In this open label trial, children aged 2 months to 12 years with uncomplicated severe anemia received immediate blood transfusion in the intervention group while in the control group, immediate transfusion was withheld. Children in the intervention group were further randomized to receive higher (30 mL/kg whole blood/ 15 mL/kg packed cells) or lower (20 mL/kg whole blood/ 10 mL/kg packed cells) volume, administered immediately after enrolment. Hemoglobin (Hb) was measured 8-hourly, and an additional transfusion using the original volume was given if the criteria for transfusion were met. For children requiring further transfusions, only 20 mL/kg whole blood (or 10 mL/kg packed cells) was used. In the control group, transfusion with 20 mL/kg of whole-blood equivalent was triggered by new signs of clinical severity or a drop in Hb to below 4 g/dL during 8-hourly monitoring, The primary out-come was 28-day mortality. Three other randomizations investigated transfusion volume, post-discharge supplementation with micronutrients, and post-discharge prophylaxis with trimethoprim–sulfamethoxazole.

A total of 1565 children underwent randomization, with 778 assigned to the immediate-transfusion group and 787 to the control group. 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%) in the control group (median time to transfusion, 1.3 hours vs. 24.9 hours). 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. Seven children (0.9%) in the immediate-transfusion group and 13 (1.7%) in the control group died by 28 days (HR 0.54; 95% CI 0.22, 1.36; P=0.19), and 35 (4.5%) and 47 (6.0%), respectively (HR 0.75; 95% CI, 0.48, 1.15) by 180 days, without evidence of interaction with other randomizations or evidence of between-group differences in readmissions, serious adverse events, or hemoglobin recovery at 180 days. The authors concluded that there was no evidence of differences in clinical outcomes over 6 months between the children who received immediate transfusion and those who did not.

Relevance: Severe anemia (defined as hemoglobin less than 6 g/dL), is a frequent cause of childhood hospitalization in many African countries [1,2]. The traditional approach in such children is to offer blood transfusion only if hemoglobin (Hb) is less than 4 g/dL, or when Hb is 4-6 g/dL in the presence of clinical features like dehydration, shock, altered sensorium, cardiac failure, breathing difficulty, hemoglobinuria, or underlying sickle cell disease. This somewhat conservative approach is based on the World Health Organization (WHO) recommendations [3], which are based on dated observational studies with methodological limitations. This randomized clinical trial [4] compared a liberal (i.e., immediate blood transfusion) versus conservative (i.e., as per WHO guidelines) approach in children with uncomplicated severe anemia (defined as mentioned above). Table I outlines the characteristics of the trial [1].

Critical appraisal: Table II outlines the methodological aspects of the trial. Overall, the methodological quality was high. The trial protocol was published [5], and there are no deviations discernible. However, some points require careful consideration.

In this trial [4], the mortality rate in both arms was far lower than the anticipated baseline mortality rate of 9%. Thus, although there was approximately 50% lower mortality in the intervention arm (0.9% compared to 1.7%), the trial remained underpowered to confirm if a true difference existed. The investigators acknowledged this issue, explaining that screening of children for possible enrolment in the trial was ceased when blood was unavailable for transfusion. Although this is a reasonable explanation, it raises the problem of logistic feasibility. Even if immediate transfusion had been superior, it seems unlikely that eligible children could/would get transfused on account of limited supplies of blood. This gap between research and practice needs to be addressed before the research findings could be implemented.

The investigators did not report the cause of severe anemia in the enrolled children. Although it could be argued that this may not affect the internal validity of the study, it is important to determine comparability between the study arms. It is also interesting to wonder how/why children with Hb <6 g/dL were relatively stable. This suggests that they were suffering from chronic anemia related to underlying disease, since severe malnutrition was present in very few (<4%) enrolled children. This is also borne by the fact that after the study, sickle cell disease was confirmed in a significant proportion of the children. Further, it appears that three-quarters of the control group children who received transfusion had a drop in Hb while under observation, suggesting ongoing blood loss or hemolysis, neither of which were investigated further. It is also somewhat unusual that nearly a quarter of the children had received transfusion prior to the current illness, yet were not investigated further.

The WHO clinical practice guidelines for medical interns [6] prescribes 5 mL/kg of packed cells or 10 mL/kg whole blood in children with severe uncomplicated anemia; although, the handbook prescribes larger volume [3]. The first transfusion is recommended rapidly to restore oxygen carrying capacity, whereas subsequent transfusions (if required.) should not exceed 5 mL/kg/h. Oral or intravenous frusemide in the dose 1 mg/kg is mentioned if there is likelihood of circulatory overload. The transfusion protocol used in this trial [4] was not described; hence, the rate of transfusion and duration cannot be ascertained. This is especially important considering that not a single one of over 1000 transfused children developed transfusion-related fluid overload or lung injury, despite the deliberate avoidance of frusemide midway. Similarly, only eight children had an allergic reaction. These impressive findings beg for more data on how this was achieved.

In the majority of resource-limited settings, especially sub-Saharan Africa, most blood transfusions are administered as whole blood. In contrast, developed healthcare systems prefer component transfusions with packed red cells [7,8]. This is related to potential circulatory overload with whole blood, and benefit of use in multiple patients when components are used. However, there are logistic challenges to fractionate blood in most developing country settings. A recent systematic review [9] examined 14 national transfusion practice guidelines published in African countries. Among those covering the pediatric age group, three recommended transfusing packed cells, whereas two permitted either to be used. However, none of these guidelines provided a basis for the recommendation. It appears that although component transfusion is preferred despite the lack of robust supporting evidence, it is often logistically infeasible. The issue is important in this trial [4] because facilities existed for both whole blood as well as packed cell transfusion. In fact, almost half the children transfused (in either group) received packed cells. However, the basis for deciding which individual child would receive whole blood (versus packed cells) was not clarified. The investigators have not reported subgroup analysis to judge the relative efficacy and safety, within as well as between groups.

Although the trial showed a distinct inter-group difference in Hb level during the first 48 hours, the gap narrowed to clinically insignificant values at the follow-up visits on days 28, 90 and 180. Unfortunately, the figures in the publication [4] did not clarify whether this happened only to transfused control group children, or to all in the control group. There is also no ready explanation about why the transfused children showed increase in Hb from around 5 g/dL at 48 hours to nearly 9 g/dL by day 180.

The investigators reported a statistically significant difference in the overall duration of hospital stay between the groups, with a day less hospitalization in those who were transfused immediately. However, this outcome was not specified a priori, and appears to a post hoc analysis. The investigators did not compare the outcomes among those receiving higher versus lower transfusion volume in the immediate transfusion group; hence, this aspect cannot be appraised.

Although cost-effectiveness was expected to be reported, the investigators undertook a cost minimization exercise, showing that the total cost of conventional transfusion was approximately USD 5.6 less than the cost of immediate transfusion. Calculation of the incremental cost-effectiveness ratio (ICER) would have been more useful. But since the gain in life years was the same in both groups, the analysis would have favored the conservative approach. In terms of costs, it is intriguing that mean cost of hospitalization over 4-5 days was merely (approximately) USD 30. This is especially remarkable considering the sickness level of the children, and that almost two-thirds had malaria. It is even more remarkable considering that the costs of measuring Hb 5 times during hospitalization was approximately one-third as much as the total hospitalization cost. These observations suggest that the actual cost of hospitalization may have been higher than represented, thereby widening the gap between the two groups.

Extendibility and Conclusion: This trial did not find overall benefit of immediate blood transfusion over traditional conservative approach. However, there are several methodological issues requiring clarification, to understand the true value of this study. There are several major differences from the trial setting and the Indian setting. These include the relatively high burden of uncomplicated severe anemia in sub-Saharan Africa, underlying causes of severe anemia (chronic disease with a high burden of malaria, but relatively uncommon severe malnutrition), underlying sickle cell disease in a significant proportion, and management protocols to pragmatically manage severe anemia in children. In India, the National Family Health Survey-4 [10] used a cut-off of 11 g/dL to identify anemia in over half of the children younger than 5 years, highlighting the stark difference from sub-Saharan Africa. Further, most hospital protocols in Asian countries correct anemia below 7 g/dL using packed cells, with careful monitoring and interventions to prevent fluid overload [11]. For these reasons, the findings in this trial [4] may not be directly applicable to Indian context.

Funding: None; Competing interests: None stated.

Joseph L Mathew

1. Kiguli S, Maitland K, George EC, Olupot-Olupot P, Opoka RO, Engoru C, et al. Anaemia and blood transfusion in African children presenting to hospital with severe febrile illness. BMC Med. 2015;13:21.

2. Opoka RO, Ssemata AS, Oyang W, Nambuya H, John CC, Tumwine JK, et al. High rate of inappropriate blood transfusions in the management of children with severe anemia in Ugandan hospitals. BMC Health Serv Res. 2018;18:566.

3. World Health Organization. Pocket Book of Hospital Care for Children: Guidelines for the Management of Common Childhood Illnesses. 2nd ed. 2013. Available from: https://books.google.co.in/books?hl=en&lr=&id=FLEXDAAA QBAJ&oi=fnd&pg=PP1&ots=4PjQU619dg&sig= t19Ob9T5ZYKwWtaIlwBHv1WtbYo&redir_esc=y#v= onepage&q=transfusion&f=false. Accessed October 12, 2019.

4. Maitland K, Kiguli S, Olupot-Olupot P, Engoru C, Mallewa M, Saramago Goncalves P, et al. Immediate transfusion in African children with uncomplicated severe anemia. N Engl J Med 2019;381:407-19.

5. Mpoya A, Kiguli S, Olupot-Olupot P, Opoka RO, Engoru C, Mallewa M, et al. Transfusion and Treatment of severe anemia in African children (TRACT): A study protocol for a randomized controlled trial. Trials. 2015;16:593.

6. World Health Organization. Clinical Transfusion Practice Guidelines for Medical Interns. Available from: https://www.who.int/bloodsafety/transfusion_services/Clinical TransfusionPracticeGuidelinesforMedicalInterns Bangladesh.pdf ?ua=1. Accessed October 13, 2019.

7. New York State Council on Human Blood and Transfusion Services: Blood and Tissue Resources Program 2016. Available from: https://www.wadsworth. org/sites/default/files/WebDoc/ped_tx_ guidelines_2.pdf. Accessed October 13, 2019.

8. Lau W. Neonatal and Pediatric Transfusion. Available from:https://professionaleducation.blood.ca/en/transfusion/guide-clinique/neonatal-and-pediatric-transfusion. Accessed October 14, 2019.

9. Kohli N, Bhaumik S, Jagadesh S, Sales RK, Bates I. Packed red cells versus whole blood transfusion for severe paediatric anemia, pregnancy-related anemia and obstetric bleeding: an analysis of clinical practice guidelines from sub-Saharan Africa and evidence underpinning recommendations. Trop Med Int Health. 2019;24:11-22

10. National Family Health Survey, India. Key Findings from NFHS-4. Available from: http://rchiips.org/nfhs/factsheet _nfhs-4.shtml. Accessed October 14, 2019.

11. Ali N. Red blood cell transfusion in infants and children- Current perspectives. Pediatr Neonatol. 2018;59:227-30.

The prevalence of childhood anemia in India has remained high over the last few decades and as per NFHS-4 estimates, 58% children under 5 years of age anemic and 2% have severe anemia [1]. Restrictive red blood cell (RBC) transfusion strategy at a hemoglobin cut-off level of 7 g/dL has been advocated to reduce transfusion requirements without significant increase in adverse effects [2].

In the current multicenter study, Maitland, et al. [3] have demonstrated that immediate transfusion led to early hemoglobin recovery than the triggered transfusion strategy, and also reduced the number of children who developed profound anemia (Hb <4 g/dL) but the hospital readmission rates did not differ in the two groups. In the trial settings, clinical and Hb monitoring was an inbuilt component of the treatment strategy, which is usually not possible rigorously in the actual clinical and field settings. This also contributes significantly to the associated mortality in these children.

Considering the fact that India still has a very high prevalence of malnutrition and a large burden of children with severe acute malnutrition [4], unlike that reported by Maitland et al. [3], wherein it has been shown that early transfusion within the first 48 hours of admission has less adverse effects and mortality than RBC transfusion later during the course of management, it seems prudent to perform immediate transfusion in children with uncomplicated severe anemia.

Despite the rigorous trial design, there were patients lost to follow-up. In day-to-day clinical practice in the resource constrained settings with patients coming from far off distances, it is extremely difficult for the treating clinicians to ensure follow-up, and it will be a challenge to closely monitor such children with severe anemia who are discharged without transfusion and may decompensate in the community setting.

In the current study, there is no mention of anti-helminthic treatment received by any of the participants. In settings with a high burden of helminthic and parasitic infestations, if left untreated, anemia may recur, which may be a significant contributor to the readmission rates to the hospital; the current study was not able to find a difference in the readmission rate in the two groups.

Although, the immediate transfusion strategy may overburden the blood bank resources, the benefits of improved survival in children with severe anemia may outweigh this burden.

Funding: None; Competing interests: None stated.

Department of Pediatrics,
AIIMS, Bhopal, India.
Email: [email protected] 

1. Ministry of Health and Family Welfare. International Institute for Population Sciences (IIPS) and ICF. 2017. National Family Health Survey (NFHS-4), 2015-16: India. Mumbai: IIPS. Available from: http://rchiips.org/nfhs/NFHS-4Reports/India.pdf. Accessed October 23, 2019.

2. Lacroix J, Hébert PC, Hutchison JS, Hume HA, Tucci M, Ducruet T, et al. Transfusion strategies for patients in pediatric intensive care units. N Engl J Med. 2007;356:1609-19.

3. Maitland K, Kiguli S, Olupot-Olupot P, Engoru C, Mallewa M, Saramago Goncalves P, et al. Immediate transfusion in African children with uncomplicated severe anemia. N Engl J Med. 2019;381:407-19.

4. National Health Mission. Ministry of Health and Family Welfare. Operational Guidelines for Facility-based Management of Children with Severe Acute Malnutrition. 2011:India. Available from: https://nhm.gov.in/index1. php?lang=1&level=3&sublinkid=1182&lid=364. Accessed October 23, 2019.