Weight and mid-upper arm circumference gain velocities during treatment of young children with severe acute malnutrition, a prospective study in Uganda

Background: Weight gain is routinely monitored to assess hydration and growth during treatment of children with complicated severe acute malnutrition (SAM). However, changes in weight and mid-upper arm circumference (MUAC) gain velocities over time are scarcely described. We assessed weight and MUAC gain velocities in 6–59 mo-old children with complicated SAM by treatment phase and edema status. Methods: This was a prospective study, nested in a randomized/probiotic trial (ISRCTN16454889). Weight and MUAC gain velocities were assessed by treatment phase and edema at admission using linear mixed-effects models. Results: Among 400 children enrolled, the median (IQR) age was 15.0 (11.2;19.2) months, 58% were males, and 65% presented with edema. During inpatient therapeutic care (ITC), children with edema vs no edema at admission had negative weight gain velocity in the stabilization phase [differences at day 3 and 4 were − 11.26 (95% CI: − 20.73; − 1.79) g/kg/d and − 13.09 (95% CI: − 23.15; − 3.02) g/kg/d, respectively]. This gradually changed into positive weight gain velocity in transition and eventually peaked at 12 g/kg/d early in the rehabilitation phase, with no difference by edema status (P > 0.9). During outpatient therapeutic care (OTC), overall, weight gain velocity showed a decreasing trend over time (from 5 to 2 g/kg/d), [difference between edema and non-edema groups at week 2 was 2.1 (95% CI: 1.0;3.2) g/kg/d]. MUAC gain velocity results mirrored those of weight gain velocity [differences were − 2.30 (95% CI: − 3.6; − 0.97) mm/week at week 1 in ITC and 0.65 (95% CI: − 0.07;1.37) mm/week at week 2 in OTC]. Conclusions: Weight and MUAC gain velocities among Ugandan children with complicated SAM showed an increasing trend during transition and early in the rehabilitation phase, and a decreasing trend thereafter, but, overall, catch-up growth was prolonged. Further research to establish specific cut-offs to assess weight and MUAC gain velocities during different periods of rehabilitation is needed. This was a prospective cohort study among 400 children admitted with complicated SAM to Mwanamugimu Nutrition Unit (MNU), Mulago National Referral Hospital in Kampala, the capital city of Uganda between March 2014 and October 2015. The study was nested within a double blind randomized clinical trial (ProbiSAM), which investigated the effect of probiotics on diarrhoea in children with SAM (ISRCTN16454889) as detailed elsewhere [30]. Inclusion criteria were: children aged 6–59 months with complicated SAM defined as WHZ < − 3 or MUAC < 11.5 cm or bipedal pitting edema and having any medical complications and/or any integrated management of childhood illness danger sign(s), according to WHO criteria [3], with caregivers who provided written informed consent, and were willing to come back for follow-up. Exclusion criteria were: children in shock and or severe respiratory distress at admission (once stabilized, these children were considered for inclusion), admission weight less than 4.0 kg, obvious congenital anomalies and admission with SAM in the previous 6 months. Patient management has been described in detail elsewhere [31, 32]. In brief, all patients in the study received standard treatment following the WHO guidelines [3] and the integrated management of acute malnutrition (IMAM) guidelines for Uganda [33]. The in-patient treatment was divided into two phases, phase 1 or stabilization phase and phase 2 or rehabilitation phase, with a transition stage in between. In the initial stabilization phase, all patients received F-75 (Nutriset, Malaunay, France) at 100-130 ml/kg/day depending on the grade of edema and routine medical treatment usually intravenous ampicillin and gentamycin. For breastfed children, mothers were encouraged to breastfeed in-between the therapeutic feeds. All children with diarrhoea were given Rehydration Solution for the Malnourished (ReSoMal, Nutriset, Malaunay, France), according to their body weight and degree of dehydration. When children were ready for transition as indicated by return of appetite, edema subsiding to grade one or two and medical complications resolving, they were subjected to acceptance test for Ready-to-Use-Therapeutic Food (RUTF), Plumpy’nut® (Nutriset, Malaunay, France). Children who passed the acceptance test were gradually transitioned from F-75 to RUTF over 2–3 days while those who failed were given F-100 (Nutriset, Malaunay, France), prescribed to provide 100–135 kcal/kg/day. For children on F-100, RUTF was re-tried after 2–3 days. In the rehabilitation phase, children were given increasing amounts of RUTF or F-100 based on their weight and appetite and, were also introduced to kitobeero, a multi-mix and nutritious local dish. The feeds offered provided 150–200 kcal/kg/day. When the children were clinically well, with good appetite and edema resolved to grade 1 or 2, they were discharged to OTC with RUTF, and together with their caregivers, they were appointed for follow-up every second week. Children continued to receive RUTF and were followed up to for a minimum of 8 weeks, and those who had not recovered by then were followed up to a maximum of 12 weeks. The main study outcomes were weight and MUAC gain velocities during the different treatment phases in ITC and in OTC. Weight gain velocity expressed as g/kg/d was calculated in accordance with WHO [7] as follows: where W2 is the weight at current measurement and W1 is the weight at previous measurement and t is the number of days between measurements (for ITC, t = 1 and for OTC, t = 14, on average). MUAC gain velocity was defined as gain in mm per week and was calculated as follows: where M2 is the MUAC (cm) at current measurement and M1 is the MUAC (cm) at the previous measurement, t is the number of days between measurements (for ITC, t = 7 and for OTC, t = 14, on average). Other outcomes included duration of stay in stabilization phase, transition and rehabilitation phase in ITC and OTC, duration of hospitalization, proportion of children recovered and not recovered. Proportions of children recovered and not recovered were defined as (number of children who reached or did not reach nutritional recovery after 12 weeks in OTC/total number of children discharged to OTC) × 100. Nutritional recovery was defined as reaching the WHO (2013) discharge criteria of WHZ ≥ − 2 or MUAC ≥12.5 cm and no oedema for 2 consecutive weeks and clinically well and alert. The same anthropometric criteria used to diagnose a child as SAM was used to decide whether the child had reached nutritional recovery. Further, if a child met both anthropometric criteria or had edema at admission, the child was discharged based on WHZ ≥ − 2. A child was only considered self-discharged if they did not return to the ward or the OTC site before the week 12 visit. A case report form (CRF) was used to systematically document all data obtained from the caregiver and patient examination findings. At admission, data was collected on the child’s socio-demographic information, breastfeeding and medical history, as well as presenting symptoms. Caregivers were asked to grade the severity of illness using a Visual Analogue Scale (VAS) and about household information where the child had lived two months prior to admission. Data on maternal age, marital status, education level and occupation were collected, if available. Food insecurity was assessed using the validated Household Food Insecurity Access Scale (HFIAS) [34]. A full physical examination including grade of edema, dehydration status, skin changes and vital signs was performed by a study pediatrician. On admission, weekly during hospitalization, at discharge and during OTC visits, child’s anthropometric measurements (weight, MUAC and length/ height) were taken in accordance with the WHO guidelines [3]. The same trained study nutritionists took measurements at different time points during ITC and OTC. Child’s body weight was measured (naked and without shoes) in triplicate using a digital scale (Seca 813, Hamburg, Germany) to the nearest 100 g. Triple MUAC measurements were taken on the child’s left arm without clothes, using standard non-elastic color coded tapes for under 5-year-old children (Child 11.5 red/pac-50, UNICEF) to the nearest 1 mm. Length/ height was measured in triplicate using an infant length board (Infant/ Child Shorr-Board®, Maryland, USA) to the nearest 1 mm (supine length was measured for children less than 24 months of age). Body weight was further measured once daily at 7:00 AM before the 8:00 AM feed during hospitalization. On admission, maternal body weight was measured in triplicate using a digital scale (Seca 813, Hamburg, Germany) to the nearest 100 g. Height was measured in triplicate using an adult height board (adult Shorr-Board®, Maryland, USA) to the nearest 1 mm. Before measurements were taken, mothers were asked to remove shoes and any extra clothes. For measurements taken in triplicate, the average was considered. WHZ and height/length-for-age z-score (HAZ) were computed using WHO Anthro version 3.2.2 [15]. Maternal body mass index (BMI) expressed in kg/m2 was calculated as weight in kg divided by the square of the height in meters [35]. Throughout the study period, clinical evaluation of patients was performed by the same study pediatricians. Likewise, the same study nutritionists were responsible for conducting nutritional evaluation. This included monitoring of vital signs, grade of edema, appetite, anthropometry, type and amount of feeding regimens given daily during ITC and bi-weekly during OTC visits. Based on this, decisions regarding management of the patients were jointly made. Four [4] ml of blood was drawn by venipuncture and placed into heparinized vacutainer tubes (Becton Dickinson, Franklin lakes, NJ USA) by the study doctor or nurse. Complete blood counts were analyzed using a coulter counter at the Uganda cancer institute laboratory. HIV serological testing was done at MNU side lab using rapid tests (Determine HIV-1/2 [Abbot Laboratories USA], and positive samples were confirmed with HIV-1/2 Stat-Pak Dipstick Assay kit. HIV DNA/PCR test was done at the hospital’s HIV clinic for all children aged below 18 months with a positive serology test. Plasma was obtained by centrifuging at 1300-2200G for 10 min, then stored at − 80 °C at Immunology Laboratory, Mulago Hospital until shipped on dry ice to the Department of Nutrition, Exercise and Sports, University of Copenhagen, Denmark. Plasma C-reactive Protein (CRP) was measured by high sensitive kit on an ABK Pentra 400 (Horiba, Montpellier, France). All data were double entered into Epidata Version3.1 (Odense, Denmark) and analyzed using R version 3.5.1 (R Core Team, 2017), with the extension packages plyr, dplyr, lme4, multcomp, car and ggplot2. Missing daily weight data were imputed using the “linear interpolation” approach, whereby a missing value was linearly interpolated by using values before and after the missing one [36]. Daily weight gain data were organized according to days of follow-up per treatment phase depending on the feeds received and daily energy intake. For ITC, weight gain velocity is presented based on 8, 4 and 5 days in stabilization, transition and rehabilitation phases, respectively. For OTC, it is presented based on 8 and 12 weeks. MUAC gain velocity is presented weekly and bi-weekly for ITC and OTC, respectively. The terms “rehabilitation phase” and “OTC” refer to the rehabilitation phase in ITC and OTC, respectively. Baseline child, maternal and household characteristics based on continuous variables were presented as means ± standard deviations (SD) or median [interquartile range (IQR)], and categorical variables were presented as percentages (n). To evaluate whether median duration of treatment phases differed by edema at admission, we used Mann-Whitney U Test. Linear mixed-effects models (with restricted maximum likelihood estimation) were used to investigate the changes in weight and MUAC gain velocities between time points during ITC and OTC, adjusted for a priori potential confounders (age, sex, HIV status). The models included child-specific random intercepts and robust SEs were used. Because weight gain differs by edema at admission [5, 7], the models also included interaction terms between time of follow-up and edema at admission. To obtain estimate changes (b-coefficients) due to exposure between time points, unadjusted and age-sex adjusted models were fitted separately for stabilization, transition, rehabilitation and OTC. All models were checked based on residuals and predicted random effects using residuals plots and normal probability plots. P-values below 0.05 were considered statistically significant.