Optimizing (Longer, Deeper) Cooling for Neonatal Hypoxic-Ischemic Encephalopathy(HIE)

The Optimizing Cooling trial will compare four whole-body cooling treatments for infants born at 36 weeks gestational age or later with hypoxic-ischemic encephalopathy: (1) cooling for 72 hours to 33.5°C; (2) cooling for 120 hours to 33.5°C; (3) cooling for 72 hours to 32.0°C; and (4) cooling for 120 hours to 32.0°C. The objective of this study is to evaluate whether whole-body cooling initiated at less than 6 hours of age and continued for 120 hours and/or a depth at 32.0°C in will reduce death and disability at 18-22 months corrected age.

Inclusion Criteria: Eligibility will be determined in a stepped process: 1. All infants with a gestational age ≥ 36 weeks will be screened for study entry if they are admitted to the NICU with a diagnosis of fetal acidosis, perinatal asphyxia, neonatal depression or encephalopathy. 2. Infants will be eligible if: * They have a pH ≤ 7.0 or a base deficit ≥ 16m mEq/ L on umbilical cord or any postnatal sample within 1 hour of age. * If, during this interval, they have a pH between 7.01 and 7.15, a base deficit is between 10 and 15.9 mEq/L, or a blood gas is not available, AND they have an acute perinatal event AND either a 10-minute Apgar score ≤ 5 or assisted ventilation initiated at birth and continued for at least 10 minutes. 3. Once these criteria are met, eligible infants will have a standardized neurological examination performed by a certified physician examiner. Infants will be candidates for the study when encephalopathy or seizures are present. For this study, encephalopathy is defined as the presence of 1 or more signs in 3 of the following 6 categories: * Level of consciousness: lethargy, stupor or coma; * Spontaneous activity: decreased, absent; * Posture: distal flexion, decerebrate; * tone: hypotonia, flaccid or hypertonia, rigid; * Primitive reflexes: a) suck, weak, absent; b) Moro, incomplete, flaccid; * Autonomic nervous system: a) pupils: constricted, unequal, skew deviation or non reactive to light; b) heart rate: bradycardia, variable heart rate or c) respiration: periodic breathing, apnea. Eligible infants from multiple births will be enrolled in the same arm of the study. Exclusion Criteria: * Inability to randomize by 6 hours of age * Major congenital abnormality * Major chromosomal abnormality (including Trisomy 21), * Severe growth restriction (≤ 1800gm birth weight), * Infant is moribund and will not receive any further aggressive treatment, * Refusal of consent by parent * Refusal of consent by attending neonatologist * Infants with a core temperature \< 33.5°C for \> 1 hour at the time of screening by the research team would not be eligible for the study.