• Death or moderate or severe disability [ Time Frame: 18-22 months corrected age ] [ Designated as safety issue: Yes ]
  

• Length of hospital stay [ Time Frame: Until discharge ] [ Designated as safety issue: No ]
  
• Frequency of multi-organ dysfunction [ Time Frame: Until discharge ] [ Designated as safety issue: Yes ]
  
• Withdrawal of support [ Time Frame: Until discharge ] [ Designated as safety issue: Yes ]
  
• Post-neonatal deaths [ Time Frame: 18-22 months corrected age ] [ Designated as safety issue: Yes ]
  
• Multiple disability [ Time Frame: 18-22 months corrected age ] [ Designated as safety issue: Yes ]
  
• Seizure disorders [ Time Frame: 18-22 months corrected age ] [ Designated as safety issue: Yes ]
  
• Rehospitalizations [ Time Frame: 18-22 months corrected age ] [ Designated as safety issue: Yes ]
  

Perinatal cerebral hypoxia-ischemia injury is an important cause of death and neurodevelopmental disability. Data from animal models suggest that brain cooling immediately after injury is neuroprotective. Experience with total body cooling during surgery, accidental near drownings, and one Phase I trial of term infants suggest that it is effective and safe in children. This large multicenter trial will test whether cerebral cooling initiated within 6 hrs of birth and continued for 72 hrs will reduce the risk of death and moderate to severe neurodevelopmental injury at 18-22 mos. Infants at least 36 weeks gestation with an abnormal blood gas within 1 hr of birth event or a history of an acute perinatal event and a 10-min Apgar score less than 5 or continued need for ventilation will be identified. Those with moderate to severe encephalopathy will be randomized to a 72 hr period of total body cooling (cooling blanket, followed by slow rewarming). The study will be conducted in two phases: Phase I (20 infants) will examine safety of an esophageal temperature of 34-35 C, Phase II (main trial, 200 infants) will evaluate the safety and efficacy of an esophageal temperature of 33-34 C. The primary outcome is death or moderate/severe disability at 18-22 mos of age; secondary outcomes include length of hospital stay, frequency of multi-organ dysfunction; withdrawal of support; post-neonatal deaths; multiple disability; seizure disorders; rehospitalization.

The sample size was based on a 50 percent incidence of death or disability (defined as cerebral palsy, Bayley MDI less than 70, deafness or blindness) following moderate to severe encephalopathy in the control group; a 30 percent reduction in the cooled group; 80 percent power; a two-tailed Type 1 error of 0.05; and 10 percent loss to follow up.

Cardio-respiratory, EEG, renal,metabolic and hematologic status and esophageal and abdominal skin temperature will be monitored during 72 hours of intervention.

Neurodevelopmental outcome will be assessed at 18-22 mos of age by masked certified examiners.

The outcome at 18-22 months has shown that whole body cooling reduces the risk of death or moderate to severe disability in infants with hypoxic ischemic encephalopathy.

Follow up will be assessed at 6-7 years in the surviving cohort of infants.