Pediatric Blood TransfusionsAnneke Brand; Sanquin Blood Supply & Immunohematologydepartment, Leiden University Medical Centre, Netherlands

No disclosures to report

Who is pediatric?United Nations Convention on the rights of the childUnited Nations Convention on the rights of the child

(resolution 44/25; 1989)

Minors:

Wells et al, BMJ 2006/Cobain TM 2007

• Hemolytic disease newbornMinors:• Fetus• Newborns < 27 days

• Prematurity

• (Cardiac )surgery/ECMONewborns < 27 days• Infants/todlers 28 d-2 yrs• Children 2-11 yrs

( ) g y/

• Inherited blood disorders/MaligancyChildren 2 11 yrs

• Youngsters 12-16(18) yrs • (Trauma) surgery

Every pediatric age category has different transfusion aspects

Perinatal Mortality Rh antagonism: in 1939 the major (45%†) cause of perinatal death

Per 100.000 live borns:1939 450†≥2000 1†

Circle of WillisACM flow velocity

IUTs feasible from the 18-20th gestational weeks onwards;

27 December 2015CONFIDENTIAL 3

Anti-D is still the major (85%) cause severe HDFN ; 15% c and K, < 1% misc

IUT: one product , two recipientsEvery IUT uses another donor

1 : the Fetus

Every IUT uses another donor

1 : the Fetus

• IUT procedure risk ~0.5-1,5%

• is immunocompromised

2: the Mother

• Increased fetomaternal hemorrhage• is immunocompromised

S l t f h ( l li i ) RBC < 3d

• Risk for new additional antibodies

• Select fresh ( long living) RBC < 3d

• High hematocrit ~80-85

L i f i i k (CMV P B19)

• Fetal antigens cannot be avoided

• New anti IUT donor antibodies may• Low infectious risk (CMV, ParvoB19)

• Irradiate 25 Gy

New anti IUT donor antibodies maybe avoidable

80% f IUT 80 l RBC ith Ht 85 l 100 200 l d bl d i80% of IUT use < 80 ml RBC with Ht 85; so only 100-200 ml donor blood is used

Period 1987-1992 1994-2003 2007-2014New maternal RBC antibodies after 3 (1-10) IUT at delivery 1987-2014

IUT matching HDN antigens Rh and K Rh, K, Jk, Fy, S

N woman 91 212 142N woman 91 212 142

N IUT 280 686 481

Median N IUT (range) 3 (1-6) 3 (1-8) 3 (1-10)Median N IUT (range) 3 (1-6) 3 (1-8) 3 (1-10)

New immunisations:

All N / % * 24/26 53/25 20/14Rh/K N / %* 9/10 29/14 11/8

Schonewille Transfusion 2015Duffy-Kidd-S N / %* 12/13 30/14 11/8

Other specificities N 2 3 3

IUT: 50% of no donorNo effect because of foetal FMH

48% of IUT could not be matched

11% Fy,Jk,S Ab in non-matched IUT 3.5% Ab if all IUT matched

Arch Dis Child Fetal Neonatal Ed 2011

Unicef Data 2008

IUVD HYDROPS FOETALIS ICTERUSIUVD HYDROPS FOETALIS ICTERUS

Pediatric Transfusions

Minors: Transfusion aspects:

• Viable fetuses Intrauterine transfusionsN b HDN E h T f i• Newborns HDN: Exchange Transfusions

Prematurity

• Infants/todlers 28 days-2 monthsChildren 2 11 rs• Children; 2-11 yrs

• Youngsters 12-16 (18) years

Hyperbilirubinemia in Iran Frequent (one-third) cause of hospitalization of newborns( Esfandiarpour 2012)

10% receive exchange transfusion(s); [bili > 20 mg/dL] (10% receive exchange transfusion(s); [bili > 20 mg/dL] ( Gharabachi 2010;Badiee 2007)

The 3 articles comprise ~ 200 cases of ET with causes:

ABO ~25 50%ABO ~25-50%Rh ~9-12%ABO + Rh ~14%ABO + Rh 14%G6PD ~4-37%G6PD ± ABO ± Rh ~18%

Despite guidelines : Intravenous Immunoglobulin does NOT reducep g gExchange Transfusions in HDN Smit-Wientjes Pediatrics 2011;127:680-6

IVIG 0.75 g/kg N=41

Placebo N=39

Exchange Transf N=7 (17%) N=6 (15%)

Median ET 0 (0-2) 0 (0-2)

Max bili (mg/dL) 14.8 ±4.7 14.1 ± 4.9

Phototherapy 4.7 ± 1.8 days 5.1±2.1 daysPhototherapy 4.7 ± 1.8 days 5.1±2.1 days

Hospital stay 7 ± 4 days 7 ± 3 days

Top p N 34 (83%) N 34 (87%)Top-up transfusions

N=34 (83%)2 (0-6) units

N=34 (87%)2 (0-6) units

Pediatric Transfusions

Minors: Transfusion aspects:

• Viable fetuses Intrauterine transfusionsN b HDN E h T f i• Newborns HDN: Exchange Transfusions

Prematurity: IVH, thrombocytopenia, and anemia

• Infants/todlers: 27 days-2 monthsChildren 2 11 rs• Children 2 -11 yrs

• Youngsters 12-16 (18) years

Prematurity: IVH Grade (I-) IVN l b 0 5%• Normal newborns: 0.5%

• Haemophilia: 1-5%• Prematurity: ( up to 30%)

• <1500 gram: 20%

• <1000 gram 45%y ( p )

• Gestational age is main risk • 50% < 8 hours; 90% <48 hrs after birth

• Immaturity of Germinal vascularized matrix :• Birth:↓ Vascularity (↑ oxygenation) + intracranial volume fluctuations ±y ( yg )

inflammatory cytokines in infections • Preventive platelet /plasma /gelofusin transfusions not effective• RBC transfusions associated with progression severity grade I (causal?) • Placental transfusion by later cord clamping (Meta-analysis, Ghavam

Transfusion 2014) better short term outcome and trend for lower ICH butTransfusion 2014) better short term outcome and trend for lower ICH, butworse neurodevelopmental outcome at 2 yrs

Thrombocytopenia < 100 x 109/L

75% < 72 hrs post-partum: 25% >72 hr postpartum

•Thrombosis: ( exclude HIT): LMWH, i f bl di l l f

•Antibodies (NAIT; ITP): IVIG ±in case of bleeding + platelet transf. • Maternal ITP (nadir 4-5 days): IVIG•ECMO: >50/100

(HPA)-matched platelet transfus•Inherited platelet disorder: avoid

l l if ibl •ECMO: >50/100 platelets if possible•ECMO: > 50/100

Hospital infections•Line sepsis

Maternal & delivery complications •Placental insufficiency/Asfyxia

•Necrotizing enterocolitis (NEC)

Prophylactic platelet transfusions? Which trigger?

ff y/ fy• Congenital infections (CMV)

p y p f gg

V Lindern (Retrospective) Tale of two Cities : Liberal/preventive: < 30 in stable infants; < 50 ill infants; < 100 and bleeding; Restrictive/therapeutic: < 50 AND bleedinginfants; < 100 and bleeding; Restrictive/therapeutic: < 50 AND bleeding

Leiden/Liberal Groningen/RestrictiveN 326 353GA (wks) 28.9 28.9( )Sepsis 30% 25%NEC 3% 4%Platelet cts(10E9/L)100-150 28% 40%50-100 39% 34%30-50 15% 13%

30 17% 14%<30 17% 14%

Platelet transfusionsN (%) 44(31%) 21(15%)N (%) 44(31%) 21(15%)U/ transfused infant 3.6+/-4.6 1.6+/-0.9Mortality 7% 7%IVH Gr 1+2 18% 22%IVH Gr 1 2 18% 22%Gr 3+4 11% 8%NO SIGNIFICANT DIFFERENCES IN OUTCOME

PrematurityIVH, Thrombocytopenia and Anemia of Prematurity (AoP)

Causes:

, y p y ( )

- Suboptimal erythropoietin response to anemia (EPO still produced in the liver). Unfortunately EPO is hardly effective in sick LBW newborns- Growth (↑ blood volume)- Shorter survival of foetal RBC- Blood letting for diagnosis- Blood letting for diagnosisVLBW < 1000 g: depending on NICU: 60-05% receives transfusions

Burning transfusion questions- Fresh or older blood?- Restricted or liberal Hb trigger?

Transfusion of fresher versus older red blood cells: Brunskill SJ, 2015 )

This analysis also included : 5 trials in newborns:This analysis also included : 5 trials in newborns:Liu 1994 N=27Strauss 1996 N=40Strauss 2000 N=21Fernandez 2005 N=52Ferguson 2012 N = 377Total N= 517No effect of storage on mortality day 7 day andNo effect of storage on mortality day 7 day and 30 and on morbidity

Trigger Trials in preterm newborns revealed controversial results :At short term ( ~3months): less composite of complications in restricted armsA l ( 2 ) f ll i i d l b i lib lAt longer (> 2 year) folluw-up neurocognitive development better in liberal arm

RCT in critically ill ICU children 40 wks-14 yrs :Leukoreduced RBC : transfusion trigger and multi-organ failure (MODS) Lacroix 2007)organ failure (MODS) Lacroix 2007)

Hb 7.3 g/dL4 5 mmol/L

Hb 9.5 g/dL6 mol/L4.5 mmol/L 6 mol/L

N patients N=320 N=317 N=637MODS 12% 12% nsMODS 12% 12% ns

No transfusion 54% 2% P<0.001

U RBC/pat 0.9 +/- 2.6 1.7 +/- 2.2 P< 0.001

≤2U>2U

38%8%

87%11%

Trigger Trials in preterm newborns revealed controversial results :At short term ( ~3months): less composite of complications in restricted arms

l ( ) f ll d l b l b lAt longer (> 2 year) folluw-up neurocognitive development better in liberal arm

Determinants for transfusion are:Gestational age, Hb, respiratory support Ongoing RBC loss

Written transfusion instructions:Volume and rate of administrationKi d f d TR i i 8,9 ,10 g/dL ?Kind of pre- and post TR monitoring Syringe or pumps Report of adverse events

HOW LOW CAN WE GO?FOR PRETERMS WE DO NOT KNOW!

Pediatric Transfusions

Minors: Transfusion aspects:

• Viable fetuses Intrauterine transfusionsN b < 27 d HDN E h T f i• Newborns < 27 days HDN: Exchange Transfusions

Prematurity

• Infants/todlers 28 days-2 yrs Cardiac surgeryChildren 2 11 rs• Children; 2-11 yrs

• Youngsters 12-16 (18) years

Red cell transfusions for patients undergoing cardiac surgery for congenital heart disease Wilkinson et al The Cochrane Library 2014

11 RCTs; 862 patients ; mixed cyanotic/non cyanotic11 RCTs; 862 patients ; mixed cyanotic/non-cyanotic2 RCT: restrictive vs liberal2 RCT: leukoreduced vs non-reduced7 RCT: priming extracorporeal circuit

30 d and long-term mortality and postop complications NO differencen =628 , including:3RCTs liberal vs restrictive TT n 1253RCTs liberal vs restrictive TT: n=125Washed vs non-washed RBC: n= 128Red cell salvage vs non-salvage n= 309 , less renal failure whenRed cell salvage vs non salvage n 309 , less renal failure whenautologous salvaged blood is used RR 0.26; 95%CI 0.09-0.79)

Red cell transfusions for patients undergoing cardiac surgery for congenital heart disease Wilkinson et al The Cochrane Library 2014

11 RCTs; 862 patients ; mixed cyanotic/non cyanotic11 RCTs; 862 patients ; mixed cyanotic/non-cyanotic2 RCT: restrictive vs liberal2 RCT: leukoreduced vs non-reduced7 RCT: priming extracorporeal circuit

30 d and long-term mortality and postop complications NO differencen =628 , including:3RCTs liberal vs restrictive TT n 1253RCTs liberal vs restrictive TT: n=125Washed vs non-washed RBC: n= 128Red cell salvage vs non-salvage n= 309 , less renal failure whenRed cell salvage vs non salvage n 309 , less renal failure whenautologous salvaged blood is used RR 0.26; 95%CI 0.09-0.79)

Pediatric Transfusions

Minors: Transfusion aspects:

• Viable fetuses Intrauterine transfusionsN b < 27 d HDN E h T f i• Newborns < 27 days HDN: Exchange Transfusions

PrematurityI f t 28 d 2 C di d ECMO• Infants 28 days-2 yrs: Cardiac syrgery and ECMO

• Children; 2-11 yrs Hb -pathy)Yo ngsters 12 16 (18) ears• Youngsters 12-16 (18) years

Absolute transfusion indications for Hb-Pathy:Absolute transfusion indications for Hb Pathy:Stroke in SCD and sequels of ineffective erythopoiesis in ß-Thal

Patiënt Y.A. born 20/1/2005 β-Thal major

• Growth retardation ; 1st RBC 20-9- 2006; CcDee, K matched

• Hb 7.7 g/dL14 g/dL)

• 12 oct ( after 3 weeks) fever, Hb ↓↓ 4.4 g/dL)

• 2nd RBC :13-oct 2006; Hb ↑ 9.7 g/dL

20 t F 38 2 t 40 5 C• 20-oct; Fever 38.2 to 40.5 C• Hematuria; LDH 4980 U/L• 23 oct Hb 5 g/dL; DAT negativeg/ ; g• 25 oct DAT+ / anti-C• Rituximab; IVIG, EPO, methylprednisolon ineffective

J 2007 B M T l t ti (RIC)• Jan 2007 Bone Marrow Transplantation (RIC)• March 2007: Relaps hemolysis (donor and patient cells), DAT

w+; finally splenectomy and recovery

Severe Transfusion complication in SCD and ß-Thal

•Post Transfusion HyperHemolysis PTHH = bystander/reactive hemolysis of autologous and donor RBCP f i Hb l h d i l i•Post-transfusion Hb lower than pre and reticulopenia

• Who is susceptible for PTHH?b h l ( & ) fHbSS >>>, Thalassemia(major & int)>, PNH, B-GVHD after SCT, AIHA, DTHR

Pathogenesis: Possible partners in crime:Pathogenesis: Possible partners in crime:Phagocytic system: upregulated by cytokinesComplement: activated by IXC; alternative pathwayRBC: eat me signalsRBC allo/auto-antibody causing cytokine storm

Transfusion complications in pediatricsSHOT 1995-2008 (Stainsby BJH 2008)SHOT 1995 2008 (Stainsby BJH 2008)

Transfusion reactions Per product transfused

Adults : 2771 (85%) 0.013%( )< 18 yrs: 321 (10%) 0.018%< 12 months: 147 (4.5%) 0.037%

Pediatrics: FFP and platelets (TC) are 5-6 x more frequent causing AE than RBCUnerreporting in SHOT is likely: Prospective reporting SAE in pediatric ICU (2509 transfusies, Canada); Gauvin ea Transfusion 2006;46:1899

Type N product SymptomsBacterial infection 1 FFP Fever, hypotensionSevere allergic 17 RBC Hypotension erythroderma dyspnoeaSevere allergic 17 RBC Hypotension, erythroderma, dyspnoeaTRALI 1 RBC Dyspnoea, sat 82% Hypotension 3 (2) TC > 25 mmHg syst dropTotal 22 (0 9%)Total 22 (0.9%)

7 cases, 3 died

S Wh f h RBC i di i ?Summary When use fresh RBC in pediatrics ?

• IUT (< 3 days) to maximize the intervals between IUT• Large volume transfusions > 25 ml/kg• Exchange transfusions 1-2 bloodvolumes < 7 days: irradiation and 100% depletion 2,3 DPGg y p ,• Cardiac surgery (<15 days: hyperkalaemia)• Chronic anemia ( RBC < 14 days: transfusion efficiency)• Wh i di i i d d• When irradiation is needed

• None of these advices are evidence-base, but based on cases, theoretical reasoning and precautionaryg p yintentions

• Much work to do as only very small steps can be taken

Required volumes for IUT with Ht ~85

IS ONE DEDICATED DONOR A SOLUTION?Required volumes for IUT with Ht ~85

• RBC (Ht 84-87) Required WB Result

• 27%: < 40 ml 100 ml 44 ± 4 ml Ht 84L/L • 52%: < 80 ml 200 ml 84 ± 5 ml Ht 87 L/L52%: 80 ml 200 ml 84 ± 5 ml Ht 87 L/L

~ 80% WBC < 0.01 x 106

• 15%: 80-100 ml 250- ml• 6%: > 100ml 300 ml

~ 20%~ 20% Period of IUT is max from 18-38 gestational weeks; male donors may give1,25 L in this period.

• Bonte, p

Bontekoe Transfusion 2015

Editing humanity? Avoid prematurity (~1-2%)

Economist 2015

Summary 1: can we prevent or improve outcome of (non-immune; non coagulopathic) IVH/ICH of prematurity?y p p g p p y

• Not with FFP or volume administration

• Not with preventive platelet transfusions when platelet cts are < 150 x 10E9/L

O t ith t i ti /th ti bl di l t l t t f i• Outcome with a restrictive/therapeutic bleeding platelet transfusion policy is similar

• Negative effect of RBC ( confounder for viscosity? nitric oxide• Negative effect of RBC ( confounder for viscosity? nitric oxide scavenging?) must be investigated

• Positive effect of delayed cord clamping needs more evidencePositive effect of delayed cord clamping needs more evidence