An Evidence-Based Approach to Transfusion of the Preterm Infant

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

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

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

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

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”

Pre Tx 97-113 g/l Pre Tx 97-113 g/l Pre Tx 113-129 g/l Pre Tx Hgb<97 Pre Tx Hgb<97 Pre Tx 113-129 g/l

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

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

More NEC with restrictive transfusions 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 RCT Data More NEC with restrictive transfusions Favours Restrictive Favours Liberal

More NEC with liberal transfusions Do transfusions cause NEC? Kirpalani H, Zupancic JA. Sem Perinatol 2012 36:269 More NEC with liberal transfusions Observational Studies Favours Liberal Favours Restrictive OR of 7.5 is implausibly high

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

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) .

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

- 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

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.

PICOT Iowa Population <32 wks GA Intervention Liberal Hgb Tx Comparison Restrictive Hgb Tx Outcomes No. of RBC Tx Time frame 36 wks PMA

PRIMARY OUTCOME IOWA Number of Transfusions Low Hgb High Hgb 3.3 + 2.9 5.2 + 4.5 The Primary Outcome of the Iowa trial was number of transfusions and this was reduced to a statistically significant degree. p = 0.025

ADDITIONAL OUTCOMES IN IOWA STUDY

J Pediatr 2006:149; 301

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

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

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 135 115 120 100 100 85 120 100 100 85 85 75

PRIMARY OUTCOME PINT Death, BPD, severe ROP, Brain Injury Low Hgb High Hgb 165/223 (74%) 159/228 (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 = 1.3 95% CI 0.8-2.0 p = 0.26

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 18-24 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

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

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?

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 NCT01702805

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