Therapeu(c Hypothermia: The Status of its Use for Hypoxic-Ischemic Encephalopathy (HIE)

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1 Therapeu(c Hypothermia: The Status of its Use for Hypoxic-Ischemic Encephalopathy (HIE) Abbot R. Laptook, M.D. Medical Director, NICU Women and Infants Hospital of RI Professor of Pediatrics Alpert Medical School of Brown University

2 Disclosure Speaker: Abbot Laptook 1. Dr. Laptook has no financial relahonships to disclose or conflicts of Interest to resolve. Any real or apparent conflicts of interest related to the content of this presentahon have been resolved. 2. This presentahon will not involve discussion of unapproved or off-label, experimental or inveshgahonal use of a drug.

3 Objec(ves Current status of hypothermia treatment for HIE NICHD workshops/cofn: research gaps Evidence for target temperature Evidence for durahon of cooling Evidence for Hme of inihahon Evidence for use in premature infants Evidence for use in mild encephalopathy

4 Components of a Hypothermia Regimen Time of inihahon DuraHon of cooling Temperature depth Rate of rewarming Method of cooling Body cooling Head cooling Phases of Hypothermia Tx InducHon Maintenance Rewarming

5 Parameters of Hypothermia Regimens Used in Clinical Trials Hypothermia Regimen GestaHonal age 36 weeks Encephalopathy IniHaHon age Mode of cooling Target Temperature DuraHon of hypothermia Rewarming rate Moderate or severe < 6 hours Body or head 33.5 o C or 34.5 o C 72 hours 0.5 o C hour

6 Clinical Trials of Therapeu(c Hypothermia for Newborn HIE Trial Year Cooled (n) Control (n) CoolCap NICHD TOBY Chinese European ICE Lancet 2005;365: NEJM 2005;353: NEJM 2009;361: J Pediatrics 2010;157: Pediatrics 2010;126:e Arch Pediatr Adol Med 2011;165:

7 Primary Outcome in Therapeu(c Hypothermia Trials in Newborns Death or disability assessed at 18 months Disability: typically severe GMFCS: Index of motor disability/cerebral palsy Developmental delay < 2 SDs Bayley Scales of Infant Development MDI Griffiths assessment Gesell Child Development Age Scale Blindness Deafness

8 Death or Disability among Infants with HIE at 18 months treated with Hypothermia or Usual Care < 6 hours Cooling Hypothermia Usual Care RR 95% CI SelecHve Head n % outcome n % outcome Body Jacobs, SE et al, Cochrane Database of SystemaHc Reviews, 2013

9 J Pediatr, 2006: 148: Research Gaps v Long term safety/efficacy v Optimizing cooling v Value in preterm infants J Pediatr, 2011: 159: v Biomarkers for prognosis v Organized dissemination v Low resource countries v Adjunctive therapies Pediatrics 2014:133: v Evidence based practice v Comprehensive care v Out-reach education v Role of research

10 NICHD Neonatal Research Network: Studies of Knowledge Gaps for Hypothermia Treatment of Encephalopathy Long term outcome following hypothermia Benefit to a lower target temperature Benefit to longer cooling Benefit for later inihahon of cooling Benefit for cooling preterm infants

11 6-7 Year Outcome Following Hypothermia for Encephalopathy: NRN Trial % Hypothermia n=97 1 o outcome* Death or IQ < 70 2 o outcomes Control n=93 RR (95%CI) p value ( ).06 Death ( ).04 Survivors IQ < ( ).51 Disabling CP ( ).28 * Primary outcome available for 190 of 208 NICHD trial enrollees (91%) Shankaran et al, NEJM 2012;366:

12 6-7 Year Outcome Following Hypothermia for Encephalopathy: TOBY Trial N, (%) Hypothermia n=163 1 o outcome* Survival with IQ 85 2 o outcomes Control n=162 RR (95%CI) p value 75/145 (52) 52/132 (39) 1.31 ( ).04 Death 47/163 (29) 79/162 (30).95 ( ).81 Survivors IQ 85 75/98 (77) 52/83 (63) 1.22 ( ).05 Disabling CP 21/98 (21) 31/86 (36).59 ( ).03 * IQ scores could not be determined: Hypothermia group: 18 Control group: 30 Azzopardi D et al, NEJM 2014:371:

13 Evidence for a Target Temperature of 33.5 o C

14 Target Temperature: Neuroprotection in Newborn/Fetal Animals with Delayed Cooling Model Age Temperature Site Temperature Decrement Δ T Reference Rat 7d Rectal o C 7 o C Peds Res 2002;51:354 Pigs 48hrs Tympanic o C 4 o C Peds Res 1997;41:505 Pigs 7d Rectal o C 2.5 o C Peds Res 1997;42:17 Fetal lambs d Extra-dural o C 6.7 o C JCI 1997;99:248 Neuroprotection: associated with a spectrum of in temperature

15 Target Temperature: Clinical Trials Should it be: An absolute temperature Change in temperature from baseline Trade off for the target temperature: Extent of neuroprotection vs harm of a lower temperature

16 Hypothermia Treatment in Newborns with Encephalopathy: Pilot Trials Gunn et al 1 Head cooling + minimal body cooling (72 hrs) Randomization T: 37.0 o C (n=10), 36.3±.2 o C (n=6), 35.7±.2 o C (n=6) Thoresen et al 2 Head cooling + body cooling (72 hrs) T: o C (n=6) Body cooling (72 hrs), T: o C (n=3) Shankaran et al 3 Body cooling (72 hrs) Randomization T: 37.0 o C (n=10), 34.5 o C (n=9) Conclusions: modest cooling is feasible and safe 1 Pediatrics 1998; 102: Pediatrics 2000; 106:92-99 Pediatrics 2002; 110:

17 Use of Lower Temperatures for Therapeutic Hypothermia: Feasibility Retrospective Safety assessment v Control group, n=11 v o C, n=10 v o C, n=18 No differences in safety endpoints Compagnoni G et al, Neonatology 2008; 93:230

18 Evidence for 72 hour duration of Cooling

19 Duration of Hypothermia: Neuroprotection in Adult/Newborn/Fetal Animals with Cooling Adult rodents (gerbils, rats) 1-3 Ischemia models (global or focal) duration of cooling (immediate or delayed) brain injury Rat pups 4 Hypoxia-ischemia model duration of cooling (immediate) brain injury Fetal sheep 5 Ischemia model (global) Epileptiform activity triggered with stopping cooling at 48 hrs compared to 72 hrs. 1 Carroll et al, Met Brain Dis 1992;7:45 2 Colbourne et al, Brain Res 1994; 654:265 3 Yanamoto et al, Brain Res 1996;718:207 4 Sirimanne et al, Ped Res 199 6; 39: Gunn et al, JCI 1997; 99:

20 Temporal Profile of the Mechanisms of Brain Injury Ferriero DM, NEJM 2004;351:1985

21 Refining Hypothermia: Op(mizing Cooling RCT (NCT ) P: Newborn infants with moderate or severe HIE at < 6 hours of age I: Cooling to 32 o C or cooling for 120 hours C: Cooling to 33.5 o C or cooling for 72 hours O: Death or disability T: months Factorial 2 x 2 design (assumes no interachon) 33.5 o C 72 hours 32.0 o C 72 hours Dura(on(n=363) 72 hr 33.5 o C 120 hours 32.0 o C 120 hours 120 hr Depth (n=363) 33.5 o C 32.0 o C

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23 Trial Closure v Trial was stopped amer enrollment of 364 infants v Death up to 18 months of age 33.5 C for 72 h: 9% 32.0 C for 72 h: 18% 33.5 C for 120 h: 19% 32.0 C for 120 h: 19% v CondiHonal fuhlity analysis: probability of detechng a significant treatment benefit of longer or deeper cooling for inhospital mortality was < 2% v An interachon was present (p=.05)

24 Outcome of Deeper Cooling: 33.5 o C vs 32.0 o C Dura(on 72 hrs 72 hrs RR ǂ 95% CI Depth 33.5 o C 32.0 o C n Death or disability* 29% 35% Death 9% 18% Disability* 23% 20% Disabling Cerebral Palsy 16% 14% * Disability was moderate or severe in extent ǂ adjusted for level of encephalopathy and center Shankaran S, PAS 2016

25 Outcome of Longer Cooling: 72 vs 120 hours Dura(on 72 hrs 120 hrs RR ǂ 95% CI Depth 33.5 o C 33.5 o C n Death or disability* 29% 34% Death 9% 19% Disability* 23% 19% Disabling Cerebral Palsy 16% 12% * Disability was moderate or severe in extent ǂ adjusted for level of encephalopathy and center Shankaran S, PAS 2016

26 Outcome of Longer and Deeper Cooling: 33.5 o C/72 hrs vs 32.0 o C/120 hrs Dura(on 72 hrs 120 hrs RR ǂ 95% CI Depth 33.5 o C 32.0 o C n Death or disability* 29% 28% Death 9% 19% Disability* 23% 11% Disabling Cerebral Palsy 16% 8% * Disability was moderate or severe in extent ǂ adjusted for level of encephalopathy and center Shankaran S, PAS 2016

27 Lessons From the Op(mizing Cooling Trial (JAMA 2014; 312: ) Among term infants with HIE, longer cooling was not superior to usual durahon and deeper cooling was not superior to usual depth of cooling Avoid drims in adherence to established protocols based on randomized trials Whole body cooling regimens: Target Tes of 33.5 o C for 72 hours

28 Evidence for Cooling beyond 6 hours of age

29 Time of Ini(a(on of Hypothermia: Dura(on of Therapeu(c Window JCI 1997:99;248 Ped 1998:102;1098 Ped Res 1999:46;274

30 Hypothermia Ini(ated at 8.5 hours ajer Brain Ischemia in Fetal Sheep (Late) Sham cooling: n = 13 Cooling: n = 5 IntervenHon for 72 hr Outcome at 5 d Neuronal loss score, p=.11, NS 90.3±4.5% vs 82.0±9.0% p=.03 p=.06 Gunn AJ et al, Pediatr Res 1999; 46(3):

31 Implementa(on of Therapeu(c Hypothermia in the UK DistribuHon of cooling centers in the UK PLoS One 2012;7;e38504 TOBY registry, Dec 2006-July 2011, n= hrs: 9-10% > 12hrs: 2.2%

32 Ra(onale to Study Ini(a(on of Hypothermia Ajer 6 hours of Age Available data: Does not exclude the possibility of benefit when hypothermia is inihated amer 6 hours Clinical rahonale: Timing of fetal hypoxia-ischemia may not be accurate Some infants manifest symptoms at > 6 hours Geographic constraints PracHce creep in the absence of evidence

33 The Late Hypothermia RCT (NCT ) P: Infants 36 wks with moderate or severe HIE who are between 6-24 hours of age I: Cooling to 33.5 o C (Tes) for 96 hours C: Maintenance of Tes at 37.0 o C ( o C) O: Death or disability T: months Laptook et al, PAS 2017

34 Sample Size Considera(ons Frequen6st analysis: probability of the observed data or more extreme data if the null hypothesis is true Primary outcome: 60%, 10% absolute reduchon (17% RR) 392 infants per group Bayesian analysis: probability that the hypothesis is true based on the observed data A formal method to assess the range of treatment effects compahble with the best available evidence and eshmate the probability of a benefit Recommended for trials with limited sample size Provides useful data even when a definihve result is unlikely

35 Sample Size and Pre-specified Analyses Bayesian analysis: pre-specified Sample size, N=168, pre-defined Largest feasible number of infants that could be studied EsHmated from the NRN 1 st hypothermia trial 1 and reports 2 of progression from stage 1 to 2 or 3 Primary analyses adjusted for level of encephalopathy and age at randomizahon P values: provided for descriphve stahshcs and components of the primary outcome 1 NEJM 2005;353: Pediatrics2003;111:351

36 Bayesian Analysis Prior distribu6on Observed data Posterior distribu6on: Point eshmate 95% credible intervals Probability of posterior treatment benefit (P-TB) Area under the curve which lies < RR 1.0

37 Posterior Probability of Reduced Death or Disability with Late Hypothermia: Neutral Prior Death or mod/sev disability Cooled (n=78) Non-cooled (n=79) Neutral prior n % n % arr, 95% credible intervals ( ) P-TB RR< arr: Adjusted for level of encephalopathy and age at randomizahon

38 Posterior Probability of Treatment Benefit (P-TB): Secondary Outcomes using a Neutral Prior Cooled (n=78) Non-cooled (n=79) Neutral prior n % n % arr, 95% credible intervals P-TB RR<1.0 Death ( ) Severe disability ( ) Moderate disability arr: Adjusted for level of encephalopathy and age at randomizahon

39 Other Outcomes Among Survivors Cooled (n=69) Non-cooled (n=70) p value n X±sd or % n X±sd, or % Age at FU ± ± 3.83 Bayley cognihve < X±sd ± ± Cerebral Palsy Moderate Severe

40 Conclusions: Late Hypothermia Trial Bayesian analysis suggests a possible treatment benefit but is not conclusive 76% likelihood of reduced death or disability 3 in 4 chance of treatment benefit compared to the neutral prior (2 in 4 chance) What is the minimum probability of benefit that jushfies a treatment? Outcome involved PotenHal harm The results should not delay efforts to recognize HIE early and inihate hypothermia within 6 h of birth

41 Evidence for Cooling Infants < 36 Weeks GestaHon

42 Therapeu(c Hypothermia for Infants < 36 weeks Gesta(on Limited data on efficacy and safety: RCT 1,2 : 7 infants with outcome (all weeks) Registry Data 3,4 : VON and TOBY 3-6% of infants being cooled: no outcome data Single center 5 : wks (n=31) vs 39.3±.8 wks (n=32) RetrospecHve, all cooled, PT deaths/complicahons > term No follow-up Single center 6 : wks (n=31), no comparison group 17% IVH, FU (75%), death or disability 65% 1 Pediatr Neurol 2005;32:11 2 Arch Pediatr Adolesc Med, 2011;165:692 3 PLOS One, 2012;e PAS, 2013, abstract J Peds 2017; 183: Herrera PAS 2017

43 Preterm Hypothermia RCT (NCT ) P: Infants wks with moderate or severe HIE who are between 6-24 hours of age I: Cooling to 33.5 o C (Tes) for 72 hours C: Maintenance of Tes at 37.0 o C ( o C) O: Death or disability T: months Sample size: 168, current enrollment: 63 FrequenHst and Bayesian analyses

44 Preterm Hypothermia Trial v Safety and efficacy

45 Should Infants with Mild HIE Receive ExisHng data: Hypothermia Treatment? Adverse outcomes among some infants not meehng cooling criteria 1 Center reports: Similar frequency of MRI abnormalihes among mild and moderate HIE 2,3 California: 50% of mild HIE are cooled (CPQCC & CPTS) 4 5 yr outcome: FSIQ normal but.5 SD < controls 5 Data quality All retrospechve reports No criteria to diagnose mild encephalopathy No follow-up except for reference 5 No randomized controlled trials 1 J Peds 2013; 162:35-41, 2 Am J Perinatol 2016; 33: , 3 J Peds 2017 epub 4 J Peds 2014; 165: , 5 Pediatrics 2016; 138: e

46 Prospec(ve Research on Infants with Mild Encephalopathy: The PRIME Study Hypothesis: 20% of infants evaluated at < 6 hours for hypothermia with exam abnormalihes but not meehng criteria for treatment will have neurological dysfunchon ObservaHonal cohort 6 centers: McGill University, WIH/Brown, UTSW, WSU, Mahidol University, Imperial College Primary outcome: Abnormality of any of the following: MRI, aeeg or neurological exam at discharge Secondary outcome: Neurodevelopmental outcome at 18 months Sample size: 54 Santa Anna, G et al, PAS 2016

47 PRIME Study: Short Term Outcomes Neurodevelopment at 18 months in progress Outcome Results (n=54) Abnormality of aeeg, MRI or discharge exam 28 (54%) Abnormal aeeg 4 (7%) Abnormal MRI 9 (17%) Abnormal discharge exam 22 (41%)

48 Clinical Implica(ons: Use an Evidenced Based Approach to Therapeu(c Hypothermia Structured program Establish screening guidelines for pahent criteria Train transport teams RecogniHon of encephalopathy Temperature control on transport Cooling regimen Start at < 6 hours; consider late cooling Cool for 72 hours Use a core temperature of 33.5 o C for whole body cooling Use a controlled rate of increasing temperature (0.5 o C/hour) Ensure follow-up Monitor for late complicahons (eg, subcutaneous fat necrosis) Program to assess neurodevelopment

49 Thank You Any questions?