Whole-Body Hypothermia for Term and Near-Term Newborns With Hypoxic-Ischemic Encephalopathy: A Randomized Controlled Trial

Abstract

Hypoxic-ischemic encephalopathy (HIE) in term newborns is an important cause of mortality and long-term sensorineural disabilities. Several studies published in the past 6 years have demonstrated the neuroprotective benefit of therapeutic hypothermia in term neonates born with HIE. Initiating therapeutic hypothermia within 6 hours of birth is considered critical, but few newborns are admitted to tertiary neonatal intensive care units (NICUs) before 6 hours. Pooled analyses of 4 published systematic reviews have reported that hypothermia reduced mortality in neonates with HIE. The Infant Cooling Evaluation trial investigated the effectiveness and safety of moderate whole-body hypothermia in newborns with HIE treated in neonatal nontertiary settings in regard to the composite outcome of mortality or major sensorineural disability at 2 years of age. This multicenter, international, randomized controlled trial was conducted at hospitals in Australia, New Zealand, Canada, and the United States from 2001 to 2007. Infants born with moderate to severe HIE at ≥35 weeks' gestation were randomized to either whole-body hypothermia at 33.5°C (within 6 hours of birth) for 72 hours (cooled group, n = 110)) or standard care at 37°C (control group, n = 111). Hypothermia at the target temperature was achieved by turning the radiant warmer off, exposing the infant to the ambient temperature, and applying refrigerated gel packs as needed to maintain rectal temperature at 33°C to 34°C. After the initial nontertiary care, the cooled infants were then managed at the birth hospital or were transported for tertiary care at a regional NICU. The absolute risk reduction of death or major sensorineural disability at 2 years of age was 15% by therapeutic hypothermia (51.4% 55 of 107 in the cooled group vs. 66.3% 67 of 101 in the control group), with a relative risk ratio of 0.77 and a 95% confidence interval of 0.62 to 0.98. With respect to secondary outcomes, there was a decrease in the mortality rate (P = 0.04) and an increase in the survival rate free of any sensorineural disability (P = 0.01). No significant adverse effects were observed. These findings demonstrate that whole-body hypothermia is effective and appears safe when initiated within 6 hours of birth at the birth hospital in term and near-term newborns with HIE. The data suggest that this simple method of hypothermia may be used routinely in neonatal nontertiary settings before transport to the regional NICU.