1. An Evidence-Based Approach to Transfusion of the Preterm Infant

2. I am on the speakers bureau for: Ikari and Fisher Paykell
Disclosure
I am on the speakers bureau for:
Ikari
and
Fisher Paykell

3. Clinical burden and effects Risk : benefit ratio Placental transfusion
Anemia of Prematurity
1. ANEMIA
Definitions
Clinical burden and effects
Risk : benefit ratio
2. REDUCING TRANSFUSION
Placental transfusion
Minimizing iatrogenic anemia
Erythropoietin
3. WHAT HEMOGLOBIN TRIGGERS TO USE?
Randomized Trial Data

4. Hemoglobin and reticulocytes during first year of life
“Rapid developmental changes and complex interactions for oxygen delivery (prevent) developing clear cut criteria for transfusion. Consequently
clinical practices vary widely.’’
Lundstrom 1977
Saarnen and Siimes 1978
Cited by:
Dallman PR 1981

5. International survey of transfusion practices for extremely premature infants. Guillén U Sem Perinatol 2012;36:244

6. Risk : benefit ratio of transfusions
Higher hemoglobin may improve
oxygen transport
cardiac output
weight gain
apnea
BUT may increase
infections - donor related
iron stores
necrotising enterocolitis
children & adults - death rates
complications from “old blood”

7. Pre Tx g/l
Pre Tx g/l
Pre Tx g/l
Pre Tx Hgb<97
Pre Tx Hgb<97
Pre Tx g/l

8. (J Pediatr 2014;164:475-80).

9. Intra-hospital death to day 28 in 1077 infants with BW < 1500 g
Transfused
Non-Transfused
Red Blood cell transfusions are independently associated with intra-hospital mortality in VLBW: J Pediatrics 2011; 159; 371

10. More NEC with restrictive transfusions
Do transfusions cause NEC?
Kirpalani H, Zupancic JA. Sem Perinatol :269;
Whyte R, Kirpalani H. Low vs high haemoglobin threshold for blood transfusion in very low birth weight infants. Cochrane Database Syst Rev. 2011:CD000512
RCT Data
More NEC with restrictive transfusions
Favours Restrictive
Favours Liberal

11. More NEC with liberal transfusions
Do transfusions cause NEC?
Kirpalani H, Zupancic JA. Sem Perinatol :269
More NEC with liberal transfusions
Observational Studies
Favours Liberal
Favours Restrictive
OR of 7.5 is implausibly high

12. Clinical burden and effects Risk : benefit ratio Placental transfusion
Anemia of Prematurity
1. ANEMIA
Definitions
Clinical burden and effects
Risk : benefit ratio
2. REDUCING TRANSFUSION
Placental transfusion
Minimizing iatrogenic anemia
Erythropoietin
3. WHAT HEMOGLOBIN TRIGGERS TO USE?
Randomized Trial Data

13. Effects of placental transfusion in ELBW: long and short-term outcomes Ghavam S, Batra D, Mercer J, Kugelman A, Hosono S, Oh W, Rabe H, Kirpalani H. Transfusion. 2014;54:1192

14. Phlebotomy overdraw in the neonatal intensive care nursery.
Lin JC, et al: Pediatrics. 2000;106(2) .

15. Early Erythropoietin. Ohlsson A, Aher SM. Cochrane 2014 4:CD004863.
OUTCOME:Transfusions ROP > Stage 3
862 Infants
614 Infants
RR 0.79 (0.73, 0.84)
RR 1.48 (1.02, 2.13)
Favours EPO Control
Favours EPO Control

16. - Placental Transfusion
Anemia of Prematurity
1. ANEMIA
- Definitions
- Clinical burden and effects
- Risk : benefit ratio
2. REDUCING TRANSFUSION
- Placental Transfusion
- Minimizing iatrogenic anemia
- Erythropoietin
3. WHAT HEMOGLOBIN TRIGGERS TO USE?
- Randomized Trial Data

17. Comparison of Trial Design
Iowa Trial
PINT Trial
Restrictive
Liberal
Participating centers 1 10
No. of subjects
100
451
Treatment allocation
Randomized
Stratification
Birth weight
Birth weight, center
Mean BW (g)
954
958
771
769
Mean GA (wk) 28 26
This compares the study designs of the two relevant trials. One was a single center trial and the other had 10 centers – and one trial had lower mean BW and GAs.

18. PICOT Iowa
Population <32 wks GA Intervention Liberal Hgb Tx Comparison Restrictive Hgb Tx Outcomes No. of RBC Tx Time frame wks PMA

19. PRIMARY OUTCOME IOWA Number of Transfusions
Low Hgb
High Hgb
The Primary Outcome of the Iowa trial was number of transfusions and this was reduced to a statistically significant degree.
p = 0.025

20. ADDITIONAL OUTCOMES IN IOWA STUDY

21. J Pediatr 2006:149; 301

22. PICOT PINT
Population <1000 g BW Intervention Liberal Hgb Tx Comparison Restrictive Hgb Tx Outcomes Intact Survival Time frame 36 wks PMA

23. Inclusions
< 1000 g BW
< 48 hours age
< 31 wks GA

24. 135 115 120 100 100 85 120 100 100 85 85 75 Respiratory support Yes No
TRANSFUSION THRESHOLDS
PINT
Respiratory support
Yes No
Age
Week one
Week two
≥ Week three
High Low High Low

25. PRIMARY OUTCOME PINT Death, BPD, severe ROP, Brain Injury
Low Hgb
High Hgb
165/223 (74%)
159/ (70%)
The primary outcome of the PINT trial was the composite of death, or survival with either BPD or severe ROP or brain injury (defined as Ventricular Enlargement, echodense lesions or PVL) – AT FINAL HOSPITAL DISCHARGE - and this was not statistically significantly different between groups.
OR = % CI p = 0.26

26. PINT-Outcome Study (PINT-OS) Primary Outcome & a-priori components
0.1 1 10
100 OR
Composite
1.45 (0.94, 2.21)
1.18 (0.72,1.93)
1.32 (0.53, 3.27)
1.74 (0.98, 3.11)
2.16 (0.19, 24.1)
1.45 (0.32, 6.58)
p=0.09
Death
Cerebral Palsy
p=0.06
Cognitive Delay <70
The PINT FU Study of survivors at months.
It had a stated primary composite outcome of death; and/or: cerebral palsy, or cognitive delay, or blindness or
deafness. Cognitive delay was assessed by the standard Bayley II scales, and the primary component was defined
as 2 SDs below the norm.
93% of survivors were successfully followed.
This shows the OR and 95% CIs Firstly for the primary composite:
And below for the a-priori secondary analysis of components of the composite.
The point estimate of the OR of all components exceeds 1, and all 95% CI are insignificant.
However the cognitive delay showed benefit in the point estimate, without quite achieving statistical significance – at p=0.06.
There is no statistical adjustment shown here for multiple outcomes.
Blindness
Deafness
Favors Low Favors High

27. PINT-Outcome Study (PINT-OS) Post-Hoc Secondary Analysis
0.1 1 10
100 OR
1.71
1.12, 2.61
1.18
0.72 , 1.93
1.32
0.53 , 3.27
1.81
1.12,2.93
2.16
0.19 , 24.1
1.45
0.32 , 6.58
Composite
p=0.013
Death
Cerebral Palsy
Cognitive Delay <85
p=0.016
Seeing the interesting p values, forced the PINT investigators to ask in a secondary analysis:
“What would have happened if cognitive delay was assessed by the standard categorized by 1 SD below the norm?”
With this cut-off for the cognitive delay, there is an apparent benefit favouring higher Hemoglobins which is of
statistical significance”.
Blindness
Deafness
Favors Low Favors High

28. RCT era: Risk : benefit ratio of transfusions
Higher hemoglobin may improve
oxygen transport
cardiac output
weight gain - Not true
apnea Not true
NEC ?
Neurocognitive outcomes ?
BUT may increase or unknown
Infections - donor related
iron stores
death rates - unlikely

29. WHEN SHOULD WE TRANSFUSE?

30. NICHD – NEONATAL RESEARCH NETWORK
Transfusions For Prematures (TOP) Does a Liberal Red Blood Cell Transfusion Strategy Improve Neurologically-Intact Survival of ELBW Infants as Compared to a Restrictive Strategy? Clinicaltrials.gov NCT

31. 1. Low thresholds of PINT and Iowa studies were comparable
CONCLUSIONS
1. Low thresholds of PINT and Iowa studies were comparable
2. It is reasonable to maintain infants above these lower thresholds
3. The high threshold was higher in Iowa than in PINT
4. The benefit of higher thresholds remains uncertain
16th Century dissection