Late Hypothermia for Hypoxic-Ischemic Encephalopathy

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.

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