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