1. Neonatal ECMO Study of Temperature NEST

2. Basic ECMO circuit

3. ECMO Study follow-up at four ECMO 93 Conventional 92 Deaths 31 Deaths 54 Lost to follow-up 1 Lost to follow-up 3 Assessed at four 61 Assessed at four 35 Recruited 185

4. Outcome classification Normal ImpairmentNo functional loss Disability MildLittle or no support ModerateNeeds aids or assistance SevereConstant supervision

5. Results – Cognitive

7. Results - Neuromotor

8. Results – General health

9. Results – Behaviour

10. Results – Hearing

11. Outcome at four years of age ECMO 60 % Conventional 35 % Normal12 20 4 11 Impairment18 30 9 26 Mild disability18 30 12 34 Moderate disability 9 15 10 29 Severe disability 3 5 0

12. Results – Overall

13. Overall outcome

14. “Concept” Infants receiving ECMO represent a high risk group for cerebral injury Mild hypothermia appears to be a promising means of offering neuroprotection following hypoxic ischaemic injury

15. Pilot Study Progress Stage I: 1998 -1999 Twenty neonates recruited Cooled for first 12 hours of ECMO No significant problems found. Stage II: 2000 -2001 Twenty neonates recruited Cooled for the first 24 hours of ECMO Stage III: 2001 Five neonates recruited Cooled to 34 0 c core temperature for the first 48 hours of ECMO

16. Methods 25 consecutive neonates referred for ECMO (n = 5 per group) Group 1 (Control): Core temp at 37 0 c for five days Group 2: 36 0 c for 24 hours Group 3: 35 0 c for 24 hours Group 4: 34 0 c for 24 hours Group 5: 34 0 c for 48 hours

17. Method Protocol: Blood Sampling Points Baseline 2 H 12 H 24 H 48 H 48 H Day 3 Day 4 Day 5 ECMO Cannulation (VA or VV-DLC) Cooling Cooling 37 0 C Infants were carefully assessed clinically and biologically Blood Samples were drawn from the ECMO circuit sampling port at the times shown 36 H

18. Serum Assays Cytokines: IL6 and IL8 Molecular Markers of Coagulation: Thrombin-Antithrombin III, Antithrombin III, Plasmin  2 plasminogen Complement: C3a Measurements

19. Heparin and Platelet Transfusion Requirements Oxygenator resistance: calculated 2, 12 and 24 hourly thereafter using the formula: Pre-oxygenator pressure - post-oxygenator pressure(mmHg) circuit blood flow (ml/min)

20. Summary of Demographic Data for Study Groups *Comparison of groups by Kruskal-Wallis test (df = 4) values are median (range)

21. Median Group Core Temperature During Study Period *Comparing groups 1-5, median rectal temperature SD at 24 hours (Kruskal-Wallis chi-squared = 23.3, df = 4, p<0.001)

22. Progress and Complications During the Study * Comparison of groups by Kruskal-Wallis (df = 4) † Bleeding at cannula site due to heparin bolus

23. Cardiovascular Data During Cooling and Rewarming *Denotes patients not cooled Values are median (range)

24. Results No systemic difference between groups for: –Molecular markers of coagulation –Complement C3a –Cytokines IL6 and IL8 –Platelet transfusion requirements –Oygenator resistance

25. Mean IL6 (Temperature Groups)

26. Mean C3a (Temperature Groups)

27. Conclusions Applying mild hypothermia (34 0 C) for 24 or 48 hours of neonatal ECMO appears feasible and safe No major complications related to mild hypothermia were observed in this study.

28. The next steps A randomised controlled trial

29. Trial outline Research question to be addressed: Does cooling neonates (neonate: less than or equal to 28 days of age) requiring ECMO to 34 o C for the first 48 to 72 hours of their ECMO run result in improved Bayley scores at 2 years of age? Trial design: Pragmatic multi-centre randomised controlled trial.

30. Trial outline Eligibility –Meeting standard ECMO criteria but no congenital diaphragmatic hernias and no post cardiac ECMO

31. Trial outline Blinding Randomisation Consent

32. Trial outline Minimisation by approach to ECMO (VV or VA).

33. Trial outline ECMO management Organisation

34. Trial outline Trial end points –Primary outcome: MDI of the Bayley scales (34) at age of 2 years (24 - 27 months). –Note: Where the MDI cannot be assessed because of severe disability or death, a score of either 40 or 0 will be recorded respectively.

35. Trial outline Secondary outcomes: Death Outcome of a structured neurological assessment Results of simple questionnaire completed by parents about their child’s health at two years of age. PDI of the Bayley scales Visuospatial assessment Testers rating of child behaviour

36. Assumed mean Bayley scores of the two arms Assumed SD of Bayley scores Significance Power to detect difference between the two arms Sample sizeNumber needed to be recruited assuming 80%survival to 2 years 85 & 9515 5%9094118 85 & 95 105%904253 90 & 95 105%90168210 Trial Size

37. Analysis Intention-to-treat analysis Pre specified secondary analyses by disease severity and diagnosis

38. Other issues Timescale aEEG MRI

39. Thank you