Effect of Therapeutic Hypothermia Initiated After 6 Hours of Age on Death or Disability Among Newborns With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial

Abstract

IMPORTANCE-Hypothermia 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. OBJECTIVE-To 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 PARTICIPANTS-A 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.INTERVENTIONS-Targeted 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 MEASURES-The composite of death or disability (moderate or severe) at 18 to 22 months adjusted for level of encephalopathy and age at randomization. RESULTS-Hypothermic 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 RELEVANCE-Among 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 REGISTRATION-clinicaltrials.gov Identifier: NCT00614744Hypoxic-ischemic encephalopathy represents a subset of neonatal encephalopathy, occurring in approximately 1.5 per 1000 live births. 1 It is an important etiology of neonatal mortality and serious or devastating lifelong cerebral palsy, neurosensory deficits, and cognitive impairments. 2 Therapeutic hypothermia initiated...

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“…However, this may be at the expense of the reliability of the treatment estimates derived from the trial [88]. Bayesian approaches which make use of prior information can be used to provide a quantitative summary of treatment effect when traditional approaches for defining statistical significance are impractical [89]. Registry-based trials and trials which obtain follow-up data through administrative data sources may reduce the burden and cost of data collection [90,91].…”

Major concerns about late hypothermia study

“…All intervals of level 38% or more contain the null hypothesis value RR = 1.00; there is hence no reason to reject that value. The main conclusion from the Laptook et al study (1) ought to be that there is simply no real difference between the therapeutic probabilities for the two groups. In addition, with a normal prior as in Laptook et al (1), the posterior distribution should be skewed with a tail to high RR values, not normal as in their figure 2.…”

Therapeutic Hypothermia in Neonatal Hypoxic-Ischemic Encephalopathy

“…Neurodevelopmental outcome was assessed in survivors at 18-22 months with the Bayley III. Outcome was available for 78 cooled (9 died and 10 had moderate to severe disability) and 79 normothermic patients (9 died and 13 had moderate to severe disability) [50]. This difference was not significant (p >0.5, Chi-squared test).…”