A reduced-carbohydrate and lactose-free formulation for stabilization among hospitalized children with severe acute malnutrition: A double-blind, randomized controlled trial.

BACKGROUND: Children with medically complicated severe acute malnutrition (SAM) have high risk of inpatient mortality. Diarrhea, carbohydrate malabsorption, and refeeding syndrome may contribute to early mortality and delayed recovery. We tested the hypothesis that a lactose-free, low-carbohydrate F75 milk would serve to limit these risks, thereby reducing the number of days in the stabilization phase. METHODS AND FINDINGS: In a multicenter double-blind trial, hospitalized severely malnourished children were randomized to receive standard formula (F75) or isocaloric modified F75 (mF75) without lactose and with reduced carbohydrate. The primary endpoint was time to stabilization, as defined by the World Health Organization (WHO), with intention-to-treat analysis. Secondary outcomes included in-hospital mortality, diarrhea, and biochemical features of malabsorption and refeeding syndrome. The trial was registered at clinicaltrials.gov (NCT02246296). Four hundred eighteen and 425 severely malnourished children were randomized to F75 and mF75, respectively, with 516 (61%) enrolled in Kenya and 327 (39%) in Malawi. Children with a median age of 16 months were enrolled between 4 December 2014 and 24 December 2015. One hundred ninety-four (46%) children assigned to F75 and 188 (44%) to mF75 had diarrhea at admission. Median time to stabilization was 3 days (IQR 2-5 days), which was similar between randomized groups (0.23 [95% CI -0.13 to 0.60], P = 0.59). There was no evidence of effect modification by diarrhea at admission, age, edema, or HIV status. Thirty-six and 39 children died before stabilization in the F75 and in mF75 arm, respectively (P = 0.84). Cumulative days with diarrhea (P = 0.27), enteral (P = 0.42) or intravenous fluids (P = 0.19), other serious adverse events before stabilization, and serum and stool biochemistry at day 3 did not differ between groups. The main limitation was that the primary outcome of clinical stabilization was based on WHO guidelines, comprising clinical evidence of recovery from acute illness as well as metabolic stabilization evidenced by recovery of appetite. CONCLUSIONS: Empirically treating hospitalized severely malnourished children during the stabilization phase with lactose-free, reduced-carbohydrate milk formula did not improve clinical outcomes. The biochemical analyses suggest that the lactose-free formulae may still exceed a carbohydrate load threshold for intestinal absorption, which may limit their usefulness in the context of complicated SAM. TRIAL REGISTRATION: ClinicalTrials.gov NCT02246296.

Ready-to-use therapeutic food with elevated n-3 polyunsaturated fatty acid content, with or without fish oil, to treat severe acute malnutrition: a randomized controlled trial.

BACKGROUND: Ready-to-use therapeutic foods (RUTF) are lipid-based pastes widely used in the treatment of acute malnutrition. Current specifications for RUTF permit a high n-6 polyunsaturated fatty acid (PUFA) content and low n-3 PUFA, with no stipulated requirements for preformed long-chain n-3 PUFA. The objective of this study was to develop an RUTF with elevated short-chain n-3 PUFA and measure its impact, with and without fish oil supplementation, on children's PUFA status during treatment of severe acute malnutrition. METHODS: This randomized controlled trial in children with severe acute malnutrition in rural Kenya included 60 children aged 6 to 50 months who were randomized to receive i) RUTF with standard composition; ii) RUTF with elevated short chain n-3 PUFA; or iii) RUTF with elevated short chain n-3 PUFA plus fish oil capsules. Participants were followed-up for 3 months. The primary outcome was erythrocyte PUFA composition. RESULTS: Erythrocyte docosahexaenoic acid (DHA) content declined from baseline in the two arms not receiving fish oil. Erythrocyte long-chain n-3 PUFA content following treatment was significantly higher for participants in the arm receiving fish oil than for those in the arms receiving RUTF with elevated short chain n-3 PUFA or standard RUTF alone: 3 months after enrollment, DHA content was 6.3% (interquartile range 6.0-7.3), 4.5% (3.9-4.9), and 3.9% (2.4-5.7) of total erythrocyte fatty acids (P <0.001), respectively, while eicosapentaenoic acid (EPA) content was 2.0% (1.5-2.6), 0.7% (0.6-0.8), and 0.4% (0.3-0.5) (P <0.001). RUTF with elevated short chain n-3 PUFA and fish oil capsules were acceptable to participants and carers, and there were no significant differences in safety outcomes. CONCLUSIONS: PUFA requirements of children with SAM are not met by current formulations of RUTF, or by an RUTF with elevated short-chain n-3 PUFA without additional preformed long-chain n-3 PUFA. Clinical and growth implications of revised formulations need to be addressed in large clinical trials. TRIAL REGISTRATION: Clinicaltrials.gov NCT01593969. Registered 4 May 2012.

Changes in susceptibility to life-threatening infections after treatment for complicated severe malnutrition in Kenya.

Background: Goals of treating childhood severe acute malnutrition (SAM), in addition to anthropometric recovery and preventing short-term mortality, include reducing the risks of subsequent serious infections. How quickly and how much the risk of serious illness changes during rehabilitation are unknown but could inform improving the design and scope of interventions. Objective: The aim of this study was to investigate changes in the risk of life-threatening events (LTEs) in relation to anthropometric recovery from SAM. Design: This was a secondary analysis of a clinical trial including 1778 HIV-uninfected Kenyan children aged 2-59 mo with complicated SAM, enrolled after the inpatient stabilization phase of treatment, and followed for 12 mo. The main outcome was LTEs, defined as infections requiring rehospitalization or causing death. We examined anthropometric variables measured at months 1, 3, and 6 after enrollment in relation to LTEs occurring during the 6 mo after each of these time points. Results: Over 12 mo, there were 823 LTEs (257 fatal), predominantly severe pneumonia and diarrhea. At months 1, 3, and 6, 557 (34%), 764 (49%), and 842 (56%) children had a weight-for-height or -length z score (WHZ) ≥-2, respectively, which, compared with a WHZ <-3, was associated with lower risks of subsequent LTEs [adjusted HRs (95% CIs): 0.50 (0.40, 0.64), 0.30 (0.23, 0.39), and 0.23 (0.16, 0.32), respectively]. However, children with a WHZ ≥-2 at 1, 3, and 6 mo still had 39 (95% CI: 32, 47), 26 (95% CI: 22, 32), and 15 (95% CI: 12, 20) LTEs/100 child-years of observation during the following 6 mo. WHZ at study enrollment predicted subsequent WHZ but not the risk of LTEs. Changes in height-for-age z score did not predict LTEs. Conclusions: Anthropometric response was associated with a rapid and substantial reduction in risk of LTEs. However, reduction in susceptibility lagged behind anthropometric improvement. Disease events, together with anthropometric assessment, may provide a clearer picture of the effectiveness of interventions. Robust protocols for detecting and treating poor anthropometric recovery and addressing broader vulnerabilities that complicated SAM indicates may save lives. This trial was registered at www.clinicaltrials.gov as NCT00934492.

Dosing of Ceftriaxone and Metronidazole for Children With Severe Acute Malnutrition.

Infants and young children with severe acute malnutrition (SAM) are treated with empiric broad-spectrum antimicrobials. Parenteral ceftriaxone is currently a second-line agent for invasive infection. Oral metronidazole principally targets small intestinal bacterial overgrowth. Children with SAM may have altered drug absorption, distribution, metabolism, and elimination. Population pharmacokinetics of ceftriaxone and metronidazole were studied, with the aim of recommending optimal dosing. Eighty-one patients with SAM (aged 2-45 months) provided 234 postdose pharmacokinetic samples for total ceftriaxone, metronidazole, and hydroxymetronidazole. Ceftriaxone protein binding was also measured in 190 of these samples. A three-compartment model adequately described free ceftriaxone, with a Michaelis-Menten model for concentration and albumin-dependent protein binding. A one-compartment model was used for both metronidazole and hydroxymetronidazole, with only 1% of hydroxymetronidazole predicted to be formed during first-pass. Simulations showed 80 mg/kg once daily of ceftriaxone and 12.5 mg/kg twice daily of metronidazole were sufficient to reach therapeutic targets.

What influences feeding decisions for HIV-exposed infants in rural Kenya?

BACKGROUND: Infant feeding in the context of human immunodeficiency virus (HIV) poses unique challenges to mothers and healthcare workers in balancing the perceived risks of HIV transmission and nutritional requirements. We aimed to describe the decision-making processes around infant feeding at a rural HIV clinic in Kenya. METHODS: We used a qualitative study design. Between March and August 2011, we conducted in-depth interviews (n = 9) and focus group discussions (n = 10) with purposively selected hospital and community respondents at Kilifi County Hospital, Kenya. These respondents had all experienced of infant feeding in the context of HIV. These interviews were informed by prior structured observations of health care worker interactions with carers during infant feeding counselling sessions. RESULTS: Overall, women living with HIV found it difficult to adhere to the HIV infant feeding guidance. There were three dominant factors that influenced decision making processes: 1) Exclusive breastfeeding was not the cultural norm, therefore practising it raised questions within the family and community about a mother's parenting capabilities and HIV status. 2) Women living with HIV lacked autonomy in decision-making on infant feeding due to socio-cultural factors. 3) Non-disclosure of HIV status to close members due to the stigma. CONCLUSION: Infant feeding decision-making by women living with HIV in rural Kenya is constrained by a lack of autonomy, stigma and poverty. There is an urgent need to address these challenges through scaling up psycho-social and gender empowerment strategies for women, and introducing initiatives that promote the integration of HIV infant feeding strategies into other child health services.

Daily co-trimoxazole prophylaxis to prevent mortality in children with complicated severe acute malnutrition: a multicentre, double-blind, randomised placebo-controlled trial.

BACKGROUND: Children with complicated severe acute malnutrition (SAM) have a greatly increased risk of mortality from infections while in hospital and after discharge. In HIV-infected children, mortality and admission to hospital are prevented by daily co-trimoxazole prophylaxis, despite locally reported bacterial resistance to co-trimoxazole. We aimed to assess the efficacy of daily co-trimoxazole prophylaxis on survival in children without HIV being treated for complicated SAM. METHODS: We did a multicentre, double-blind, randomised, placebo-controlled study in four hospitals in Kenya (two rural hospitals in Kilifi and Malindi, and two urban hospitals in Mombasa and Nairobi) with children aged 60 days to 59 months without HIV admitted to hospital and diagnosed with SAM. We randomly assigned eligible participants (1:1) to 6 months of either daily oral co-trimoxazole prophylaxis (given as water-dispersible tablets; 120 mg per day for age <6 months, 240 mg per day for age 6 months to 5 years) or matching placebo. Assignment was done with computer-generated randomisation in permuted blocks of 20, stratified by centre and age younger or older than 6 months. Treatment allocation was concealed in opaque, sealed envelopes and patients, their families, and all trial staff were masked to treatment assignment. Children were given recommended medical care and feeding, and followed up for 12 months. The primary endpoint was mortality, assessed each month for the first 6 months, then every 2 months for the second 6 months. Secondary endpoints were nutritional recovery, readmission to hospital, and illness episodes treated as an outpatient. Analysis was by intention to treat. This trial was registered at ClinicalTrials.gov, number NCT00934492. FINDINGS: Between Nov 20, 2009, and March 14, 2013, we recruited and assigned 1778 eligible children to treatment (887 to co-trimoxazole prophylaxis and 891 to placebo). Median age was 11 months (IQR 7-16 months), 306 (17%) were younger than 6 months, 300 (17%) had oedematous malnutrition (kwashiorkor), and 1221 (69%) were stunted (length-for-age Z score <-2). During 1527 child-years of observation, 122 (14%) of 887 children in the co-trimoxazole group died, compared with 135 (15%) of 891 in the placebo group (unadjusted hazard ratio [HR] 0·90, 95% CI 0·71-1·16, p=0·429; 16·0 vs 17·7 events per 100 child-years observed (CYO); difference -1·7 events per 100 CYO, 95% CI -5·8 to 2·4]). In the first 6 months of the study (while participants received study medication), 63 suspected grade 3 or 4 associated adverse events were recorded among 57 (3%) children; 31 (2%) in the co-trimoxazole group and 32 (2%) in the placebo group (incidence rate ratio 0·98, 95% CI 0·58-1·65). The most common adverse events of these grades were urticarial rash (grade 3, equally common in both groups), neutropenia (grade 4, more common in the co-trimoxazole group), and anaemia (both grades equally common in both groups). One child in the placebo group had fatal toxic epidermal necrolysis with concurrent Pseudomonas aeruginosa bacteraemia. INTERPRETATION: Daily co-trimoxazole prophylaxis did not reduce mortality in children with complicated SAM without HIV. Other strategies need to be tested in clinical trials to reduce deaths in this population. FUNDING: Wellcome Trust, UK.