The PINT StudyThe PINT StudyJournal of Pediatrics Sept 2006;149:301-7Journal of Pediatrics Sept 2006;149:301-7

Yulia Lin, MD FRCPCYulia Lin, MD FRCPCTransfusion Medicine Resident, University of TorontoTransfusion Medicine Resident, University of Toronto

Transfusion Medicine Residents Journal ClubTransfusion Medicine Residents Journal ClubJanuary 24, 2007January 24, 2007

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RationaleRationale

Extremely low birth weight infants Extremely low birth weight infants (ELBW<1000g) account for 9% of NICU (ELBW<1000g) account for 9% of NICU admissionsadmissions– 94% received RBC transfusion (lab sampling 94% received RBC transfusion (lab sampling

and immature hematopoietic system)and immature hematopoietic system) Risks and benefits of transfusion unclearRisks and benefits of transfusion unclear

– Risks: transfusion-associated infections and Risks: transfusion-associated infections and iron overload iron overload

– Benefits: avoiding morbidities associated with Benefits: avoiding morbidities associated with chronic anemic hypoxemiachronic anemic hypoxemia

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QuestionQuestion

Population: ELBW newborn infantsPopulation: ELBW newborn infants

Intervention: Transfusion algorithmIntervention: Transfusion algorithm– Restrictive Hb thresholdsRestrictive Hb thresholds– Liberal Hb thresholdsLiberal Hb thresholds

Outcome:Outcome:– Composite of death or survival with severe Composite of death or survival with severe

morbidity at time of dischargemorbidity at time of discharge

PICOT

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PopulationPopulation

Enrolled from 10 NICUs in Enrolled from 10 NICUs in Canada, US, AustraliaCanada, US, Australia

InclusionInclusion ELBW < 1000gELBW < 1000g GA < 31 weeksGA < 31 weeks < 48 hrs at enrollment< 48 hrs at enrollment Informed consent from Informed consent from

parent/guardianparent/guardian

ExclusionExclusion Transfusion after 6 hrs of Transfusion after 6 hrs of

ageage Deemed non-viableDeemed non-viable Cyanotic heart diseaseCyanotic heart disease Acute shockAcute shock Congenital anemiaCongenital anemia Family history of anemia or Family history of anemia or

hemolytic diseasehemolytic disease Anticipated epo useAnticipated epo use Known parental opposition Known parental opposition

to transfusionto transfusion

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InterventionIntervention Randomized to low (restrictive) or high (liberal) Randomized to low (restrictive) or high (liberal)

Hb thresholdHb threshold– Allocation done at coordinating centreAllocation done at coordinating centre– Stratified by center and birth weightStratified by center and birth weight

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InterventionIntervention

InterventionIntervention– Transfusions: washed, packed RBCs 15ml/kg Transfusions: washed, packed RBCs 15ml/kg

given within 6 hours of Hb valuegiven within 6 hours of Hb value– Non-algorithm dictated RBC transfusions in Non-algorithm dictated RBC transfusions in

event of shock, severe sepsis, coagulation event of shock, severe sepsis, coagulation defects, surgery or for unanticipated defects, surgery or for unanticipated emergenciesemergencies

– Caregivers not blinded to algorithmCaregivers not blinded to algorithm– Did not dictate how often Hb measuredDid not dictate how often Hb measured

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Patient FlowPatient Flow

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Baseline characteristicsBaseline characteristics

Are the columns equal?Who is the typical pt?Any missing factors?

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Primary OutcomePrimary Outcome

Primary outcomePrimary outcome– Composite of death or survival with one or more of Composite of death or survival with one or more of

Retinopathy of prematurity: Grade 3 through 5 (blinded)Retinopathy of prematurity: Grade 3 through 5 (blinded) Bronchopulmonary dysplasia: supplemental oxygen at Bronchopulmonary dysplasia: supplemental oxygen at

postconceptual age of 36 weeks or later (clinical)postconceptual age of 36 weeks or later (clinical) Brain injury: presence of cystic periventricular Brain injury: presence of cystic periventricular

leukomalacia, intra-parenchymal echodensity, leukomalacia, intra-parenchymal echodensity, porencephalic cyst, or ventriculomegaly on the “worst” porencephalic cyst, or ventriculomegaly on the “worst” cranial ultrasound available before discharge (blinded)cranial ultrasound available before discharge (blinded)

All independently associated with neurodevelopment All independently associated with neurodevelopment outcome at 18 months’ ageoutcome at 18 months’ age

– Assessments performed in 1Assessments performed in 1stst week and pre-discharge week and pre-discharge from tertiary care hospitalfrom tertiary care hospital

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Primary OutcomePrimary Outcome

StatisticsStatistics– Sample size of 424 neonates based on Sample size of 424 neonates based on

detecting with 90% power an absolute risk detecting with 90% power an absolute risk reduction of 15% in either direction (two-sided reduction of 15% in either direction (two-sided of 0.05) for primary outcome of 0.05) for primary outcome

1111

Primary OutcomePrimary Outcome

Median followup of 12 weeksMedian followup of 12 weeks Followup completeFollowup complete

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Secondary OutcomesSecondary Outcomes

Hematologic and Transfusion OutcomesHematologic and Transfusion Outcomes– Separation between groups of about 10g/L by 4 weeksSeparation between groups of about 10g/L by 4 weeks

No difference for other secondary outcomesNo difference for other secondary outcomes– Duration of ventilatory support, growth, length of hospital Duration of ventilatory support, growth, length of hospital

staystay

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Authors’ conclusionsAuthors’ conclusions

The present findings provide evidence that The present findings provide evidence that transfusion thresholds in ELBW infants can transfusion thresholds in ELBW infants can be moved downwards by at least 10g/L be moved downwards by at least 10g/L without incurring a clinically important without incurring a clinically important increase in the risk of death or major increase in the risk of death or major neonatal morbidityneonatal morbidity

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Critical AppraisalCritical Appraisal

StrengthsStrengths– Large difficult multi-centre trialLarge difficult multi-centre trial– Predefined primary outcomePredefined primary outcome– Powered to detect difference of 15%Powered to detect difference of 15%

WeaknessesWeaknesses– Clinicians and caregivers not blinded (but most Clinicians and caregivers not blinded (but most

outcomes assessed blindly)outcomes assessed blindly)– Non-algorithm transfusions given (but still kept Non-algorithm transfusions given (but still kept

separation in Hb)separation in Hb)– Did not dictate how often Hb measuredDid not dictate how often Hb measured

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Critical AppraisalCritical Appraisal Are the results valid?Are the results valid?

Did groups begin the study with similar prognosis?Did groups begin the study with similar prognosis?– Randomized?Randomized? YesYes– Randomization concealed?Randomization concealed? YesYes– Intention to treat?Intention to treat? YesYes– Groups similar at baseline?Groups similar at baseline? YesYesDid groups retain similar prognosis after starting?Did groups retain similar prognosis after starting?– Were pts blinded? Were pts blinded? YesYes– Were clinicians blinded?Were clinicians blinded? NoNo– Were outcomes assessors blinded?Were outcomes assessors blinded? Yes (exc BPD)Yes (exc BPD)– Was followup complete?Was followup complete? YesYes

Guyatt G, Rennie D. Users’ Guide to the Medical Literature.

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Critical AppraisalCritical Appraisal

What are the results?What are the results?– What was the treatment effect?What was the treatment effect? 2.7%2.7%– How precise was the estimate?How precise was the estimate? -3.7 to 9%-3.7 to 9%

How can I apply the results to patient care?How can I apply the results to patient care?– Were the study pts similar to my pts?Were the study pts similar to my pts? YesYes– Were all clinically important outcomes considered?Were all clinically important outcomes considered?

YesYes– Are the likely treatment benefits worth the Are the likely treatment benefits worth the

potential harm and costs?potential harm and costs? Yes?Yes?

Guyatt G, Rennie D. Users’ Guide to the Medical Literature.

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2005: Iowa Trial2005: Iowa Trial

RCT in 100 preterm infants (500-1300g)RCT in 100 preterm infants (500-1300g) Liberal vs. restrictive transfusion groupLiberal vs. restrictive transfusion group Powered to detect difference in # of Powered to detect difference in # of

transfusionstransfusions ResultsResults

– Greater separation of Hb 27 g/LGreater separation of Hb 27 g/L– More RBC transfusions (5.2 More RBC transfusions (5.2 4.5 vs 3.3 4.5 vs 3.3 2.9) 2.9)– No difference in donors (2.8 No difference in donors (2.8 2.5 vs 2.2 2.5 vs 2.2 2.0) 2.0)– No difference in infants not transfused (12% vs No difference in infants not transfused (12% vs

10%)10%)

Bell et al. Pediatrics 2005;115:1685-91

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2005: Iowa Trial2005: Iowa Trial

Secondary neurologic outcomesSecondary neurologic outcomes

OutcomeOutcome Liberal Liberal RestrictiveRestrictive PP

IVHIVH-Any gradeAny grade-Grade 3/4Grade 3/4-Grade 4Grade 4

17 (33)17 (33)

8 (16)8 (16)

0 (0)0 (0)

14 (29)14 (29)

5 (10)5 (10)

4 (8)4 (8)

0.6690.669

0.5550.555

0.0540.054

PVLPVL 0 (0)0 (0) 4 (8)4 (8) 0.1150.115

IVH 4 / PVLIVH 4 / PVL 0 (0)0 (0) 6 (12)6 (12) 0.0120.012

Bell et al. Pediatrics 2005;115:1685-91

Grade 4 hemorrhages developed by 9 days of ageGrade 4 hemorrhages developed by 9 days of age PVL assessed in late ultrasound examinationsPVL assessed in late ultrasound examinations

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2005: Iowa Trial2005: Iowa Trial

Authors’ conclusions: results suggest that Authors’ conclusions: results suggest that growing use of restrictive RBC transfusion growing use of restrictive RBC transfusion is not without cost and should be is not without cost and should be reexamined carefullyreexamined carefully

CriticismsCriticisms– Not powered for brain US outcomesNot powered for brain US outcomes– No baseline ultrasoundsNo baseline ultrasounds– Followup incomplete for this outcomeFollowup incomplete for this outcome

All 100 pts had day 7 ultrasounds but only 52 (24 All 100 pts had day 7 ultrasounds but only 52 (24 liberal and 28 restrictive) had day 42 examinations liberal and 28 restrictive) had day 42 examinations

– Presumably same mechanism of Grade 3 vs. 4Presumably same mechanism of Grade 3 vs. 4

Bell et al. Pediatrics 2005;115:1685-91

2020

2005: Iowa Trial2005: Iowa Trial

Secondary neurologic outcomesSecondary neurologic outcomes

OutcomeOutcome Liberal Liberal RestrictiveRestrictive PP

IVHIVH-Any gradeAny grade-Grade 3/4Grade 3/4-Grade 4Grade 4

17 (33)17 (33)

8 (16)8 (16)

0 (0)0 (0)

14 (29)14 (29)

5 (10)5 (10)

4 (8)4 (8)

0.6690.669

0.5550.555

0.0540.054

PVLPVL 0 (0)0 (0) 4 (8)4 (8) 0.1150.115

IVH 4 / PVLIVH 4 / PVL 0 (0)0 (0) 6 (12)6 (12) 0.0120.012

Bell et al. Pediatrics 2005;115:1685-91

Grade 4 hemorrhages developed by 9 days of ageGrade 4 hemorrhages developed by 9 days of age PVL assessed in late ultrasound examinationsPVL assessed in late ultrasound examinations

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The PINT EditorialThe PINT Editorial

Bell EF. J Pediatr 2006;149:287-9

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ConclusionsConclusions

PINT study: transfusion thresholds in ELBW PINT study: transfusion thresholds in ELBW infants can be moved downward by at infants can be moved downward by at least 10 g/L without incurring a clinically least 10 g/L without incurring a clinically important increase in the risk of death or important increase in the risk of death or major neonatal morbiditymajor neonatal morbidity

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Additional commentsAdditional comments

Composite outcome: always bewareComposite outcome: always beware– Was it appropriate?Was it appropriate?– Are the components equally important to patients? (is Are the components equally important to patients? (is

BPD as important as ROP or brain injury or death)BPD as important as ROP or brain injury or death)– Are they occurring at the same frequency? Yes in this Are they occurring at the same frequency? Yes in this

studystudy This is a superiority study and not a non-This is a superiority study and not a non-

inferiority study so have to be careful about inferiority study so have to be careful about conclusionsconclusions– If you were to do another study comparing a lower 10g If you were to do another study comparing a lower 10g

threshold and found no difference, could you really say threshold and found no difference, could you really say that decreasing by 20g has no effect on outcomes?that decreasing by 20g has no effect on outcomes?

– Need to proceed with cautionNeed to proceed with caution

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Additional commentsAdditional comments

Another study coming PINTOSAnother study coming PINTOS– Looking at neurodevelopmental outcomes at Looking at neurodevelopmental outcomes at

18 months: composite of death, CP, cognitive 18 months: composite of death, CP, cognitive delay, blindness and deafness showing no delay, blindness and deafness showing no difference between the groupsdifference between the groups

Also now with combination of TRICC/PINT Also now with combination of TRICC/PINT and montreal pediatric study that we can and montreal pediatric study that we can say transfusion does not need to be based say transfusion does not need to be based solely on a number and perhaps a lower solely on a number and perhaps a lower Hb level may be appropriate in some Hb level may be appropriate in some cases.cases.