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TerminatedNCT01192776Updated Jun 24, 2026Results posted

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

An interventional study of Whole-body Cooling in Infant, Newborn, Hypoxia, Brain and Hypoxia-Ischemia, Brain, sponsored by NICHD Neonatal Research Network. Terminated at 19 sites in United States. Open to participants aged Up to 6 Hours. Per ClinicalTrials.gov, last updated 2026-06-24.

Primary conditionHypoxia-Ischemia, BrainRegistry: Hypoxia, BrainReclassifiedWhy we changed it
Registry
Hypoxia, Brain — the first condition term the registry derived for this study.
ClinicalTrials.gg
Hypoxia-Ischemia, Brain
Why
  1. The study's listed conditions name Hypoxia-Ischemia, Brain, a narrower term within Hypoxia, Brain.
Confidence
High: the new condition is named in the study's own listed conditions. Of 351 hand-checked studies reclassified this way, 68% were exactly right and 84% in the right disease family; the registry's first term was right for 5% (measured 2026-10-21). How we classify →
Wrong?
Tell us the study's main condition →

Sponsored by NICHD Neonatal Research Network · Not applicable, Interventional, and Treatment

Why this study was terminated
The trial closed for emerging safety profile and futility analysis and will not resume.
Phase
Not applicable
Study type
Interventional
Enrollment
364
Allocation
Randomized
Ages
Up to 6 Hours
Sex
All
01

Study 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.

Read the 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.

02

Conditions studied

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

Browse trials for

Keywords

  • NICHD Neonatal Research Network
  • Hypoxic-ischemic encephalopathy (HIE)
  • Hypothermia
  • Neonatal depression
  • Perinatal asphyxia
  • Fetal acidosis
03

In context

Hypoxia-Ischemia, Brain Reclassified

261 studies on the registry are indexed under Hypoxia-Ischemia, Brain; 95 are open to participants now.

This study's enrollment of 364 is above the median of 50 across 156 interventional studies indexed under Hypoxia-Ischemia, Brain.

Browse Hypoxia-Ischemia, Brain studies →

Lead sponsor

NICHD Neonatal Research Network is the lead sponsor of 63 studies on the registry; 5 are open to participants now.

Of its 8 completed or terminated interventional studies of FDA-regulated products, 7 (88%) have results posted.

Compared within Hypoxia-Ischemia, Brain, this study's primary condition as ClinicalTrials.gg classifies it; the registry's first condition term is Hypoxia, Brain. The counts are of registry records indexed under each term, refreshed daily. How we classify →

04

Who can participate

Ages eligible
Up to 6 Hours
Sexes eligible
All
Accepts healthy volunteers
No

Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.

Inclusion criteria

Eligibility will be determined in a stepped process:

  1. 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.

  2. 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.

  3. 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

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.
05

Study design

Phase
Not applicable
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Factorial assignment
Masking
None (open label)
Enrollment
364 participants (actual)

Study arms

  • Active comparator
    33.5°C for 72 hours

    Target Temp: 33.5°C Duration: 72 hrs

    Procedure: Whole-body Cooling

  • Experimental
    33.5°C for 120 hours

    Target Temp: 33.5°C Duration: 120 hrs

    Procedure: Whole-body Cooling

  • Experimental
    32.0°C for 72 hours

    Target Temp: 32.0°C Duration: 72 hrs

    Procedure: Whole-body Cooling

  • Experimental
    32.0°C for 120 hours

    Target Temp: 32.0°C Duration:120 hrs

    Procedure: Whole-body Cooling

Interventions

  • ProcedureWhole-body Cooling

    Whole-body cooling using a Blanketrol II or III to reach either a target core temperature of 33.5°C or 32.0°C for a duration of either 72 hours or 120 hours.

    Also known as: Blanketrol II Model 222R, Blanketrol III Model 233 (used in the II mode)

06

What researchers measure

Primary outcomes

  1. Death or Moderate to Severe Disability

    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.

    Time frame: Birth to 22 months corrected age

Secondary outcomes

  1. Death

    Death includes any mortality prior to follow up at 18-22 months.

    Time frame: Birth to 22 months corrected age

  2. Level of Disability Among Survivors

    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.

    Time frame: Follow up at 18-22 months corrected age

  3. Withdrawal of Care

    Number of infants for whom aggressive care is withdrawn

    Time frame: Birth through hospital discharge, average 22 days.

  4. Clinical Neonatal Seizures

    Documented seizures during hospital course

    Time frame: Through death, discharge, or transfer

  5. Bayley Cognitive Score

    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.

    Time frame: Follow up at 18-22 months corrected age

  6. Cerebral Palsy

    Time frame: Follow up at 18-22 months corrected age

  7. Level of Disability Among Survivors, by Level of HIE

    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.

    Time frame: Follow up at 18-22 months corrected age

  8. Visual Impairment

    Visual impairment is defined as bilateral blindness with some/no useful vision

    Time frame: Follow up at 18-22 months corrected age

  9. Hearing Impairment

    Hearing impairment is defined as hearing impairment despite amplification

    Time frame: Follow up at 18-22 months corrected age

  10. Multiple Disabilities

    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.

    Time frame: Follow up at 18-22 months corrected age

  11. Multiorgan Dysfunction

    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.

    Time frame: Until death, discharge, or transfer

Other outcomes

  1. Severe Neonatal Brain Abnormalities

    Total hemispheric devastation based on MRI taken between 7-14 days of life

    Time frame: 7-14 days of life

07

Results

Posted Aug 15, 2017
Limitations and caveats
This RCT was stopped for safety and futility reasons by the Data Safety and Monitoring Committee so did not enroll the target number of participants needed to achieve target power and statistically reliable results.

Participant flow

1261 infants assessed for eligibility. 897 were excluded for not meeting eligibility criteria (N=747) or not having parental or physician consent (N=150).

Participant flow — Overall Study
Milestone33.5°C for 72 Hours32.0°C for 72 Hours33.5°C for 120 Hours32.0°C for 120 Hours
Started95909683
Died prior to discharge7131514
Died after discharge1231
Completed84697563
Not completed11212120
Withdrew: Death8151815
Withdrew: Lost to follow-up3635

Outcome measures

PrimaryDeath or Moderate to Severe Disability

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.

Time frame:
Birth to 22 months corrected age
Reported as:
Count of participants · Participants
Death or Moderate to Severe Disability
Participants33.5°C for 72 Hours32.0°C for 72 Hours33.5°C for 120 Hours32.0°C for 120 Hours
Death or Moderate to Severe Disability27293222
Statistical analysis
  • 33.5°C for 72 Hours vs 32.0°C for 72 Hours · Risk ratio (rr): 1.23 · 95% CI 0.76 to 1.98
  • 33.5°C for 72 Hours vs 33.5°C for 120 Hours · Risk ratio (rr): 1.21 · 95% CI 0.78 to 1.87
  • 33.5°C for 72 Hours vs 32.0°C for 120 Hours · Risk ratio (rr): 0.85 · 95% CI 0.53 to 1.35
SecondaryDeath

Death includes any mortality prior to follow up at 18-22 months.

Time frame:
Birth to 22 months corrected age
Reported as:
Count of participants · Participants
Death
Participants33.5°C for 72 Hours32.0°C for 72 Hours33.5°C for 120 Hours32.0°C for 120 Hours
Death8151815
Statistical analysis
  • 33.5°C for 72 Hours vs 32.0°C for 72 Hours · Risk ratio (rr): 2.16 · 95% CI 0.55 to 8.49
  • 33.5°C for 72 Hours vs 33.5°C for 120 Hours · Risk ratio (rr): 2.52 · 95% CI 1.06 to 5.95
  • 33.5°C for 72 Hours vs 32.0°C for 120 Hours · Risk ratio (rr): 1.85 · 95% CI 0.79 to 4.31
SecondaryLevel of Disability Among Survivors

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.

Time frame:
Follow up at 18-22 months corrected age
Reported as:
Count of participants · Participants
Level of Disability Among Survivors
Participants33.5°C for 72 Hours32.0°C for 72 Hours33.5°C for 120 Hours32.0°C for 120 Hours
Severe disability1811147
Moderate disability1300
Mild disability16152218
Normal46403638
SecondaryWithdrawal of Care

Number of infants for whom aggressive care is withdrawn

Time frame:
Birth through hospital discharge, average 22 days.
Reported as:
Count of participants · Participants
Withdrawal of Care
Participants33.5°C for 72 Hours32.0°C for 72 Hours33.5°C for 120 Hours32.0°C for 120 Hours
Withdrawal of Care6121413
SecondaryClinical Neonatal Seizures

Documented seizures during hospital course

Time frame:
Through death, discharge, or transfer
Reported as:
Count of participants · Participants
Clinical Neonatal Seizures
Participants33.5°C for 72 Hours32.0°C for 72 Hours33.5°C for 120 Hours32.0°C for 120 Hours
Clinical Neonatal Seizures50434440
SecondaryBayley Cognitive Score

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.

Time frame:
Follow up at 18-22 months corrected age
Reported as:
Median · scores on a scale
Bayley Cognitive Score
scores on a scale33.5°C for 72 Hours32.0°C for 72 Hours33.5°C for 120 Hours32.0°C for 120 Hours
Bayley Cognitive Score90 (80 to 100)90 (75 to 100)90 (80 to 100)90 (80 to 95)
SecondaryCerebral Palsy
Time frame:
Follow up at 18-22 months corrected age
Reported as:
Count of participants · Participants
Cerebral Palsy
Participants33.5°C for 72 Hours32.0°C for 72 Hours33.5°C for 120 Hours32.0°C for 120 Hours
Cerebral Palsy1513108
Statistical analysis
  • 33.5°C for 72 Hours vs 32.0°C for 72 Hours · Risk ratio (rr): 1.23 · 95% CI 0.64 to 2.38
  • 33.5°C for 72 Hours vs 33.5°C for 120 Hours · Risk ratio (rr): 0.82 · 95% CI 0.36 to 1.90
  • 33.5°C for 72 Hours vs 32.0°C for 120 Hours · Risk ratio (rr): 0.64 · 95% CI 0.26 to 1.57
SecondaryLevel of Disability Among Survivors, by Level of HIE

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.

Time frame:
Follow up at 18-22 months corrected age
Reported as:
Count of participants · Participants
Level of Disability Among Survivors, by Level of HIE
Participants33.5°C for 72 Hours32.0°C for 72 Hours33.5°C for 120 Hours32.0°C for 120 Hours
Moderate HIE — Normal41393431
Moderate HIE — Mild disability13121913
Moderate HIE — Moderate disability1200
Moderate HIE — Severe disability97125
Severe HIE — Normal5127
Severe HIE — Mild disability3335
Severe HIE — Moderate disability0100
Severe HIE — Severe disability9422
SecondaryVisual Impairment

Visual impairment is defined as bilateral blindness with some/no useful vision

Time frame:
Follow up at 18-22 months corrected age
Reported as:
Count of participants · Participants
Visual Impairment
Participants33.5°C for 72 Hours32.0°C for 72 Hours33.5°C for 120 Hours32.0°C for 120 Hours
Visual Impairment6624
Statistical analysis
  • 33.5°C for 72 Hours vs 32.0°C for 72 Hours · Risk ratio (rr): 1.33 · 95% CI 0.63 to 2.77
  • 33.5°C for 72 Hours vs 33.5°C for 120 Hours · Risk ratio (rr): 0.42 · 95% CI 0.09 to 2.04
  • 33.5°C for 72 Hours vs 32.0°C for 120 Hours · Risk ratio (rr): 0.78 · 95% CI 0.20 to 2.99
SecondaryHearing Impairment

Hearing impairment is defined as hearing impairment despite amplification

Time frame:
Follow up at 18-22 months corrected age
Reported as:
Count of participants · Participants
Hearing Impairment
Participants33.5°C for 72 Hours32.0°C for 72 Hours33.5°C for 120 Hours32.0°C for 120 Hours
Hearing Impairment4241
Statistical analysis
  • 33.5°C for 72 Hours vs 32.0°C for 72 Hours · Risk ratio (rr): 0.65 · 95% CI 0.14 to 3.01
  • 33.5°C for 72 Hours vs 33.5°C for 120 Hours · Risk ratio (rr): 1.31 · 95% CI 0.44 to 3.91
  • 33.5°C for 72 Hours vs 32.0°C for 120 Hours · Risk ratio (rr): 0.28 · 95% CI 0.03 to 2.89
SecondaryMultiple Disabilities

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.

Time frame:
Follow up at 18-22 months corrected age
Reported as:
Count of participants · Participants
Multiple Disabilities
Participants33.5°C for 72 Hours32.0°C for 72 Hours33.5°C for 120 Hours32.0°C for 120 Hours
Multiple Disabilities14975
Statistical analysis
  • 33.5°C for 72 Hours vs 32.0°C for 72 Hours · Risk ratio (rr): 0.87 · 95% CI 0.37 to 2.07
  • 33.5°C for 72 Hours vs 33.5°C for 120 Hours · Risk ratio (rr): 0.64 · 95% CI 0.30 to 1.35
  • 33.5°C for 72 Hours vs 32.0°C for 120 Hours · Risk ratio (rr): 0.47 · 95% CI 0.13 to 1.64
SecondaryMultiorgan Dysfunction

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.

Time frame:
Until death, discharge, or transfer

No measurements were reported for this outcome.

Other pre-specifiedSevere Neonatal Brain Abnormalities

Total hemispheric devastation based on MRI taken between 7-14 days of life

Time frame:
7-14 days of life
Reported as:
Count of participants · Participants
Severe Neonatal Brain Abnormalities
Participants33.5°C for 72 Hours32.0°C for 72 Hours33.5°C for 120 Hours32.0°C for 120 Hours
Total hemispheric devastation = YES101147
Total hemispheric devastation = NO72647654

Adverse events

Collected over During study intervention period: 72 or 120 hours from baseline, based on treatment arm. Non-serious events are listed at a 1% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
33.5°C for 72 Hours8/92 (8.7%)10/95 (10.5%)5/95 (5.3%)
32.0°C for 72 Hours15/84 (17.9%)15/90 (16.7%)3/90 (3.3%)
33.5°C for 120 Hours18/93 (19.4%)11/96 (11.5%)6/96 (6.3%)
32.0°C for 120 Hours15/78 (19.2%)23/83 (27.7%)9/83 (10.8%)
Most frequent serious events
Most frequent serious events
Event33.5°C for 72 Hours32.0°C for 72 Hours33.5°C for 120 Hours32.0°C for 120 Hours
Death during interventionNervous system disorders5/955/907/9612/83
OtherGeneral disorders5/9510/906/9611/83
Cardiac ArrythmiaCardiac disorders1/951/901/967/83
Major BleedingNervous system disorders3/952/901/961/83
ThrombosisNervous system disorders0/950/900/961/83
Most frequent other events
Most frequent other events
Event33.5°C for 72 Hours32.0°C for 72 Hours33.5°C for 120 Hours32.0°C for 120 Hours
Alteration of Skin IntegrityMusculoskeletal and connective tissue disorders3/953/905/965/83
Metabolic acidosis developing >3 hours after initiation of intervention and persisting >3 hoursGeneral disorders2/950/901/964/83

Baseline characteristics

Age, Continuous
Age, Continuous(hours)33.5°C for 72 Hours32.0°C for 72 Hours33.5°C for 120 Hours32.0°C for 120 HoursTotal
Mean5.1 ± 1.04.9 ± 1.24.8 ± 1.15.0 ± 1.64.9 ± 1.2
Sex/Gender, Customized
Sex/Gender, Customized(Participants)33.5°C for 72 Hours32.0°C for 72 Hours33.5°C for 120 Hours32.0°C for 120 HoursTotal
Male52535156212
Female43374427151
Ambiguous00101
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)33.5°C for 72 Hours32.0°C for 72 Hours33.5°C for 120 Hours32.0°C for 120 HoursTotal
Black29283225114
White60565548219
Other657725
Birthweight
Birthweight(grams)33.5°C for 72 Hours32.0°C for 72 Hours33.5°C for 120 Hours32.0°C for 120 HoursTotal
Mean3230 ± 5283360 ± 5443354 ± 6763511 ± 6153359 ± 599
Level of encephalopathy
Level of encephalopathy(Participants)33.5°C for 72 Hours32.0°C for 72 Hours33.5°C for 120 Hours32.0°C for 120 HoursTotal
Moderate74707858280
Severe2120182584
08

Study locations

19 sites
  • University of Alabama at Birmingham
    Birmingham, Alabama 35233, United States
  • University of California - Los Angeles
    Los Angeles, California 90025, United States
  • Stanford University
    Palo Alto, California 94304, United States
  • Emory University
    Atlanta, Georgia 30303, United States
  • Indiana University
    Indianapolis, Indiana 46202, United States
  • University of Iowa
    Iowa City, Iowa 52242, United States
  • Wayne State University
    Detroit, Michigan 48201, United States
  • Children's Mercy Hospital
    Kansas City, Missouri 64108, United States
  • University of New Mexico
    Albuquerque, New Mexico 87131, United States
  • University of Rochester
    Rochester, New York 14642, United States
  • RTI International
    Durham, North Carolina 27705, United States
  • Duke University
    Durham, North Carolina 27710, United States
  • Cincinnati Children's Medical Center
    Cincinnati, Ohio 45267, United States
  • Case Western Reserve University, Rainbow Babies and Children's Hospital
    Cleveland, Ohio 44106, United States
  • Research Institute at Nationwide Children's Hospital
    Columbus, Ohio 43205, United States
  • Univeristy of Pennsylvania
    Philadelphia, Pennsylvania 19104, United States
  • Brown University, Women & Infants Hospital of Rhode Island
    Providence, Rhode Island 02905, United States
  • University of Texas Southwestern Medical Center at Dallas
    Dallas, Texas 75235, United States
  • University of Texas Health Science Center at Houston
    Houston, Texas 77030, United States
09

References and documents

Publications

  • Shankaran S, Laptook AR, Guimaraes C, Murnick J, McDonald SA, Das A, Petrie Huitema CM, Pappas A, Higgins RD, Hintz SR, Zaterka-Baxter KM, Van Meurs KP, Sokol GM, Chalak LF, Colaizy TT, Devaskar U, Tyson JE, Reynolds AM, DeMauro SB, Sanchez PJ, Laughon MM, Carlo WA, Watterberg K, Puopolo KM, Hibbs AM, Hamrick SEG, Cotten CM, Barks J, Poindexter BB, Truog WE, D'Angio CT; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. NICHD Magnetic Resonance Brain Imaging Score in Term Infants With Hypoxic-Ischemic Encephalopathy: A Secondary Analysis of a Randomized Clinical Trial. JAMA Pediatr. 2025 Apr 1;179(4):383-395. doi: 10.1001/jamapediatrics.2024.6209. PubMed 39960680 ↗
  • Bonifacio SL, Chalak LF, Van Meurs KP, Laptook AR, Shankaran S. Neuroprotection for hypoxic-ischemic encephalopathy: Contributions from the neonatal research network. Semin Perinatol. 2022 Nov;46(7):151639. doi: 10.1016/j.semperi.2022.151639. Epub 2022 Jun 10. PubMed 35835616 ↗
  • Shukla VV, Bann CM, Ramani M, Ambalavanan N, Peralta-Carcelen M, Hintz SR, Higgins RD, Natarajan G, Laptook AR, Shankaran S, Carlo WA. Predictive Ability of 10-Minute Apgar Scores for Mortality and Neurodevelopmental Disability. Pediatrics. 2022 Apr 1;149(4):e2021054992. doi: 10.1542/peds.2021-054992. PubMed 35296895 ↗
  • Chalak LF, Pappas A, Tan S, Das A, Sanchez PJ, Laptook AR, Van Meurs KP, Shankaran S, Bell EF, Davis AS, Heyne RJ, Pedroza C, Poindexter BB, Schibler K, Tyson JE, Ball MB, Bara R, Grisby C, Sokol GM, D'Angio CT, Hamrick SEG, Dysart KC, Cotten CM, Truog WE, Watterberg KL, Timan CJ, Garg M, Carlo WA, Higgins RD; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Association Between Increased Seizures During Rewarming After Hypothermia for Neonatal Hypoxic Ischemic Encephalopathy and Abnormal Neurodevelopmental Outcomes at 2-Year Follow-up: A Nested Multisite Cohort Study. JAMA Neurol. 2021 Dec 1;78(12):1484-1493. doi: 10.1001/jamaneurol.2021.3723. PubMed 34882200 ↗
  • Ambalavanan N, Shankaran S, Laptook AR, Carper BA, Das A, Carlo WA, Cotten CM, Duncan AF, Higgins RD; EUNICE KENNEDY SHRIVER NICHD NEONATAL RESEARCH NETWORK. Early Determination of Prognosis in Neonatal Moderate or Severe Hypoxic-Ischemic Encephalopathy. Pediatrics. 2021 Jun;147(6):e2020048678. doi: 10.1542/peds.2020-048678. Epub 2021 May 13. PubMed 33986149 ↗
  • Shankaran S, Laptook AR, Pappas A, McDonald SA, Das A, Tyson JE, Poindexter BB, Schibler K, Bell EF, Heyne RJ, Pedroza C, Bara R, Van Meurs KP, Huitema CMP, Grisby C, Devaskar U, Ehrenkranz RA, Harmon HM, Chalak LF, DeMauro SB, Garg M, Hartley-McAndrew ME, Khan AM, Walsh MC, Ambalavanan N, Brumbaugh JE, Watterberg KL, Shepherd EG, Hamrick SEG, Barks J, Cotten CM, Kilbride HW, Higgins RD; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Effect of Depth and Duration of Cooling on Death or Disability at Age 18 Months Among Neonates With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial. JAMA. 2017 Jul 4;318(1):57-67. doi: 10.1001/jama.2017.7218. PubMed 28672318 ↗
  • Pedroza C, Tyson JE, Das A, Laptook A, Bell EF, Shankaran S; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Advantages of Bayesian monitoring methods in deciding whether and when to stop a clinical trial: an example of a neonatal cooling trial. Trials. 2016 Jul 22;17(1):335. doi: 10.1186/s13063-016-1480-4. PubMed 27450203 ↗
  • Shankaran S, Laptook AR, Pappas A, McDonald SA, Das A, Tyson JE, Poindexter BB, Schibler K, Bell EF, Heyne RJ, Pedroza C, Bara R, Van Meurs KP, Grisby C, Huitema CM, Garg M, Ehrenkranz RA, Shepherd EG, Chalak LF, Hamrick SE, Khan AM, Reynolds AM, Laughon MM, Truog WE, Dysart KC, Carlo WA, Walsh MC, Watterberg KL, Higgins RD; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Effect of depth and duration of cooling on deaths in the NICU among neonates with hypoxic ischemic encephalopathy: a randomized clinical trial. JAMA. 2014 Dec 24-31;312(24):2629-39. doi: 10.1001/jama.2014.16058. PubMed 25536254 ↗
  • Shankaran S. Outcomes of hypoxic-ischemic encephalopathy in neonates treated with hypothermia. Clin Perinatol. 2014 Mar;41(1):149-59. doi: 10.1016/j.clp.2013.10.008. PubMed 24524452 ↗
10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Jun 24, 2026, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT01192776
Lead sponsor
NICHD Neonatal Research Network
Collaborators
National Center for Research Resources (NCRR), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Responsible party
Sponsor
First posted
Sep 1, 2010
Start date
Sep 2010
Primary completion
Mar 2016
Completion
Mar 2016
Results posted
Aug 15, 2017
Last update
Jun 24, 2026

Study contacts

Seetha Shankaran, MD
study chair · Wayne State University
Abbot R Laptook, MD
principal investigator · Brown University, Women & Infants Hospital of Rhode Island
Michele C Walsh, MD MS
principal investigator · Case Western Reserve University, Rainbow Babies and Children's Hospital
Ronald N. Goldberg, MD
principal investigator · Duke University
Barbara J. Stoll, MD
principal investigator · Emory University
Brenda B. Poindexter, MD MS
principal investigator · Indiana University
Abhik Das, PhD
principal investigator · RTI International
Krisa P. Van Meurs, MD
principal investigator · Stanford University
Kurt Schibler, MD
principal investigator · Children's Hospital Medical Center, Cincinnati
Waldemar A. Carlo, MD
principal investigator · University of Alabama at Birmingham
Edward F. Bell, MD
principal investigator · University of Iowa
Kristi L. Watterberg, MD
principal investigator · University of New Mexico
Pablo J. Sanchez, MD
principal investigator · University of Texas, Southwestern Medical Center at Dallas
Kathleen A. Kennedy, MD MPH
principal investigator · The University of Texas Health Science Center, Houston
William Truog, MD
principal investigator · Children's Mercy Hospital Kansas City
Barbara Schmidt, MD, MSc
principal investigator · University of Pennsylvania
Carl D'Angio, MD
principal investigator · University of Rochester
Uday Devaskar, MD
principal investigator · University of California, Los Angeles
Leif Nelin, MD
principal investigator · Research Institute at Nationwide Children's Hospital

Oversight

Data monitoring committee
Yes
View the source record on ClinicalTrials.gov ↗

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