The document discusses issues with blood transfusions in sub-Saharan Africa. It notes that severe anemia is a major cause of pediatric hospital admissions in the region and outcomes are often poor. Current WHO transfusion guidelines are not evidence-based and may not improve outcomes. A clinical trial is evaluating different transfusion strategies and long-term management approaches to address questions about which children should receive transfusions, how much blood should be given, and whether nutritional supplements can improve long-term outcomes. Pre-trial audits revealed problems with blood supply quality, storage, and viability that could impact the trial and transfusions in the region more broadly. Strengthening blood transfusion systems comes at the cost of reducing access and quality in some

1. Transfusion- Issues in Africa
Professor Kathryn Maitland
I have no conflicts of interest.
Cipla have donated the Cotrimoxale for the TRACT trial but have had no involvement
in trial design/conduct/analysis/manuscript preparation

2. The undifferentiated critically sick child

3. Severe anaemia in sub Saharan Africa: the
context
• Severe anaemia major cause of paediatric admission
• Aetiology multifactorial: infection / sickle cell disease /
nutritional
• Outcome poor
6-8% in-hospital mortality
10-14% die or are re-admitted within 6 months
Infection and micronutrient deficiency associated with poor
outcome

4. WHO Recommendations for
Paediatric transfusion
Give a transfusion (20mls/kg whole blood or 10mls/kg packed cells to
all children with a Hb of ≤4 g/dl (profound anaemia)
 less severely anaemic children (Hb 4–6 g/dl) +features of severity
Concerns
Current recommendation developed by ‘blood safety’ committee of WHO
(transfusion specialists) not by the paediatric guideline committee
• Designed to protect supplies of blood
• Not evidence based- but driven by necessity
• Evidence suggests that doctors usually ignore these
• One size fits all: leads to 30% under transfused (Kiguli BMC Med
2015)

5. Pattern of
usage of
blood:
demand
UK
Africa
Largely elective-use
Pre-planned and predictable
¾’s blood use: paediatric
& pregnancy-related
Largely emergency use
Unpredictable
Highly seasonal

6. Supply: In SSA: < 5 units/1000 population
WHO estimates needs are > 20 units/1000 for current demand

7. Transfusion questions
• Which children should receive a transfusion?
Current WHO guidelines have not been evaluated in
clinical trials. We don’t know if giving blood to all
children with Hb <6g/dl improves outcome
• How much blood should be given in a transfusion?
A quarter of children receiving transfusions remain
severely anaemic and up to one third get two or more
blood transfusions during a single hospital admission.
Will a larger initial volume reduce re-transfusion and
improve outcome?

8. Key correlates with poor outcome
Bacterial infection: Associated with longer term
mortality
Nutrition: Vitamin B12 deficiency (30%) & Vitamin A
deficiency (33%) are major causes of severe anaemia
and lead to poor long term outcome
Addressing long-term outcome:
Would giving multi-mineral multi-vitamin
supplements versus or antibioticto prevent
infections improve long term outcome?

9. Designing the optimal trial

10. Dominance of 2-arm trials
Data from Clinicaltrials.gov
Search terms
• Registered from Jan-
2010
to Jul-2012
• Clinical trial
• Randomised
• Interventional
• Superiority
• Met inclusion criteria
 632 trials
2
3
4
5 to 7
8+
0 100 200 300 400 500
Number of trials
N=632 trials meeting inclusion criteria
Arms by registered trial - confirmed
2 arm = 80%
courtesy of Matt Sydes, MRC CTU at UCL

11. Potential for efficiency savings?
Control
Research A
Research B
Research C
5 comparisons
6 arms
1 trial
Research D
Research E
Control
Research A
Control
Research B
Control
Research C
Control
Research D
Control
Research E
5 comparisons
10 arms
5 trials
courtesy of Matt Sydes

12. Factorial trials
• A 2x2 factorial design randomises each patient
twice
– if comparing A versus nothing and B versus nothing,
four possible treatment allocations: nothing, A only, B
only, A+B
• Various extensions
– optional/partial factorial
• some patients only randomised once (not eligible for both
randomisations, institution/patient may not wish to do both)
– conditional factorial
• one randomisation is later in time, conditional on some
other event happening (ie is also partial)

13. Advantages
• Efficiency: maximise questions answered for
patients randomised
– do have to adjust (inflate) sample size in
superiority trials to allow for the fact that patients
randomised to multiple “interventions” (A+B) are
expected to get benefit from both, ie fewer events
overall than just (A) vs (control)
• Allow you to investigate components of a
“bundle”

14. Factorial design : 4 randomisations
3950 children with severe anaemia
• Transfusion strategies
• Long-term management
Blantyre
Malawi
Uganda
TRansfusion and TReatment of severe Anaemia in
African Children Trial
ISRCTN84086586
Mpoya, 2015 Trials

15. Eligible Child >2m with Hb <6g/dl
30 ml/kg
whole blood
transfusion
20 ml/kg
whole blood
transfusion
no
whole
blood transfusion
<4g/dl or prostration or
respiratory distress or
haemoglobinuria or sickle cell
RANDOMISE (R1A)
TRANSFUSION
4-6g/dl, no prostration,
no respiratory distress, no
haemoglobinuria , no sickle cell
RANDOMISE (R1B)
30 ml/kg
whole blood
transfusion
20 ml/kg
whole blood
transfusion
Transfusion randomisations
Or 15 mls/kg
if packed
cells
Or 10 mls/kg
if packed
cells
Profound anaermia and severe complicated Uncomplicated severe anarmia 4-6 g/dl
Mpoya, 2015 Trials

16. Phase II safety comparing higher 30mls/kg (Tx30) v standard 20mls/kg (Tx20)
in 180 children

17. Mean haemoglobin (95% confidence intervals) over 28 days by arm
4
6
8
10
12
MeanHaemoglobin(95%CI)
0hrs 8hrs 16hrs24hrs 48hrs 28days
Time since Admission
Arm A: 20mls/kg Arm B: 30mls/kg
Time: 0hrs 8hrs 16hrs 24hrs 48hrs 28days
N Arm A: 82 73 76 77 76 70
N Arm B: 78 75 76 74 74 71
P <0.0001 <0.0001 0.008 0.002 0.59
Global test of difference between the arms in change in haemoglobin from enrolment
through to 28 days: p<0.0001
Tx30
Tx20

18. Long term interventions

19. The next step
Designed the trial protocol
Identified trial sites
Secured the funding
Operationalising the trial……………..

22. Stock outs?

23. Certificate of Analysis?

24. Whole blood
Viable for 30-42 days
Red cell concentrate from
gravitational settllng
Viable for 30-42 days
Packed cell
Viable for 1 day only
Red cell concentrate
from centrifugation
Viable for 30-42 days
WHO indicates packed
cells but these are only
viable for one day!!

25. Pre-trial audit

26. whole blood packed cells
0
20
40
60
80
100
120
140
haematocrit%
Packed cell??
Whole blood??
these were all ‘red cell concentrates’ settled by gravity

27. Donor blood-certificate of analysis?

28. Age of Blood?

29. What happens to an ageing red blood cell?
Soluble lipids
Cellular membrane changes
-Reduced deformability
-Increased osmotic fragility
-Formation of microparticles
2,3-DPG depletion
-Increased oxygen affinity
-Decreased cytoskeletal plasticity
ATP depletion
-Less resistance to oxidation
-Reduced enzymatic activity
-Reduced transporter function
Haemolysis
Osmotic fragility
Membrane rigidity
Cell aggregability
Cell adhesiveness
2,3-DPG
2,3-DPG
2,3-DPG
2,3-DPG
histamine
Additive solution changes
Capillary occlusion
Endothelial dysfunction
Inappropriate immunomodulation
Increased clot formation

30. Red cell polymorphisms in donor blood

31. Strengthening BTS: comes at a cost!
Plos Med Sept 2012

32. Lessons learnt
• TRACT trial has been the first opportunity in Africa to
highlight issues arising out of ‘strengthening BTS’
• Lack of communication between donor initiatives and
users – risks lives
• ‘Strengthening’ of BTS practices using western models
– consequences on
 quality of blood, storage lesion (cold chain, age of blood)
 Access to blood for transfusion in rural areas – excess
mortality but metrics not being collected
 Lack of quality control of blood issued for transfusion.
• last words from Peter…..

33. Reason for pack not being transfused Number
Wrong blood to right patient 0
Wrong blood to wrong patient 0
Evidence of haemolysis 1
Other – blood had clots 3
Other – blood too old/expired 2
Total
Relationship to transfusion
Definitely 4
Probably 14
Possibly 12
Relationship to transfusion volume
Possibly 6
Total (% of packs) 36 (1.2%)
Total
Packs used 2953
Number of packs halted 124 (4%)
Number due to suspected reaction 20 (1%)

34. TRACT progress
• Started in Sept 2014
• February 2016 (~18mths) : 2140/3954 (~55%)
enrolled
• 690 SAE’S (death, re-hospitalisation (449), life
threatening; other(<3))
• Retention: AtD 90 and D180 is currently 98%
and 97% including deaths (primary and
secondary endpoints) are retained.