Late Hypothermia for Hypoxic-Ischemic Encephalopathy

Not Applicable

Completed

Conditions: Hypoxia, Brain
Hypoxia-Ischemia, Brain
Encephalopathy, Hypoxic-Ischemic
Hypoxic-Ischemic Encephalopathy
Ischemic-Hypoxic Encephalopathy
Infant, Newborn

Interventions: Procedure: Normothermic Control
Procedure: Hypothermia

Registration Number: NCT00614744

Lead Sponsor: NICHD Neonatal Research Network

Brief Summary: This study is a randomized, placebo-controlled, clinical trial to evaluate whether induced whole-body hypothermia initiated between 6-24 hours of age and continued for 96 hours in infants ≥ 36 weeks gestational age with hypoxic-ischemic encephalopathy will reduce the incidence of death or disability at 18-22 months of age. The study will enroll 168 infants with signs of hypoxic-ischemic encephalopathy at 16 NICHD Neonatal Research Network sites, and randomly assign them to either receive hypothermia or participate in a non-cooled control group.

Detailed Description: Hypoxic-ischemic encephalopathy (HIE) is a rare, but life-threatening condition characterized by acute or subacute brain injury due to asphyxia. In most cases the underlying cause and timing of injury are unknown, but many cases are diagnosed at or shortly after birth.

According to the World Health Organization, more than 722,000 children died from birth asphyxia and birth trauma worldwide in 2004. An estimated 50-75 percent of infants with severe (stage 3) HIE will die, with 55 percent of these deaths occurring in the first month.

The incidence of long-term complications depends on the severity of HIE. Up to 80 percent of infants who survive stage 3 HIE develop significant long-term neurological disabilities - mental retardation, epilepsy, and cerebral palsy with hemiplegia, paraplegia, or quadriplegia; 10-20 percent develop moderately serious disabilities; and up to 10 percent are normal.

Because animal data suggests that brain injury from HIE evolves over several hours to days after the initial asphyxic insult, induced hypothermia holds promise as a neuroprotective therapy. Additional trials are needed to help define the most effective cooling strategies.

With this in mind, and knowing that many babies with HIE arrive at neonatal intensive care units several hours after birth, this study will evaluate the safety and efficacy of initiating hypothermia 6-24 hours after birth.

Study subjects: Infants born at 36 0/7ths weeks or greater gestational age that have been diagnosed with neonatal depression, perinatal asphyxia, or encephalopathy. The goal is to enroll 168 subjects.

Stratification: After informed consent is obtained, infants will be randomized to either a hypothermia arm (with a target esophageal temperature of 33.5°C) or a control arm (37.0°C) for 96 hours. Enrolled infants will be stratified by age of enrollment (≤ 12 and \> 12 hours) and stage of encephalopathy (moderate or severe).

Informed Consent: Parents of eligible infants will be approached for consent to enroll in the study if the infant has a high probability of acute hemodynamic compromise, as defined above. Subsequent screening will determine whether the infant meets all inclusion criteria.

Randomization: eligible and consented infants will be randomly assigned to either a hypothermia intervention group, or a non-cooled (control) group.

Study Intervention: Induced whole-body hypothermia (with a target esophageal temperature of 33.5°C) or a control group (37.0°C) for 96 hours.

Interim Study Interruptions: None to date.

Secondary Study includes determining an association between MRI detectable injury and neurodevelopment at 18-22 months.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 168

Inclusion Criteria

Infants born at 36 0/7ths weeks gestational age or greater (by best obstetrical estimate)
Postnatal age between 6 and 24 hours following birth
Infants with a high probability of acute hemodynamic compromise, such as those with:
- An acute perinatal event (abruptio placenta, cord prolapse, severe FHR abnormality)
- An Apgar score ≤ 5 at 10 minutes
- Continued need for ventilation initiated at birth for at least 10 minutes
- Cord pH or first postnatal blood gas pH at ≤ 1 hour of ≤ 7.0
- Base deficit on cord gas or first postnatal blood gas at ≤ 1 hour of ≥ 16 mEq/L
Infants matching the above criteria who also have an abnormal neurological exam showing the presence of moderate or severe encephalopathy
Infants whose parents/legal guardians have provided consent for enrollment.

NOTE: These inclusion criteria are identical to the NICHD Neonatal Research Network's 2005 Hypothermia study (see links below), except for the time of entry (6-24 hours vs. < 6 hours of age).

Exclusion Criteria

Any infant with a core body temperature (axilla, rectal) less than 34.0°C for greater than 1 hour
Presence of a known anomaly or chromosomal aberration
Birth weight < 1,800 grams
Infant in extremis
Infants whose parents/legal guardians or attending physician refuse consent

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Normothermia	Normothermic Control	Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours
Whole-body Hypothermia	Hypothermia	Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours

Primary Outcome Measures

Name	Time	Method
Death or Moderate or Severe Disability	Birth to 18-22 months corrected gestational age	Severe disability was defined by any of the following: a Bayley III cognitive score \< 70 or Gross Motor Functional (GMF) Level of 3-5 blindness or profound hearing loss requiring amplification but still unable to follow commands/communicate. Moderate disability was defined as a Bayley III cognitive score between 70-84 and either a GMF level of 2 or a seizure disorder or a hearing deficit.

Secondary Outcome Measures

Name	Time	Method
Number of Infants With a DNR Order	Birth to 18-22 months corrected gestational age
Number of Deaths in the NICU and Following Discharge	Birth to 18-22 months corrected gestational age
Number of Infants With Mild, Moderate and Severe Disability	Birth to 18-22 months corrected gestational age	Mild disability will be defined by either a Bayley III cognitive score of 70-84 alone or a Bayley III cognitive score \>= 85 and any of the following: presence of a GMF level 1 or 2 OR seizure disorder or hearing loss. Moderate disability was defined as a Bayley III cognitive score between 70-84 and either a GMF level of 2 or a seizure disorder or a hearing deficit. Severe disability will be defined by any of the following: a Bayley III cognitive score \< 70 OR Gross Motor Functional (GMF) Level of 3-5 OR blindness or profound hearing loss requiring amplification but still unable to follow commands/communicate.
Number of Infants With Any Disability Based on Level of Encephalopathy at Randomization	Birth to 18-22 months corrected gestational age	Mild disability will be defined by either a Bayley III cognitive score of 70-84 alone or a Bayley III cognitive score \>= 85 and any of the following: presence of a GMF level 1 or 2OR seizure disorder or hearing loss. Moderate disability was defined as a Bayley III cognitive score between 70-84 and either a GMF level of 2 or a seizure disorder or a hearing deficit. Severe disability will be defined by any of the following: a Bayley III cognitive score \< 70 OR Gross Motor Functional (GMF) Level of 3-5 OR blindness or profound hearing loss requiring amplification but still unable to follow commands/communicate.
Number of Infants With Non-CNS Organ System Dysfunction	Birth to 18-22 months corrected gestational age	Based on observing presence of organ dysfunction on at least one of the following: Pulmonary (Meconium aspiration syndrome, PPHN, Pulmonary hemorrhage, Pneumonia, Chronic lung disease, ECMO, INO), Cardiovascular (Cardiomegaly, Cardiac failure, Cardiac dysfunction (by echo), Cardiac ischemia (by EKG and/or increased enzymes), Hypotension, Arrhythmia), Renal (Oliguria, Anuria, Dialysis), Gastrointestinal (NEC, Hepatic dysfunction), Hematologic (DIC) and Metabolic (Hypoglycemia, Hypocalcemia, Hypomagnesemia)
Number of Infants With a DNR Order and Support is Withdrawn	Birth to 18-22 months corrected gestational age
Number of Infants With Neonatal Seizures, With and Without EEG Abnormalities	Birth to 18-22 months corrected gestational age
Number of Infants With Moderate and Severe Disability	Birth to 18-22 months corrected gestational age	Moderate disability will be defined as a Bayley III cognitive score between 70-84 and either a GMF level of 2 or a seizure disorder or a hearing deficit. Severe disability will be defined by any of the following: a Bayley III cognitive score \< 70 or Gross Motor Functional (GMF) Level of 3-5 or blindness or profound hearing loss requiring amplification but still unable to follow commands/communicate.
Number of Infants With a DNR Order That Died	Birth to 18-22 months corrected gestational age

Trial Locations

Locations (22): Case Western Reserve University, Rainbow Babies and Children's Hospital
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Cleveland, Ohio, United States
Univeristy of Pennsylvania
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Philadelphia, Pennsylvania, United States
University of Texas Southwestern Medical Center at Dallas
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Dallas, Texas, United States
Duke University
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Durham, North Carolina, United States
University of California - Los Angeles
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Los Angeles, California, United States
Tufts Medical Center
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Boston, Massachusetts, United States
Children's Mercy Hospital
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Kansas City, Missouri, United States
Emory University
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Atlanta, Georgia, United States
Research Institute at Nationwide Children's Hospital
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Columbus, Ohio, United States
Stanford University
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Palo Alto, California, United States
Indiana University
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Indianapolis, Indiana, United States
University of Iowa
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Iowa City, Iowa, United States
University of New Mexico
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Albuquerque, New Mexico, United States
Brown University, Women & Infants Hospital of Rhode Island
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Providence, Rhode Island, United States
Wayne State University
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Detroit, Michigan, United States
RTI International
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Durham, North Carolina, United States
University of Alabama at Birmingham
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Birmingham, Alabama, United States
University of Rochester
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Rochester, New York, United States
Cincinnati Children's Medical Center
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Cincinnati, Ohio, United States
University of Texas Health Science Center at Houston
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Houston, Texas, United States
University of Utah
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Salt Lake City, Utah, United States
Yale University
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New Haven, Connecticut, United States