Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Mpoya A

PROVIDER: S-EPMC4696199 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Publications

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

Mpoya Ayub A Kiguli Sarah S Olupot-Olupot Peter P Opoka Robert O RO Engoru Charles C Mallewa Macpherson M Chimalizeni Yami Y Kennedy Neil N Kyeyune Dorothy D Wabwire Benjamin B M'baya Bridon B Bates Imelda I Urban Britta B von Hensbroek Michael Boele MB Heyderman Robert R Thomason Margaret J MJ Uyoga Sophie S Williams Thomas N TN Gibb Diana M DM George Elizabeth C EC Walker A Sarah AS Maitland Kathryn K

Trials 20151229

<h4>Background</h4>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%), ...[more]

PMID: 26715196

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Project description:BackgroundSickle cell anaemia (SCA) has historically been associated with high levels of childhood mortality in Africa. Although malaria has a major contribution to this mortality, to date, the clinical pathology of malaria among children with SCA has been poorly described. We aimed to explore the relationship between SCA and Plasmodium falciparum malaria in further detail by investigating the burden and severity of malaria infections among children recruited with severe anaemia to the TRACT trial of blood transfusion in Africa.MethodsThis study is a post-hoc secondary analysis of the TRACT trial data, conducted after trial completion. TRACT was an open-label, multicentre, factorial, randomised controlled trial enrolling children aged 2 months to 12 years who presented with severe anaemia (haemoglobin <6·0 g/dL) to four hospitals in Africa. This secondary analysis is restricted to Uganda, where the birth prevalence of SCA is approximately 1% and malaria transmission is high. Children were classified as normal (HbAA), heterozygous (HbAS), or homozygous (HbSS; SCA) for the rs334 A→T sickle mutation in HBB following batch-genotyping by PCR at the end of the trial. To avoid confounding from SCA-specific medical interventions, we considered children with an existing diagnosis of SCA (known SCA) separately from those diagnosed at the end of the trial (unknown SCA). The outcomes considered in this secondary analysis were measures of P falciparum parasite burden, features of severe malaria, and mortality at day 28 in malaria-positive children.FindingsBetween Sept 17, 2014, and May 15, 2017, 3944 children with severe anaemia were enrolled into the TRACT trial. 3483 children from Uganda were considered in this secondary analysis. Overall, 1038 (30%) of 3483 Ugandan children had SCA. 1815 (78%) of 2321 children without SCA (HbAA) tested positive for P falciparum malaria, whereas the prevalence was significantly lower in children with SCA (347 [33%] of 1038; p<0·0001). Concentrations of plasma P falciparum histidine-rich protein 2 (PfHRP2), a marker of the total burden of malaria parasites within an individual, were significantly lower in children with either known SCA (median 8 ng/mL; IQR 0-57) or unknown SCA (7 ng/mL; 0-50) than in HbAA children (346 ng/mL; 21-2121; p<0·0001). In contrast to HbAA children, few HbSS children presented with classic features of severe and complicated malaria, but both the frequency and severity of anaemia were higher in HbSS children. We found no evidence for increased mortality at day 28 in those with SCA compared with those without SCA overall (hazard ratios 1·07 [95% CI 0·31-3·76] for known SCA and 0·67 [0·15-2·90] for unknown SCA).InterpretationThe current study suggests that children with SCA are innately protected against classic severe malaria. However, it also shows that even low-level infections can precipitate severe anaemic crises that would likely prove fatal without rapid access to blood transfusion services.FundingUK Medical Research Council, Wellcome, and UK National Institute for Health and Care Research.

Project description:BackgroundThe TRACT trial established the timing of transfusion in children with uncomplicated anaemia (haemoglobin 4-6 g/dL) and the optimal volume (20 vs 30 mL/kg whole blood or 10 vs 15 mL/kg red cell concentrates) for transfusion in children admitted to hospital with severe anaemia (haemoglobin <6 g/dL) on day 28 mortality (primary endpoint). Because data on the safety of blood components are scarce, we conducted a secondary analysis to examine the safety and efficacy of different pack types (whole blood vs red cell concentrates) on clinical outcomes.MethodsThis study is a secondary analysis of the TRACT trial data restricted to those who received an immediate transfusion (using whole blood or red cell concentrates). TRACT was an open-label, multicentre, factorial, randomised trial conducted in three hospitals in Uganda (Soroti, Mbale, and Mulago) and one hospital in Malawi (Blantyre). The trial enrolled children aged between 2 months and 12 years admitted to hospital with severe anaemia (haemoglobin <6 g/dL). The pack type used (supplied by blood banks) was based only on availability at the time. The outcomes were haemoglobin recovery at 8 h and 180 days, requirement for retransfusion, length of hospital stay, changes in heart and respiratory rates until day 180, and the main clinical endpoints (mortality until day 28 and day 180, and readmission until day 180), measured using multivariate regression models.FindingsBetween Sept 17, 2014, and May 15, 2017, 3199 children with severe anaemia were enrolled into the TRACT trial. 3188 children were considered in our secondary analysis. The median age was 37 months (IQR 18-64). Whole blood was the first pack provided for 1632 (41%) of 3992 transfusions. Haemoglobin recovery at 8 h was significantly lower in those who received packed cells or settled cells than those who received whole blood, with a mean of 1·4 g/dL (95% CI -1·6 to -1·1) in children who received 30 mL/kg and -1·3 g/dL (-1·5 to -1·0) in those who received 20 mL/kg packed cells versus whole blood, and -1·5 g/dL (-1·7 to -1·3) in those who received 30 mL/kg and -1·0 g/dL (-1·2 to -0·9) in those who received 20 mL/kg settled cells versus whole blood (overall p<0·0001). Compared to whole blood, children who received blood as packed or settled cells in their first transfusion had higher odds of receiving a second transfusion (odds ratio 2·32 [95% CI 1·30 to 4·12] for packed cells and 2·97 [2·18 to 4·05] for settled cells; p<0·001) and longer hospital stays (hazard ratio 0·94 [95% CI 0·81 to 1·10] for packed cells and 0·86 [0·79 to 0·94] for settled cells; p=0·0024). There was no association between the type of blood supplied for the first transfusion and mortality at 28 days or 180 days, or readmission to hospital for any cause. 823 (26%) of 3188 children presented with severe tachycardia and 2077 (65%) with tachypnoea, but these complications resolved over time. No child developed features of confirmed cardiopulmonary overload.InterpretationOur study suggests that the use of packed or settled cells rather than whole blood leads to additional transfusions, increasing the use of a scarce resource in most of sub-Saharan Africa. These findings have substantial cost implications for blood transfusion and health services. Nevertheless, a clinical trial comparing whole blood transfusion with red cell concentrates might be needed to inform policy makers.FundingUK Medical Research Council (MRC) and the Department for International Development.TranslationFor the French translation of the abstract see Supplementary Materials section.

Project description:BackgroundSevere 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.MethodsWithin 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.FindingsFrom 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).InterpretationNeither 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.FundingMedical Research Council and Department for International Development.

Project description:BackgroundThe 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.MethodsIn 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.ResultsA 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.ConclusionsThere 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.).

Project description: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.

Project description:BackgroundSevere malarial anaemia requiring blood transfusion is a life-threatening condition affecting millions of children in sub-Saharan Africa. Up to 40% of children with severe malarial anaemia have associated lactic acidosis. Lactic acidosis in these children is strongly associated with fatal outcomes and is corrected by blood transfusion. However, it is not known whether the storage age of blood for transfusion affects resolution of lactic acidosis. The objective of this pilot study was to evaluate the effect of blood storage age on resolution of lactic acidosis in children with severe malarial anaemia and demonstrate feasibility of conducting a large trial.MethodsChildren aged six to 59 months admitted to Acute Care Unit of Mulago Hospital (Kampala, Uganda) with severe malarial anaemia (haemoglobin ≤ 5 g/dL) and lactic acidosis (blood lactate ≥5 mmol/L), were randomly assigned to receive either blood of short storage age (one to 10 days) or long storage age (21-35 days) by gravity infusion. Seventy-four patients were enrolled and randomized to two equal-sized study arms. Physiological measurements, including blood lactate, oxygen saturation, haemoglobin, and vital signs, were taken at baseline, during and after transfusion. The primary outcome variable was the proportion of children whose lactic acidosis resolved by four hours after transfusion.ResultsThirty-four of 37 (92%) of the children in the short storage treatment arm compared to 30/37 (81%) in the long storage arm achieved a blood lactate <5 mmol/L by four hours post transfusion (p value = 0.308). The mean time to lactic acidosis resolution was 2.65 hours (95% CI; 2.25-3.05) in the short storage arm, compared to 3.35 hours (95% CI; 2.60-4.10) in the long storage arm (p value = 0.264).ConclusionPilot data suggest that among children with severe malarial anaemia and lactic acidosis transfused with packed red blood cells, the storage age of blood does not affect resolution of lactic acidosis. The results support a larger and well-powered study which is under way.Trial registrationclinicaltrials.gov NCT01580111.

Project description:BackgroundAfrican children with severe malaria are at increased risk of non-typhoidal salmonellae co-infection. Broad-spectrum antibiotics are recommended by guidelines but the optimal class and dose have not been established. We investigated the optimal dose of oral dispersible azithromycin and whether simple clinical criteria and point-of-care biomarkers could target antibiotics to those at greatest risk of bacterial co-infection.MethodsWe conducted a phase I/II trial in Ugandan children with severe malaria comparing a 5-day course of azithromycin: 10, 15 and 20 mg/kg of azithromycin (prescribed by weight bands) spanning the dose-range effective for other salmonellae infection. We generated relevant pharmacokinetic (PK) data by sparse sampling during dosing intervals and investigated associations between azithromycin exposure and potential mechanisms (PK-pharmacodynamics) using change in C-reactive protein (CRP), a putative marker of sepsis, at 72 h (continuous) and microbiological cure (7-day) (binary), alone and as a composite with 7-day and 90-day survival. To assess whether clinical or biomarkers could identify those at risk of sepsis, a non-severe malaria control was concurrently enrolled.ResultsBetween January 2020 and January 2022, 105 cases were randomised azithromycin doses: 35 to 10 mg/kg, 35 to 15 mg/kg and 35 to 20 mg/kg. Fifty non-severe malaria controls were concurrently enrolled. CRP reduced in all arms by 72 h with a mean reduction of 65.8 mg/L (95% CI 57.1, 74.5) in the 10 mg/kg arm, 64.8 mg/L (95% CI 56.5, 73.1; p = 0.87) in the 20 mg/kg arm and a smaller reduction 51.2 mg/L (95% CI 42.9, 59.5; p = 0.02) in the 15 mg/kg arm. Microbiological cure alone outcome was not analysed as only one pathogen was found among cases. Three events contributed to the composite outcome of 7-day survival and microbiological cure, with no events in the 15 mg/kg arm. The odds ratio comparing 20 vs 10 mg/kg was 0.50 (95% CI 0.04, 5.79); p = 0.58. Due to the low number of pathogens identified, it was not possible to identify better methods for targeting antibiotics including both the cases and controls.ConclusionsWe found no evidence for an association between systemic azithromycin exposure and reduction in CRP. Further work is needed to better identify children at highest risk from bacterial co-infection.Trial registrationISRCTN49726849 (registered on 27th October 2017).

Dataset Information

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

Background

Methods/design

Discussion

Trial registration

Publications

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

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