Immediate Transfusion in African Children with Uncomplicated Severe Anaemia

K.Maitland et al. New England Journal of Medicine; August 1st 2019; 381:407-419; doi:10.1056/NEJMoa1900105

Clinical Question

• In children hospitalised with uncomplicated severe anaemia, is an immediate blood transfusion strategy superior to delayed transfusion in reducing 28-day mortality?

Background

• World Health Organisation guidelines encourage a restrictive transfusion approach in children in sub-Saharan Africa with anaemia
• The current recommendation is not to transfuse if haemoglobin levels are 4 to 6 g/dL WHO guideline
• Compliance with these guidelines is poor Data from FEAST study
• Blood is a scarce resource, particularly in sub-Saharan Africa, and it also has a significant cost implication
• Previous studies in the sub-Saharan African population have challenged traditional practice in relation to intravenous fluid therapy SSSP2 study; FEAST study
• In the developed world, restrictive transfusion in critically ill adults has been shown to be consistent with improved or similar mortality outcomes when compared with more liberal strategies TRISS study; TRICC study; TRICS-III study; TITRe2 study
• This is the first randomised controlled trial to investigate delayed versus immediate transfusion in African children

Design

• Open-label, multi-centre, factorial, randomised controlled trial
• Children randomised in a 1:1 ratio to undergo immediate transfusion (intervention group) or no immediate transfusion (control group)
• Computer-generated randomisation sequence with permuted blocks of variable size
• Allocation concealment using opaque, sealed envelopes
• Patients stratified according to trial centre
• Factorial design meant that children in intervention arm underwent a second randomisation to receive either 20 ml or 30 ml of whole blood per kilogram of body weight
• 80% power calculation performed for study to detect a 50% relative difference in 28-day mortality from 9% in the control group to 4.5% in the treatment group
• Primary outcome was mortality at 28 days after randomisation
• Secondary outcomes were mortality at 48 hours, 90 days and 180 days; development of new profound anaemia (HgB < 4 g/dL) during the primary hospitalisation or severe anaemia (HgB < 6 g/dL) after hospital discharge; hospital readmission; the percentage of children who had correction of anaemia (defined as HgB > 9 g/dL); suspected transfusion reactions; serious adverse events; and cost and cost effectiveness
• Adverse events determined by a blinded end-point review committee

Setting

• Three hospitals in Uganda and one hospital in Malawi
• September 2014 to May 2017

Population

• Inclusion: Children aged between 2 months and 12 years of age who were hospitalised for uncomplicated severe anaemia (defined as a haemoglobin level of 4 to 6 g/dL)
• Exclusion:
  • Signs of clinical severity: reduced level of consciousness; respiratory distress; acute haemoglobinuria; known sickle cell disease
  • Severe anaemia: Haemoglobin level < 4 g/dL
  • Children with known chronic disease
  • Children who were exclusively breast fed
• 6171 children assessed for eligibility
  • 2452 excluded due to clinical severity
  • 1415 children did not have anaemia
  • 329 refused consent
  • 410 excluded for other reasons
• 1565 children underwent randomisation. 778 randomised to immediate blood transfusion. 787 children randomised to the control group
  • Median age 26 months (IQR 12-50)
  • 62.6% children positive for malaria
  • 56.6% male sex
  • No major baseline imbalances between groups

Intervention

• Immediate transfusion
• 20 or 30 ml/kg of whole blood (or 10-15 mls of packed or settled cells) transfusion administered depending on secondary randomisation group as part of factorial study design. See Transfusion Volume for Children with Severe Anemia in Africa
• Second transfusions if indicated at designated randomisation volume
• Additional transfusions administered with 20 ml/kg blood volume, regardless of secondary randomisation group

Control

• Delayed transfusion
• 20 ml/kg of whole blood transfusion if haemoglobin dropped below 4 g/dL or if new signs of clinical severity developed

Management common to both groups

• All children treated in general paediatric wards
• No ventilatory facilities available
• Point of care testing available for haemoglobin, glucose and lactate
• Other treatments, including antimalarial and antibiotic regimens, were administered according to national guidelines
• Bedside observations were performed at admission, every 30 minutes for the first 2 hours, and then 4,8,16,24 and 48 hours after initiation of the first transfusion or randomisation
• Haemoglobin assessed with the use of the HaemoCue system every 8 hours during the first 24 hours and then at 48 hours or if indicated by clinical deterioration

Outcome

• Primary outcome: No difference between intervention and control groups in 28 day mortality
  • 7  children out of 778 died in the immediate transfusion group and 6 children out of 787 died in the control group (0.9% vs 0.8%; hazard ratio 0.54; 95% confidence interval 0.22 to 1.36; p=0.19)
  • Median time to transfusion in immediate-transfusion group was 1.3 hours versus 24.9 hours in the delayed transfusion group
  • 44.8% of children in the delayed transfusion group had received a transfusion by 96 hours, compared with 100% of children in the immediate-transfusion group
• Secondary outcomes: Median length of hospital stay 3 days (IQR 3 to 4) in immediate-transfusion group and 4 days (IQR 3 to 6) in the delayed-transfusion group (HR for time to discharge 1,62; 95% CI 1.46 to 1.80)
• The immediate transfusion group were more likely to have correction of anaemia (defined as a haemoglobin of great than 9.0 g/dL) (51.3% vs. 5.5%; HR 11.73 (95% CI 8.69-15.84)
  • The delayed-transfusion group were more likely to develop profound anaemia during hospitalisation (39.3% vs. 1.4%; HR 0.03 (95% CI 0.02-0.05) and more likely to develop severe anaemia after hospital discharge (18.0% vs. 13.6%; HR 0.73 (95% CI 0.56 – 0.94)
• No difference in death at 90 days, death at 180 days, hospital readmission rates or adverse events
• Economic analysis found that overall costs were, on average, $5.63 less in the control group.

Authors’ Conclusions

Strengths

• A well-conducted, multicentre randomised controlled trial, with power calculation performed to detect a difference in a patient centred outcome
• Good compliance with assigned study intervention
• Minimal loss to follow-up (5%) despite a resource-poor setting and follow-up occurring to 180 days
• Important clinical question addressed
• Assessors for adverse events were blinded to the study group
• Economic analysis performed

Weaknesses

• Sub-Saharan African setting limits generalisability to the developed world
• Study was underpowered to detect a mortality difference. This was overestimated in the power calculation
• Unclear how standard of care in the study reflected real-world practice, particularly in frequency of haemoglobin monitoring. The lower than expected mortality rate leads one to suspect that study participants received superior care than usual

The Bottom Line

• Compliance with the WHO recommendation of a restrictive transfusion strategy in physiologically stable children with a haemoglobin of 4 to 6 g/dL is safe, provided they have haemoglobin measured at regular intervals and have ongoing clinical assessment performed.

External Links

• [abstract] Maitland. Immediate Transfusion in African Children with Uncomplicated Severe Anemia
• [editorial] Immediate Transfusion and Transfusion Volume in African Children with Severe Anemia
• [further reading] Maitland. Transfusion Volume for Children with Severe Anemia in Africa

Metadata

Summary author: Fraser Magee
Summary date: 7th August 2019
Peer-review editor: Adrian Wong