• Abbot R Laptook, Seetha Shankaran, Jon E Tyson, Breda Munoz, Edward F Bell, Ronald N Goldberg, Nehal A Parikh, Namasivayam Ambalavanan, Claudia Pedroza, Athina Pappas, Abhik Das, Aasma S Chaudhary, Richard A Ehrenkranz, Angelita M Hensman, Krisa P Van Meurs, Lina F Chalak, Amir M Khan, HamrickShannon E GSEGEmory University School of Medicine, Department of Pediatrics, Children's Healthcare of Atlanta, Atlanta, Georgia., Gregory M Sokol, Michele C Walsh, Brenda B Poindexter, Roger G Faix, Kristi L Watterberg, Ivan D Frantz, Ronnie Guillet, Uday Devaskar, William E Truog, Valerie Y Chock, Myra H Wyckoff, Elisabeth C McGowan, David P Carlton, Heidi M Harmon, Jane E Brumbaugh, C Michael Cotten, Pablo J Sánchez, Anna Maria Hibbs, Rosemary D Higgins, and Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.
• Department of Pediatrics, Women & Infants Hospital, Brown University, Providence, Rhode Island.
• JAMA. 2017 Oct 24; 318 (16): 155015601550-1560.

ImportanceHypothermia initiated at less than 6 hours after birth reduces death or disability for infants with hypoxic-ischemic encephalopathy at 36 weeks' or later gestation. To our knowledge, hypothermia trials have not been performed in infants presenting after 6 hours.ObjectiveTo estimate the probability that hypothermia initiated at 6 to 24 hours after birth reduces the risk of death or disability at 18 months among infants with hypoxic-ischemic encephalopathy.Design, Setting, And ParticipantsA randomized clinical trial was conducted between April 2008 and June 2016 among infants at 36 weeks' or later gestation with moderate or severe hypoxic-ischemic encephalopathy enrolled at 6 to 24 hours after birth. Twenty-one US Neonatal Research Network centers participated. Bayesian analyses were prespecified given the anticipated limited sample size.InterventionsTargeted esophageal temperature was used in 168 infants. Eighty-three hypothermic infants were maintained at 33.5°C (acceptable range, 33°C-34°C) for 96 hours and then rewarmed. Eighty-five noncooled infants were maintained at 37.0°C (acceptable range, 36.5°C-37.3°C).Main Outcomes And MeasuresThe composite of death or disability (moderate or severe) at 18 to 22 months adjusted for level of encephalopathy and age at randomization.ResultsHypothermic and noncooled infants were term (mean [SD], 39 [2] and 39 [1] weeks' gestation, respectively), and 47 of 83 (57%) and 55 of 85 (65%) were male, respectively. Both groups were acidemic at birth, predominantly transferred to the treating center with moderate encephalopathy, and were randomized at a mean (SD) of 16 (5) and 15 (5) hours for hypothermic and noncooled groups, respectively. The primary outcome occurred in 19 of 78 hypothermic infants (24.4%) and 22 of 79 noncooled infants (27.9%) (absolute difference, 3.5%; 95% CI, -1% to 17%). Bayesian analysis using a neutral prior indicated a 76% posterior probability of reduced death or disability with hypothermia relative to the noncooled group (adjusted posterior risk ratio, 0.86; 95% credible interval, 0.58-1.29). The probability that death or disability in cooled infants was at least 1%, 2%, or 3% less than noncooled infants was 71%, 64%, and 56%, respectively.Conclusions And RelevanceAmong term infants with hypoxic-ischemic encephalopathy, hypothermia initiated at 6 to 24 hours after birth compared with noncooling resulted in a 76% probability of any reduction in death or disability, and a 64% probability of at least 2% less death or disability at 18 to 22 months. Hypothermia initiated at 6 to 24 hours after birth may have benefit but there is uncertainty in its effectiveness.Trial Registrationclinicaltrials.gov Identifier: NCT00614744.

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