Preemie Hypothermia for Neonatal Encephalopathy

Not Applicable

Completed

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

Interventions: Device: Hypothermia
Procedure: Normothermic Control

Registration Number: NCT01793129

Lead Sponsor: NICHD Neonatal Research Network

Brief Summary: This study is a randomized, controlled trial to assess safety and effectiveness of whole body hypothermia for 72 hours in preterm infants 33-35 weeks gestational age (GA) who present at \<6 hours postnatal age with moderate to severe neonatal encephalopathy (NE). The study will enroll infants with signs of NE at 18 NICHD Neonatal Research Network sites, and randomly assign them to either receive hypothermia or participate in a non-cooled control group.

Detailed Description: Most clinical studies of neonatal encephalopathy (NE) and potential interventions have focused on infants ≥36 weeks GA. Although many interventions have been suggested and assessed for prevention or palliation of NE, the only one currently supported by rigorous clinical evidence to improve outcome in human newborns has been hypothermia implemented at \<6 hours of postnatal age and maintained for 72 hrs. Data about diagnosis, frequency, severity, and outcome of NE in infants 33-35 weeks GA are sparse.

This trial will assess safety and effectiveness of whole body hypothermia for 72 hours in preterm infants 33-35 weeks gestational age (GA) who present at \<6 hrs postnatal age with moderate to severe neonatal encephalopathy. Infants 33 0/7 to 35 6/7 weeks GA (best obstetrical estimate) and greater than or equal to 1500 grams birth weight (selected to minimize potential difficulties placing esophageal probe) who meet clinical, biochemical and neurologic criteria for moderate to severe NE will be randomized to either whole body hypothermia or participate in a non-cooled control group. The primary outcome will be death or moderate to severe disability at 18-22 months corrected age. The presence or absence of disability will be determined by the standard NRN interdisciplinary follow-up exam.

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

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 168

Inclusion Criteria

Infants 33 0/7 to 35 6/7 weeks GA (best obstetrical estimate)
Infants weight greater than or equal to 1500 grams at birth
Postnatal age less than 6 hours
Infants who meet clinical, biochemical and neurologic criteria for moderate to severe NE:

Biochemical: Cord gas or blood gas within first hour of life with pH ≤7.00 or base deficit (BD) ≥16 mEq/L OR

Acute perinatal event (e.g., abruptio placenta, cord prolapse, uterine rupture, severe FHR abnormality such as variable or late decelerations) AND Requirement for positive pressure ventilation for apnea or poor respiratory effort since birth for at least 10 minutes OR 10 minute Apgar score ≤5

AND

Neurologic:

Seizures OR modified Sarnat score with abnormalities in at least 3 of the 6 categories; at least one must be altered level of consciousness (lethargy or stupor/coma) as determined by a certified examiner (All infants who meet criteria for potential inclusion will undergo standard neurologic exam as for infants ≥36 wks GA being considered for hypothermia, with findings recorded)

Exclusion Criteria

Receipt of sedative, analgesic or paralytic agent that may confound the qualifying neurologic exam
Etiology of NE not likely to be hypoxic-ischemic in origin
Major congenital anomaly that may confound outcome
Considered to be moribund and will not be receiving full intensive care
Equipment and/or appropriate staff not available
Core temperature < 33.5oC for more than one hour at time of screening
Unable to randomize by 6 hours of age
Infant needs ECMO
All blood gases (cord and postnatal at < 1hr of age) have a pH > 7.15 AND a base deficit < 10mEq/L

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Whole-body Hypothermia	Hypothermia	Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 72 hours
Normothermia	Normothermic Control	Control group (with esophageal temperature at or near 37.0°C) for 72 hours

Primary Outcome Measures

Name	Time	Method
Death or Moderate or Severe Disability	Birth to 18-22 months corrected age	Severe disability was defined by any of the following: a Bayley III cognitive score \< 70 or Gross Motor Function (GMF) Level of 3-5 blindness or profound hearing loss requiring amplification but still unable to following 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

Name	Time	Method
Causes of Death	Birth to 18-22 months corrrected age	Causes of any deaths that occurred through 18-22 months corrected age.
Number of Infants With Moderate or Severe Disability	Birth to 18-22 months corrrected age	Number of infants with moderate or severe disability among survivors through 18-22 months corrected age.
Number of Infants With Abnormal MRIs During Post-intervention Period	Post-intervention to through discharge, death, or transfer (whichever comes first), average of 29 days	An MRI was considered abnormal if any abnormal findings were indicated on the CRF form.
Neurological Injury by Cranial Ultrasound During Intervention	Within 6 hours of life to 72 hours after start of intervention	Infants with recorded events of intraventricular hemorrhage grade I, II, III, or IV, posterior fossa hemorrhage with/without shift of midline structures, intraparenchymal hemorrhage.
Number of Deaths in the NICU and Following Discharge	Birth to 18-22 months corrected age	Number of deaths in the NICU and following discharge among infants with a primary outcome.

Trial Locations

Locations (18): Case Western Reserve University, Rainbow Babies and Children's Hospital
🇺🇸
Cleveland, Ohio, United States
Research Institute at Nationwide Children's Hospital
🇺🇸
Columbus, Ohio, United States
University of Alabama at Birmingham
🇺🇸
Birmingham, Alabama, United States
Stanford University
🇺🇸
Palo Alto, California, United States
Emory University
🇺🇸
Atlanta, Georgia, United States
Indiana University
🇺🇸
Indianapolis, Indiana, United States
University of Iowa
🇺🇸
Iowa City, Iowa, United States
Wayne State University
🇺🇸
Detroit, Michigan, United States
University of New Mexico
🇺🇸
Albuquerque, New Mexico, United States
Univeristy of Pennsylvania
🇺🇸
Philadelphia, Pennsylvania, United States
Brown University, Women & Infants Hospital of Rhode Island
🇺🇸
Providence, Rhode Island, United States
University of Texas Southwestern Medical Center at Dallas
🇺🇸
Dallas, Texas, United States
University of Rochester
🇺🇸
Rochester, New York, United States
University of Utah
🇺🇸
Salt Lake City, Utah, United States
RTI International
🇺🇸
Durham, North Carolina, United States
Duke University
🇺🇸
Durham, North Carolina, United States
Cincinnati Children's Medical Center
🇺🇸
Cincinnati, Ohio, United States
University of Texas Health Science Center at Houston
🇺🇸
Houston, Texas, United States