Blood transfusion and intestinal perfusion in preterm infants Narendra Aladangady

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1 Blood transfusion and intestinal perfusion in preterm infants Narendra Aladangady MD, FRCPCH, PhD Consultant Neonatologist Hon Clinical Professor in Child Health

2 History of blood transfusion First report of the circulation of blood Continuous circulation of blood Animal to animal blood transfusion Animal to human blood transfusion Human to human blood transfusion Khairallah AA. Ann Surg Harvey W. Lumleian Lecture Denis JB. Jean Cusson Blundell J. Lancet 1828

3 Blood transfusion of preterm infants Maier RF et al. J Pediatr 2000 Widness JA et al. J Pediatr 1996

4 Blood transfusion guidelines Clinical status UK guideline 1 American guideline 2 Anaemia in the first 24 hours Infants receiving intensive care Severe cardiopulmonary disease (FiO 2 >0.35) Chronic oxygen dependency Moderate cardiopulmonary disease (CPAP or O 2 ) Late anaemia, stable infant Hb<12 g/dl or Hct < Hb<12 g/dl or Hct <0.36 Hct 40 45% Hb<11 g/dl Hct 30 35% Hb< 7g/dl Hct 20 25% Gibson BE et al. Br J Haematol 2004 Miller. American Red Cross 2007

5 BCSH guidelines on blood transfusion New et al. Guidelines on blood transfusion for foetuses, neonates and older children. BCSH 2016

6 Blood transfusion thresholds Trials Restrictive threshold Liberal threshold Blank et al (1984) Transfusion according to clinical indication Transfuse if Hb <100 g/l Ransome et al (1989) Hb levels <70 g/l or clinically symptomatic Hb levels <100 g/l Brooks et al (1999) Connelly et al (1998) Mukhopadhyay et al (2004) Bell et al (2005) Kirpalani et al (2006) PRBC transfusion when clinically symptomatic 1 st postnatal week:110 g/l 2 nd postnatal week: a.fio 2 >40%: 110 g/l b.fio 2 <40%: 90g/l 3 rd postnatal week: 80 g/l* Hb levels 100 g/l or Hct 30% Intubated: 113 g/l O 2 or CPAP: 93 g/l No respiratory support: 67 g/l For infants requiring respiratory support (ventilation, CPAP or oxygen): Postnatal week 1: 115 g/l Week 2: 100 g/l Week 3 till discharge: 85 g/l For infants not requiring respiratory support: Postnatal week 1: 100 g/l Week 2: 85 g/l Week 3 till discharge: 75 g/l PRBC transfusion if Hb<133 g/l 1 st postnatal week: 130 g/l 2 nd postnatal week: a.fio 2 >40%: 130 g/l b.fio 2 <40%: 100 g/l 3 rd postnatal week: 80 g/dl* Hb levels 133 g/l or Hct 40% Intubated: 153 g/l O 2 or CPAP: 127 g/l No respiratory support: 73 g/l For infants requiring respiratory support (ventilation, CPAP or oxygen): Postnatal week 1: 135 g/l Week 2: 120 g/l Week 3 till discharge: 100 g/l For infants not requiring respiratory support: Postnatal week 1: 120 g/l Week 2: 100 g/l Week 3 till discharge: 85 g/l Chen et al (2009) Intubated: 116 g/l CPAP: 100 g/l No respiratory support: 73 g/l Intubated: 150 g/l CPAP: 133 g/l No respiratory support: 100 g/l

7 Blood transfusion thresholds PINT study No difference in death or survival with BPD, severe ROP, or brain injury at discharge Kirpalani et al. J Pediatrics 2006 Iowa study Higher number of severe adverse brain events in those infants who received restrictive transfusion compared to liberal transfusion Bell et al. Pediatrics 2005

8 Circulating blood volume prediction?

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10 Blood transfusion and short term outcomes Aladangady N et al. PAS 2014

11 Blood transfusion and short term outcomes Aladangady N et al. PAS 2014

12 Blood transfusion and short term outcomes in preterm infants <28 weeks gestation Aladangady N et al. PAS 2014

13 Blood transfusion and gut injury Mohamed A et al. Ped 2012

14 Blood transfusion and gut injury Kirpalani & Zupancic. Semin Perinatol 2012

15 Banerjee J et al. BMC Med 2015 Anaemia and gut injury

16 Patel MR et al. JAMA 2016 Anaemia and gut injury

17 Blood transfusion, anaemia and gut injury It is not clear whether excess blood transfusion or anaemia predisposes to gut injury The impact of anaemia and blood transfusion on organ perfusion is not well studied This has been highlighted as priority research area Nickel RS and Josephson CD. Clin Perinatol 2015

18 Primary objectives: Objectives 1. To investigate gut oxygenation and perfusion response to blood transfusion in preterm infants according to postnatal age 2. To investigate the influence of pre transfusion red cell volume (RCV) on gut perfusion in preterm infants receiving first blood transfusion Secondary objectives: To investigate these responses in relation to PDA To investigate these responses in relation to feeds

19 Methods: Inclusion criteria Study groups Group 1 Group 2 Group 3 Study population (Infants receiving BT for clinical indication) 20 preterm infants ( weeks) in the first 7 days of life 20 preterm infants between 8 and 28 days of life 20 preterm infants 29 days of life Exclusion criteria 1. Major congenital malformation 2. Established abdominal pathology 3. Unstable babies

20 Methods: Overview of measurements Measurements performed Hb, ph, pco 2, Lactate Doppler USS SMA PSV, Diastolic velocity Vital parameters using ixtrend NIRS measurements sthi, stoi

21 Measurement of gut blood flow SMA flow 1 measured in infra diaphragmatic longitudinal view Leidig et al. Arch Dis Child 1989

22 Measurement of gut oxygenation using NIRS NIRO 300, Hamamatsu Photonics KK, Japan Measurements: ΔHbO 2, ΔHHb, sthi and stoi

23 Measurement of Red Cell Volume (RCV) Using HbF dilution method 1 : RCV Where, V = Total donor red cell volume transfused Post T%HbF = Post transfusion HbF percentage Pre T%HbF = Pre transfusion HbF percentage Aladangady N et al. Pediatric Anesthesia 2008 Measurement of Vital Parameters HR, RR, BP (invasive and/or non invasive) and SaO 2 were continuously measured and downloaded using: ixtrend 2.0.1, ixellence GmbH Germany

24 Other data collected Demographic details Antenatal details and Hb at birth Clinical and feeding details

25 Statistical analysis SPSS 22.0 Doppler & NIRS measurement changes were compared using repeated measures ANOVA with Bonferroni correction and Student t test Pre transfusion Doppler and NIRS measurements between the different chronological age groups were compared using ANOVA and unpaired t tests Multivariate analysis was performed A p value of <0.05 was considered significant

26 Research Funding and Ethics Funding: Garfield Weston Foundation, HCA International and Hamamatsu Photonics Ltd, Japan Approved by Charing Cross Research Ethics Committee NIHR Portfolio study (Study ID: 13594) Informed written consent obtained

27 Results

28 Results Infant characteristics * Median (Range) Number (Percentage)

29 Results are expressed in Mean values Vital parameters

30 Results are expressed in Mean values Laboratory parameters

31 SMA PSV and diastolic velocity

32 SMA PSV PDA groups * p<0.05 comparison between baseline pre transfusion measurements

33 SMA PSV Feeding groups * p<0.05 comparison between baseline pre transfusion measurements

34 Gut oximetry postnatal age sthi stoi T1 15 to 20 minutes before the start of the blood transfusion, T2 1 hour into blood transfusion, T3 2 hour into blood transfusion T4 15 to 20 minutes post blood transfusion

35 Gut oximetry PDA * stoi levels (%) * PDA present PDA absent T1 T2 T3 T4 T1 15 to 20 minutes before the start of the blood transfusion, T2 1 hour into blood transfusion, T3 2 hour into blood transfusion T4 15 to 20 minutes post blood transfusion

36 Multivariate analysis The pre transfusion SMA PSV and stoi as well as their degree of changes following blood transfusion in the postnatal age group were not influenced by gestational age, birth weight, feeding volume, pre transfusion Hb, PDA and mean blood pressure. Banerjee J et al. Vox Sanguinis 2016

37 Results RCV Infant characteristics Median (Range) Gestational age (weeks) 26 (23 27) Birth weight (grams) 830 ( ) Chronological age at Blood transfusion (days) 2 (1 14) Total volume of fluids (ml/kg/day) 150 (90 180) Total volume of feeds (ml/kg/day) 15 (0 180) Pre transfusion haemoglobin (g/dl) 11.2 ( ) Pre transfusion haematocrit (%) 32 (26 38) Weight of baby on day of BT (grams) 810 ( ) Pre transfusion RCV (ml/kg) 29.9 ( ) Banerjee et al. PAS 2016

38 Results RCV RCV<25ml/kg n=5 RCV 25ml/kg n=9 p value (95% CI) Gestational age (weeks) 25.8 (1.5) 25.7 (0.8) 0.84 (1.3 to 1.7) Birth weight (grams) (215.7) (104.6) 0.74 (170.2 to ) Age of transfusion (d) 7.6 (4.8) 2.8 (1.9) 0.03 (0.6 to 9.4) Pre transfusion Hb (g/dl) 9.8 (0.8) 12.1 (0.8) (1.3 to 3.4) Pre transfusion Hct (%) 0.28 (0.02) 0.34 (0.02) (0.02 to 0.08) Total volume of fluids (ml/kg) (19.0) (34.0) 0.25 (17.1 to 60.4) Total volume of feeds (ml/kg) 83.0 (68.7) 4.0 (7.5) (24.6 to 133.5) Weight of baby at BT (grams) (202.1) (102.5) 0.88 (177.8 to 205.8) Pre transfusion RCV (%) 23.3 (1.6) 33.2 (4.3) (5.2 to 14.6) Results in Mean (Standard Deviation)

39 RCV, gut blood flow and oximetry Parameters measured Mean (SD) RCV <25ml/kg (n=5) RCV 25ml/kg (n=9) Pre BT Post BT P value; CI Pre BT Post BT P value; CI SMA PSV (m/sec) 0.77 (0.11) 0.59 (0.07) 0.03; 0.01 to (0.28) 0.56 (0.16) 0.57; 0.17 to 0.28 sthi (arbitrary units) 35.3 (7.9) 51.3 (15.9) 0.83; 36.9 to (14.4) 67.2 (17.0) 0.001; 26.3 to 10.7 stoi (%) 45.4 (22.6) 45.0 (10.5) 0.97; 35.6 to (11.1) 56.8 (21.5) 0.005; 30.9 to 7.9 sftoe (%) 51.7 (24) 51.3 (13) 0.97; 37.2 to (11) 38.9 (14) 0.03; 1.07 to 21.2 Banerjee et al. PAS 2016

40 Conclusion Pre transfusion baseline SMA PSV and stoi varied with postnatal age Blood transfusion improved intestinal tissue oxygenation without altering intestinal blood flow velocity In infants with RCV <25ml/kg the SMA blood flow velocity decreased following blood transfusion The gut oximetry markers improved significantly following transfusion in those infants with RCV 25ml/kg, but these improvements were not noticed in those with RCV <25ml/kg

41 Future Plans Hypotheses: Anaemia causes gut hypoperfusion and hypoxia, which may trigger an inflammatory cascade in preterm infants Blood transfusion induces a reperfusion injury of the gut in chronically anaemic preterm infants Primary objectives: To investigate the association between haemoglobin level and intestinal tissue hypoxia, and the effect of blood transfusion on intestinal tissue hypoxia and reperfusion injury in anaemic preterm infants

42 Acknowledgements Dr Terence Leung, Dept. of Med Physics and Bioengineering, University College London Dr Jayanta Banerjee Neonatologist Imperial College Healthcare NHS Trust Dr Paul Fleming Neonatologist Homerton University Hospital Prof Joan Morris Professor of Medical statistics, QMUL Dr Simon Eaton Paediatric Surgery UCL and ICH Dr Claire Howarth Research Fellow Homerton University Hospital Medical & Nursing staff, Neonatal Unit; IT Dept. & Medical Electronics Dept., Homerton Hospital Babies and their parents

43 Hudson I et al. Arch Dis Child 1990