Effect of Depth and Duration of Cooling on Death or Disability at Age 18 Months Among Neonates With Hypoxic-Ischemic Encephalopathy

Abstract

IMPORTANCE Hypothermia for 72 hours at 33.5°C for neonatal hypoxic-ischemic encephalopathy reduces death or disability, but rates continue to be high. OBJECTIVE To determine if cooling for 120 hours or to a temperature of 32.0°C reduces death or disability at age 18 months in infants with hypoxic-ischemic encephalopathy. DESIGN, SETTING, AND PARTICIPANTS Randomized 2 × 2 factorial clinical trial in neonates (≥36 weeks’ gestation) with hypoxic-ischemic encephalopathy at 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network between October 2010 and January 2016. INTERVENTIONS A total of 364 neonates were randomly assigned to 4 hypothermia groups: 33.5°C for 72 hours (n = 95), 32.0°C for 72 hours (n = 90), 33.5°C for 120 hours (n = 96), or 32.0°C for 120 hours (n = 83). MAIN OUTCOMES AND MEASURES The primary outcome was death or moderate or severe disability at 18 to 22 months of age adjusted for center and level of encephalopathy. Severe disability included any of Bayley Scales of Infant Development III cognitive score less than 70, Gross Motor Function Classification System (GMFCS) level of 3 to 5, or blindness or hearing loss despite amplification. Moderate disability was defined as a cognitive score of 70 to 84 and either GMFCS level 2, active seizures, or hearing with amplification. RESULTS The trial was stopped for safety and futility in November 2013 after 364 of the planned 726 infants were enrolled. Among 347 infants (95%) with primary outcome data (mean age at follow-up, 20.7 [SD, 3.5] months; 42% female), death or disability occurred in 56 of 176 (31.8%) cooled for 72 hours and 54 of 171 (31.6%) cooled for 120 hours (adjusted risk ratio, 0.92 [95% CI, 0.68–1.25]; adjusted absolute risk difference, −1.0% [95% CI, −10.2% to 8.1%]) and in 59 of 185 (31.9%) cooled to 33.5°C and 51 of 162 (31.5%) cooled to 32.0°C (adjusted risk ratio, 0.92 [95% CI, 0.68–1.26]; adjusted absolute risk difference, −3.1% [95% CI, −12.3% to 6.1%]). A significant interaction between longer and deeper cooling was observed (P = .048), with primary outcome rates of 29.3% at 33.5°C for 72 hours, 34.5% at 32.0°C for 72 hours, 34.4% at 33.5°C for 120 hours, and 28.2% at 32.0°C for 120 hours. CONCLUSIONS AND RELEVANCE Among term neonates with moderate or severe hypoxic-ischemic encephalopathy, cooling for longer than 72 hours, cooling to lower than 33.5°C, or both did not reduce death or moderate or severe disability at 18 months of age. However, the trial may be underpowered, and an interaction was found between longer and deeper cooling. These results support the current regimen of cooling for 72 hours at 33.5°C. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01192776

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

“…During this trial, the Neonatal Research Network initiated the Optimizing Cooling trial to study longer (120 hours) or deeper (32°C) cooling initiated at less than 6 hours of age. 36,37 The Optimizing Cooling trial was stopped early partly owing to safety concerns for increased in-hospital mortality among infants cooled for 120 rather than 72 hours. Whether the current trial results would differ if the intervention was shortened to 72 hours cannot be answered.…”

Behavioral and neuroanatomical outcomes in a rat model of preterm hypoxic‐ischemic brain Injury: Effects of caffeine and hypothermia

“…Overall there is little evidence to address the impact of cooling duration in a preterm model. Importantly, the single human study of prolonging cooling time in term HIE infants (from 3 to 5 days) did not show any long-term detrimental effect on the brain (Shankaran et al, 2017). Future studies will be needed to determine whether a shorter interval of cooling (for example the brief and mild (2 h) period of cooling used in Smith et al, 2015) might still provide benefits in a moderately premature (P6 HI) rat model.…”

Major concerns about late hypothermia study

“…In addition, an observational human cooling study (6) 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. There is also a concern that both human and experimental data suggest that longer cooling may be harmful (7,8). In the foetal sheep experiments, cooling for 120 hours was less protective than cooling for 72 hours (8).When Laptook et al provide probabilities for the relative risk parameter RR = p 1 /p 0 being less than 1, or less than 588…”