Optimizing Cooling Strategies at <6 hours of Age for Neonatal Hypoxic-Ischemic Encephalopathy(HIE)
A prospective, randomized, 2x2 factorial design multicenter trial where all study infants will receive whole body hypothermia. The intervention will be unmasked. The individual factors tested will be (a) a comparison of two cooling durations (72 versus 120 hours) and (b) a comparison of two different depths of cooling (33.5[Degrees]C versus 32.0[Degrees]C). Infants will be randomized to either usual depth of cooling (33.5[Degrees]C) or deeper cooling (32.0[Degrees]C) and then to usual length of cooling (72 hours) or longer cooling (120 hours). The primary outcome will be death or moderate/severe disability at 18-22 months of age.
All infants will be cooled using the Cincinnati Sub-Zero Hyper-Hypothermia Blanketrol System. An esophageal temperature probe will be placed in the lower third of the esophagus and the probe will be interfaced with the Blanketrol System. The esophageal temperature will be controlled in the automatic control mode (servo) at the target temperature for the duration of cooling. At the completion of cooling, the control set point will be increased 0.5oC per hour until the esophageal temperature is and amp;gt; 36.5 oC for four hours. Once achieved, the esophageal probe will be removed, the infant will be taken off the cooling/heating blanket, and continued temperature control will be adjusted per skin temperature if servo- controlled, or environmental temperature if in an incubator (not on servo) to maintain temperature (axillary) between 36.5[Degrees]C and 37.0[Degrees]C. The esophageal temperatures of all infants will be monitored closely on an ongoing basis to evaluate overshoot, depth of overshoot and time to equilibration. In addition, decreases of temperature following the initial overshoot and following equilibration will be monitored on an on-going basis. The type and timing of sedatives, analgesics and anticonvulsants will be recorded; use of these medications will be based on site practices. In addition, infants will be continuously monitored with amplitude EEG and NIR Spectroscopy during study intervention (cooling/rewarming to baseline temperature). The primary outcome with be abnormalities detected via amplitude eeg and or NIR Spectroscopy. All surviving infants will be followed to at least 18-22 months of age. Tracking information will be recorded at the time of discharge from the NICU. An attempt will be made to obtain an autopsy in case of death occurring prior to and following NICU discharge. Growth parameters, a neurological examination and psychometric testing will be performed and vision and audiometric assessments will be recorded. Individuals performing the psychometric testing and the neurological evaluations will be masked to intervention status and they will undergo training and annual certification as per NICHD NRN Follow-Up protocol. In addition, the family[Right Quote]s socio-economic and educational status will be assessed.
1) a) If Blood Gas is available (cord or drawn less than or equal to 60 minutes of age)
- cord pH or any postnatal blood gas pH less than or equal to 7.0 or cord base deficit or any postnatal blood gas base deficit greater than or equal to 16 mEg/L, OR
b) If Blood Gas is not available or pH 7.01 - 7.15, or base deficit is 10 - 15.9 mEq/L (cord or drawn less than or equal to 60 minutes of age), must have acute perinatal event AND an Apgar score less than or equal to 5 at 10 minutes, OR continued need for ventilation initiated at birth and continued for at least 10 minutes
2) In order to determine the level of encephalopathy, all infants wil have a neurological exam performed by a physician examiner, even in the presence of seizures. The presence of moderate or severe HIE will be defined as either: seizures or the presence of one or more signs in three of the six following categories :
1) level of consciousness
2) spontaneous activity
5) primitive reflexes
6) autonomic system
Infants who meet criteria 1 and 2 above will be eligible for study entry.