Legume-supplemented feed for children hospitalised with severe malnutrition: A Phase II trial.

Children hospitalised with severe malnutrition have high mortality and readmission rates post-discharge. Current milk-based formulations target restoring ponderal growth but not modification of gut barrier integrety or microbiome which increase risk of gram-negative sepsis and poor outcomes. We propose that legume-based feeds rich in fermentable carbohydrates will promote better gut health and improve overall outcomes.We conducted an open-label Phase II trial at Mbale and Soroti Regional Referral Hospitals, Uganda involving 160 children aged 6 months-5 years with severe malnutrition (mid-upper arm circumference (MUAC) <11.5cm and/or nutritional oedema). Children were randomised to a lactose-free, chickpea-enriched legume paste feed (LF) (n=80) versus WHO standard F75/F100 feeds (n=80). Co-primary outcomes were change in MUAC and mortality to Day 90. Secondary outcomes included weight gain (>5 g/kg/day), de novo development of diarrhoea, time to diarrhoea and oedema resolution.Day 90 MUAC increase was marginally lower in LF versus WHO arm (1.1 cm (IQR 1.1) vs 1.4cm (IQR 1.40) p=0.09; Day 90 mortality was similar 11/80 (13.8%) vs 12/80 (15%) respectively OR 0.91 (95% CI 0.40 -2.07) p=0.83. There were no differences in any of the other secondary outcomes. Owing to initial poor palatability of the legume feed 10 children switched to WHO feeds. Per protocol analysis indicated a trend to lower Day 90 mortality and readmission rates in the legume feed (6/60: (10%) and (2/60: 3%) vs WHO feeds (12/71: 17.5%) and (4/71: 6%) respectively.Further refinement of legume feeds and clinical trials are warrented given the poor outcomes in children with severe malnutrition.Trial registration ISRCTN 10309022.

Cardiovascular abnormalities in chest radiographs of children with pneumonia, Uganda.

Objective: To describe chest radiograph findings among children hospitalized with clinically diagnosed severe pneumonia and hypoxaemia at three tertiary facilities in Uganda. Methods: The study involved clinical and radiograph data on a random sample of 375 children aged 28 days to 12 years enrolled in the Children's Oxygen Administration Strategies Trial in 2017. Children were hospitalized with a history of respiratory illness and respiratory distress complicated by hypoxaemia, defined as a peripheral oxygen saturation (SpO2) < 92%. Radiologists blinded to clinical findings interpreted chest radiographs using standardized World Health Organization method for paediatric chest radiograph reporting. We report clinical and chest radiograph findings using descriptive statistics. Findings: Overall, 45.9% (172/375) of children had radiological pneumonia, 36.3% (136/375) had a normal chest radiograph and 32.8% (123/375) had other radiograph abnormalities, with or without pneumonia. In addition, 28.3% (106/375) had a cardiovascular abnormality, including 14.9% (56/375) with both pneumonia and another abnormality. There was no significant difference in the prevalence of radiological pneumonia or of cardiovascular abnormalities or in 28-day mortality between children with severe hypoxaemia (SpO2: < 80%) and those with mild hypoxaemia (SpO2: 80 to < 92%). Conclusion: Cardiovascular abnormalities were relatively common among children hospitalized with severe pneumonia in Uganda. The standard clinical criteria used to identify pneumonia among children in resource-poor settings were sensitive but lacked specificity. Chest radiographs should be performed routinely for all children with clinical signs of severe pneumonia because it provides useful information on both cardiovascular and respiratory systems.

A Clinical and Physiological Prospective Observational Study on the Management of Pediatric Shock in the Post-Fluid Expansion as Supportive Therapy Trial Era.

OBJECTIVES: Fluid bolus resuscitation in African children is harmful. Little research has evaluated physiologic effects of maintenance-only fluid strategy. DESIGN: We describe the efficacy of fluid-conservative resuscitation of septic shock using case-fatality, hemodynamic, and myocardial function endpoints. SETTING: Pediatric wards of Mbale Regional Referral Hospital, Uganda, and Kilifi County Hospital, Kenya, conducted between October 2013 and July 2015. Data were analysed from August 2016 to July 2019. PATIENTS: Children (≥ 60 d to ≤ 12 yr) with severe febrile illness and clinical signs of impaired perfusion. INTERVENTIONS: IV maintenance fluid (4 mL/kg/hr) unless children had World Health Organization (WHO) defined shock (≥ 3 signs) where they received two fluid boluses (20 mL/kg) and transfusion if shock persisted. Clinical, electrocardiographic, echocardiographic, and laboratory data were collected at presentation, during resuscitation and on day 28. Outcome measures were 48-hour mortality, normalization of hemodynamics, and cardiac biomarkers. MEASUREMENT AND MAIN RESULTS: Thirty children (70% males) were recruited, six had WHO shock, all of whom died (6/6) versus three of 24 deaths in the non-WHO shock. Median fluid volume received by survivors and nonsurvivors were similar (13 [interquartile range (IQR), 9-32] vs 30 mL/kg [28-61 mL/kg], z = 1.62, p = 0.23). By 24 hours, we observed increases in median (IQR) stroke volume index (39 mL/m 2 [32-42 mL/m 2 ] to 47 mL/m 2 [41-49 mL/m 2 ]) and a measure of systolic function: fractional shortening from 30 (27-33) to 34 (31-38) from baseline including children managed with no-bolus. Children with WHO shock had a higher mean level of cardiac troponin ( t = 3.58; 95% CI, 1.24-1.43; p = 0.02) and alpha-atrial natriuretic peptide ( t = 16.5; 95% CI, 2.80-67.5; p < 0.01) at admission compared with non-WHO shock. Elevated troponin (> 0.1 µg/mL) and hyperlactatemia (> 4 mmol/L) were putative makers predicting outcome. CONCLUSIONS: Maintenance-only fluid therapy normalized clinical and myocardial perturbations in shock without compromising cardiac or hemodynamic function whereas fluid-bolus management of WHO shock resulted in high fatality. Troponin and lactate biomarkers of cardiac dysfunction could be promising outcome predictors in pediatric septic shock in resource-limited settings.

Children's Oxygen Administration Strategies And Nutrition Trial (COAST-Nutrition): a protocol for a phase II randomised controlled trial.

Background: To prevent poor long-term outcomes (deaths and readmissions) the integrated global action plan for pneumonia and diarrhoea recommends under the 'Treat' element of Protect, Prevent and Treat interventions the importance of continued feeding but gives no specific recommendations for nutritional support. Early nutritional support has been practiced in a wide variety of critically ill patients to provide vital cell substrates, antioxidants, vitamins, and minerals essential for normal cell function and decreasing hypermetabolism. We hypothesise that the excess post-discharge mortality associated with pneumonia may relate to the catabolic response and muscle wasting induced by severe infection and inadequacy of the diet to aid recovery. We suggest that providing additional energy-rich, protein, fat and micronutrient ready-to-use therapeutic feeds (RUTF) to help meet additional nutritional requirements may improve outcome. Methods: COAST-Nutrition is an open, multicentre, Phase II randomised controlled trial in children aged 6 months to 12 years hospitalised with suspected severe pneumonia (and hypoxaemia, SpO 2 <92%) to establish whether supplementary feeds with RUTF given in addition to usual diet for 56-days (experimental) improves outcomes at 90-days compared to usual diet alone (control). Primary endpoint is change in mid-upper arm circumference (MUAC) at 90 days and/or as a composite with 90-day mortality. Secondary outcomes include anthropometric status, mortality, readmission at days 28 and 180. The trial will be conducted in four sites in two countries (Uganda and Kenya) enrolling 840 children followed up to 180 days. Ancillary studies include cost-economic analysis, molecular characterisation of bacterial and viral pathogens, evaluation of putative biomarkers of pneumonia, assessment of muscle and fat mass and host genetic studies.   Discussion: This study is the first step in providing an option for nutritional support following severe pneumonia and will help in the design of a large Phase III trial. Registration: ISRCTN10829073 (6 th June 2018) PACTR202106635355751 (2 nd June 2021).

Gastroenteritis Rehydration Of children with Severe Acute Malnutrition (GASTROSAM): A Phase II Randomised Controlled trial: Trial Protocol.

Background: Children hospitalised with severe acute malnutrition (SAM) are frequently complicated (>50%) by diarrhoea ( ≥3 watery stools/day) which is accompanied by poor outcomes. Rehydration guidelines for SAM are exceptionally conservative and controversial, based upon expert opinion. The guidelines only permit use of intravenous fluids for cases with advanced shock and exclusive use of low sodium intravenous and oral rehydration solutions (ORS) for fear of fluid and/or sodium overload. Children managed in accordance to these guidelines have a very high mortality. The proposed GASTROSAM trial is the first step in reappraising current recommendations. We hypothesize that liberal rehydration strategies for both intravenous and oral rehydration in SAM children with diarrhoea may reduce adverse outcomes. Methods An open Phase II trial, with a partial factorial design, enrolling Ugandan and Kenyan children aged 6 months to 12 years with SAM hospitalised with gastroenteritis (>3 loose stools/day) and signs of moderate and severe dehydration.  In Stratum A (severe dehydration) children will be randomised (1:1:2) to WHO plan C (100mls/kg Ringers Lactate (RL) with intravenous rehydration given over 3-6 hours according to age including boluses for shock), slow rehydration (100 mls/kg RL over 8 hours (no boluses)) or  WHO SAM rehydration regime (ORS only (boluses for shock (standard of care)).  Stratum B incorporates all children with moderate dehydration and severe dehydration post-intravenous rehydration and compares (1:1 ratio) standard WHO ORS given for non-SAM (experimental) versus WHO SAM-recommended low-sodium ReSoMal. The primary outcome for intravenous rehydration is urine output (mls/kg/hour at 8 hours post-randomisation), and for oral rehydration a change in sodium levels at 24 hours post-randomisation. This trial will also generate feasibility, safety and preliminary data on survival to 28 days. Discussion. If current rehydration strategies for non-malnourished children are safe in SAM this could prompt future evaluation in Phase III trials.

Incidence and predictors of hospital readmission in children presenting with severe anaemia in Uganda and Malawi: a secondary analysis of TRACT trial data.

BACKGROUND: Severe anaemia (haemoglobin < 6 g/dL) is a leading cause of recurrent hospitalisation in African children. We investigated predictors of readmission in children hospitalised with severe anaemia in the TRACT trial (ISRCTN84086586) in order to identify potential future interventions. METHODS: Secondary analyses of the trial examined 3894 children from Uganda and Malawi surviving a hospital episode of severe anaemia. Predictors of all-cause readmission within 180 days of discharge were identified using multivariable regression with death as a competing risk. Groups of children with similar characteristics were identified using hierarchical clustering. RESULTS: Of the 3894 survivors 682 (18%) were readmitted; 403 (10%) had ≥2 re-admissions over 180 days. Three main causes of readmission were identified: severe anaemia (n = 456), malaria (n = 252) and haemoglobinuria/dark urine syndrome (n = 165). Overall, factors increasing risk of readmission included HIV-infection (hazard ratio 2.48 (95% CI 1.63-3.78), p < 0.001); ≥2 hospital admissions in the preceding 12 months (1.44(1.19-1.74), p < 0.001); history of transfusion (1.48(1.13-1.93), p = 0.005); and missing ≥1 trial medication dose (proxy for care quality) (1.43 (1.21-1.69), p < 0.001). Children with uncomplicated severe anaemia (Hb 4-6 g/dL and no severity features), who never received a transfusion (per trial protocol) during the initial admission had a substantially lower risk of readmission (0.67(0.47-0.96), p = 0.04). Malaria (among children with no prior history of transfusion) (0.60(0.47-0.76), p < 0.001); younger-age (1.07 (1.03-1.10) per 1 year younger, p < 0.001) and known sickle cell disease (0.62(0.46-0.82), p = 0.001) also decreased risk of readmission. For anaemia re-admissions, gross splenomegaly and enlarged spleen increased risk by 1.73(1.23-2.44) and 1.46(1.18-1.82) respectively compared to no splenomegaly. Clustering identified four groups of children with readmission rates from 14 to 20%. The cluster with the highest readmission rate was characterised by very low haemoglobin (mean 3.6 g/dL). Sickle Cell Disease (SCD) predominated in two clusters associated with chronic repeated admissions or severe, acute presentations in largely undiagnosed SCD. The final cluster had high rates of malaria (78%), severity signs and very low platelet count, consistent with acute severe malaria. CONCLUSIONS: Younger age, HIV infection and history of previous hospital admissions predicted increased risk of readmission. However, no obvious clinical factors for intervention were identified. As missing medication doses was highly predictive, attention to care related factors may be important. TRIAL REGISTRATION: ISRCTN ISRCTN84086586 .

Modifying gut integrity and microbiome in children with severe acute malnutrition using legume-based feeds (MIMBLE): A pilot trial.

Case fatality among African children with severe acute malnutrition remains high. We report a 3-arm pilot trial in 58 Ugandan children, comparing feeds targeting disordered gastrointestinal function containing cowpea (CpF, n = 20) or inulin (InF, n = 20) with conventional feeds (ConF, n = 18). Baseline measurements of gut permeability (lactulose:mannitol ratio 1.19 ± SD 2.00), inflammation (fecal calprotectin 539.0 µg/g, interquartile range [IQR] 904.8), and satiety (plasma polypeptide YY 62.6 pmol/l, IQR 110.3) confirm gastrointestinal dysfunction. By day 28, no differences are observable in proportion achieving weight gain >5 g/kg/day (87%, 92%, 86%; p > 0.05), mortality (16%, 30%, 17%; p > 0.05), or edema resolution (83%, 54%, 91%; p > 0.05) among CpF, InF, and ConF. Decreased fecal bacterial richness from day 1 (abundance-based coverage estimator [ACE] 53.2) to day 7 (ACE 40.8) is observed only in ConF (p = 0.025). Bifidobacterium relative abundance increases from day 7 (5.8% ± 8.6%) to day 28 (10.9% ± 8.7%) in CpF (corrected p = 1.000). Legume-enriched feeds support aspects of gut function and the microbiome. Trial registration PACTR201805003381361.

Pharmacokinetics and pharmacodynamics of azithromycin in severe malaria bacterial co-infection in African children (TABS-PKPD): a protocol for a Phase II randomised controlled trial.

Background: African children with severe malaria are susceptible to Gram-negative bacterial co-infection, largely non-typhoidal Salmonellae, leading to a substantially higher rates of in-hospital and post-discharge mortality than those without bacteraemia. Current evidence for treating co-infection is lacking, and there is no consensus on the dosage or length of treatment required. We therefore aimed to establish the appropriate dose of oral dispersible azithromycin as an antimicrobial treatment for children with severe malaria and to investigate whether antibiotics can be targeted to those at greatest risk of bacterial co-infection using clinical criteria alone or in combination with rapid diagnostic biomarker tests. Methods: A Phase I/II open-label trial comparing three doses of azithromycin: 10, 15 and 20 mg/kg spanning the lowest to highest mg/kg doses previously demonstrated to be equally effective as parenteral treatment for other salmonellae infection. Children with the highest risk of bacterial infection will receive five days of azithromycin and followed for 90 days. We will generate relevant pharmacokinetic data by sparse sampling during dosing intervals. We will use population pharmacokinetic modelling to determine the optimal azithromycin dose in severe malaria and investigate azithromycin exposure to change in C-reactive protein, a putative marker of sepsis at 72 hours, and microbiological cure (seven-day), alone and as a composite with seven-day survival. We will also evaluate whether a combination of clinical, point-of-care diagnostic tests, and/or biomarkers can accurately identify the sub-group of severe malaria with culture-proven bacteraemia by comparison with a control cohort of children hospitalized with severe malaria at low risk of bacterial co-infection. Discussion: We plan to study azithromycin because of its favourable microbiological spectrum, its inherent antimalarial and immunomodulatory properties and dosing and safety profile. This study will generate new data to inform the design and sample size for definitive Phase III trial evaluation. Registration: ISRCTN49726849 (27 th October 2017).

Mortality risk over time after early fluid resuscitation in African children.

BACKGROUND: African children hospitalised with severe febrile illness have a high risk of mortality. The Fluid Expansion As Supportive Therapy (FEAST) trial (ISCRTN 69856593) demonstrated increased mortality risk associated with fluid boluses, but the temporal relationship to bolus therapy and underlying mechanism remains unclear. METHODS: In a post hoc retrospective analysis, flexible parametric models were used to compare change in mortality risk post-randomisation in children allocated to bolus therapy with 20-40 ml/kg 5% albumin or 0.9% saline over 1-2 h or no bolus (control, 4 ml/kg/hour maintenance), overall and for different terminal clinical events (cardiogenic, neurological, respiratory, or unknown/other). RESULTS: Two thousand ninety-seven and 1041 children were randomised to bolus vs no bolus, of whom 254 (12%) and 91 (9%) respectively died within 28 days. Median (IQR) bolus fluid in the bolus groups received by 4 h was 20 (20, 40) ml/kg and was the same at 8 h; total fluids received in bolus groups at 4 h and 8 h were 38 (28, 43) ml/kg and 40 (30, 50) ml/kg, respectively. Total fluid volumes received in the control group by 4 h and 8 h were median (IQR) 10 (6, 15) ml/kg and 10 (10, 26) ml/kg, respectively. Mortality risk was greatest 30 min post-randomisation in both groups, declining sharply to 4 h and then more slowly to 28 days. Maximum mortality risk was similar in bolus and no bolus groups; however, the risk declined more slowly in the bolus group, with significantly higher mortality risk compared to the no bolus group from 1.6 to 101 h (4 days) post-randomisation. The delay in decline in mortality risk in the bolus groups was most pronounced for cardiogenic modes of death. CONCLUSIONS: The increased risk from bolus therapy was not due to a mechanism occurring immediately after bolus administration. Excess mortality risk in the bolus group resulted from slower decrease in mortality risk over the ensuing 4 days. Thus, administration of modest bolus volumes appeared to prevent mortality risk declining at the same rate that it would have done without a bolus, rather than harm associated with bolus resulting from a concurrent increased risk of death peri-bolus administration. TRIAL REGISTRATION: ISRCTN69856593. Date of registration 15 December 2008.

Informing thresholds for paediatric transfusion in Africa: the need for a trial.

Background: Owing to inadequate supplies of donor blood for transfusion in sub-Saharan Africa (sSA) World Health Organization paediatric guidelines recommend restrictive transfusion practices, based on expert opinion. We examined whether survival amongst hospitalised children by admission haemoglobin and whether this was influenced by malaria infection and/or transfusion. Methods: A retrospective analysis of standardised clinical digital records in an unselected population of children admitted to a rural hospital in Kenya over an 8-year period. We describe baseline parameters with respect to categories of anaemia and outcome (in-hospital death) by haemoglobin (Hb), malaria and transfusion status. Results: Among 29,226 children, 1,143 (3.9%) had profound anaemia (Hb <4g/dl) and 3,469 (11.9%) had severe anaemia (Hb 4-6g/d). In-hospital mortality rate was 97/1,143 (8.5%) if Hb<4g/dl or 164/2,326 (7.1%) in those with severe anaemia (Hb ≥4.0-<6g/dl). Admission Hb <3g/dl was associated with higher risk of death versus those with higher Hbs (OR=2.41 (95%CI: 1.8 - 3.24; P<0.001), increasing to OR=6.36, (95%CI: 4.21-9.62; P<0.001) in malaria positive children. Conversely, mortality in non-malaria admissions was unrelated to Hb level. Transfusion was associated with a non-significant improvement in outcome if Hb<3g/dl (malaria-only) OR 0.72 (95%CI 0.29 - 1.78), albeit the number of cases were too few to show a statistical difference. For those with Hb levels above 4g/dl, mortality was significantly higher in those receiving a transfusion compared to the non-transfused group. For non-malarial cases, transfusion did not affect survival-status, irrespective of baseline Hb level compared to children who were not transfused at higher Hb levels. Conclusion: Although severe anaemia is common among children admitted to hospital in sSA (~16%), our data do not indicate that outcome is improved by transfusion irrespective of malaria status. Given the limitations of observational studies, clinical trials investigating the role of transfusion in outcomes in children with severe anaemia are warranted.

Co-trimoxazole or multivitamin multimineral supplement for post-discharge outcomes after severe anaemia in African children: a randomised controlled trial.

BACKGROUND: Severe anaemia is a leading cause of paediatric admission to hospital in Africa; post-discharge outcomes remain poor, with high 6-month mortality (8%) and re-admission (17%). We aimed to investigate post-discharge interventions that might improve outcomes. METHODS: Within the two-stratum, open-label, multicentre, factorial randomised TRACT trial, children aged 2 months to 12 years with severe anaemia, defined as haemoglobin of less than 6 g/dL, at admission to hospital (three in Uganda, one in Malawi) were randomly assigned, using sequentially numbered envelopes linked to a second non-sequentially numbered set of allocations stratified by centre and severity, to enhanced nutritional supplementation with iron and folate-containing multivitamin multimineral supplements versus iron and folate alone at treatment doses (usual care), and to co-trimoxazole versus no co-trimoxazole. All interventions were administered orally and were given for 3 months after discharge from hospital. Separately reported randomisations investigated transfusion management. The primary outcome was 180-day mortality. All analyses were done in the intention-to-treat population; follow-up was 180 days. This trial is registered with the International Standard Randomised Controlled Trial registry, ISRCTN84086586, and follow-up is complete. FINDINGS: From Sept 17, 2014, to May 15, 2017, 3983 eligible children were randomly assigned to treatment, and followed up for 180 days. 164 (4%) were lost to follow-up. 1901 (95%) of 1997 assigned multivitamin multimineral supplement, 1911 (96%) of 1986 assigned iron and folate, and 1922 (96%) of 1994 assigned co-trimoxazole started treatment. By day 180, 166 (8%) children in the multivitamin multimineral supplement group versus 169 (9%) children in the iron and folate group had died (hazard ratio [HR] 0·97, 95% CI 0·79-1·21; p=0·81) and 172 (9%) who received co-trimoxazole versus 163 (8%) who did not receive co-trimoxazole had died (HR 1·07, 95% CI 0·86-1·32; p=0·56). We found no evidence of interactions between these randomisations or with transfusion randomisations (p>0·2). By day 180, 489 (24%) children in the multivitamin multimineral supplement group versus 509 (26%) children in the iron and folate group (HR 0·95, 95% CI 0·84-1·07; p=0·40), and 500 (25%) children in the co-trimoxazole group versus 498 (25%) children in the no co-trimoxazole group (1·01, 0·89-1·15; p=0·85) had had one or more serious adverse events. Most serious adverse events were re-admissions, occurring in 692 (17%) children (175 [4%] with at least two re-admissions). INTERPRETATION: Neither enhanced supplementation with multivitamin multimineral supplement versus iron and folate treatment or co-trimoxazole prophylaxis improved 6-month survival. High rates of hospital re-admission suggest that novel interventions are urgently required for severe anaemia, given the burden it places on overstretched health services in Africa. FUNDING: Medical Research Council and Department for International Development.

Transfusion Volume for Children with Severe Anemia in Africa.

BACKGROUND: Severe anemia (hemoglobin level, <6 g per deciliter) is a leading cause of hospital admission and death in children in sub-Saharan Africa. The World Health Organization recommends transfusion of 20 ml of whole-blood equivalent per kilogram of body weight for anemia, regardless of hemoglobin level. METHODS: In this factorial, open-label trial, we randomly assigned Ugandan and Malawian children 2 months to 12 years of age with a hemoglobin level of less than 6 g per deciliter and severity features (e.g., respiratory distress or reduced consciousness) to receive immediate blood transfusion with 20 ml per kilogram or 30 ml per kilogram. Three other randomized analyses investigated immediate as compared with no immediate transfusion, the administration of postdischarge micronutrients, and postdischarge prophylaxis with trimethoprim-sulfamethoxazole. The primary outcome was 28-day mortality. RESULTS: A total of 3196 eligible children (median age, 37 months; 2050 [64.1%] with malaria) were assigned to receive a transfusion of 30 ml per kilogram (1598 children) or 20 ml per kilogram (1598 children) and were followed for 180 days. A total of 1592 children (99.6%) in the higher-volume group and 1596 (99.9%) in the lower-volume group started transfusion (median, 1.2 hours after randomization). The mean (±SD) volume of total blood transfused per child was 475±385 ml and 353±348 ml, respectively; 197 children (12.3%) and 300 children (18.8%) in the respective groups received additional transfusions. Overall, 55 children (3.4%) in the higher-volume group and 72 (4.5%) in the lower-volume group died before 28 days (hazard ratio, 0.76; 95% confidence interval [CI], 0.54 to 1.08; P = 0.12 by log-rank test). This finding masked significant heterogeneity in 28-day mortality according to the presence or absence of fever (>37.5°C) at screening (P=0.001 after Sidak correction). Among the 1943 children (60.8%) without fever, mortality was lower with a transfusion volume of 30 ml per kilogram than with a volume of 20 ml per kilogram (hazard ratio, 0.43; 95% CI, 0.27 to 0.69). Among the 1253 children (39.2%) with fever, mortality was higher with 30 ml per kilogram than with 20 ml per kilogram (hazard ratio, 1.91; 95% CI, 1.04 to 3.49). There was no evidence of differences between the randomized groups in readmissions, serious adverse events, or hemoglobin recovery at 180 days. CONCLUSIONS: Overall mortality did not differ between the two transfusion strategies. (Funded by the Medical Research Council and Department for International Development, United Kingdom; TRACT Current Controlled Trials number, ISRCTN84086586.).

Immediate Transfusion in African Children with Uncomplicated Severe Anemia.

BACKGROUND: The World Health Organization recommends not performing transfusions in African children hospitalized for uncomplicated severe anemia (hemoglobin level of 4 to 6 g per deciliter and no signs of clinical severity). However, high mortality and readmission rates suggest that less restrictive transfusion strategies might improve outcomes. METHODS: In this factorial, open-label, randomized, controlled trial, we assigned Ugandan and Malawian children 2 months to 12 years of age with uncomplicated severe anemia to immediate transfusion with 20 ml or 30 ml of whole-blood equivalent per kilogram of body weight, as determined in a second simultaneous randomization, or no immediate transfusion (control group), in which transfusion with 20 ml of whole-blood equivalent per kilogram was triggered by new signs of clinical severity or a drop in hemoglobin to below 4 g per deciliter. The primary outcome was 28-day mortality. Three other randomizations investigated transfusion volume, postdischarge supplementation with micronutrients, and postdischarge prophylaxis with trimethoprim-sulfamethoxazole. RESULTS: A total of 1565 children (median age, 26 months) underwent randomization, with 778 assigned to the immediate-transfusion group and 787 to the control group; 984 children (62.9%) had malaria. The children were followed for 180 days, and 71 (4.5%) were lost to follow-up. During the primary hospitalization, transfusion was performed in all the children in the immediate-transfusion group and in 386 (49.0%) in the control group (median time to transfusion, 1.3 hours vs. 24.9 hours after randomization). The mean (±SD) total blood volume transfused per child was 314±228 ml in the immediate-transfusion group and 142±224 ml in the control group. Death had occurred by 28 days in 7 children (0.9%) in the immediate-transfusion group and in 13 (1.7%) in the control group (hazard ratio, 0.54; 95% confidence interval [CI], 0.22 to 1.36; P = 0.19) and by 180 days in 35 (4.5%) and 47 (6.0%), respectively (hazard ratio, 0.75; 95% CI, 0.48 to 1.15), without evidence of interaction with other randomizations (P>0.20) or evidence of between-group differences in readmissions, serious adverse events, or hemoglobin recovery at 180 days. The mean length of hospital stay was 0.9 days longer in the control group. CONCLUSIONS: There was no evidence of differences in clinical outcomes over 6 months between the children who received immediate transfusion and those who did not. The triggered-transfusion strategy in the control group resulted in lower blood use; however, the length of hospital stay was longer, and this strategy required clinical and hemoglobin monitoring. (Funded by the Medical Research Council and Department for International Development; TRACT Current Controlled Trials number, ISRCTN84086586.).

Gastroenteritis aggressive versus slow treatment for rehydration (GASTRO): a phase II rehydration trial for severe dehydration: WHO plan C versus slow rehydration.

BACKGROUND: World Health Organization rehydration management guidelines (plan C) for severe dehydration are widely practiced in resource-poor settings, but never formally evaluated in a trial. The Fluid Expansion as a Supportive Therapy trial raised concerns regarding the safety of bolus therapy for septic shock, warranting a formal evaluation of rehydration therapy for gastroenteritis. METHODS: A multi-centre open-label phase II randomised controlled trial evaluated two rehydration strategies in 122 Ugandan/Kenyan children aged 60 days to 12 years with severe dehydration secondary to gastroenteritis. We compared the safety and efficacy of standard rapid rehydration using Ringer's lactate (100 ml/kg over 3 h (6 h if < 1 year), incorporating 0.9% saline boluses for children with shock (plan C) versus slower rehydration: 100 ml/kg Ringer's lactate over 8 h (all ages) without boluses (slow: experimental). The primary outcome was the frequency of serious adverse events (SAE) within 48 h including cardiovascular, respiratory and neurological complications. Secondary outcomes included clinical, biochemical and physiological measures of response to treatment by intravenous rehydration. RESULTS: One hundred twenty-two eligible children (median (IQR) age 8 (6-12) months) were randomised to plan C (n = 61) or slow (n = 61), with two (2%) lost to follow-up at day 7). Following randomisation mean (SD) time to start intravenous rehydration started was 15 min (18) in both arms. Mean (SD) fluid received by 1 hour was greater in plan C (mean 20.2 ml/kg (12.2) and 33.1 ml/kg (17) for children < 1 year and >- 1 year respectively) versus 10.4 ml/kg (6.6) in slow arm. By 8 hours volume received were similar mean (SD) plan C: 96.3 ml/kg (15.6) and 97.8 ml/kg (10.0) for children < 1 and ≥ 1 year respectively vs 93.2 ml/kg (12.2) in slow arm. By 48-h, three (5%) plan C vs two (3%) slow had an SAE (risk ratio 0.67, 95% CI 0.12-3.85, p = 0.65). There was no difference in time to the correction of dehydration (p = 0.9) or time to discharge (p = 0.8) between groups. Atrial natriuretic peptide levels rose substantially by 8 hours in both arms, which persisted to day 7. Day 7 weights suggested only 33 (29%) could be retrospectively classified as severely dehydration (≥ 10% weight loss). CONCLUSION: Slower rehydration over 8 hours appears to be safe, easier to implement than plan C. Future large trials with mortality as the primary endpoint are warranted. TRIAL REGISTRATION: ISRCTN67518332 . Date applied 31 August 2016.

Haematological quality and age of donor blood issued for paediatric transfusion to four hospitals in sub-Saharan Africa.

BACKGROUND AND OBJECTIVES: Paediatric blood transfusion for severe anaemia in hospitals in sub-Saharan Africa remains common. Yet, reports describing the haematological quality of donor blood or storage duration in routine practice are very limited. Both factors are likely to affect transfusion outcomes. MATERIALS AND METHODS: We undertook three audits examining the distribution of pack types, haematological quality and storage duration of donor blood used in a paediatric clinical trial of blood at four hospitals in Africa (Uganda and Malawi). RESULTS: The overall distribution of whole blood, packed cells (plasma-reduced by centrifugation) and red cell concentrates (RCC) (plasma-reduced by gravity-dependent sedimentation) used in a randomised trial was 40·7% (N = 1215), 22·4% (N = 669) and 36·8% (N = 1099), respectively. The first audit found similar median haematocrits of 57·0% (50·0,74·0), 64·0% (52·0,72·5; P = 0·238 vs. whole blood) and 56·0% (48·0,67·0; P = 0·462) in whole blood, RCC and packed cells, respectively, which resulted from unclear pack labelling by blood transfusion services (BTS). Re-training of the BTS, hospital blood banks and clinical teams led to, in subsequent audits, significant differences in median haematocrit and haemoglobins across the three pack types and values within expected ranges. Median storage duration time was 12 days (IQR: 6, 19) with 18·2% (537/2964) over 21 days in storage. Initially, 9 (2·8%) packs were issued past the recommended duration of storage, dropping to 0·3% (N = 7) in the third audit post-training. CONCLUSION: The study highlights the importance of close interactions and education between BTS and clinical services and the importance of haemovigilance to ensure safe transfusion practice.

Assessment of Myocardial Function in Kenyan Children With Severe, Acute Malnutrition: The Cardiac Physiology in Malnutrition (CAPMAL) Study.

Importance: Mortality among African children hospitalized with severe malnutrition remains high, with sudden, unexpected deaths leading to speculation about potential cardiac causes. Malnutrition is considered high risk for cardiac failure, but evidence is limited. Objective: To investigate the role of cardiovascular dysfunction in African children with severe, acute malnutrition (SAM). Design, Setting, and Participants: A prospective, matched case-control study, the Cardiac Physiology in Malnutrition (CAPMAL) study, of 88 children with SAM (exposed) vs 22 severity-matched patients without SAM (unexposed) was conducted between March 7, 2011, and February 20, 2012; data analysis was performed from October 1, 2012, to March 1, 2016. Exposures: Echocardiographic and electrocardiographic (ECG) recordings (including 7-day Holter monitoring) at admission, day 7, and day 28. Main Outcomes and Measures: Findings in children with (cases) and without (controls) SAM and in marasmus and kwashiorkor phenotypes were compared. Results: Eighty-eight children (52 with marasmus and 36 with kwashiorkor) of the 418 admitted with SAM and 22 severity-matched controls were studied. A total of 63 children (57%) were boys; median age at admission was 19 months (range, 12-39 months). On admission, abnormalities more common in cases vs controls included severe hypokalemia (potassium <2.5 mEq/L) (18 of 81 [22%] vs 0%), hypoalbuminemia (albumin level <3.4 g/dL) (66 of 88 [75%] vs 4 of 22 [18%]), and hypothyroidism (free thyroxine level <0.70 ng/dL or thyrotropin level >4.2 mU/L) (18 of 74 [24%] vs 1 of 21 [5%]) and were associated with typical electrocardiographic changes (T-wave inversion: odds ratio, 7.3; 95% CI, 1.9-28.0; P = .001), which corrected as potassium levels improved. Fourteen children with SAM (16%) but no controls died. Myocardial mass was lower in cases on admission but not by day 7. Results of the Tei Index, a measure of global cardiac function, were within the reference range and similar in cases (median, 0.37; interquartile range [IQR], 0.26-0.45) and controls (median, 0.36; IQR, 0.28-0.42). Echocardiography detected no evidence of cardiac failure among children with SAM, including those receiving intravenous fluids to correct hypovolemia. Cardiac dysfunction was generally associated with comorbidity and typical of hypovolemia, with low cardiac index (median, 4.9 L/min/m2; IQR, 3.9-6.1 L/min/m2), high systemic vascular resistance index (median, 1333 dyne seconds/cm5/m2; IQR, 1133-1752 dyne seconds/cm5/m2), and with few differences between the marasmus and kwashiorkor manifestations of malnutrition. Seven-day continuous ECG Holter monitoring during the high-risk initial refeeding period demonstrated self-limiting significant ventricular arrhythmias in 33 of 55 cases (60%) and 6 of 18 controls (33%) (P = .049); none were temporally related to adverse events, including fatalities. Conclusions and Relevance: There is little evidence that African children with SAM are at greater risk of cardiac dysfunction or clinically significant arrhythmias than those without SAM or that marasmus and kwashiorkor differed in cardiovascular profile. These findings should prompt a review of current guidelines.

Modifying Intestinal Integrity and Micro Biome in Severe Malnutrition with Legume-Based Feeds (MIMBLE 2.0): protocol for a phase II refined feed and intervention trial.

Background: Changes in intestinal mucosal integrity and gut microbial balance occur in severe acute malnutrition (SAM), resulting in treatment failure and adverse clinical outcomes (gram-negative sepsis, diarrhoea and high case-fatality). Transient lactose intolerance, due to loss of intestinal brush border lactase, also complicates SAM, thus milk based feeds may not be optimal for nutritional rehabilitation. Since the gut epithelial barrier can be supported by short chain fatty acids, derived from microbiota fermentation by particular fermentable carbohydrates, we postulated that an energy-dense nutritional feed comprising of legume-based fermentable carbohydrates, incorporated with lactose-free versions of standard World Health Organization (WHO) F75/F100 nutritional feeds will enhance epithelial barrier function in malnourished children, reduce and promote resolution of diarrhoea and improve overall outcome. Methods: We will investigate in an open-label trial in 160 Ugandan children with SAM, defined by mid-upper arm circumference <11.5cm and/or presence of kwashiorkor. Children will be randomised to a lactose-free, chickpea-enriched feed containing 2 kcal/ml, provided in quantities to match usual energy provision (experimental) or WHO standard treatment F75 (0.75 kcal/ml) and F100 (1 kcal/ml) feeds on a 1:1 basis, conducted at Mbale Regional Referral Hospital nutritional rehabilitation unit. The primary outcomes are change in MUAC at day 90 and survival to day 90. Secondary outcomes include: i) moderate to good weight gain (>5 g/kg/day), ii) de novo development of diarrhoea (>3 loose stools/day), iii) time to diarrhoea resolution (if >3 loose stools/day), and iv) time to oedema resolution (if kwashiorkor) and change in intestinal biomarkers (faecal calprotectin). Discussion: We hypothesize that, if introduced early in the management of malnutrition, such lactose-free, fermentable carbohydrate-based feeds, could safely and cheaply improve global outcome by reducing lactose intolerance-related diarrhoea, improving mucosal integrity and enhancing immunity, and limiting the risk of systemic infection and associated broad-spectrum antibiotic resistance. Registration: ISRCTN 10309022.

Gastroenteritis Aggressive Versus Slow Treatment For Rehydration (GASTRO). A pilot rehydration study for severe dehydration: WHO plan C versus slower rehydration.

BACKGROUND: The World Health Organization (WHO) rehydration management guidelines (Plan C) for children with acute gastroenteritis (AGE) and severe dehydration are widely practiced in resource-poor settings, yet have never been formally evaluated in a clinical trial. A recent audit of outcome of AGE at Kilifi County Hospital, Kenya noted that 10% of children required high dependency care (20% mortality) and a number developed fluid-related complications. The fluid resuscitation trial, FEAST, conducted in African children with severe febrile illness, demonstrated higher mortality with fluid bolus therapy and raised concerns regarding the safety of rapid intravenous rehydration therapy. Those findings warrant a detailed physiological study of children's responses to rehydration therapy incorporating quantification of myocardial performance and haemodynamic changes.  Methods: GASTRO is a multi-centre, unblinded Phase II randomised controlled trial of 120 children aged 2 months to 12 years admitted to hospital with severe dehydration secondary to AGE. Children with severe malnutrition, chronic diarrhoea and congenital/rheumatic heart disease are excluded. Children will be enrolled over 18 months in 3 centres in Kenya and Uganda and followed until 7 days post-discharge. The trial will randomise children 1:1 to standard rapid rehydration using Ringers Lactate  (WHO plan 'C' - 100mls/kg over 3-6 hours according to age, plus additional 0.9% saline boluses for children presenting in shock) or to a slower rehydration regimen (100mls/kg given over 8 hours and without the addition of fluid boluses). Enrolment started in November 2016 and is on-going. Primary outcome is frequency of adverse events, particularly related to cardiovascular compromise and neurological sequelae.  Secondary outcomes focus on clinical, biochemical, and physiological measures related to assessment of severity of dehydration, and response to treatment by intravenous rehydration. DISCUSSION: Results from this pilot will contribute to generating robust definitions of outcomes (in particular for non-mortality endpoints) for a larger Phase III trial.

Children's Oxygen Administration Strategies Trial (COAST): A randomised controlled trial of high flow versus oxygen versus control in African children with severe pneumonia.

Background: In Africa, the clinical syndrome of pneumonia remains the leading cause of morbidity and mortality in children in the post-neonatal period. This represents a significant burden on in-patient services. The targeted use of oxygen and simple, non-invasive methods of respiratory support may be a highly cost-effective means of improving outcome, but the optimal oxygen saturation threshold that results in benefit and the best strategy for delivery are yet to be tested in adequately powered randomised controlled trials. There is, however, an accumulating literature about the harms of oxygen therapy across a range of acute and emergency situations that have stimulated a number of trials investigating permissive hypoxia. Methods: In 4200 African children, aged 2 months to 12 years, presenting to 5 hospitals in East Africa with respiratory distress and hypoxia (oxygen saturation < 92%), the COAST trial will simultaneously evaluate two related interventions (targeted use of oxygen with respect to the optimal oxygen saturation threshold for treatment and mode of delivery) to reduce shorter-term mortality at 48-hours (primary endpoint), and longer-term morbidity and mortality to 28 days in a fractional factorial design, that compares: Liberal oxygenation (recommended care) compared with a strategy that permits hypoxia to SpO 2 > or = 80% (permissive hypoxia); andHigh flow using AIrVO 2 TM compared with low flow delivery (routine care). Discussion: The overarching objective is to address the key research gaps in the therapeutic use of oxygen in resource-limited setting in order to provide a better evidence base for future management guidelines. The trial has been designed to address the poor outcomes of children in sub-Saharan Africa, which are associated with high rates of in-hospital mortality, 9-10% (for those with oxygen saturations of 80-92%) and 26-30% case fatality for those with oxygen saturations <80%. Clinical trial registration: ISRCTN15622505 Trial status: Recruiting.

Transfusion and Treatment of severe anaemia in African children (TRACT): a study protocol for a randomised controlled trial.

BACKGROUND: In sub-Saharan Africa, where infectious diseases and nutritional deficiencies are common, severe anaemia is a common cause of paediatric hospital admission, yet the evidence to support current treatment recommendations is limited. To avert overuse of blood products, the World Health Organisation advocates a conservative transfusion policy and recommends iron, folate and anti-helminthics at discharge. Outcomes are unsatisfactory with high rates of in-hospital mortality (9-10%), 6-month mortality and relapse (6%). A definitive trial to establish best transfusion and treatment strategies to prevent both early and delayed mortality and relapse is warranted. METHODS/DESIGN: TRACT is a multicentre randomised controlled trial of 3954 children aged 2 months to 12 years admitted to hospital with severe anaemia (haemoglobin < 6 g/dl). Children will be enrolled over 2 years in 4 centres in Uganda and Malawi and followed for 6 months. The trial will simultaneously evaluate (in a factorial trial with a 3 x 2 x 2 design) 3 ways to reduce short-term and longer-term mortality and morbidity following admission to hospital with severe anaemia in African children. The trial will compare: (i) R1: liberal transfusion (30 ml/kg whole blood) versus conservative transfusion (20 ml/kg) versus no transfusion (control). The control is only for children with uncomplicated severe anaemia (haemoglobin 4-6 g/dl); (ii) R2: post-discharge multi-vitamin multi-mineral supplementation (including folate and iron) versus routine care (folate and iron) for 3 months; (iii) R3: post-discharge cotrimoxazole prophylaxis for 3 months versus no prophylaxis. All randomisations are open. Enrolment to the trial started September 2014 and is currently ongoing. Primary outcome is cumulative mortality to 4 weeks for the transfusion strategy comparisons, and to 6 months for the nutritional support/antibiotic prophylaxis comparisons. Secondary outcomes include mortality, morbidity (haematological correction, nutritional and infectious), safety and cost-effectiveness. DISCUSSION: If confirmed by the trial, a cheap and widely available 'bundle' of effective interventions, directed at immediate and downstream consequences of severe anaemia, could lead to substantial reductions in mortality in a substantial number of African children hospitalised with severe anaemia every year, if widely implemented. TRIAL REGISTRATION: Current Controlled Trials ISRCTN84086586 , Approved 11 February 2013.