Refined Hypothermia Parameters for Infants With Encephalopathy

Seetha Shankaran MD Director, Neonatal-Perinatal Medicne Children's Hospital of Michigan and Hutzel Women's Hospital Detroit, MI Interview with:
Seetha Shankaran MD

Director, Neonatal-Perinatal Medicne
Children’s Hospital of Michigan and Hutzel Women’s Hospital
Detroit, MI

Medical Research: What is the background for this study? What are the main findings?

Dr. Shankaran: The background for this study is that term newborn infants born following lack of blood flow and oxygen to the brain are at high risk for death or disability, including motor and developmental handicaps. Hypothermia (lowering the core body temperature to 33-34°C for 72 hours has been shown to decrease the rate of death or disability to 44 to 55%. Hypothermia is currently the only proven therapy to reduce these devastating outcomes. The hypothermia therapy provided to term newborns was based on laboratory experiments that demonstrated that in animal models subjected to hypoxia and ischemia, cooling reduced brain injury. In the NICHD Neonatal Research Network (a group of academic centers across the US), in 2005 we reported the first trial of whole-body cooling to 33.5°C for 72 hours and noted a reduction in death or disability in infancy. When the infants in the study where followed to childhood, we noted that this reduction in death or disability continued to childhood.

Recent laboratory experiments have demonstrated that brain injury continues for days or weeks after the hypoxic-ischemic injury. Other laboratory experiments noted that cooling for a greater depth than 33-34°C (as long as the temperature does not decrease much lower) can reduce brain injury further. Based on this information, in the NICHD Neonatal Research Network we designed a study, among term infants with moderate or severe encephalopathy to compare longer cooling and deeper cooling to see if death or disability can be reduced. Term infants with moderate or severe encephalopathy were randomly assigned at <6 hours of age to 4 groups of therapy; 33.5°C for 72 hours, 32.0°C for 72 hours, 33.5°C for 120 hours and 32.0°C for 120 hours. The goal was to compare death or disability rates between the 2 durations of cooling (72 hours vs. 120 hours) and 2 depths of cooling (33.5 C vs. 32.0°C) and was designed to recruit 726 infants. A independent data safety and monitoring committee was appointed by the director of NICHD to monitor safety events after the first 50 infants were enrolled and then following the enrollment of every 25 infants. The safety events monitored included mortality in the neonatal intensive care unit (NICU), cardiac arrhythmia, persistent acidosis and major vessel bleeding or thrombosis. The study was started in October 2010.

Medical Research: What is the background for this study? What are the main findings?

Dr. Shankaran: In November 2013 the study was closed by the data safety and monitoring committee after 8 reviews of study data, following recruitment of 364 neonates because of emerging safety concerns as well as futility analyses. The NICU death rates were 7% (7 of 95) for the 33.5°C for 72 hour group, 14% (13 of 90) for the 32.0°C for 72hr group, 16% (15 of 96) in the 33.5°C for 120 hour group and 17% for the 32.0°C for 120 hour group. The adjusted risk ratio (95% CI) for death for the 120 hour vs. the 72 hour was not significantly different 1.37 (0.92-2.04) nor was it significantly different for the 32.0°C group compared to the 33.5°C group 1.24 (0.69-2.25). The safety outcomes were similar between the 120 vs. 72 hour groups and the 32.0°C vs. the 33.5°C groups, except that major bleeding occurred among 1% in the 120 group vs. 3% in the 72 hours group, RR 0.25 (0.07-0.91). Futility analyses noted that the probability of detecting benefit of longer cooling, deeper cooling or both for death in the NICU was <2%. The follow -up of infants enrolled into the study for 18 months is on-going.

Medical Research: What should clinicians and patients take away from your report?

Dr. Shankaran: Clinicians and parents should be aware that term newborn infants with moderate or severe encephalopathy should receive hypothermia at 33.0-34°C for 72 hours; cooling for greater length of time or for greater depth may not be safe. The rate of death in the NICU, using this depth and duration of temperature was 7% in our study and may be indicative of a lower rate of enrollment of neonates with severe encephalopathy than our first study. There have been reports of infants being admitted to the NICU with core temperatures <33.0°C resulting from cooling during transport to an NICU and also reports of cooling for >72 hours; clinicians should avoid these practices. Parents should be encouraged to discuss the temperature depth and duration of cooling of their infants being cooled with their doctors.

The rates of disability at 18 months will be reported in our study once follow up of all enrolled infants completed.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Shankaran: The current rates of death or disability, especially for neonates with severe encephalopathy continues to be high, so research needs to continue to reduce these rates. The future of neuroprotection is hypothermia in combination with additional therapies. There are a number of these therapies being investigated.

The recommendation for these investigators is to evaluate hypothermia at a depth of 33.5°C for a duration of 72 hours with the additional therapy being investigated.

The second recommendation is to calculate the number of infants to be enrolled into these studies based on the current rate of death or disability at 18 months of age as these rates may be different from those published in previous randomized controlled trials of hypothermia for neonatal encephalopathy. All infants enrolled in research studies should be followed for at least 18 months; 18 months of age is a good predictor of outcome in childhood among infants with moderate or severe encephalopathy receiving hypothermia.


Shankaran S, Laptook AR, Pappas A, et al. Effect of Depth and Duration of Cooling on Deaths in the NICU Among Neonates With Hypoxic Ischemic Encephalopathy: A Randomized Clinical Trial. JAMA. 2014;312(24):2629-2639. doi:10.1001/jama.2014.16058.