Late Hypothermia for Hypoxic-Ischemic Encephalopathy

• Sponsor: NICHD Neonatal Research Network (Other)
• Overall Status: Completed
• CT.gov ID: NCT00614744
• Collaborator: National Center for Research Resources (NCRR) (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH)
• Enrollment: 168
• Locations: 22
• Arms: 2
• Duration (Months): 98
• Patients Per Site: 7.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Infant, Newborn; Hypoxia, Brain; Hypoxia-Ischemia, Brain; Encephalopathy, Hypoxic-Ischemic; Hypoxic-Ischemic Encephalopathy; Ischemic-Hypoxic Encephalopathy	Procedure: Hypothermia; Procedure: Normothermic Control	N/A

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 168 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: Apr 1, 2008
• Actual Primary Completion Date: Jun 1, 2016
• Actual Study Completion Date: Jun 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Whole-body Hypothermia Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours	Procedure: Hypothermia; Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours
Active Comparator: Normothermia Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours	Procedure: Normothermic Control; Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours

Outcome Measures

Primary Outcome Measures

1. 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

1. Number of Deaths in the NICU and Following Discharge [Birth to 18-22 months corrected gestational age]

2. 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.

3. 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.

4. 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.

5. 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)

6. Number of Infants With a DNR Order [Birth to 18-22 months corrected gestational age]

7. Number of Infants With a DNR Order and Support is Withdrawn [Birth to 18-22 months corrected gestational age]

8. Number of Infants With a DNR Order That Died [Birth to 18-22 months corrected gestational age]

9. Number of Infants With Neonatal Seizures, With and Without EEG Abnormalities [Birth to 18-22 months corrected gestational age]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Hours to 24 Hours
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35233
2	University of California - Los Angeles	Los Angeles	California	United States	90025
3	Stanford University	Palo Alto	California	United States	94304
4	Yale University	New Haven	Connecticut	United States	06504
5	Emory University	Atlanta	Georgia	United States	30303
6	Indiana University	Indianapolis	Indiana	United States	46202
7	University of Iowa	Iowa City	Iowa	United States	52242
8	Tufts Medical Center	Boston	Massachusetts	United States	02111
9	Wayne State University	Detroit	Michigan	United States	48201
10	Children's Mercy Hospital	Kansas City	Missouri	United States	64108
11	University of New Mexico	Albuquerque	New Mexico	United States	87131
12	University of Rochester	Rochester	New York	United States	14642
13	RTI International	Durham	North Carolina	United States	27705
14	Duke University	Durham	North Carolina	United States	27710
15	Cincinnati Children's Medical Center	Cincinnati	Ohio	United States	45267
16	Case Western Reserve University, Rainbow Babies and Children's Hospital	Cleveland	Ohio	United States	44106
17	Research Institute at Nationwide Children's Hospital	Columbus	Ohio	United States	43205
18	Univeristy of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
19	Brown University, Women & Infants Hospital of Rhode Island	Providence	Rhode Island	United States	02905
20	University of Texas Southwestern Medical Center at Dallas	Dallas	Texas	United States	75235
21	University of Texas Health Science Center at Houston	Houston	Texas	United States	77030
22	University of Utah	Salt Lake City	Utah	United States	84108

Sponsors and Collaborators

• NICHD Neonatal Research Network
• National Center for Research Resources (NCRR)
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

• Principal Investigator: Abbot R. Laptook, MD, Brown University, Women & Infants Hospital of Rhode Island
• Principal Investigator: Michele C. Walsh, MD MS, Case Western Reserve University, Rainbow Babies and Children's Hospital
• Principal Investigator: Ronald N. Goldberg, MD, Duke University
• Principal Investigator: Barbara J. Stoll, MD, Emory University
• Principal Investigator: Brenda B. Poindexter, MD MS, Indiana University
• Principal Investigator: Abhik Das, PhD, RTI International
• Principal Investigator: Krisa P. Van Meurs, MD, Stanford University
• Principal Investigator: Ivan D. Frantz III, MD, Tufts Medical Center
• Principal Investigator: Kurt Schibler, MD, Children's Hospital Medical Center, Cincinnati
• Principal Investigator: Waldemar A. Carlo, MD, University of Alabama at Birmingham
• Principal Investigator: Edward F. Bell, MD, University of Iowa
• Principal Investigator: Kristi L. Watterberg, MD, University of New Mexico
• Principal Investigator: Myra Wyckoff, MD, University of Texas, Southwestern Medical Center at Dallas
• Principal Investigator: Kathleen A. Kennedy, MD MPH, The University of Texas Health Science Center, Houston
• Principal Investigator: Roger G. Faix, MD, University of Utah
• Principal Investigator: Seetha Shankaran, MD, Wayne State University
• Principal Investigator: Richard A. Ehrenkranz, MD, Yale University
• Principal Investigator: William Truog, MD, Children's Mercy Hospital Kansas City
• Principal Investigator: Barbara Schmidt, MD, MSc, University of Pennsylvania
• Principal Investigator: Carl D'Angio, MD, University of Rochester
• Principal Investigator: Uday Devaskar, MD, University of California, Los Angeles
• Principal Investigator: Pablo Sanchez, M.D, Ohio State University

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• NICHD Neonatal Research Network

Publications

None provided.

• Responsible Party: NICHD Neonatal Research Network
• ClinicalTrials.gov Identifier: NCT00614744
• Other Study ID Numbers: NICHD-NRN-0038; U10HD036790; U10HD021364; U10HD021373; U10HD021385; U10HD027851; U10HD027853; U10HD027856; U10HD027871; U10HD027880; U10HD027904; U10HD034216; U10HD040492; U10HD040689; U10HD053089; U10HD053109; U10HD053119; U10HD053124; UL1RR024139; UL1RR025744; UL1RR024979; U10HD068244; 1U10HD068263-01; U10HD068270; U10HD068278; U10HD068284
• First Posted: Feb 13, 2008
• Last Update Posted: Mar 9, 2021
• Last Verified: Feb 1, 2021

• Keywords provided by NICHD Neonatal Research Network: NICHD Neonatal Research Network; Hypoxic-ischemic encephalopathy (HIE); Hypothermia; Neonatal depression; Perinatal asphyxia
• Additional relevant MeSH terms: Brain Diseases; Brain Ischemia; Hypoxia-Ischemia, Brain; Hypoxia, Brain; Ischemia; Hypoxia; Hypothermia

Study Results

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.

Arm/Group Title	Whole-body Hypothermia	Normothermia
Arm/Group Description	Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours	Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours
Period Title: Overall Study
STARTED	83	85
COMPLETED	78	79
NOT COMPLETED	5	6

Baseline Characteristics

Arm/Group Title	Whole-body Hypothermia	Normothermia	Total
Arm/Group Description	Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours	Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours	Total of all reporting groups
Overall Participants	83	85	168
Age, Customized (Count of Participants)
<= 12 Hours	26 31.3%	28 32.9%	54 32.1%
> 12 Hours	57 68.7%	57 67.1%	114 67.9%
Sex: Female, Male (Count of Participants)
Female	47 56.6%	55 64.7%	102 60.7%
Male	36 43.4%	30 35.3%	66 39.3%
Level of Encephalopathy (Count of Participants)
Moderate	73 88%	78 91.8%	151 89.9%
Severe	10 12%	7 8.2%	17 10.1%
Birthweight (grams) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [grams]	3379 (528)	3303 (553)	3340 (541)
Length (centimeters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeters]	51 (3)	51 (3)	51 (3)
Gestational Age (weeks) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [weeks]	39 (2)	39 (1)	39 (1)

Outcome Measures

1. Primary Outcome

Title	Death or Moderate or Severe Disability
Description	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.
Time Frame	Birth to 18-22 months corrected gestational age

Outcome Measure Data

Analysis Population Description

Does not include 9 lost to follow up and 2 infants without outcome for behavior issues

Arm/Group Title	Whole-body Hypothermia	Normothermia
Arm/Group Description	Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours	Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours
Measure Participants	78	79
Count of Participants [Participants]	19 22.9%	22 25.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Whole-body Hypothermia, Normothermia
	Comments	Whole-body Hypothermia vs. Normothermia (Normothermia is the comparison group)
	Type of Statistical Test	Superiority
	Comments	This trial estimated the probability that the intervention has no effect on the outcome (or conversely, the probability that it does), given the data obtained in the trial and any prior evidence.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.86
	Confidence Interval	(2-Sided) 95%; 0.59 to 1.29
	Parameter Dispersion	Type: Value:
	Estimation Comments	In log binomial models used Normal (0, sd=0.35) neutral prior in the log RR scale. Estimation used Normal weakly informative priors. Reported posterior medians & 95% credible intervals for the RR above instead of confidence intervals.
Other Statistical Analysis		We fitted all Bayesian models via Markov chain Monte Carlo methods (MCMC) using JAGS (version 3.4) and OpenBUGS (3.2.3) in R (version 3.2.5). For each analysis we ran 3 MCMC chains with starting values randomly drawn from the estimated parameters from a frequentist log binomial model. A burn-in of 1,000 iterations was used, with sampling from a further 10,000 iterations for each chain. To monitor convergence, trace plots and the Gelman-Rubin convergence diagnostic (Rhat) were used for all parameters. For all analyses, the trace plots show good mixing of the 3 chains with Rhat < 1.01 for all parameters, indicating convergence.

2. Secondary Outcome

Title	Number of Deaths in the NICU and Following Discharge
Time Frame	Birth to 18-22 months corrected gestational age

Outcome Measure Data

Analysis Population Description

Does not include 9 lost to follow up and 2 infants without outcome for behavior issues

Arm/Group Title	Whole-body Hypothermia	Normothermia
Arm/Group Description	Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours	Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours
Measure Participants	78	79
Count of Participants [Participants]	9 10.8%	9 10.6%

3. Secondary Outcome

Title	Number of Infants With Moderate and Severe Disability
Description	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.
Time Frame	Birth to 18-22 months corrected gestational age

Outcome Measure Data

Analysis Population Description

Does not include 9 lost to follow up and 2 infants without outcome for behavior issues

Arm/Group Title	Whole-body Hypothermia	Normothermia
Arm/Group Description	Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours	Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours
Measure Participants	78	79
Count of Participants [Participants]	10 12%	13 15.3%

4. Secondary Outcome

Title	Number of Infants With Mild, Moderate and Severe Disability
Description	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.
Time Frame	Birth to 18-22 months corrected gestational age

Outcome Measure Data

Analysis Population Description

Does not include 9 lost to follow up and 2 infants without outcome for behavior issues

Arm/Group Title	Whole-body Hypothermia	Normothermia
Arm/Group Description	Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours	Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours
Measure Participants	78	79
Count of Participants [Participants]	26 31.3%	25 29.4%

5. Secondary Outcome

Title	Number of Infants With Any Disability Based on Level of Encephalopathy at Randomization
Description	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.
Time Frame	Birth to 18-22 months corrected gestational age

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Whole-body Hypothermia	Normothermia
Arm/Group Description	Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours	Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours
Measure Participants	69	70
Moderate encephalopathy	24 28.9%	25 29.4%
Severe encephalopathy	2 2.4%	0 0%
Total	26 31.3%	25 29.4%

6. Secondary Outcome

Title	Number of Infants With Non-CNS Organ System Dysfunction
Description	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)
Time Frame	Birth to 18-22 months corrected gestational age

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Whole-body Hypothermia	Normothermia
Arm/Group Description	Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours	Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours
Measure Participants	83	85
Count of Participants [Participants]	63 75.9%	59 69.4%

7. Secondary Outcome

Title	Number of Infants With a DNR Order
Time Frame	Birth to 18-22 months corrected gestational age

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Whole-body Hypothermia	Normothermia
Arm/Group Description	Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours	Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours
Measure Participants	83	85
Count of Participants [Participants]	7 8.4%	8 9.4%

8. Secondary Outcome

Title	Number of Infants With a DNR Order and Support is Withdrawn
Time Frame	Birth to 18-22 months corrected gestational age

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Whole-body Hypothermia	Normothermia
Arm/Group Description	Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours	Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours
Measure Participants	83	85
Count of Participants [Participants]	6 7.2%	8 9.4%

9. Secondary Outcome

Title	Number of Infants With a DNR Order That Died
Time Frame	Birth to 18-22 months corrected gestational age

Outcome Measure Data

Analysis Population Description

Only infants with DNR order

Arm/Group Title	Whole-body Hypothermia	Normothermia
Arm/Group Description	Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours	Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours
Measure Participants	83	85
Count of Participants [Participants]	5 6%	7 8.2%

10. Secondary Outcome

Title	Number of Infants With Neonatal Seizures, With and Without EEG Abnormalities
Time Frame	Birth to 18-22 months corrected gestational age

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Whole-body Hypothermia	Normothermia
Arm/Group Description	Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours	Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours
Measure Participants	83	85
Count of Participants [Participants]	63 75.9%	56 65.9%

Adverse Events

Time Frame	During study intervention period: 124 hours from baseline (time of insertion of esophageal probe).
Arm/Group Title	Whole-body Hypothermia		Normothermia
Arm/Group Description	Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours		Normothermic Control group (with esophageal temperature at or near 37.0°C) for 96 hours
All Cause Mortality
	Whole-body Hypothermia		Normothermia
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/83 (7.2%)		5/85 (5.9%)
Serious Adverse Events
	Whole-body Hypothermia		Normothermia
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/83 (6%)		1/85 (1.2%)
Respiratory, thoracic and mediastinal disorders
PPHN/Acidosis	2/83 (2.4%)	2	0/85 (0%)	0
Skin and subcutaneous tissue disorders
Alteration of skin integrity	1/83 (1.2%)	1	0/85 (0%)	0
Vascular disorders
Bleeding	4/83 (4.8%)	4	1/85 (1.2%)	1
Other (Not Including Serious) Adverse Events
	Whole-body Hypothermia		Normothermia
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/83 (0%)		0/85 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Investigators must adhere to the Neonatal Research Network Publication policies.