Whole-Body Cooling for Birth Asphyxia in Term Infants

NICHD Neonatal Research Network

Status and phase: Completed; Phase 3

Conditions: Infant, Newborn; Hypoxia-Ischemia, Brain

Treatments: Device: Control; Device: Induced hypothermia

Study type: Interventional

Funder types: NETWORK; NIH

Identifiers

NCT00005772

M01RR016587 (U.S. NIH Grant/Contract)

M01RR006022 (U.S. NIH Grant/Contract)

U10HD021364 (U.S. NIH Grant/Contract)

U10HD027880 (U.S. NIH Grant/Contract)

U10HD027856 (U.S. NIH Grant/Contract)

U10HD027851 (U.S. NIH Grant/Contract)

M01RR000039 (U.S. NIH Grant/Contract)

U10HD040689 (U.S. NIH Grant/Contract)

NICHD-NRN-0021

M01RR008084 (U.S. NIH Grant/Contract)

U10HD027871 (U.S. NIH Grant/Contract)

M01RR000080 (U.S. NIH Grant/Contract)

U10HD021373 (U.S. NIH Grant/Contract)

U10HD027853 (U.S. NIH Grant/Contract)

M01RR000044 (U.S. NIH Grant/Contract)

M01RR000070 (U.S. NIH Grant/Contract)

U10HD040521 (U.S. NIH Grant/Contract)

M01RR000633 (U.S. NIH Grant/Contract)

U10HD040498 (U.S. NIH Grant/Contract)

U10HD040492 (U.S. NIH Grant/Contract)

M01RR007122 (U.S. NIH Grant/Contract)

M01RR000030 (U.S. NIH Grant/Contract)

M01RR000750 (U.S. NIH Grant/Contract)

U10HD021397 (U.S. NIH Grant/Contract)

U10HD034216 (U.S. NIH Grant/Contract)

U10HD021385 (U.S. NIH Grant/Contract)

U10HD027904 (U.S. NIH Grant/Contract)

U10HD040461 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

This large multicenter trial tested whether cerebral cooling initiated within 6 hours of birth and continued for 72 hours would reduce the risk of death and moderate to severe neurodevelopmental injury at 18-22 months corrected age. Infants at least 36 weeks gestation with an abnormal blood gas within 1 hour of birth, or a history of an acute perinatal event and a 10-min Apgar score <5, or continued need for ventilation were screened. Following a neurological exam, those with moderate to severe encephalopathy were randomized to a 72-hour period of total body cooling (cooling blanket, followed by slow re-warming). The study was conducted in two phases: Phase I (20 infants) were examined for the safety of an esophageal temperature of 34-35 C; Phase II (main trial, 200 infants) were evaluated for the safety and efficacy of an esophageal temperature of 33-34 C. Cardio-respiratory, electroencephalograms (EEGs), renal, metabolic, and hematologic status, and esophageal and abdominal skin temperature were monitored during the 72 hours of intervention. Surviving children were given neurodevelopmental examinations at 18-22 months corrected age and again at school age (6-7 years of age).

Full description

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 tested whether cerebral cooling initiated within 6 hours of birth and continued for 72 hours would reduce the risk of death and moderate to severe neurodevelopmental injury at 18-22 months corrected age. Infants at least 36 weeks gestation with an abnormal blood gas within 1 hour of birth, or a history of an acute perinatal event and a 10-min Apgar score <5, or continued need for ventilation were screened. Following a neurological exam, those with moderate to severe encephalopathy were randomized to a 72-hour period of total body cooling (cooling blanket, followed by slow re-warming). The study was conducted in two phases: Phase I (20 infants) were examined for the safety of an esophageal temperature of 34-35 C; Phase II (main trial, 200 infants) were evaluated for the safety and efficacy of an esophageal temperature of 33-34 C. Cardio-respiratory, electroencephalograms (EEGs), renal, metabolic, and hematologic status, and esophageal and abdominal skin temperature were monitored during the 72 hours of intervention.

Neurodevelopmental outcome was assessed at 18-22 mos of age by masked certified examiners. The outcome at 18-22 months showed that whole-body cooling reduces the risk of death or moderate to severe disability in infants with hypoxic ischemic encephalopathy.

Surviving infants were assessed at 6-7 years (school age).

Enrollment: 208 patients

Sex: All

Ages: Under 6 hours old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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208 participants in 2 patient groups, including a placebo group

Hypothermia

Experimental group

Description:

Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours

Treatment:

Device: Induced hypothermia

Normothermic

Placebo Comparator group

Description:

Placebo: Normothermic control group (with esophageal temperature at or near 37.0°C) for 96 hours

Treatment:

Device: Control