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: NCT00614744.

Conflict of interest statement

Conflict of Interest: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.

Figures

Figure 1

Flow Diagram of Neonates With Hypoxic-Ischemic Encephalopathy Through a Trial of Hypothermia Initiated at 6 to 24 Hours After Birth

Figure 2. Posterior Probability of Death or Disability With Hypothermia Initiated at 6 to 24 Hours After Birth vs Noncooling

A, The probability density describes the frequency distribution of observed values and is unit-less. The curves are scaled so that the total area under the curve is 1, and the area between any 2 values on the x-axis equals the probability of observing a value in that range. The blue line plots a neutral prior distribution centered at a risk ratio of 1.0 and indicates an equal number of infants would be expected to benefit by either temperature management group, hypothermia or noncooled. The posterior probability of treatment effect is derived by combining the prior distribution with the trial results. The distribution is shifted to the left of a risk ratio of 1.0 with a point estimate of 0.86. The area under the curve that is less than a risk ratio of 1.0 (light blue) represents the posterior probability of any reduction in death or disability (76% for this trial). The area under the curve that is greater than a risk ratio of 1.0 (dark blue) represents the posterior probability of an increase in death or disability (24% for this trial). B, The light blue portion indicates a 64% probability that death or disability in infants treated with hypothermia is at least 2% less than noncooled infants (benefit). The pale blue area (near zero) is an arbitrary zone of indifference to illustrate the probability of risk differences where hypothermia and noncooling may be viewed as equivalent. The dark blue indicates the probability of death or disability among infants treated with hypothermia is higher than for noncooled infants (harm). In this example, a 2% absolute risk difference was associated with a 3.2-times (64%/20%) higher probability of reduced compared with increased death or disability risk among hypothermia relative to noncooled infants.