Encephalopathy, Hypoxic-Ischemic, Hypoxia, Brain, Hypoxia-Ischemia, Brain, Hypoxic-Ischemic Encephalopathy, Infant, Newborn, Ischemic-Hypoxic Encephalopathy
Conditions
Keywords
NICHD Neonatal Research Network, Hypoxic-ischemic encephalopathy (HIE), Hypothermia, Neonatal depression, Perinatal asphyxia, Fetal acidosis
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.
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.
Sponsors
NICHD Neonatal Research Network
National Center for Research Resources (NCRR)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 6 Years
Healthy volunteers
No
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
* 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Death | Birth to 22 months corrected age | Death includes any mortality prior to follow up at 18-22 months. |
| 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. |
| 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 |
| 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 | — |
| 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. |
| Visual Impairment | Follow up at 18-22 months corrected age | Visual impairment is defined as bilateral blindness with some/no useful vision |
| Hearing Impairment | Follow up at 18-22 months corrected age | Hearing impairment is defined as hearing impairment despite amplification |
| 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. |
| 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. |
Countries
United States
Contacts
STUDY_CHAIRSeetha Shankaran, MD
Wayne State University
PRINCIPAL_INVESTIGATORAbbot R Laptook, MD
Brown University, Women & Infants Hospital of Rhode Island
PRINCIPAL_INVESTIGATORMichele C Walsh, MD MS
Case Western Reserve University, Rainbow Babies and Children's Hospital
PRINCIPAL_INVESTIGATORRonald N. Goldberg, MD
Duke University
PRINCIPAL_INVESTIGATORBarbara J. Stoll, MD
Emory University
PRINCIPAL_INVESTIGATORBrenda B. Poindexter, MD MS
Indiana University
PRINCIPAL_INVESTIGATORAbhik Das, PhD
RTI International
PRINCIPAL_INVESTIGATORKrisa P. Van Meurs, MD
Stanford University
PRINCIPAL_INVESTIGATORKurt Schibler, MD
Children's Hospital Medical Center, Cincinnati
PRINCIPAL_INVESTIGATORWaldemar A. Carlo, MD
University of Alabama at Birmingham
PRINCIPAL_INVESTIGATOREdward F. Bell, MD
University of Iowa
PRINCIPAL_INVESTIGATORKristi L. Watterberg, MD
University of New Mexico
PRINCIPAL_INVESTIGATORPablo J. Sanchez, MD
University of Texas, Southwestern Medical Center at Dallas
PRINCIPAL_INVESTIGATORKathleen A. Kennedy, MD MPH
The University of Texas Health Science Center, Houston
PRINCIPAL_INVESTIGATORWilliam Truog, MD
Children's Mercy Hospital Kansas City
PRINCIPAL_INVESTIGATORBarbara Schmidt, MD, MSc
University of Pennsylvania
PRINCIPAL_INVESTIGATORCarl D'Angio, MD
University of Rochester
PRINCIPAL_INVESTIGATORUday Devaskar, MD
University of California, Los Angeles
PRINCIPAL_INVESTIGATORLeif Nelin, MD
Research Institute at Nationwide Children's Hospital
Participant flow
Recruitment details
1261 infants assessed for eligibility. 897 were excluded for not meeting eligibility criteria (N=747) or not having parental or physician consent (N=150).
Pre-assignment details
All eligible infants with consent were randomized to one of four treatment arms/groups.
Participants by arm
| Arm | Count |
|---|---|
| 33.5°C for 72 Hours Target Temp: 33.5°C Duration: 72 hrs
Whole-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. | 95 |
| 32.0°C for 72 Hours Target Temp: 32.0°C Duration: 72 hrs
Whole-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. | 90 |
| 33.5°C for 120 Hours Target Temp: 33.5°C Duration: 120 hrs
Whole-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. | 96 |
| 32.0°C for 120 Hours Target Temp: 32.0°C Duration:120 hrs
Whole-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. | 83 |
| Total | 364 |
Baseline characteristics
| Characteristic | 33.5°C for 72 Hours | Total | 32.0°C for 120 Hours | 33.5°C for 120 Hours | 32.0°C for 72 Hours |
|---|---|---|---|---|---|
| Age, Continuous | 5.1 hours STANDARD_DEVIATION 1 | 4.9 hours STANDARD_DEVIATION 1.2 | 5.0 hours STANDARD_DEVIATION 1.6 | 4.8 hours STANDARD_DEVIATION 1.1 | 4.9 hours STANDARD_DEVIATION 1.2 |
| Birthweight | 3230 grams STANDARD_DEVIATION 528 | 3359 grams STANDARD_DEVIATION 599 | 3511 grams STANDARD_DEVIATION 615 | 3354 grams STANDARD_DEVIATION 676 | 3360 grams STANDARD_DEVIATION 544 |
| Level of encephalopathy Moderate | 74 Participants | 280 Participants | 58 Participants | 78 Participants | 70 Participants |
| Level of encephalopathy Severe | 21 Participants | 84 Participants | 25 Participants | 18 Participants | 20 Participants |
| Race/Ethnicity, Customized Black | 29 Participants | 114 Participants | 25 Participants | 32 Participants | 28 Participants |
| Race/Ethnicity, Customized Other | 6 Participants | 25 Participants | 7 Participants | 7 Participants | 5 Participants |
| Race/Ethnicity, Customized White | 60 Participants | 219 Participants | 48 Participants | 55 Participants | 56 Participants |
| Sex/Gender, Customized Ambiguous | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Sex/Gender, Customized Female | 43 Participants | 151 Participants | 27 Participants | 44 Participants | 37 Participants |
| Sex/Gender, Customized Male | 52 Participants | 212 Participants | 56 Participants | 51 Participants | 53 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 8 / 92 | 15 / 84 | 18 / 93 | 15 / 78 |
| other Total, other adverse events | 5 / 95 | 3 / 90 | 6 / 96 | 9 / 83 |
| serious Total, serious adverse events | 10 / 95 | 15 / 90 | 11 / 96 | 23 / 83 |
Outcome results
Primary
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
Population: Includes all deaths and all infants followed at 18-22 months. Does not include 17 infants lost to follow up.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 33.5°C for 72 Hours | Death or Moderate to Severe Disability | 27 Participants |
| 32.0°C for 72 Hours | Death or Moderate to Severe Disability | 29 Participants |
| 33.5°C for 120 Hours | Death or Moderate to Severe Disability | 32 Participants |
| 32.0°C for 120 Hours | Death or Moderate to Severe Disability | 22 Participants |
Comparison: 32.0°C for 72 hours vs. 33.5°C for 72 hours (33.5°C for 72 hours is the comparison group)95% CI: [0.76, 1.98]
Comparison: 33.5°C for 120 hours vs. 33.5°C for 72 hours (33.5°C for 72 hours is the comparison group)95% CI: [0.78, 1.87]
Comparison: 32.0°C for 120 hours vs. 33.5°C for 72 hours (33.5°C for 72 hours is the comparison group)95% CI: [0.53, 1.35]
Secondary
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
Population: Infants who survived and were followed at 18-22 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 33.5°C for 72 Hours | Bayley Cognitive Score | 90 scores on a scale |
| 32.0°C for 72 Hours | Bayley Cognitive Score | 90 scores on a scale |
| 33.5°C for 120 Hours | Bayley Cognitive Score | 90 scores on a scale |
| 32.0°C for 120 Hours | Bayley Cognitive Score | 90 scores on a scale |
Secondary
Cerebral Palsy
Time frame: Follow up at 18-22 months corrected age
Population: Infants who survived and were followed at 18-22 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 33.5°C for 72 Hours | Cerebral Palsy | 15 Participants |
| 32.0°C for 72 Hours | Cerebral Palsy | 13 Participants |
| 33.5°C for 120 Hours | Cerebral Palsy | 10 Participants |
| 32.0°C for 120 Hours | Cerebral Palsy | 8 Participants |
Comparison: 32.0°C for 72 hours vs. 33.5°C for 72 hours (33.5°C for 72 hours is the comparison group)95% CI: [0.64, 2.38]
Comparison: 33.5°C for 120 hours vs. 33.5°C for 72 hours (33.5°C for 72 hours is the comparison group)95% CI: [0.36, 1.9]
Comparison: 32.0°C for 120 hours vs. 33.5°C for 72 hours (33.5°C for 72 hours is the comparison group)95% CI: [0.26, 1.57]
Secondary
Clinical Neonatal Seizures
Documented seizures during hospital course
Time frame: Through death, discharge, or transfer
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 33.5°C for 72 Hours | Clinical Neonatal Seizures | 50 Participants |
| 32.0°C for 72 Hours | Clinical Neonatal Seizures | 43 Participants |
| 33.5°C for 120 Hours | Clinical Neonatal Seizures | 44 Participants |
| 32.0°C for 120 Hours | Clinical Neonatal Seizures | 40 Participants |
Secondary
Death
Death includes any mortality prior to follow up at 18-22 months.
Time frame: Birth to 22 months corrected age
Population: Includes all deaths and all infants followed at 18-22 months. Does not include 17 infants lost to follow up.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 33.5°C for 72 Hours | Death | 8 Participants |
| 32.0°C for 72 Hours | Death | 15 Participants |
| 33.5°C for 120 Hours | Death | 18 Participants |
| 32.0°C for 120 Hours | Death | 15 Participants |
Comparison: 33.5°C for 120 hours vs. 33.5°C for 72 hours (33.5°C for 72 hours is the comparison group)95% CI: [1.06, 5.95]
Comparison: 32.0°C for 72 hours vs. 33.5°C for 72 hours (33.5°C for 72 hours is the comparison group)95% CI: [0.55, 8.49]
Comparison: 32.0°C for 120 hours vs. 33.5°C for 72 hours (33.5°C for 72 hours is the comparison group)95% CI: [0.79, 4.31]
Secondary
Hearing Impairment
Hearing impairment is defined as hearing impairment despite amplification
Time frame: Follow up at 18-22 months corrected age
Population: Infants who survived and were followed at 18-22 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 33.5°C for 72 Hours | Hearing Impairment | 4 Participants |
| 32.0°C for 72 Hours | Hearing Impairment | 2 Participants |
| 33.5°C for 120 Hours | Hearing Impairment | 4 Participants |
| 32.0°C for 120 Hours | Hearing Impairment | 1 Participants |
Comparison: 32.0°C for 72 hours vs. 33.5°C for 72 hours (33.5°C for 72 hours is the comparison group)95% CI: [0.14, 3.01]
Comparison: 33.5°C for 120 hours vs. 33.5°C for 72 hours (33.5°C for 72 hours is the comparison group)95% CI: [0.44, 3.91]
Comparison: 32.0°C for 120 hours vs. 33.5°C for 72 hours (33.5°C for 72 hours is the comparison group)95% CI: [0.03, 2.89]
Secondary
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
Population: Includes all infants followed at 18-22 months except for 6 infants who could not be distinguished between normal and mild. Does not include 17 infants lost to follow up or 56 deaths
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 33.5°C for 72 Hours | Level of Disability Among Survivors | Severe disability | 18 Participants |
| 33.5°C for 72 Hours | Level of Disability Among Survivors | Moderate disability | 1 Participants |
| 33.5°C for 72 Hours | Level of Disability Among Survivors | Mild disability | 16 Participants |
| 33.5°C for 72 Hours | Level of Disability Among Survivors | Normal | 46 Participants |
| 32.0°C for 72 Hours | Level of Disability Among Survivors | Moderate disability | 3 Participants |
| 32.0°C for 72 Hours | Level of Disability Among Survivors | Mild disability | 15 Participants |
| 32.0°C for 72 Hours | Level of Disability Among Survivors | Normal | 40 Participants |
| 32.0°C for 72 Hours | Level of Disability Among Survivors | Severe disability | 11 Participants |
| 33.5°C for 120 Hours | Level of Disability Among Survivors | Mild disability | 22 Participants |
| 33.5°C for 120 Hours | Level of Disability Among Survivors | Moderate disability | 0 Participants |
| 33.5°C for 120 Hours | Level of Disability Among Survivors | Normal | 36 Participants |
| 33.5°C for 120 Hours | Level of Disability Among Survivors | Severe disability | 14 Participants |
| 32.0°C for 120 Hours | Level of Disability Among Survivors | Normal | 38 Participants |
| 32.0°C for 120 Hours | Level of Disability Among Survivors | Moderate disability | 0 Participants |
| 32.0°C for 120 Hours | Level of Disability Among Survivors | Severe disability | 7 Participants |
| 32.0°C for 120 Hours | Level of Disability Among Survivors | Mild disability | 18 Participants |
Secondary
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
Population: Includes all infants followed at 18-22 months, except for 6 infants who could not be distinguished between normal and mild. Does not include 17 infants lost to follow up or 56 deaths.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| 33.5°C for 72 Hours | Level of Disability Among Survivors, by Level of HIE | Moderate HIE | Normal | 41 Participants |
| 33.5°C for 72 Hours | Level of Disability Among Survivors, by Level of HIE | Moderate HIE | Mild disability | 13 Participants |
| 33.5°C for 72 Hours | Level of Disability Among Survivors, by Level of HIE | Moderate HIE | Moderate disability | 1 Participants |
| 33.5°C for 72 Hours | Level of Disability Among Survivors, by Level of HIE | Moderate HIE | Severe disability | 9 Participants |
| 33.5°C for 72 Hours | Level of Disability Among Survivors, by Level of HIE | Severe HIE | Normal | 5 Participants |
| 33.5°C for 72 Hours | Level of Disability Among Survivors, by Level of HIE | Severe HIE | Mild disability | 3 Participants |
| 33.5°C for 72 Hours | Level of Disability Among Survivors, by Level of HIE | Severe HIE | Moderate disability | 0 Participants |
| 33.5°C for 72 Hours | Level of Disability Among Survivors, by Level of HIE | Severe HIE | Severe disability | 9 Participants |
| 32.0°C for 72 Hours | Level of Disability Among Survivors, by Level of HIE | Severe HIE | Mild disability | 3 Participants |
| 32.0°C for 72 Hours | Level of Disability Among Survivors, by Level of HIE | Severe HIE | Normal | 1 Participants |
| 32.0°C for 72 Hours | Level of Disability Among Survivors, by Level of HIE | Moderate HIE | Mild disability | 12 Participants |
| 32.0°C for 72 Hours | Level of Disability Among Survivors, by Level of HIE | Severe HIE | Severe disability | 4 Participants |
| 32.0°C for 72 Hours | Level of Disability Among Survivors, by Level of HIE | Severe HIE | Moderate disability | 1 Participants |
| 32.0°C for 72 Hours | Level of Disability Among Survivors, by Level of HIE | Moderate HIE | Severe disability | 7 Participants |
| 32.0°C for 72 Hours | Level of Disability Among Survivors, by Level of HIE | Moderate HIE | Moderate disability | 2 Participants |
| 32.0°C for 72 Hours | Level of Disability Among Survivors, by Level of HIE | Moderate HIE | Normal | 39 Participants |
| 33.5°C for 120 Hours | Level of Disability Among Survivors, by Level of HIE | Severe HIE | Moderate disability | 0 Participants |
| 33.5°C for 120 Hours | Level of Disability Among Survivors, by Level of HIE | Moderate HIE | Moderate disability | 0 Participants |
| 33.5°C for 120 Hours | Level of Disability Among Survivors, by Level of HIE | Moderate HIE | Severe disability | 12 Participants |
| 33.5°C for 120 Hours | Level of Disability Among Survivors, by Level of HIE | Severe HIE | Normal | 2 Participants |
| 33.5°C for 120 Hours | Level of Disability Among Survivors, by Level of HIE | Severe HIE | Mild disability | 3 Participants |
| 33.5°C for 120 Hours | Level of Disability Among Survivors, by Level of HIE | Severe HIE | Severe disability | 2 Participants |
| 33.5°C for 120 Hours | Level of Disability Among Survivors, by Level of HIE | Moderate HIE | Normal | 34 Participants |
| 33.5°C for 120 Hours | Level of Disability Among Survivors, by Level of HIE | Moderate HIE | Mild disability | 19 Participants |
| 32.0°C for 120 Hours | Level of Disability Among Survivors, by Level of HIE | Moderate HIE | Moderate disability | 0 Participants |
| 32.0°C for 120 Hours | Level of Disability Among Survivors, by Level of HIE | Moderate HIE | Severe disability | 5 Participants |
| 32.0°C for 120 Hours | Level of Disability Among Survivors, by Level of HIE | Moderate HIE | Mild disability | 13 Participants |
| 32.0°C for 120 Hours | Level of Disability Among Survivors, by Level of HIE | Moderate HIE | Normal | 31 Participants |
| 32.0°C for 120 Hours | Level of Disability Among Survivors, by Level of HIE | Severe HIE | Normal | 7 Participants |
| 32.0°C for 120 Hours | Level of Disability Among Survivors, by Level of HIE | Severe HIE | Severe disability | 2 Participants |
| 32.0°C for 120 Hours | Level of Disability Among Survivors, by Level of HIE | Severe HIE | Moderate disability | 0 Participants |
| 32.0°C for 120 Hours | Level of Disability Among Survivors, by Level of HIE | Severe HIE | Mild disability | 5 Participants |
Secondary
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
Population: No patients were analyzed for this outcome as the study was terminated early and no additional funds available to complete this complex analysis.
Secondary
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
Population: Infants who survived and were followed at 18-22 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 33.5°C for 72 Hours | Multiple Disabilities | 14 Participants |
| 32.0°C for 72 Hours | Multiple Disabilities | 9 Participants |
| 33.5°C for 120 Hours | Multiple Disabilities | 7 Participants |
| 32.0°C for 120 Hours | Multiple Disabilities | 5 Participants |
Comparison: 32.0°C for 72 hours vs. 33.5°C for 72 hours (33.5°C for 72 hours is the comparison group)95% CI: [0.37, 2.07]
Comparison: 33.5°C for 120 hours vs. 33.5°C for 72 hours (33.5°C for 72 hours is the comparison group)95% CI: [0.3, 1.35]
Comparison: 32.0°C for 120 hours vs. 33.5°C for 72 hours (33.5°C for 72 hours is the comparison group)95% CI: [0.13, 1.64]
Secondary
Visual Impairment
Visual impairment is defined as bilateral blindness with some/no useful vision
Time frame: Follow up at 18-22 months corrected age
Population: Infants who survived and were followed at 18-22 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 33.5°C for 72 Hours | Visual Impairment | 6 Participants |
| 32.0°C for 72 Hours | Visual Impairment | 6 Participants |
| 33.5°C for 120 Hours | Visual Impairment | 2 Participants |
| 32.0°C for 120 Hours | Visual Impairment | 4 Participants |
Comparison: 32.0°C for 72 hours vs. 33.5°C for 72 hours (33.5°C for 72 hours is the comparison group)95% CI: [0.63, 2.77]
Comparison: 33.5°C for 120 hours vs. 33.5°C for 72 hours (33.5°C for 72 hours is the comparison group)95% CI: [0.09, 2.04]
Comparison: 32.0°C for 120 hours vs. 33.5°C for 72 hours (33.5°C for 72 hours is the comparison group)95% CI: [0.2, 2.99]
Secondary
Withdrawal of Care
Number of infants for whom aggressive care is withdrawn
Time frame: Birth through hospital discharge, average 22 days.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 33.5°C for 72 Hours | Withdrawal of Care | 6 Participants |
| 32.0°C for 72 Hours | Withdrawal of Care | 12 Participants |
| 33.5°C for 120 Hours | Withdrawal of Care | 14 Participants |
| 32.0°C for 120 Hours | Withdrawal of Care | 13 Participants |
Other Pre-specified
Severe Neonatal Brain Abnormalities
Total hemispheric devastation based on MRI taken between 7-14 days of life
Time frame: 7-14 days of life
Population: Note that 66 infants are not included (total N for OC study=364); 49 were excluded due to lack of MRI of adequate quality, 16 due to missing primary outcome, and 1 due to genetic abnormality.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 33.5°C for 72 Hours | Severe Neonatal Brain Abnormalities | Total hemispheric devastation = YES | 10 Participants |
| 33.5°C for 72 Hours | Severe Neonatal Brain Abnormalities | Total hemispheric devastation = NO | 72 Participants |
| 32.0°C for 72 Hours | Severe Neonatal Brain Abnormalities | Total hemispheric devastation = NO | 64 Participants |
| 32.0°C for 72 Hours | Severe Neonatal Brain Abnormalities | Total hemispheric devastation = YES | 11 Participants |
| 33.5°C for 120 Hours | Severe Neonatal Brain Abnormalities | Total hemispheric devastation = YES | 4 Participants |
| 33.5°C for 120 Hours | Severe Neonatal Brain Abnormalities | Total hemispheric devastation = NO | 76 Participants |
| 32.0°C for 120 Hours | Severe Neonatal Brain Abnormalities | Total hemispheric devastation = YES | 7 Participants |
| 32.0°C for 120 Hours | Severe Neonatal Brain Abnormalities | Total hemispheric devastation = NO | 54 Participants |