Late Hypothermia for Hypoxic-Ischemic Encephalopathy

Evaluation of Systemic Hypothermia Initiated After 6 Hours of Age in Infants ≥36 Weeks Gestation With Hypoxic-Ischemic Encephalopathy: A Bayesian Evaluation. A Protocol for the NICHD Neonatal Research Network

Status

Completed

Phases

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00614744

Enrollment

168

Registered

2008-02-13

Start date

2008-04-30

Completion date

2016-06-30

Last updated

2021-03-09

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

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

Keywords

NICHD Neonatal Research Network, Hypoxic-ischemic encephalopathy (HIE), Hypothermia, Neonatal depression, Perinatal asphyxia

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.

Interventions

PROCEDUREHypothermia

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

PROCEDURENormothermic Control

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

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

6 Hours to 24 Hours

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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 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 Deaths in the NICU and Following Discharge	Birth to 18-22 months corrected gestational age	—
Number of Infants With a DNR Order and Support is Withdrawn	Birth to 18-22 months corrected gestational age	—
Number of Infants With a DNR Order That Died	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 a DNR Order	Birth to 18-22 months corrected gestational age	—

Countries

United States

Participant flow

Recruitment details

Multicenter randomized trial to evaluate whether induced hypothermia with body cooling initiated between 6-24 hours of age and continued for 96 hours in infants \>= 36 weeks gestation with hypoxic-ischemic encephalopathy will reduce the incidence of death or disability at 18 months of age. Eligible infants were enrolled from 05/06/08 to 07/12/14.

Participants by arm

Arm	Count
Whole-body Hypothermia Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours	83
Normothermia Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours	85
Total	168

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Incomplete for Behavior Issues	0	2
Overall Study	Lost to Follow-up	5	4

Baseline characteristics

Characteristic	Whole-body Hypothermia	Normothermia	Total
Age, Customized <= 12 Hours	26 Participants	28 Participants	54 Participants
Age, Customized > 12 Hours	57 Participants	57 Participants	114 Participants
Birthweight	3379 grams STANDARD_DEVIATION 528	3303 grams STANDARD_DEVIATION 553	3340 grams STANDARD_DEVIATION 541
Gestational Age	39 weeks STANDARD_DEVIATION 2	39 weeks STANDARD_DEVIATION 1	39 weeks STANDARD_DEVIATION 1
Length	51 centimeters STANDARD_DEVIATION 3	51 centimeters STANDARD_DEVIATION 3	51 centimeters STANDARD_DEVIATION 3
Level of Encephalopathy Moderate	73 Participants	78 Participants	151 Participants
Level of Encephalopathy Severe	10 Participants	7 Participants	17 Participants
Sex: Female, Male Female	47 Participants	55 Participants	102 Participants
Sex: Female, Male Male	36 Participants	30 Participants	66 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	6 / 83	5 / 85
other Total, other adverse events	0 / 83	0 / 85
serious Total, serious adverse events	5 / 83	1 / 85

Outcome results

Primary

Death or Moderate or Severe Disability

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.