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Hypothermic Neuroprotection In The Newborn

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Hypothermic Neuroprotection In The Newborn

  1. 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
  2. 2. DISCLOSURE <ul><li>Steven M. Donn, M.D. received grant support from Olympic Medical (Seattle, WA) as an investigator for the Cool Cap ® trial. </li></ul>
  3. 3. HYPOXIC-ISCHEMIC ENCEPHALOPATHY (HIE) <ul><li>Estimated incidence: 1-4/1000 term births </li></ul><ul><li>Frequently associated with chronically disabling conditions including CP, MR, </li></ul><ul><li>and epilepsy </li></ul><ul><li>Abnormal neurologic behavior in neonatal period (SZ, EEG abnormalities) best predictors of neurologic disability and death </li></ul>
  4. 4. NEONATAL PREDICTORS OF LTND: Patient Selection Criteria <ul><li>NCPP (1988): 69% Death or Handicap if: </li></ul><ul><li>Apgar < 6 5 Neonatal encephalopathy Seizures </li></ul><ul><li>Gunn and Gunn (1997): 60% LTND if: </li></ul><ul><li>HIE Seizures </li></ul>
  5. 5. HIE PATHOPHYSIOLOGY <ul><li>Hypoxic-Ischemic Insult (transient) </li></ul><ul><li>Primary energy failure </li></ul><ul><li>Recovery </li></ul><ul><li>Secondary energy failure (6-48 hours later) </li></ul><ul><li>Irreversible Neuronal Injury </li></ul><ul><ul><li>Necrosis vs . Apoptosis </li></ul></ul>
  6. 6. HUMAN NEONATAL TRIALS <ul><li>Calcium channel antagonists and magnesium not effective, possibly dangerous </li></ul><ul><li>Some preliminary success with cerebral cooling, phenobarbital, and allopurinol </li></ul>
  7. 7. BACKGROUND <ul><li>In perinatal animal studies hypothermia can be neuroprotective when applied following asphyxial or ischemic insults </li></ul><ul><ul><li>Cooling needs to be started within ~ 6 h after birth (and earlier is better) </li></ul></ul><ul><ul><li>It needs to be continued for at least 24 h (72 h is better) </li></ul></ul><ul><ul><li>The brain needs to be cooled to 32 to 34ºC </li></ul></ul>
  8. 8. Post-HI Hypothermia in P7 Rats <ul><li>Study Time T ( °C) Outcome </li></ul><ul><li>Thoresen 3 hr. 32.5 Less damage scores at 7 d </li></ul><ul><li>Yager 3 hr. 31/34 No effect at 23 d </li></ul><ul><li>Trescher 3 hr. 32/35 7 d- protection </li></ul><ul><li>28 d- no morph. ∆ </li></ul><ul><li>Bona 6 hr. 32 7d- protection </li></ul><ul><li>42 d –morph.prot. Better motor fcn. </li></ul>
  9. 10. Prolonged Post-HI Hypothermia I <ul><li>P21 rat HI (15 min = mild) </li></ul><ul><li>Post-HI temp 22 o C v 34 o C (environment) </li></ul><ul><li>0-72 h protective * </li></ul><ul><li>0-6 h not protective </li></ul><ul><li>6-72 h not protective * cortex (72h and 21d - 66%) and striatum (72h), not hippocampus. No “neuro exam” </li></ul>
  10. 11. Prolonged Post-HI Hypothermia II <ul><li>Late term fetal sheep (Gunn et al.) </li></ul><ul><li>30 min. BCO; 72 h selective head cooling starting 1.5 or 5.5 h later. Pathol. @ 5d </li></ul><ul><li>1.5h: attenuation of neuron loss, all regions </li></ul><ul><li>5.5h: attenuated neuron loss, except hippocampus </li></ul><ul><li>Final EEG recovery better with 1.5h start </li></ul>
  11. 12. EEG – dramatically improved Time (hours) EEG (µV) Seizures not suppressed Slide c/o Alistair Gunn
  12. 13. SUMMARY of ANIMAL DATA <ul><li>The longer the hypothermia duration, the better the protection, both %damage reduction and “durability” </li></ul><ul><li>Window of opportunity may be several hours (up to 6-8) </li></ul><ul><li>Systemic toxicity not a major issue (mild reversable increases in BP, blood glucose, lactate in fetal sheep model) </li></ul><ul><li>Mechanism still unclear </li></ul>
  13. 14. The Cool Cap Study By parental permission, Dr Durand, Oakland
  14. 15. PRIMARY HYPOTHESIS <ul><li>In term neonates with moderate to severe hypoxic-ischemic encephalopathy head cooling with mild systemic hypothermia will be associated with a reduction in death and severe neurodevelopmental disability </li></ul>
  15. 16. Anticipated Issues in Trial Design <ul><li>Problem : heterogeneous population with HIE </li></ul><ul><li>Solution : </li></ul><ul><ul><li>aEEG based selection, to exclude milder cases that would be expected to have high rate of good outcome </li></ul></ul><ul><ul><li>aEEG stratification, to compare the effect in the most severe cases vs . more ‘moderate’ cases, or effect of seizures vs. no seizures </li></ul></ul><ul><ul><li>Prospectively record other baseline data that may influence outcome, and thus may be used as covariates, e.g. gestational age, BW, Apgar scores, delay from birth to initiation of cooling </li></ul></ul>
  16. 17. aEEG CRITERIA <ul><li>Local physician read (central training by D. Azzopardi, Hammersmith, London, UK) </li></ul><ul><li>Selected for randomization if: </li></ul><ul><ul><li>aEEG diagnosed seizures </li></ul></ul><ul><li>and/or </li></ul><ul><ul><li>Moderately or severely abnormal voltage on aEEG (lower margin < 5  V) </li></ul></ul>
  17. 19. Anticipated Issues in Trial Design <ul><li>Problem: risk of complications from systemic cooling in neonates </li></ul><ul><li>Systemic hypothermia < 33-34  C is associated with potential risks of coagulopathy, cardiovascular compromise, infection and metabolic acidosis </li></ul>
  18. 20. SOLUTION <ul><li>While cooling the head directly, the body was warmed by radiant heat to 34-35  C. Pilot studies in Auckland were used to develop the system and showed safety and hinted at efficacy (Gunn et al 1998). Nasopharyngeal temperatures fell by 0.8  C more than core temperature </li></ul>By parental permission, Dr Durand, Oakland
  19. 21. The Cool Cap Trial <ul><li>28 centers: NZ, Canada, USA, UK </li></ul><ul><li>Randomization, stratified by center, to selective head cooling plus mild central hypothermia with rectal temperature maintained at 34.5 ± 0.5 °C for 72 h, then controlled warming @ 0.5  C/h or routine care </li></ul><ul><li>Term (  36 weeks) infants, start within 6 h of birth </li></ul><ul><li>Staged selection </li></ul><ul><ul><li>Evidence of perinatal HIE (10 min Apgar<6 or resuscitation @ 10 min or pH<7 or BD>=16) </li></ul></ul><ul><ul><li>Moderate to severe clinical encephalopathy </li></ul></ul><ul><ul><li>Moderate to severe EEG amplitude reduction (lower margin < 5  V) on aEEG or seizures </li></ul></ul>
  20. 22. MODERATE to SEVERE HIE <ul><li>i.e., Sarnat stage II or III encephalopathy: </li></ul><ul><li>Altered state of consciousness (lethargy, stupor, coma), + ≥ 1 of </li></ul><ul><li>Hypotonia </li></ul><ul><li>Abnormal reflexes (include eyes) </li></ul><ul><li>Absent or weak suck </li></ul><ul><li>Clinical seizures </li></ul>
  21. 23. PRIMARY OUTCOME <ul><li>At 17 to 22 months </li></ul><ul><li>Death or </li></ul><ul><li>Severe disability </li></ul><ul><li>- BSID II MDI < 70, or </li></ul><ul><li>- Gross Motor Function (GMF) neuromotor impairment Level 3-5 * (Level 3: non-ambulatory, sits with support applied to the lower back; Levels 4-5: infants who have limited or no self-mobility) , or </li></ul><ul><li>- Bilateral cortical visual impairment </li></ul><ul><li>(* Palisano et al ., Dev Med Child Neurol 39:214, 1997) </li></ul>
  22. 24. TRIAL STATISTICS <ul><li>234 infants studied (to Jan. 2002) </li></ul><ul><ul><li>75% U.S. sites </li></ul></ul><ul><ul><li>25% UK, Canada, New Zealand </li></ul></ul><ul><li>Safety reviews at 25, 50 and 75% enrolment revealed no major concerns </li></ul><ul><li>Follow up available on 218 (93%) infants </li></ul><ul><ul><li>8 cooled and 8 control infants lost to follow up </li></ul></ul><ul><li>Before primary analysis was initiated, neurodevelopmental outcome independently reviewed (DF, CR) </li></ul><ul><li>The primary analysis was initiated and performed independent of trial sponsor </li></ul>
  23. 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)
  24. 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%)
  25. 27. EFFICACY RESULTS <ul><li>All infants, intention-to-treat analysis </li></ul><ul><li>Pre-specified 6-Factor Logistic Regression: </li></ul><ul><ul><li>aEEG background </li></ul></ul><ul><ul><li>aEEG seizure status </li></ul></ul><ul><ul><li>Age at randomization </li></ul></ul><ul><ul><li>Apgar score </li></ul></ul><ul><ul><li>Birth weight </li></ul></ul><ul><ul><li>Gender </li></ul></ul><ul><li>Statistically Significant Treatment Effect p=0.042, Odds Ratio = 0.53, when chance imbalances in baseline factors were accounted for by Logistic Regression </li></ul>
  26. 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)
  27. 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%)
  28. 30. Cooling Improved Intact Survival Excluding the Most Abnormal Baseline aEEG <ul><li>Mortality 39% (control) vs 29% (cooled), p=0.2 </li></ul><ul><li>Severe neuromotor disability, defined as Gross Motor Function level 3-5 in survivors </li></ul><ul><ul><li>27.8% of control infants , 11.7% of cooled infants (p=0.035) </li></ul></ul><ul><li>BSID II MDI and PDI (treated as continuous variable) p<0.05 </li></ul><ul><li>Note: p<0.025 required for significance </li></ul>
  29. 31. NUMBER NEEDED to TREAT (Per Survivor with Improved Outcome) <ul><li>Excluding most severe EEG </li></ul><ul><ul><li>6 (95% CI: 3, 27) </li></ul></ul><ul><li>aEEG entry, no exclusions </li></ul><ul><ul><li>8.5 </li></ul></ul>
  30. 32. Infants with the Most Abnormal Baseline aEEG ( Severe suppression of background plus seizures, 46/218 ) <ul><li>Unfavorable primary outcome </li></ul><ul><ul><li>19/24 infants in cooled group ( 79.2%) vs </li></ul></ul><ul><ul><li>15/22 control infants (68.2%) </li></ul></ul><ul><li>No evidence of a trend to improvement in any sub-components, p=0.51 </li></ul>
  31. 33. ADVERSE EFFECTS <ul><li>No increase in severe hypotension despite full volume and inotrope support: 3 cooled vs 3 non-cooled infants (p=1.00) </li></ul><ul><li>Scalp edema common (32 cooled and 1 control infant, p<0.0001), but transient </li></ul><ul><li>One case of scalp damage under the cap in an infant dying of severe hypotension and coagulopathy </li></ul><ul><li>Sinus bradycardia, without hypotension, was very common during cooling and reversed on rewarming </li></ul>
  32. 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
  33. 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)
  34. 36. CONCLUSIONS <ul><li>Head cooling, with rectal temperature maintained at 34-35 º C for 72 h, started soon after birth in term infants with HIE led to a modest improvement in outcome, in a mixed group of infants with moderate to severe encephalopathy </li></ul><ul><li>Head cooling had no clinically important adverse effects </li></ul>
  35. 37. CONCLUSIONS (II) <ul><li>In the large subgroup (172/218), defined a priori to exclude those with the most severe aEEG changes, there was a statistically and clinically significant reduction in death and severe disability </li></ul><ul><li>There was a similar trend to improvement in most of the components of primary outcome, including mortality, motor disability and BSID – II scores in survivors </li></ul><ul><li>There was no improvement in primary outcome in infants who exhibited severe background suppression of the aEEG plus seizures at randomization </li></ul>
  36. 38. Other Neonatal Hypothermia Trials: “South Carolina Body Cooling Trial” (I) <ul><li>RCT, N=65, 6 centers, primary outcome death or severe motor disability at 12 mo. </li></ul><ul><li>≥ 35 wks GA, ≥ 2000 gm BW </li></ul><ul><li>Evidence of perinatal or postnatal hypoxic-ischemic event, followed by neonatal encephalopathy </li></ul><ul><li>Cooling by 6h, ice bags to head and body ~2h, then cooling blanket, servo controlled to rectal temp. (T r ) 33 ±0.5˚C for 48 h (controls - radiant warmer, T r 37 ±0.5˚C) </li></ul>Eicher et al , Pediatr Neurol 32:11 & 32:18, 2005
  37. 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
  38. 40. “ South Carolina Body Cooling Trial” (III) <ul><li>Mean T r 32.8 ± 1.4˚C at 2h in cooled group </li></ul><ul><li>Safety issues in body-cooled group: </li></ul><ul><ul><li>Lower mean BP in cooled group, only during re-warming day </li></ul></ul><ul><ul><li>More PPHN needing iNO (5 vs. 1) </li></ul></ul><ul><ul><li>Greater median days on pressors (5 vs . 2) </li></ul></ul><ul><ul><li>More thrombocytopenia (105 ± 60 vs. 160 ± 65) </li></ul></ul><ul><ul><li>More use of FFP (23 vs. 11; but highest PT, lowest fibrinogen no different) </li></ul></ul>
  39. 41. Other Neonatal Hypothermia Trials: NICHD NRN Body Cooling Trial (I) <ul><li>Eligibility and exclusions similar to Cool Cap, except no aEEG selection step </li></ul><ul><li>N=208 (NT=106, HT=102) </li></ul><ul><li>Primary outcome death or moderate-severe disability at 18 mo. </li></ul><ul><ul><li>Severe: MDI<70, GMF 3-5, hearing aid, blind </li></ul></ul><ul><ul><li>Mod: MDI 70-85, GMF 2,  hearing, Sz disorder </li></ul></ul><ul><li>HT: 3 days target T es 33.5 ˚C (servo cooling mattress) </li></ul>Shankaran et al . NEJM 353:1574-84, 2005
  40. 42. Copyright ©2002 American Academy of Pediatrics Shankaran, et al. Pediatrics 2002;110:377-385 The infant lies supine on the infant-size blanket
  41. 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
  42. 44. NICHD vs . Cool Cap trials <ul><li>Broader definition of “bad outcome” in NICHD trial made it statistically easier to detect a between-group difference </li></ul><ul><li>Active temperature management in the Cool Cap trial, resulting in less hyperthermia in controls, may have decreased the apparent effect of cooling </li></ul><ul><li>Cool Cap aEEG step excluded some infants with moderate HIE who would have qualified in NICHD trial </li></ul><ul><li>Worse outcome in control group of Cool Cap trial (66% death or severe disability) vs . control group of NICHD trial (62% death or moderate or severe disability) suggests Cool Cap population had greater baseline severity of injury </li></ul>
  43. 45. Summary of Three Large Trials <ul><li>Hypothermia has a modest beneficial effect in term infants with moderate-to-severe HIE </li></ul><ul><li>Babies with HIE have multiple organ system complications, which are not worse with cooling as used in the two larger trials </li></ul><ul><li>Sinus bradycardia is a physiologic response to hypothermia </li></ul><ul><li>Skin complications with head or body cooling resolved after re-warming </li></ul>
  44. 46. Limitations of All Three Trials <ul><li>About 1/1000 live births could qualify </li></ul><ul><li>Delay to onset of cooling - nearly 5h </li></ul><ul><ul><li>Stabilization and/or transport time </li></ul></ul><ul><ul><li>Time to obtain consent </li></ul></ul><ul><li>Current standard of care is to warm all birth-depressed neonates to 37˚C </li></ul>
  45. 47. The Future of Neonatal Cooling <ul><li>Is it true? </li></ul><ul><ul><li>At least 3 ongoing RCTs of body cooling in UK, Australia, Canada, Europe, with ~270 recruits/3 years (as of Jan 2005) </li></ul></ul><ul><li>Chinese head cooling trial results? </li></ul><ul><ul><li>Recruitment slow </li></ul></ul><ul><li>How do we improve upon results? </li></ul><ul><ul><li>Cool sooner? Colder? </li></ul></ul><ul><ul><li>Combination with pharmacotherapy? </li></ul></ul><ul><li>Head cooling device under FDA review </li></ul>
  46. 48. Remember: =
  47. 49. PRACTICALITIES of BRAIN COOLING
  48. 51. Practical Issues for Referring Hospitals (I) <ul><li>Distance: Patients from Saginaw, Toledo, Holland, St. Clair </li></ul><ul><li>“ How do I know they’ll meet EEG criteria?” Sarnat III and Sarnat II with clinical SZ likely will Sarnat II without clinical SZ - about 1/3 meet aEEG criteria </li></ul><ul><li>What should you say to parents? They can have a therapy which may help their baby, and has no serious adverse effects (studied in over 200 babies); better than conventional care offers. Use analogy of icing a joint after a sports injury </li></ul><ul><li>No “prophylactic” phenobarb please (OK to treat SZ) </li></ul><ul><li>Avoid hyperthermia - check rectal temperature </li></ul>
  49. 52. Practical Issues for Referring Hospitals (II) <ul><li>Prompt notification of study center is key </li></ul><ul><li>Rapid mobilization of transport (ours or yours ) </li></ul><ul><li>Consent signed on team arrival, or by fax/phone with investigator </li></ul><ul><li>Investigators will discuss cooling details with parent(s) by phone while team en route, to save time </li></ul><ul><li>Remember: they need to arrive by 5.5 h </li></ul>
  50. 54. Rectal Temperature
  51. 55. Implications <ul><li>Cerebral hypothermia is the first treatment demonstrated in a major controlled trial to improve long term outcome of neonatal encephalopathy </li></ul><ul><li>Confirms experimental and clinical data showing that neonatal encephalopathy can be progressive and reversible, not necessarily fixed at birth </li></ul><ul><li>Trial design issues in perinatal encephalopathy </li></ul><ul><ul><li>Relatively large trials are needed for sufficient power </li></ul></ul><ul><ul><li>aEEG helped address the problem of heterogeneity of severity/timing and improved power of the study </li></ul></ul>
  52. 56. Issues Ahead <ul><li>Head vs whole body cooling </li></ul><ul><ul><li>Efficacy – unlikely to be specific to cranial cooling provided protective temperature reached </li></ul></ul><ul><ul><li>Safety – risks of cranial cooling may be less as higher rectal temperature can be maintained. The ease of systemic hypothermia may lead to uninformed use </li></ul></ul><ul><ul><li>Physiology – ?less thermogenesis with head cooling </li></ul></ul><ul><li>Degree and duration of cooling </li></ul><ul><li>Prematurity: greater risks? </li></ul><ul><li>Time to treat: can we enroll earlier? </li></ul>
  53. 57. The Cool Cap Study Group <ul><li>Executive committee : P.D.Gluckman (chair), J.S. Wyatt, A.J. Gunn (Scientific Officer) </li></ul><ul><li>Scientific advisory committee : J.S. Wyatt (chair), R. Ballard, A.D. Edwards, D.M. Ferriero, P.D. Gluckman, A.J. Gunn, R. Polin, C. Robertson, A. Whitelaw </li></ul><ul><li>Statistician : P.Y. Liu </li></ul><ul><li>aEEG advisor: D. Azzopardi </li></ul><ul><li>Data safety committee : R. Soll (chair), M. Bracken, M. Heymann, C. Palmer, A.Wilkinson. </li></ul><ul><li>Hospital investigators : J. Kaiser, M. Battin, J. Khan, T. Raju, R. Polin, R. Sahni, U. Sanocka, A. Rosenberg, J. Paisley, R. Goldberg, M. Cotten, A. Peliowski, E. Phillipos, D. Azzopardi, A.D. Edwards, F. Northington, J. Barks, S. Donn, B. Couser, D. Durand, K. Sekar, D. Davis, M. Blayney, S. Adeniyi-Jones, T. Yanowitz, R. Guillet, N. Laroia, N. Finer, F. Mannino, J. Partridge, D. Davidson, A. Whitelaw, M. Thoresen, J.S. Wyatt, F. O’Brien, B. Walsh, J. Perciaccante, M. O'Shea </li></ul><ul><li>Manufacturer’s representatives - Olympic Medical : J. Jones, T. Weiler, J. Mullane, D. Hammond </li></ul>
  54. 58. Thank you!

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