Acute birth asphyxia is a cause of death and neurological injury. At present, there is no proven treatment; however, studies in animals suggest that brain cooling may protect against brain injury. This large multicenter trial will randomize term infants with a history of problems at delivery and signs of depression to total body cooling or standard care. Eligible infants greater than 36 wks gestation identified less than 6 hours after birth will be randomized and treated for 72 hrs to determine if cooling reduces the risk of death or moderate to severe neurologic disability at 18-22 mos.

Condition	Treatment or Intervention	Phase
Hypoxic-Ischemic Encephalopathy Asphyxia Brain Ischemia Hypoxia, Brain	Procedure: Induced hypothermia	Phase III

Further Study Details: 

Expected Total Enrollment:  200

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.

Ages Eligible for Study:  up to  6 Hours,  Genders Eligible for Study:  Both

Criteria

Inclusion Criteria:

• At least 36 weeks gestation
• Any blood gas (cord, postnatal) done within the first 60 minutes had a pH less than or equal to 7.0
• Any blood gas (cord postnatal) done within the first 60 minutes had a base deficit greater than or equal to 16 mEq/L
• All infants must have seizures or signs of moderate to severe encephalopathy before randomization

Exclusion Criteria:

• Inability to randomize by 6 hours of age
• Presence of known chromosomal anomaly or major congenital anomaly
• Severe intrauterine growth restriction (weight less than 1800g)
• All blood gases done within the first 60 minutes had a pH less than 7.15 and a base deficit less than 10 mEq/L
• Infants in extremis for whom no additional intensive therapy will be offered by attending neonatologist
• Parents refuse consent
• Attending neonatologist refuses consent

Rosemary Higgins      301-496-5575    higginsr@mail.nih.gov

Alabama
      University of Alabama, Birmingham,  Alabama,  35294,  United States; Recruiting
California
      Stanford University, Palo Alto,  California,  94304,  United States; Recruiting
Connecticut
      Yale University, New Haven,  Connecticut,  06520,  United States; Recruiting
Florida
      University of Miami, Miami,  Florida,  33101,  United States; Recruiting
Georgia
      Emory University, Atlanta,  Georgia,  30335,  United States; Recruiting
Indiana
      Indiana University, Indianapolis,  Indiana,  46202-4716,  United States; Recruiting
New Mexico
      University of New Mexico, Albuquerque,  New Mexico,  87131,  United States; Recruiting
Ohio
      Case Western Reserve Univ, Cleveland,  Ohio,  44106,  United States; Recruiting
      University of Cincinnati, Cincinnati,  Ohio,  45267-0541,  United States; Recruiting
Rhode Island
      Women and Infants Hospital, Providence,  Rhode Island,  02903,  United States; Recruiting
Tennessee
      University of Tennessee, Memphis,  Tennessee,  38163,  United States; Recruiting
Texas
      University of Texas, Dallas,  Texas,  75235,  United States; Recruiting
      University of Texas, Houston,  Texas,  United States; Recruiting

Study chairs or principal investigators

Seetha Shankaran, MD,  Principal Investigator,  Wayne State University   

Study ID Numbers:  NICHD-1003; U10 HD21385; U10 HD34216; U10 HD21397; U10 HD27853; U10 HD27871; U10 HD21415; U10 HD27904; U10 HD27881; U10 HD27851; U10 HD27880; U10 HD21373; U10 HD27856; U01 HD36790; M01 RR08084; M01 RR06022; M01 RR00750; M01 RR00997; M01 RR00070
Record last reviewed:  March 2003
Last Updated:  October 13, 2004
Record first received:  June 1, 2000
ClinicalTrials.gov Identifier:  NCT00005772
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08