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Transfusion Decisions in Severe Anaemia

Reducing child mortality remains high on the global health agenda. It’s important we think about ways and means to do this with both population-based and targeted approaches. 

Let’s take the humble blood transfusion – used in emergency departments across the globe and playing a key role in critical care. Severe anaemia is a common and life-threatening cause of hospital admission in children in sub-Saharan Africa. 8% die in hospital, with a further 12% dying in the six months following discharge. However, there is a huge variation in transfusion practice globally. This can be partly explained by uncertainty regarding the clinical benefit of blood transfusions in critically unwell children. But there are two other important points to consider: 

Firstly, blood transfusions are not without risk, with children experiencing the highest incidence of serious adverse effects contributing to the burden of morbidity and mortality. 

Secondly, and most importantly, blood is a limited resource in low- and middle-income countries (LMICs). Demand very quickly outstrips supply, putting a heavy burden on transfusion services. 

These considerations led to the World Health Organisation (WHO) releasing guidance on restrictive transfusion practice in paediatric care to avoid transfusions in cases of uncomplicated severe anaemia (haemoglobin 4-6g/dl). Whilst blood transfusion remains an important treatment, there is limited evidence to support how much and when to give blood. The WHO depends almost entirely on expert opinion groups in forming recommendations designed to protect blood supplies. 

It is, therefore, unsurprising that compliance with this restrictive strategy is poor. A definitive trial was needed to help establish the best transfusion practices to prevent child mortality in LMICs.

Maitland K, Olupot-Olupot P, Kiguli S, et al. Transfusion Volume for Children with Severe Anemia in Africa. N Engl J Med. 2019;381(5):420-431. doi:10.1056/NEJMoa1900100

Maitland K, Kiguli S, Olupot-Olupot P, et al. Immediate Transfusion in African Children with Uncomplicated Severe Anemia. N Engl J Med. 2019;381(5):407-419. doi:10.1056/NEJMoa1900105

Enter the TRACT trial – an open-label, multi-centre, factorial, randomised controlled trial (RCT) which set out to do exactly that. The factorial design chosen by Dr Maitland and her research group means that several comparisons in transfusion practice could be carried out at the same time. Their results are presented in two papers in the New England Journal of Medicine.

What do the current WHO guidelines say?

Transfusion guidelines in LMICs in sub-Saharan Africa differ significantly from the Western world. Due to poor supplies, the WHO recommends reserving blood transfusion of 20mls/kg of whole blood for children with profound or complicated anaemia – defined as those with:-

Hb <4g/dl

OR 

Hb <6g/dl if accompanied by life-threatening features. 

However, these recommendations are only based on expert opinion and have not been systematically evaluated.

What were the research questions?

Poor compliance with WHO guidance stems from uncertainty among healthcare teams. Some wonder if giving blood to children with a haemoglobin <6g/dl will improve outcomes. Others query if the ‘one-size-fits-all’ 20mls/kg at all Hb levels is the right approach or whether it underestimates requirements and leads to further transfusions. 

The study asked TWO questions: 

1. Which children should receive blood? 

2. How much blood should be given?

How did the TRACT trial answer these questions?

Population

6171 children from three hospitals in Uganda and one in Malawi were assessed for eligibility. Exclusion criteria included children with known chronic diseases, exclusively breast-fed infants, or those who had already received an immediate transfusion at presentation to the hospital prior to recruitment. 

3,950 children were recruited between September 2014 to May 2017. Eligible patients were between 2 months and 12 years of age and were hospitalized for severe anaemia with a haemoglobin < 6 g/dl. 

Severity was determined by haemoglobin < 4 g/dl, respiratory distress, impaired consciousness or haemoglobinuria (suggestive of Black Water Fever).

Intervention

This factorial design was of four randomisation arms following two tracts. Children were stratified by disease severity to TRACT A and TRACT B.

1,565 children with non-severe anaemia were randomised within TRACT B to compare immediate with delayed transfusion, with 778 children receiving an immediate transfusion. In comparison, 787 children were monitored clinically and only received a transfusion if they developed severity signs or a haemoglobin <4 g/l. 

Across TRACT A and TRACT B combined, 3,199 children were included in the factorial randomization to 30mls/kg vs 20mls/kg blood volume, with 1,598 children in both the intervention and control arms.

Intervention

Immediate transfusion 

Among children in the intervention arm who received an immediate transfusion, a secondary randomisation occurred as part of the factorial design to determine transfusion volume. 

Intervention – 30 ml/kg of whole blood (15 ml/kg of packed red cells) 

Control – 20 ml/kg of whole blood (10 ml/kg of packed red cells)

Control

Delayed transfusion 

20 ml/kg of whole blood was transfused only if haemoglobin dropped below 4g/dL or if the patient developed new clinical signs of severe anaemia.

Outcomes

Primary outcome

Mortality at 28 days after randomisation. The authors chose a patient-centred, primary outcome in keeping with their pragmatic design. 

Secondary outcomes

These fell under three main categories: 

Efficacy

  • Mortality at 48 hours, 90 days, and 180 days after randomisation; 
  • Development of profound anaemia (Hb <4g/dl) during hospital stay; 
  • Development of severe anaemia after discharge (Hb <6/d); 
  • Hospital readmission;
  • Percentage with anaemia correction (Hb >9g/dl) 

Safety

Economics

  • Cost and cost-effectiveness

What were the results?

Let’s answer this in the context of the two study questions. 

Immediate vs delayed transfusion 

In uncomplicated severe anaemia, immediate blood transfusion did not alter mortality at 1- or six months compared to controls. It’s worth noting that less than half of the children with non-severe anaemia who were clinically monitored without immediate transfusion went on to require transfusion by 96 hours, compared with 100% in the intervention group. Providing that children with non-severe anaemia are monitored for signs of severe and/or complicated anaemia, an immediate transfusion is not required. 

Those randomised to the immediate transfusion strategy were more likely to achieve early haemoglobin recovery and, therefore, less likely to develop profound anaemia. Arguably, the significance of these outcomes is diminished by the lack of difference in hospital readmission or safety outcomes between groups. 

30ml/kg vs 20ml/kg blood volumes 

There was no difference in mortality outcomes for children with complicated severe or profound anaemia in respect to transfusion volume

Yet, this null result masked a significant and opposite effect in 28-day mortality, depending on the presence or absence of fever >37.5°C at screening. 

Among 1,943 children without fever, mortality was lower with a 30ml/kg transfusion volume. Whereas in 1,253 children with fever, mortality was higher with a 30ml/kg transfusion volume.

How good was the paper – the CASP Checklist

Let’s take a sceptical look at the methodology using the CASP RCT critical appraisal tool.

Does the study address a clearly focused research question?

Yes. 

It sets out to determine the optimal timing and volume of blood transfusion in children with severe anaemia to reduce mortality in low-resource settings.

Was the assignment of participants to interventions randomised? 

Yes. 

Eligible participants were randomised in an acceptable manner (1:1) using a computer-generated randomisation sequence. Allocation concealment was achieved using opaque, sealed envelopes. 

However, children meeting eligibility criteria weren’t always recruited, as enrolment was suspended when blood wasn’t available. This often coincided with the seasonal pattern of diseases such as malaria. This, in turn, may have resulted in a study population where children with anaemia secondary to malaria were underrepresented.  Even so, 64% of study participants had malaria, arguably a large enough proportion for the results to be generalisable to this group. 

Were all participants who entered the study accounted for at its conclusion?

Yes. 

Impressively, an intention-to-treat analysis was adopted with minimal loss to follow-up. With a follow-up rate of over 95%, the research group demonstrated how rigorous clinical research can be performed in low-resource, emergency care settings. 

Was blinding achieved?

No. 

It was an open-label trial by necessity, although this is unlikely to have affected the main results given the authors’ choice of an objective primary outcome in 28-day mortality. However, it may have introduced detection and performance bias, influencing secondary endpoints, including decisions regarding further transfusion requirements and discharge. 

Have the authors identified all important confounding factors?

Aside from adjusting for potential confounders in baseline characteristics, the authors carried out ten pre-specified and six additional subgroup analyses. These were presented as hazard ratios and included fever at presentation, previous transfusion ever, haemoglobinuria, malaria, sickle cell disease on enrolment, HIV, evidence of sepsis, malnutrition, shock, hypothermia, and dehydration

Were the study groups similar at the start of the trial?

Yes. 

Groups were well matched at baseline. 

Do you believe the results?

The robust study methodology allows questions on transfusion timing and volumes to be explored. The low dropout rate and computer randomisation demonstrate good internal validity with an appropriate power calculation performed to detect a difference in a patient centred outcome. 

It’s difficult to understand why their mortality rate of 2% was considerably less than the expected 9%

  • Exclusion of children with chronic disease and those who required immediate transfusion before randomisation may have made a difference.
  • Maybe the pause in recruitment during periods of insufficient blood supply was a reason. Alarmingly, when blood supplies are low or absent, children often die much earlier, within six hours of admission. 
  • Perhaps it reflects the superior care provided during the trial compared to usual care in real life, questioning the generalisability of the results to current practice in sub-Saharan Africa.
  • Alternatively, the pragmatic trial design may be responsible for the reduced mortality given that it incorporated monitoring for severe or complicated anaemia in the control group and subsequently facilitated transfusion after admission.  
  • Finally, time to address the opposing effect on mortality in the presence or absence of fever. Though very interesting data, we can’t draw any strong conclusions given the negative primary outcome. 

Can the results be applied to your local population?

No. 

But this wasn’t the intention of the TRACT trial. The authors recognise that no surrogate population exists when asking specific questions regarding transfusion strategies for children with severe anaemia in Africa. Choosing to perform a large RCT in the setting in which the guidelines will be taken up makes their research almost immediately translatable into practice. That’s exactly what they did. 

In 2020, the TRACT investigators shared their results with key stakeholders at a meeting with paediatric and blood transfusion groups from Africa. It led to the development of a consensus transfusion algorithm. This focuses on averting the need for immediate transfusion in children with severe uncomplicated anaemia by advocating for close monitoring. It recommends establishing fever status prior to transfusion to determine the volume of blood required.  Notably, the WHO have yet to change its current stance on restrictive transfusion practice.

Do the results fit with other available evidence?

This is the first trial to examine a transfusion strategy based on volume for treating severe anaemia in African children. 

A Cochrane review identified two African RCTs comparing blood transfusion vs oral haematinics. It concluded that there was insufficient evidence to determine if immediate transfusion in clinically stable children with severe anaemia reduces mortality. 

Looking at high-resource settings, the TRIPICU trial provides support for a restrictive transfusion strategy, demonstrating that a threshold of 7g/dL was as safe as 9g/dL. However, this prospective, non-inferiority RCT was conducted in relatively stable Canadian and European children. It didn’t venture to the lower thresholds of 4-6 g/dL seen in sub-Saharan Africa, nor did it consider thresholds based on physiological severity signs. 

Why is this important?

The results confirmed the WHO guideline with one very important caveat. While there is a role for allocating transfusions at the initial presentation, by choosing to monitor a particular cohort of stable children with haemoglobin between 4 and 6, you can preserve the precious supplies of donor blood. The importance of monitoring is evidenced by the 45% of children who developed severe and complicated anaemia within the next four days, requiring transfusion. 

Do we think it will change practice with respect to the management of febrile children with severe anaemia – not quite yet. 

The trial, which tested two transfusion strategies in nearly 4000 African children, provides substantial data, although no definitive answers. The authors struggled to come up with a good explanation for why fever might modify mortality risk by 50% at higher transfusion volumes. The subgroup analysis with opposing outcomes in the presence or absence of fever will need to be explored in a future study. 

Are the benefits worth the harms and costs? 

The TRACT trial’s analyses suggested that if the results were implemented and adhered to by clinicians with respect to the timing and volume of blood transfusion, there could be substantial cost savings despite the requirement for additional inpatient monitoring

Where next?

The authors present data on the opposing effects of different transfusion volumes in febrile children with severe anaemia. While they present extremely high-quality statistical evidence on how the response to volume is modified by fever status, they fail to provide mechanisms for this. Sepsis indicators and malaria positivity did not modify the risk. The question remains if, in the absence of biological explanation, guidelines can be revised with volume recommendations given that a higher transfusion volume halved mortality in children without fever.

Without any suggestion of biological plausibility, there is no credible reason to change transfusion volumes just yet. However local units may decide, in the absence of harm, to transfuse at 30ml/kg in afebrile children – a strategy which may reduce hospital stay and repeat transfusion requirements. 

Whereas, in children who present with fever, we may observe improved compliance with the WHO’s restrictive transfusion guidance with 20mL/kg transfusions becoming preferable.

However, while their results do not imply causality, the TRACT team must now focus on understanding these mechanisms. This is not entirely unfamiliar territory for the paper’s leading researcher, Kathryn Maitland, who found herself in a similar position following the release of the equally surprising and somewhat controversial FEAST trial.

And finally, a word from the lead author, Dr Kathryn Maitland:

“Severe anaemia is a common problem, and the WHO guidelines often recommend not to transfuse those who are less severely ill, even though they are very unwell because they are hospitalised.

We were able to show that you can allocate transfusions according to not just as soon as they come through the door; but if you monitor children, you can preserve supplies.

Our research group has similarities with the rest of the world in that even in emergency rooms within the UK and beyond, many guidelines have not been tested. People struggle to conduct this type of research with huge ethical and practicality challenges. We’ve been able to address those in Africa, so we think we are an example for the rest of the world”.

An extract from Kathryn Maitland’s recent podcast episode with the Centre for Tropical Medicine and Global Health entitled “Improving childhood mortality with limited resources”.

The bottom line

The TRACT trial tested two transfusion strategies based on timing and volume in nearly 4000 African children. The aim was to reduce deaths in those hospitalised with severe anaemia. 

Both trial papers led to the development of a consensus algorithm. In the absence of conclusive evidence regarding the interaction with fever, it is unlikely the WHO will change their stance on restrictive transfusion practice in this setting. 

It is difficult to know whether study conditions provided better care or the pause in recruitment or exclusion of children with chronic disease threatened its validity and power.

Switching to inpatient monitoring has the potential to preserve precious blood bank supplies and improve survival in stable children with severe anaemia.

Want to read more?

For further reading, check out the great accompanying editorial here. 

References:

Bojang KA, Palmer A, Boele van Hensbroek M, Banya WA, Greenwood BM. Management of severe malarial anaemia in Gambian children. Trans R Soc Trop Med Hyg. 1997;91(5):557-561. doi:10.1016/s0035-9203(97)90025-0 

Bolton-Maggs PH, Cohen H. Serious Hazards of Transfusion (SHOT) haemovigilance and progress is improving transfusion safety. Br J Haematol. 2013;163(3):303-314. doi:10.1111/bjh.12547 

Calis JC, Phiri KS, Faragher EB, et al. Severe anemia in Malawian children. N Engl J Med. 2008;358(9):888-899. doi:10.1056/NEJMoa072727 death stats, 

Carson JL, Guyatt G, Heddle NM, et al. Clinical Practice Guidelines From the AABB: Red Blood Cell Transfusion Thresholds and Storage. JAMA. 2016;316(19):2025-2035. doi:10.1001/jama.2016.9185 

Doctor A, Cholette JM, Remy KE, et al. Recommendations on RBC Transfusion in General Critically Ill Children Based on Hemoglobin and/or Physiologic Thresholds From the Pediatric Critical Care Transfusion and Anemia Expertise Initiative. Pediatr Crit Care Med. 2018;19(9S Suppl 1):S98-S113. doi:10.1097/PCC.0000000000001590 

Holzer BR, Egger M, Teuscher T, Koch S, Mboya DM, Smith GD. Childhood anemia in Africa: to transfuse or not transfuse?. Acta Trop. 1993;55(1-2):47-51. doi:10.1016/0001-706x(93)90047-f 

Kiguli S, Maitland K, George EC, et al. Anaemia and blood transfusion in African children presenting to hospital with severe febrile illness. BMC Med. 2015;13:21. Published 2015 Feb 2. doi:10.1186/s12916-014-0246-7 

Lacroix J, Hébert PC, Hutchison JS, et al. Transfusion strategies for patients in pediatric intensive care units. N Engl J Med. 2007;356(16):1609-1619. doi:10.1056/NEJMoa066240 

Maitland K, Kiguli S, Olupot-Olupot P, et al. Immediate Transfusion in African Children with Uncomplicated Severe Anemia. N Engl J Med. 2019;381(5):407-419. doi:10.1056/NEJMoa1900105 

Maitland K, Kiguli S, Olupot-Olupot P, et al. Transfusion management of severe anaemia in African children: a consensus algorithm. Br J Haematol. 2021;193(6):1247-1259. doi:10.1111/bjh.17429 

Maitland K, Olupot-Olupot P, Kiguli S, et al. Transfusion Volume for Children with Severe Anemia in Africa. N Engl J Med. 2019;381(5):420-431. doi:10.1056/NEJMoa1900100 

Rajasekaran S, Kort E, Hackbarth R, Davis AT, Sanfilippo D, Fitzgerald R, et al. Red cell transfusions as an independent risk for mortality in critically ill children. Journal of Intensive Care. 2016 Jan 7;4(1). 

Wang Y, Sun W, Wang X, et al. Comparison of transfusion reactions in children and adults: A systematic review and meta-analysis. Pediatr Blood Cancer. 2022;69(9):e29842. doi:10.1002/pbc.29842 

Global status report on blood safety and availability 2021: World Health Organization. Available from: https://www.who.int/publications/i/item/9789240051683 

Pocket book of hospital care for children: Second edition. Guidelines for the management of common childhood illnesses. Geneva: World Health Organization; 2013. 

Centre for Tropical Medicine and Global Health. Kathryn Maitland: Improving childhood mortality with limited resources. Available from: https://www.tropicalmedicine.ox.ac.uk/wall-of-faces/kathryn-maitland-podcast

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