The document summarizes evidence from animal studies and human clinical trials on the use of therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy (HIE). Animal studies showed that prolonged hypothermia starting within 6 hours and continuing for at least 24 hours reduced brain injury. The Cool Cap study was a randomized controlled trial in humans that found selective head cooling plus mild systemic hypothermia for 72 hours starting within 6 hours of birth reduced death and disability in infants with moderate to severe HIE, excluding those with the most severe brain abnormalities on EEG. Other trials also found benefits with whole body cooling.

1. HYPOTHERMIC NEUROPROTECTION IN THE NEWBORN: A COOL IDEA Steven M. Donn, M.D. Professor of Pediatrics Chief, Division of Neonatal-Perinatal Medicine C.S. Mott Children’s Hospital University of Michigan Health System

12. EEG – dramatically improved Time (hours) EEG (µV) Seizures not suppressed Slide c/o Alistair Gunn

14. The Cool Cap Study By parental permission, Dr Durand, Oakland

25. BASELINE DATA Cooled Control Number 116 118 Initial pH (mean, SD) 6.9 (0.2) 6.9 (0.2) Five min Apgar 0 – 3 77% 68% Pre-randomization aEEG: Moderately Abnormal 54% 64% Severely Abnormal 36% 27% Seizures present 59% 64% Age at Randomization (h) 4.8 (2.6-6) 4.7 (2.1-6.1)

26. Primary Outcome # Enrolled 235 Final Count 234 Cancelled 1 Lost to Follow-up 16 18-Month Primary Outcome 218 Cooled 108 Control 110 Favorable 49 (45%) Unfavorable 59 (55%) Favorable 37 (34%) Unfavorable 73 (66%)

28. Stratification by Baseline aEEG To allow for multiple comparisons, p<0.025 required for significance Excluding most severe abnormalities in aEEG < 6 hours A priori – anticipated to respond 172/218 In controls (n=88) 66% unfavourable outcome (39% mortality ) Most abnormal aEEG < 6 hours A priori – unlikely to respond 46/218 In controls (n=22) 68% unfavourable outcome (36% mortality)

29. Fisher’s exact p=0.02; logistic regression, OR: 0.42 (0.22, 0.80), p=0.009 A priori defined group excluding infants with severely abnormal aEEG with seizure n=172 Cooled 84 Control 88 Favorable 44 (52%) Unfavorable 40 (48%) Favorable 30 (34%) Unfavorable 58 (66%)

34. PERINATAL COMPLICATIONS Cooled Non-Cooled P Sinus Bradycardia/tachy 10 9% 1 1% 0.004 * Hypotension (<40mmHg) 62 55% 64 52% 0.60 Coagulopathy 21 19% 17 14% 0.38 Prolonged coagulation 56 50% 50 42% 0.29 Abnormal renal function 73 65% 83 70% 0.48 Hyponatremia 49 44% 46 39% 0.50 Hypokalemia 71 63% 73 62% 0.89 Bone marrow depr. 36 32% 26 22% 0.10 Elevated liver enzymes 42 38% 62 53% 0.02

35. PERINATAL COMPLICATIONS Cooled Non-Cooled P Metabolic acidosis 22 20% 27 23% 0.63 Respiratory distress 94 84% 92 78% 0.31 Hypoglycemia 14 13% 20 17% 0.36 Infection 1 1% 2 2% 1.00 Acute Mortality 27 23% 26 22% 0.88 (Deaths in the first week of life are not defined an adverse event)

39. “ South Carolina Body Cooling Trial” (II) 5 8 Lost/incomplete followup 4/17 (24%) (p=0.4) 5/12 (42%) Severe cognitive abnormality 4/17 (24%) (p=0.053) 7/11 (64%) Severe motor disability 10 (31%) (p=0.35) 14 (42%) Death 52% (p=0.019) 84% Death or severe disability Hypothermic (n=32) Normothermic (n=33) Outcome

42. Copyright ©2002 American Academy of Pediatrics Shankaran, et al. Pediatrics 2002;110:377-385 The infant lies supine on the infant-size blanket

43. NICHD NRN Body Cooling Trial (II) Shankaran et al . NEJM 353:1574 52% 40% MDI >85 NS 23% 21% MDI 70-84 25% 39% MDI < 70 .85 (.64-1.13) .69 (.44-1.07) .68 (.44-1.05) .68 (.38-1.22) .72 (.54-.95) OR (CI) 72% 85% Death/dis after Sev HIE 32% 48% Death/dis after Mod HIE 24% 37% Death by 18 mo. 19% 30% Disabling CP 44% 62% Death or mod/sev dis. HT NT Outcome

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49. PRACTICALITIES of BRAIN COOLING

54. Rectal Temperature

58. Thank you!