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

The undifferentiated critically sick child

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

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)

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

Supply: In SSA: < 5 units/1000 population

WHO estimates needs are > 20 units/1000 for current demand

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?

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?

Designing the optimal trial

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

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

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)

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”

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

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

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

Tx30

Tx20

Long term interventions

The next step

Designed the trial protocolIdentified trial sitesSecured the funding

Operationalising the trial……………..

Stock outs?

Certificate of Analysis?

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!!

Pre-trial audit

Packed cell??

Whole blood??

these were all ‘red cell concentrates’ settled by gravity

Donor blood-certificate of analysis?

Age of Blood?

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

Red cell polymorphisms in donor blood

Strengthening BTS: comes at a cost!

Plos Med Sept 2012

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…..

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%)

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.