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Optimizing Cooling Strategies for Neonatal Hypoxic-Ischemic Encephalopathy: A Randomized Controlled Trial

This randomized controlled trial investigates if longer duration cooling, deeper cooling, or both are more effective in reducing death or disability in term neonates with hypoxic-ischemic encephalopathy.

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Optimizing Cooling Strategies for Neonatal Hypoxic-Ischemic Encephalopathy: A Randomized Controlled Trial

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  1. Randomized Controlled Trial of Optimizing Cooling Strategies for Neonatal Hypoxic-Ischemic Encephalopathy Seetha Shankaran, Abbot Laptook, Athina Pappas, Scott McDonald, Abhik Das, Jon Tyson, Kurt Schibler, Brenda Poindexter, Edward Bell, Roy Heyne, Claudia Pedroza, Rebecca Bara, Krisa Van Meurs, Cathy Grisby, Carolyn Huitema, Uday Devaskar and Rosemary Higgins for the NICHD Neonatal Research Network

  2. Disclosures Speaker: Seetha Shankaran • Dr. Shankaran and co-investigators have no financial relationships to disclose or Conflicts of Interest to resolve • This presentation will not involve discussion of unapproved or off-label, experimental or investigational use of a drug

  3. Background • Cooling to 33.0°C to 34.0°C for 72 hours for neonatal HIE has decreased death or disability at 18 months in 5 major randomized controlled trials • This neuroprotection continues to childhood • However, the rate of death or disability in the cooled group remains high (up to 44-55%) Jacobs SE, Cochrane Database review 2013, Guillet R, Pediatr Research 2012, Shankaran S, New Engl J Med 2012, Azzopardi D, New Engl J Med 2014

  4. Background • Preclinical studies have demonstrated that brain injury following hypoxia-ischemia continues and evolves over days and weeks • Deeper cooling minimizes brain swelling, preserves energy and suppresses oxidative metabolism • Longer cooling may protect against apoptosis and inflammation Busto R, J Cereb blood Flow Metab 1987, Thoresen M, Pediatr Res 1995, Williams JD, Pediatr Res 1997, Iwata O, Ann Neurol 2005, Bennet L, J Physiol 2007, Perlman J, Pediatrics 2006, Johnston MV, Lancet Neurol 2011

  5. Objective and Design • To determine if longer duration cooling (120 hours), deeper cooling (32.0°C) or both is superior to cooling at 33.5°C for 72 hours in term neonates with HIE • A randomized 2 x 2 factorial design clinical trial performed in 18 US centers in the NICHD Neonatal Research Network between October 2010 and November 2013

  6. >36 weeks, <6 h No Blood Gas or pH 7.01-7.15 or BD 10.0-15.9 Blood Gas pH <7.0 or BD >16 Acute Event AND 10 min Apgar <5 OR Ventilation from birth AND SEIZURES OR MODERATE/SEVERE HIE

  7. Design Randomly assigned to 4 hypothermia groups stratified by center and level of encephalopathy • 33.5°C for 72 hours • 32.0°C for 72 hours • 33.5°C for 120 hours • 32.0°C for 120 hours Trial was powered for marginal comparisons of 33.5°C vs. 32.0°C and 72 hours vs.120 hours

  8. Outcomes • Primary outcome of death or moderate or severe disability at 18 to 22 months is still ongoing • The independent data and safety monitoring committee paused the trial to evaluate safety after the first 50 neonates were enrolled • Cardiac arrhythmia • Persistent acidosis • Major vessel thrombosis and bleeding • Death in the NICU

  9. Outcomes • Data and safety and monitoring committee monitored safety after everysubsequent 25 neonates • The trial was closed for emerging safety profile and futility analysis after the eighth review with 364 neonates enrolled of 726 planned • This report focuses on safety and NICU deaths by marginal comparisons of 72 hours vs. 120 hours duration and 33.5°C depth vs. 32.0°C depth (predefined secondary outcomes)

  10. Treatment: Cooling protocol similar to first RCT except • Neonates assigned to 32.0°C group had temperature initially lowered to 33.5°C and when stable for 15 minutes, lowered further to 32.0°C • Temperatures were monitored for the first 10 days and hyperthermia treated as per usual care

  11. Analysis Plan • Target sample size was 726 subjects (363 per marginal group comparison) based on 2-tailed type 1 error of 0.05, 80% power, 5% loss to FU and a comparison of death or disability of 37.5 and 27.5% • Intention-to-treat analysis • Primary and secondary outcomes analyzed by robust Poisson regression models • Adjust for center and level of HIE and assess treatment interactions

  12. Results

  13. Maternal and Neonatal Characteristics

  14. Perinatal and Neonatal Characteristics • Perinatal characteristics were similar between the 72 and the 120 h and the 33.5 and 32.0°C groups • Neonatal characteristics were similar between the 72 and the 120 h groups. Among the 33.5 and 32.0°C groups, birth weight was higher in the 32.0°C group, 3432+582g vs. 3292+608g (P=0.02)

  15. Serious Adverse Events During Intervention: 72 vs.120 h Adjusted P values *P=0.04, other comparisons NS

  16. Serious Adverse Events During Intervention: 33.5 vs.32°C Adjusted P values NS

  17. Hospital Course: 72 vs.120 h * Selected post-hoc by DSMC

  18. Hospital Course: 33.5 vs.32°C * Selected post-hoc by DSMC

  19. Mortality rate in 4 groups • 33.5°C for 72 h: 7% • 32.0°C for 72 h: 14% • 33.5°C for 120 h: 16% • 32.0°C for 120 h: 17%

  20. Outcomes assessed for Safety: Risk Ratio Adjusted for HIE and Center

  21. Results • Interaction between depth and duration for in-hospital mortality adjusted for level of HIE and center: P=0.20 • Futility analysis: Probability of detecting statistically significant treatment benefit of longer or deeper cooling for in-hospital mortality: <2% • Follow-up of enrolled infants on-going

  22. Conclusions • Mortality in the longer or deeper cooling or both was lower than the cooled arm of our previous RCT (19%) ; mortality in 33.5°C for 72 hours was unexpectedly low • Cooling at 32.0°C was associated with more INO and ECMO therapy and cooling for 120 hr with more arrhythmia • Need to adhere to established published protocols

  23. Conclusions • Among term neonates of at least 36 weeks gestation with moderate or severe HIE, deeper cooling or longer duration of cooling compared with hypothermia at 33.5°C for 72 hours did not reduce NICU deaths • These results have implications for patient care and design of future trials

  24. Neonatal Research Network Centers • Brown University • Case Western Reserve University • Children’s Mercy Hospitals and Clinics, University of Missouri-Kansas City • Cincinnati Children’s Medical Center • Duke University • Emory University • Indiana University • Nationwide Children’s Hospital, Ohio State University • RTI International • Stanford University • Tufts Medical Center • University of Alabama at Birmingham • University of California – Los Angeles • University of Iowa • University of New Mexico • University of Pennsylvania • University of Rochester • University of Texas Southwestern Dallas • University of Texas Health Science Center Houston • University of Utah • Wayne State University • Yale University

  25. Thank you • Questions? • sshankar@med.wayne.edu

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