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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Optimizing Cooling Strategies at < 6 Hours of Age for Neonatal Hypoxic-Ischemic Encephalopathy

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

Intervention / Treatment
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* Procedure: Whole-body Cooling


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eligibility will be determined in a stepped process: All infants with a gestational age ≥ 36 weeks will be screened for study entry if they are admitted to the NICU with a diagnosis of fetal acidosis, perinatal asphyxia, neonatal depression or encephalopathy. Infants will be eligible if: They have a pH ≤ 7.0 or a base deficit ≥ 16m mEq/ L on umbilical cord or any postnatal sample within 1 hour of age. If, during this interval, they have a pH between 7.01 and 7.15, a base deficit is between 10 and 15.9 mEq/L, or a blood gas is not available, AND they have an acute perinatal event AND either a 10-minute Apgar score ≤ 5 or assisted ventilation initiated at birth and continued for at least 10 minutes. Once these criteria are met, eligible infants will have a standardized neurological examination performed by a certified physician examiner. Infants will be candidates for the study when encephalopathy or seizures are present. For this study, encephalopathy is defined as the presence of 1 or more signs in 3 of the following 6 categories: Level of consciousness: lethargy, stupor or coma; Spontaneous activity: decreased, absent; Posture: distal flexion, decerebrate; tone: hypotonia, flaccid or hypertonia, rigid; Primitive reflexes: a) suck, weak, absent; b) Moro, incomplete, flaccid; Autonomic nervous system: a) pupils: constricted, unequal, skew deviation or non reactive to light; b) heart rate: bradycardia, variable heart rate or c) respiration: periodic breathing, apnea. Eligible infants from multiple births will be enrolled in the same arm of the study. Exclusion Criteria: Inability to randomize by 6 hours of age Major congenital abnormality Major chromosomal abnormality (including Trisomy 21), Severe growth restriction (≤ 1800gm birth weight), Infant is moribund and will not receive any further aggressive treatment, Refusal of consent by parent Refusal of consent by attending neonatologist Infants with a core temperature < 33.5°C for > 1 hour at the time of screening by the research team would not be eligible for the study.

Ages Eligible for Study
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Maximum Age: 6 Hours

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 33.5°C for 72 hours<br>Target Temp: 33.5°C Duration: 72 hrs | Procedure: Whole-body Cooling<br>* 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.<br>* Other names: Blanketrol III Model 233 (used in the II mode);|
| Experimental: 33.5°C for 120 hours<br>Target Temp: 33.5°C Duration: 120 hrs | Procedure: Whole-body Cooling<br>* 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.<br>* Other names: Blanketrol III Model 233 (used in the II mode);|
| Experimental: 32.0°C for 72 hours<br>Target Temp: 32.0°C Duration: 72 hrs | Procedure: Whole-body Cooling<br>* 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.<br>* Other names: Blanketrol III Model 233 (used in the II mode);|
| Experimental: 32.0°C for 120 hours<br>Target Temp: 32.0°C Duration:120 hrs | Procedure: Whole-body Cooling<br>* 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.<br>* Other names: Blanketrol III Model 233 (used in the II mode);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Birth to 22 months corrected age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Death | Death includes any mortality prior to follow up at 18-22 months. | Birth to 22 months corrected age | 
| 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. | Follow up at 18-22 months corrected age | 
| Withdrawal of Care | Number of infants for whom aggressive care is withdrawn | Birth through hospital discharge, average 22 days. | 
| Clinical Neonatal Seizures | Documented seizures during hospital course | Through death, discharge, or transfer | 
| 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. | Follow up at 18-22 months corrected age | 
| Cerebral Palsy |  | Follow up at 18-22 months corrected age | 
| 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. | Follow up at 18-22 months corrected age | 
| Visual Impairment | Visual impairment is defined as bilateral blindness with some/no useful vision | Follow up at 18-22 months corrected age | 
| Hearing Impairment | Hearing impairment is defined as hearing impairment despite amplification | Follow up at 18-22 months corrected age | 
| 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. | Follow up at 18-22 months corrected age | 
| 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. | Until death, discharge, or transfer | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypothermia, Fetal acidosis, NICHD Neonatal Research Network, Hypoxic-ischemic encephalopathy (HIE), Neonatal depression, Perinatal asphyxia