1. Oxygen therapy for the premature infant Retinopathy of prematurity (ROP) Teaching Evidence-based Practise 15 th September 2015 Kenneth Tan Monash Newborn

2. Objectives Preterm infants definitions Complications of preterm birth, including ROP Early trials oxygen NeoPROM collaboration trials

4. Preterm infant

5. Med J Aust. 1951;2(2):48-50

6. Campbell 1951

7. I I IIIII Macula Optic disc 3 9 12 12 3 6 6 9 Right eye Left eye Oraserrata ROP - Classification I IIIII

8. Classification of ROP Staging: 5 stages - describe abnormal vascular response. Most severe stage is used to determine the stage of the eye as whole. Stage 1: Demarcation line Stage 2: Ridge

9. Classification of ROP Stage 3: Extaretinal Fibrovascular Proliferation Stage 4: Partial Retinal Detachment 4a - Extrafoveal 4b – Foveal Stage 5: Total Retinal Detachment Major cause of childhood blindness in developed world

10. Retinopathy of Prematurity

11. Clinical trials in the 1950s confirmed that restricting oxygen reduced the risk of eye damage, then called Retrolental Fibroplasia (RLF), and blindness

13. History of oxygen use in preterm neonates

14. Children's Hospital, Buffalo, NY Accessed via http://www.nei.nih.gov/rop/photos.asp

16. Side-effects of oxygen Therapy Preterm infants lack a fully functioning antioxidant defence system (Frosali 2004) Oxygen rich environment Antioxidant defences Glutathione peroxidase, superoxide dismutase Other diseases of the preterm neonate where oxidative stress plays a role: Lungs - BPD (Davis, 2002) Brain - PVL (Kakita et al, 2009)

17. Reduced oxygen Therapy Less inspired oxygen (to target SpO2 <90%) may increase patent ductus arteriosus pulmonary vascular resistance apnoea impair survival and neurodevelopment Newburger N Engl J Med 1984, 310:1495-1499. Skinner JR, Arch Dis Child Fetal Neonatal Ed 1999, 80: F81-F87. Subhedar Arch Dis Child Fetal Neonatal Ed 2000, 82:F243-F247.

18. Cost of preventing ROP For each case of RFLP by oxygen restriction prevented about 16 infants died or had cerebral palsy Competing goals of treatment Kenneth Cross Lancet 1973;2(7835):954–956

20. Monitoring of oxygenation Monitoring paO2 Levels of pO2 that is damaging to the retina 80 mmHg Flynn JT et al N Engl J Med 1992, 326:1050-1054. tcpO2 Arterialised capillary bed Disadvantage that it heats the skin up (40 C) SpO2 Introduced in 1980s

21. History of oxygen therapy in preterm infants After trials in 1950s, very little study on oxygen therapy (Silverman 1980) Northern Neonatal Network (North of England) Newcastle, Middlesbrough et al Centres with 4 different SpO2 targets policy Problem with this was a study Shows association cannot determine cause-effect relationship

22. Outcomes – Northern Neonatal Network Arch Dis Child Fetal Neonatal Ed. 2001 Mar;84(2):F106-10 What type of study is this?

24. NeOProM

25. Aim To determine whether, in infants < 28 weeks gestation, targeting SpO2 85 – 89% versus 91 – 95% when in supplementary oxygen leads to a lower rate of death or disability at two years

26. Target 88 – 92% Alarm limits: upper - 94% lower – 86%

27. Primary Outcome Death or major disability at two years corrected for gestationon Bayley III scales Secondary outcomes: –Retinopathy, chronic lung disease, PDA, NEC, Sepsis, Growth

28. Actual target 85-89% Actual target 91-95% (3% below displayed value) (3% above displayed value) Study oximeter adjusted to display either 3% above or 3% below actual saturation for values between 85% - 95%. Outside that range the true values are displayed. Staff are asked to target display with masked study oximeter SpO 2 88-92% Lower groupHigher group Masking O 2 saturation in BOOST II

29. SUPPORT Trial SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research NetworkN Engl J Med 2010; 362:1959-1969

30. What about the other RCTs? Continue or stop RCT Data and safety monitoring committee of BOOST- Aus ANZ

31. Stopping the RCT Stenson B et al. N Engl J Med 2011;364:1680-1682.

32. BOOST-II In December 2010, a joint safety analysis of survival at 36 weeks' postmenstrual age was undertaken –2315 infants in the U.K., Australian, and New Zealand trials with the 1316 infants in the SUPPORT trial Investigators be told the results if the difference in 36-week survival between groups for all infants, or for those recruited after introducing the new calibration algorithm, exceeded 3 SE (equivalent to 99.73% CI, with P=0.003) (UK BOOST protocol) Stenson et al N Engl J Med 2011; 364:1680-1682

33. Implications for practise Main question: should we change current practise from 88-92% targetting to 91-95% Two NICUs (USA, UK) have already implementation this Most NICUs in Australia have changed practise to higher SpO2 target

34. Take home message Meta-analysis Odd ratios Cohort study Randomised control trial (double blind) Individual patient meta-analysis