Malawi

Background: The case fatality rate of severely malnourished children during inpatient treatment is high and mortality is often associated with diarrhea. As intestinal carbohydrate absorption is impaired in severe acute malnutrition (SAM), differences in dietary formulations during nutritional rehabilitation could lead to the development of osmotic diarrhea and subsequently hypovolemia and death. We compared three dietary strategies commonly used during the transition of severely malnourished children to higher caloric feeds, i.e., F100 milk (F100), Ready-to-Use Therapeutic Food (RUTF) and RUTF supplemented with F75 milk (RUTF + F75). Methods: In this open-label pilot randomized controlled trial, 74 Malawian children with SAM aged 6-60 months, were assigned to either F100, RUTF or RUTF + F75. Our primary endpoint was the presence of low fecal pH (pH ≤ 5.5) measured in stool collected 3 days after the transition phase diets were introduced. Secondary outcomes were duration of hospital stay, diarrhea and other clinical outcomes. Chi-square test, two-way analysis of variance and logistic regression were conducted and, when appropriate, age, sex and initial weight for height Z-scores were included as covariates. Results: The proportion of children with acidic stool (pH ≤5.5) did not significantly differ between groups before discharge with 30, 33 and 23% for F100, RUTF and RUTF + F75, respectively. Mean duration of stay after transitioning was 7.0 days (SD 3.4) with no differences between the three feeding strategies. Diarrhea was present upon admission in 33% of patients and was significantly higher (48%) during the transition phase (p < 0.05). There was no significant difference in mortality (n = 6) between diets during the transition phase nor were there any differences in other secondary outcomes. Conclusions: This pilot trial does not demonstrate that a particular transition phase diet is significantly better or worse since biochemical and clinical outcomes in children with SAM did not differ. However, larger and more tightly controlled efficacy studies are needed to confirm these findings. Trial registration:ISRCTN13916953Registered: 14 January 2013. This open-label pilot randomized controlled trial was carried out in Blantyre, Malawi, from January to July 2013. The primary outcome of this study was fecal pH, as a measure of carbohydrate malabsorption, 3 days after the start of the transition phase. Fecal pH of ≤5.5 was defined as acidic stool and was considered suggestive of carbohydrate malabsorption [18]. Secondary outcomes included duration of stay from the first day of the transition to discharge from the ward, days with diarrhea, duration of edema, weight at discharge, hypo- and hypernatremia, reversion to F75 diet and mortality. The sample size of 15 participants per group was based on glucose malabsorption data obtained from our previous study and calculated to detect a 20% difference in fecal pH between groups with α = 0·05 and 80% power [17]. Covariate adaptive randomization was used to achieve balance in HIV status between groups, as HIV is an important covariate. This was achieved by randomizing HIV positive and negative children separately. We performed the procedures according to the ethical standards of the Helsinki Declaration. The trial was approved by the College of Medicine Research and Ethics Committee of the University of Malawi (P.005/11/1086). Children were screened for eligibility at admission to MOYO house (Nutrition Rehabilitation and Research Unit of the Queen Elizabeth Central Hospital). Children aged 6–60 months, diagnosed with SAM and already admitted to the nutritional rehabilitation unit (NRU) but still in the stabilization phase were included in the TranSAM trial after written informed consent. We included both HIV positive and negative children, diagnosed by rapid antibody testing upon admission. Exclusion criteria were admission to the nutritional rehabilitation unit within the past year, severe hemodynamic instability, haematocrit level ≤ 15% and severe neurological symptoms. The study started when a child entered the transition phase. When clinically ready, a total of 74 patients were randomly assigned to one of the transition phase dietary regimens: F100 milk, RUTF only or RUTF+ F75 milk (Fig. ​(Fig.11). CONSORT diagram of severely malnourished children included in the study. RUTF, ready-to- use therapeutic food; SAM, severe acute malnutrition Allocation concealment was achieved by using sealed, sequentially numbered opaque envelopes containing a label for 1 of the 3 transition phase feeds. After written informed consent, when patients were ready to start a transition phase diet, guardians were asked to open the next numbered envelope showing their assigned group. The allocation sequence was computer generated by an independent collaborator. All legal guardians provided written informed consent in either vernacular Chichewa or English. The trial was registered as ISRCTN13916953. SAM patients were enrolled in the transition phase only after they had been stabilized, gained appetite and, in the case of kwashiorkor, edema had improved [3]. The full amount of the three dietary transition phase regimes were prescribed with the aim of a maximum energy intake of 135 kcal/kg/day. These regimes were based on WHO guidelines and reference tables were used to calculate the dietary amounts to be given based on body weight [3]. The first group received F100 milk at the same frequency and volume as F75 milk in the stabilization phase. The second group received RUTF given alongside with water and the amount of RUTF was increased as quickly as possible until the target intake was reached. In the third group, F75 milk was given as a top-up to RUTF to allow a gradual increase of the amount of RUTF consumed by the child as well as to ensure a minimum energy intake of 100 kcal/kg/day. We used commercially available F75, F100 and RUTF (Nutriset, Malaunay, France) (Table ​(Table1).1). The caregivers were given color-coded milk cards corresponding to a specific diet. Our research team was trained to distribute the correct milk formulae to participants. Intake was monitored by research nurses and assessed by the caregiver and these data were recorded daily. If a child was clinically deteriorating in the transition phase (e.g. loss of appetite; onset of one or more WHO danger signs: shock/systemic illness, respiratory distress or impaired consciousness), the patient was reverted to the stabilization phase and put back on F75 milk alone. A second transition phase was excluded from analysis, but the failure of completing the initial transition phase was documented. Nutritional composition of ‘Transition Phase’ dietsa RUTF ready-to-use therapeutic food, CHO carbohydrate a Values are represented as grams per 100 g Clinical signs related to malnutrition were assessed and recorded daily by a group of 3 researchers during daily rounds, using specifically designed paper-based case report forms. The clinical signs included appetite, hydration status, degree of edema and weight. Presence of diarrhea was determined on admission to the hospital, the day before entering the transition phase (Tbaseline), the first day of transition (T0) and the next 3 consecutive days of treatment (T1-T3 respectively). Diarrhea was defined as 3 or more abnormal loose or watery stools. Severe diarrhea was defined as more than 10 loose or watery stools. Diarrhea was assessed by daily maternal recall. Data was entered in Access by a specific data manager and quality control was performed by another member of the research team. Two blood samples were taken: one just before entering the transition phase and the other on transition day-3. Blood was centrifuged within 1 h of collection and plasma was stored at −80 °C for further biochemical analysis. Feces was collected on the same days and immediately stored at −80 °C. Plasma sodium was measured in the clinical laboratory of University Medical Centre Groningen, The Netherlands, using standard clinical laboratory techniques. Hyponatremia was defined as a plasma sodium concentration of <130 mmol/L and hypernatremia as >145 mmol/L. We aimed to analyse reducing substances in the stool, but the only commercially available method (Clinitest, Bayer, Leverkussen, Germany) was no longer produced after the study started, therefore, we removed this outcome measure from our study. Fecal pH-measurement was performed using nitrazine paper (Micro Essential, Brooklyn, NY, USA). Descriptive statistics were presented as percentages for categorical variables and as mean with SD for continuous ones. Baseline differences between groups were tested using, as appropriate, Chi-square, Fisher’s exact test or two-way analysis of variance (ANOVA). The associations between transition phase diets (F100, RUTF or RUTF +F75) and the presence of acidic stool (pH ≤ 5.5), hyponatremia, diarrhea were evaluated using logistic regression. Age, sex, edema status and baseline weight-for-height Z scores were included as covariates if they contributed significantly to the models. Two-way ANOVA was used to test differences in weight at discharge and duration of stay. For analysis of hospital stay, the 6 children who died during transition were excluded. A p value of <0.05 was considered significant. All statistical analyses were conducted using SPSS 22.0 software (IBM, Armonk, NY, USA).