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Transfusion- Issues in AfricaProfessor 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
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The undifferentiated critically sick child
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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
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WHO Recommendations for Paediatric transfusion
Give a transfusion (20mls/kg whole blood or 10mls/kg packed cells toall 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)
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Pattern of usage of blood:
demand
UK
Africa
Largely elective-usePre-planned and predictable
¾’s blood use: paediatric & pregnancy-related Largely emergency useUnpredictableHighly seasonal
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Supply: In SSA: < 5 units/1000 population
WHO estimates needs are > 20 units/1000 for current demand
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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?
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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?
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Designing the optimal trial
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Dominance of 2-arm trialsData 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+
Num
ber o
f arm
s
0 100 200 300 400 500Number of trials
N=632 trials meeting inc lus ion c ri teria
Arms by registered trial - confirmed
2 arm = 80%
courtesy of Matt Sydes, MRC CTU at UCL
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Potential for efficiency savings?Control
Research A
Research B
Research C
5 comparisons6 arms1 trial
Research D
Research E
Control
Research A
Control
Research B
Control
Research C
Control
Research D
Control
Research E
5 comparisons10 arms5 trials
courtesy of Matt Sydes
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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)
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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”
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Factorial design : 4 randomisations3950 children with severe anaemia• Transfusion strategies• Long-term management
BlantyreMalawi
Uganda
TRansfusion and TReatment of severe Anaemia in African Children Trial
ISRCTN84086586
Mpoya, 2015 Trials
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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
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Phase II safety comparing higher 30mls/kg (Tx30) v standard 20mls/kg (Tx20) in 180 children
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Tx30
Tx20
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Long term interventions
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The next step
Designed the trial protocolIdentified trial sitesSecured the funding
Operationalising the trial……………..
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Stock outs?
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Certificate of Analysis?
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Whole bloodViable for 30-42 days
Red cell concentrate from gravitational settllng
Viable for 30-42 days
Packed cellViable 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!!
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Pre-trial audit
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Packed cell??
Whole blood??
these were all ‘red cell concentrates’ settled by gravity
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Donor blood-certificate of analysis?
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Age of Blood?
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What happens to an ageing red blood cell?
HbHb
HistaminesEnzymes
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
CytokinesH+
H +K+
K+
Fe
Fe
Osmotic fragility
Membrane rigidity
Cell aggregability
Cell adhesiveness
capillary
2,3-DPG2,3-DPG
2,3-DPG 2,3-DPG
2,3-DPG
2,3-DPGK+
K+K+
K+
K+
K+
K+
histamine
phospholipids
Additive solution changes
Capillary occlusionEndothelial dysfunction
Inappropriate immunomodulationIncreased clot formation
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Red cell polymorphisms in donor blood
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Strengthening BTS: comes at a cost!
Plos Med Sept 2012
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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…..
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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 4Probably 14Possibly 12Relationship 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%)
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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.