The current cooling standard of 33.5°C for 72 hours remains the safest and most effective treatment for moderate-to-severe hypoxic-ischemic encephalopathy in neonates, according to the results of a randomized clinical trial published in JAMA. Longer durations and greater depth of cooling not only did not reduce later mortality and disability, but the combination was associated with higher mortality at 18 months.
An extensive team of investigators enrolled 364 neonates born at 36 weeks or later with moderate or severe encephalopathy from 18 of the Eunice Shriver Kennedy National Institute of Child Health and Human Development Neonatal Research Network US sites from October 2010 to January 2016. The newborns were randomly assigned to one of four cooling regimens in a 2 x 2 factorial design for testing 32°C and 33.5°C each for durations of 72 and 120 hours.
The trial was suspended early due to concerns of futility and in-hospital mortality. At that time, 56/176 infants who had 72 hours of cooling and 54/171 infants who had 120 hours of cooling (31.8% and 31.6%, respectively) had died or developed disabilities (most frequently severe), as had 59/185 infants who were cooled to 33.5°C and 51/162 cooled to 32°C (31.9% and 31.5%, respectively). Infants who were cooled to 32°C for 120 hours and 33.5°C for 72 hours had lower rates of mortality and disability at 18 to 22 months (28.2% and 29.3%, respectively), compared with the other 2 groups (32°C for 72 hours, 34.5%; 33.5°C for 120 hours 34.4%).
There was little impact on most secondary outcomes — including post-neonatal intensive care unit discharge mortality, rehospitalization, level of disability by stage of encephalopathy; disability rates for vision, hearing, and multiple disabilities; cognitive and motor test scores; rates of cerebral palsy; and abnormal growth rates — of cooler temperatures or longer duration. In infants with motor scores <70, the greater duration of 120 hours cooling was associated with fewer episodes requiring rehospitalization, although there were more deaths in this group compared with infants who had cooling for 72 hours.
The mortality rate was highest in the group that had the greater depth of cooling for the longest duration (32°C for 120 hours), which also had lower rates of disability. Although interactions were observed between longer cooling and lower temperatures, investigators were concerned that the study was underpowered to evaluate them.
From these results, the investigators concluded that longer times and lower temperatures did not reduce mortality or morbidity associated with encephalopathy. Therefore, they determined that the standard cooling protocol of 33.5°C for 72 hours should be maintained.
Shankaran S, Laptook AR, Pappas A, et al. Effect of depth and duration of cooling on death or disability at age 18 months among neonates with hypoxic-ischemic encephalopathy: a randomized clinical trial [published online July 4, 2017]. JAMA. doi:10.1001/jama.2017.7218