Optimizing (Longer, Deeper) Cooling for Neonatal Hypoxic-Ischemic Encephalopathy(HIE)

Not Applicable

Terminated

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

Interventions: Procedure: Whole-body Cooling

Registration Number: NCT01192776

Lead Sponsor: NICHD Neonatal Research Network

Brief Summary: The Optimizing Cooling trial will compare four whole-body cooling treatments for infants born at 36 weeks gestational age or later with hypoxic-ischemic encephalopathy: (1) cooling for 72 hours to 33.5°C; (2) cooling for 120 hours to 33.5°C; (3) cooling for 72 hours to 32.0°C; and (4) cooling for 120 hours to 32.0°C. The objective of this study is to evaluate whether whole-body cooling initiated at less than 6 hours of age and continued for 120 hours and/or a depth at 32.0°C in will reduce death and disability at 18-22 months corrected age.

Detailed Description: Hypoxic-ischemic encephalopathy (HIE) is a rare, but life-threatening condition characterized by brain injury due to asphyxia 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. Up to 80 percent of infants who survive stage 3 HIE develop significant long-term disabilities, including intellectual disabilities, epilepsy, and cerebral palsy with hemiplegia, paraplegia, or quadriplegia; 10-20 percent develop moderately serious disabilities; and up to 10 percent are normal.

Previous studies have shown treatment with hypothermia to be an effective therapy for HIE. Currently, infants diagnosed with HIE at less than six hours of age are given whole-body cooling, decreasing their core body temperature to 33.5°C (93.2° Fahrenheit) for a period 72 hours using a cooling blanket. This treatment appears to protect the brain, decreasing the rate of death and disability and improving the chances of survival and neurodevelopmental outcomes at 18 months correct age. But additional trials are needed to help define the most effective cooling strategies.

The Optimizing Cooling trial will examine whether cooling for a longer time period and/or to a lower temperature will improve the chance of survival and neurodevelopmental outcomes at 18-22 months corrected age. Eligible infants with HIE will be placed in one of four cooling groups: (1) cooling for 72 hours to 33.5°C; (2) cooling for 120 hours to 33.5°C; (3) cooling for 72 hours to 32.0°C; and (4) cooling for 120 hours to 32.0°C. Infants will be monitored closely and receive the care of the Neonatal Intensive Care Unit (NICU).

Infants enrolled in the study will be placed on a cooling blanket - the same type of blanket children's hospitals use in the NICU, in operating rooms during surgeries, and to cool children with high fevers. Each infant will be cooled according to the study group he or she is assigned to. During cooling, the infant's temperature will be very closely monitored by continuous esophageal (core)temperature readings. This will be done by placing a soft, narrow, flexible plastic tube into the infant's nose and down to just above the stomach. Skin temperatures will also be monitored closely. At the end of the assigned period of cooling, the infant will be slowly re-warmed until a normal core temperature of 36.5 to 37.0°C (97.7 to 98.6°C) is reached.

Infants will be examined at 18-22 months corrected age to assess their neurodevelopmental outcomes.

Secondary Studies include:

A. Using aEEG to 1)predict mortality or moderate to severe disability at 18-22 months in term infants with HIE treated with systemic hypothermia and 2) to record electrical seizure activity to compare rewarming initiated at 72 hours and later rewarming that is initiated at 120 hours.

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

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 364

Inclusion Criteria

Eligibility will be determined in a stepped process:

All infants with a gestational age ≥ 36 weeks will be screened for study entry if they are admitted to the NICU with a diagnosis of fetal acidosis, perinatal asphyxia, neonatal depression or encephalopathy.
Infants will be eligible if:
- They have a pH ≤ 7.0 or a base deficit ≥ 16m mEq/ L on umbilical cord or any postnatal sample within 1 hour of age.
- If, during this interval, they have a pH between 7.01 and 7.15, a base deficit is between 10 and 15.9 mEq/L, or a blood gas is not available, AND they have an acute perinatal event AND either a 10-minute Apgar score ≤ 5 or assisted ventilation initiated at birth and continued for at least 10 minutes.
Once these criteria are met, eligible infants will have a standardized neurological examination performed by a certified physician examiner. Infants will be candidates for the study when encephalopathy or seizures are present. For this study, encephalopathy is defined as the presence of 1 or more signs in 3 of the following 6 categories:
- Level of consciousness: lethargy, stupor or coma;
- Spontaneous activity: decreased, absent;
- Posture: distal flexion, decerebrate;
- tone: hypotonia, flaccid or hypertonia, rigid;
- Primitive reflexes: a) suck, weak, absent; b) Moro, incomplete, flaccid;
- Autonomic nervous system: a) pupils: constricted, unequal, skew deviation or non reactive to light; b) heart rate: bradycardia, variable heart rate or c) respiration: periodic breathing, apnea.

Eligible infants from multiple births will be enrolled in the same arm of the study.

Exclusion Criteria

Inability to randomize by 6 hours of age
Major congenital abnormality
Major chromosomal abnormality (including Trisomy 21),
Severe growth restriction (≤ 1800gm birth weight),
Infant is moribund and will not receive any further aggressive treatment,
Refusal of consent by parent
Refusal of consent by attending neonatologist
Infants with a core temperature < 33.5°C for > 1 hour at the time of screening by the research team would not be eligible for the study.

Study & Design

Study Type: INTERVENTIONAL

Study Design: FACTORIAL

Arm && Interventions

Group	Intervention	Description
32.0°C for 120 hours	Whole-body Cooling	Target Temp: 32.0°C Duration:120 hrs
33.5°C for 120 hours	Whole-body Cooling	Target Temp: 33.5°C Duration: 120 hrs
33.5°C for 72 hours	Whole-body Cooling	Target Temp: 33.5°C Duration: 72 hrs
32.0°C for 72 hours	Whole-body Cooling	Target Temp: 32.0°C Duration: 72 hrs

Primary Outcome Measures

Name	Time	Method
Death or Moderate to Severe Disability	Birth to 22 months corrected age	Death includes any mortality prior to follow up at 18-22 months. Severe disability was defined by any of the following: a Bayley III cognitive score \<70, a GMFCS level of 3-5, blindness or profound hearing loss (inability to understand commands despite amplification). Moderate disability was defined as a Bayley cognitive score of 70-84 and either a GMFCS level of 2, seizure disorder, or a hearing deficit requiring amplification to understand commands.

Secondary Outcome Measures

Name	Time	Method
Death	Birth to 22 months corrected age	Death includes any mortality prior to follow up at 18-22 months.
Withdrawal of Care	Birth through hospital discharge, average 22 days.	Number of infants for whom aggressive care is withdrawn
Clinical Neonatal Seizures	Through death, discharge, or transfer	Documented seizures during hospital course
Visual Impairment	Follow up at 18-22 months corrected age	Visual impairment is defined as bilateral blindness with some/no useful vision
Bayley Cognitive Score	Follow up at 18-22 months corrected age	Bayley Scale of Infant Development Composite Cognitive Score. The total composite score is reported, ranging from the lowest score of 55 to the highest score of 145. Lower values specify worse outcome.
Cerebral Palsy	Follow up at 18-22 months corrected age
Hearing Impairment	Follow up at 18-22 months corrected age	Hearing impairment is defined as hearing impairment despite amplification
Multiorgan Dysfunction	Until death, discharge, or transfer	The data needed for this analysis are not collected directly, and will not be analyzed as the study was terminated early and no funds available to complete this complex analysis. The data for this study will be stored at the NICHD-DASH for investigators.
Multiple Disabilities	Follow up at 18-22 months corrected age	Multiple disabilities is defined as two or more of the following 5 components: disabling CP, GMFCS level 3-5, Bayley cognitive score \< 70, blindness, or deafness.
Level of Disability Among Survivors	Follow up at 18-22 months corrected age	Among survivors number of normal infants and infants with mild, moderate, and severe disability Severe disability was defined by any of the following: a Bayley III cognitive score \<70, a GMFCS level of 3-5, blindness or profound hearing loss (inability to understand commands despite amplification). Moderate disability was defined as a Bayley cognitive score of 70-84 and either a GMFCS level of 2, seizure disorder, or a hearing deficit requiring amplification to understand commands. Mild impairment was defined by a cognitive score 70-84, or a cognitive score ≥ 85 and any of the following: presence of a GMFCS level 1 or 2, seizure disorder or hearing loss not requiring amplification. Normal was defined by a cognitive score ≥ 85 in the absence of any neurosensory deficits or seizures after NICU discharge.
Level of Disability Among Survivors, by Level of HIE	Follow up at 18-22 months corrected age	Among survivors, number of normal infants and infants with mild, moderate and severe disability Severe disability was defined by any of the following: a Bayley III cognitive score \<70, a GMFCS level of 3-5, blindness or profound hearing loss (inability to understand commands despite amplification). Moderate disability was defined as a Bayley cognitive score of 70-84 and either a GMFCS level of 2, seizure disorder, or a hearing deficit requiring amplification to understand commands. Mild impairment was defined by a cognitive score 70-84, or a cognitive score ≥ 85 and any of the following: presence of a GMFCS level 1 or 2, seizure disorder or hearing loss not requiring amplification. Normal was defined by a cognitive score ≥ 85 in the absence of any neurosensory deficits or seizures after NICU discharge.

Trial Locations

Locations (19): University of California - Los Angeles
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Los Angeles, California, United States
Research Institute at Nationwide Children's Hospital
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Columbus, Ohio, United States
University of Texas Southwestern Medical Center at Dallas
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Dallas, Texas, United States
RTI International
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Durham, North Carolina, United States
Indiana University
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Indianapolis, Indiana, 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
Children's Mercy Hospital
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Kansas City, Missouri, United States
Univeristy of Pennsylvania
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Philadelphia, Pennsylvania, United States
Case Western Reserve University, Rainbow Babies and Children's Hospital
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Cleveland, Ohio, United States
Brown University, Women & Infants Hospital of Rhode Island
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Providence, Rhode Island, United States
University of Iowa
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Iowa City, Iowa, United States
Emory University
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Atlanta, Georgia, United States
Wayne State University
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Detroit, Michigan, United States
University of Alabama at Birmingham
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Birmingham, Alabama, United States
Stanford University
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Palo Alto, California, United States
University of Rochester
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Rochester, New York, United States
Duke University
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Durham, North Carolina, United States
University of New Mexico
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Albuquerque, New Mexico, United States