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An Evidence-Based Approach to Transfusion of the Preterm Infant
Disclosure I am on the speakers bureau for:Ikari andFisher Paykell
Anemia of Prematurity 1. ANEMIA
Definitions Clinical burden and effects Risk : benefit ratio
2. REDUCING TRANSFUSIONPlacental transfusionMinimizing iatrogenic anemiaErythropoietin
3. WHAT HEMOGLOBIN TRIGGERS TO USE? Randomized Trial Data
Hemoglobin and reticulocytes during first year of life
Lundstrom 1977
Saarnen and Siimes 1978
Cited by:Dallman PR 1981
“Rapid developmental changes and complex interactions for oxygen delivery (prevent) developing clear cut criteria for transfusion. Consequentlyclinical practices vary widely.’’
International survey of transfusion practices for extremely premature infants. Guillén U Sem Perinatol 2012;36:244
Risk : benefit ratio of transfusions Higher hemoglobin may improveHigher 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”
Pre Tx Hgb<97 Pre Tx 113-129 g/l Pre Tx Hgb<97
Pre Tx 113-129 g/l
Pre Tx 97-113 g/l
Pre Tx 97-113 g/l
(J Pediatr 2014;164:475-80).
Red Blood cell transfusions are independently associated with intra-hospital mortality in VLBW: J Pediatrics 2011; 159; 371
Intra-hospital death to day 28 in 1077 infants with BW < 1500 g
Transfused
Non-Transfused
Do transfusions cause NEC? Kirpalani H, Zupancic JA. Sem Perinatol 2012 36:269;Whyte R, Kirpalani H. Low vs high haemoglobin threshold for blood transfusion in very low birth weight infants. Cochrane Database Syst Rev. 2011:CD000512
Favours Restrictive
Favours Liberal
More NEC with restrictive transfusions
RCT Data
Favours Restrictive
Favours Liberal
Observational Studies
OR of 7.5 is implausibly high
More NEC with liberal transfusions
Do transfusions cause NEC? Kirpalani H, Zupancic JA. Sem Perinatol 2012 36:269
Anemia of Prematurity 1. ANEMIA
Definitions Clinical burden and effects Risk : benefit ratio
2. REDUCING TRANSFUSIONPlacental transfusionMinimizing iatrogenic anemiaErythropoietin
3. WHAT HEMOGLOBIN TRIGGERS TO USE? Randomized Trial Data
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
Phlebotomy overdraw in the neonatal intensive care nursery.Lin JC, et al: Pediatrics. 2000;106(2) .
862 Infants
Early Erythropoietin. Ohlsson A, Aher SM. Cochrane 2014 4:CD004863.
RR 0.79 (0.73, 0.84)
614 Infants
RR 1.48 (1.02, 2.13)
Favours EPO Control
Favours EPO Control
OUTCOME:Transfusions ROP > Stage 3
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
Comparison of Trial Design
Iowa Trial PINT Trial
Restrictive Liberal Restrictive Liberal
Participating centers
1 10
No. of subjects 100 451
Treatment allocation
Randomized Randomized
Stratification Birth weight Birth weight, center
Mean BW (g) 954 958 771 769
Mean GA (wk) 28 28 26 26
Population <32 wks GA
Intervention Liberal Hgb Tx
Comparison Restrictive Hgb Tx
Outcomes No. of RBC Tx
Time frame 36 wks PMA
PICOT Iowa
PRIMARY OUTCOME IOWA Number of Transfusions
5.2 + 4.5
High Hgb Low Hgb
p = 0.025
3.3 + 2.9
ADDITIONAL OUTCOMES IN IOWA STUDY
J Pediatr 2006:149; 301
Population <1000 g BW
Intervention Liberal Hgb Tx
Comparison Restrictive Hgb Tx
Outcomes Intact Survival
Time frame 36 wks PMA
PICOT PINT
< 1000 g BW < 48 hours age < 31 wks GA
TRANSFUSION THRESHOLDS
Yes No High Low High Low
Respiratory support
135 115
120 100
100 85
120 100
100 85
85 75
Age
Week one
Week two
≥ Week three
PRIMARY OUTCOME PINT Death, BPD, severe ROP, Brain Injury
165/223 (74%)
159/228 (70%)
High Hgb Low Hgb
OR = 1.3 95% CI 0.8-2.0 p = 0.26
PINT-Outcome Study (PINT-OS)PINT-Outcome Study (PINT-OS) PrimaryPrimary Outcome & a-priori components Outcome & a-priori components
Favors Low Favors High
Composite
0.1 1 10 100
Death
Cerebral Palsy
Cognitive Delay <70
Blindness
Deafness
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)
OR
p=0.06
p=0.09
PINT-Outcome Study (PINT-OS) PINT-Outcome Study (PINT-OS) Post-Hoc Secondary Analysis Post-Hoc Secondary Analysis
Favors Low Favors High
Composite
0.1 1 10 100
Death
Cerebral Palsy
Cognitive Delay <85
Blindness
Deafness
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
p=0.013
p=0.016
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
WHEN SHOULD WE TRANSFUSE?
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 NCT01702805
NICHD – NEONATAL RESEARCH NETWORK
16th Century dissection
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
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