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

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: NCT00614744

Major concerns about late hypothermia study

“…The results presented by Laptook et al. support that the findings from the two animal species of no effect of late cooling are also valid for newborn humans. In addition, an observational human cooling study showed that starting cooling between zero and three hours resulted in better motor outcome at 18 months than those who started cooling between three and six hours.…”

“…The main conclusion from the Laptook et al. study 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.…”

“…An important neonatal hypothermia (HT) trial on hypoxic–ischaemic encephalopathy was published in November 2017 by Laptook and the NICHD group . One hundred and sixty‐eight newborn term infants who failed the six‐hour time‐window for HT were recruited by 21 centres over an eight‐year period into a trial of HT versus normothermia (NT) if they were more than six hours and less than 24 hours old.…”

Elicitation of prior probability distributions for a proposed Bayesian randomized clinical trial of whole blood for trauma resuscitation

“…We also provided a simple example (based on Grigore et al) to familiarize them with the online tool. Finally, we included examples of Bayesian trials and analyses using informative priors . Two weeks before the elicitation workshop, we sent an evidence dossier to participants.…”

Impact of Education on Hypothermia Delivery during Neonatal Transport

“…However, many term or near-term infants with HIE are born in non-tertiary centres without the resources or expertise to perform servo-controlled cooling and the other care modalities required by this population. The need for postnatal stabilisation and transfer to a tertiary NICU therefore precludes some infants from the benefits of optimally delivered TH and increases the risk of HIE-associated brain injury [10]. …”