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JAMA. 2017 Oct 24;318(16):1550-1560. doi: 10.1001/jama.2017.14972.

Effect of Therapeutic Hypothermia Initiated After 6 Hours of Age on Death or Disability Among Newborns With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial.

Author information

1
Department of Pediatrics, Women & Infants Hospital, Brown University, Providence, Rhode Island.
2
Department of Pediatrics, Wayne State University, Detroit, Michigan.
3
Department of Pediatrics, McGovern Medical School at the University of Texas Health Science Center at Houston.
4
Social, Statistical, and Environmental Sciences Unit, RTI International, Research Triangle Park, North Carolina.
5
Department of Pediatrics, University of Iowa, Iowa City.
6
Department of Pediatrics, Duke University, Durham, North Carolina.
7
Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
8
Division of Neonatology, University of Alabama at Birmingham.
9
Social, Statistical, and Environmental Sciences Unit, RTI International, Rockville, Maryland.
10
Department of Pediatrics, University of Pennsylvania, Philadelphia.
11
Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut.
12
Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, California.
13
Lucile Packard Children's Hospital, Palo Alto, California.
14
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas.
15
Emory University School of Medicine, Department of Pediatrics, Children's Healthcare of Atlanta, Atlanta, Georgia.
16
Department of Pediatrics, Indiana University School of Medicine, Indianapolis.
17
Department of Pediatrics, Rainbow Babies & Children's Hospital, Case Western Reserve University, Cleveland, Ohio.
18
Department of Pediatrics, Division of Neonatology, University of Utah School of Medicine, Salt Lake City.
19
University of New Mexico Health Sciences Center, Albuquerque.
20
Division of Newborn Medicine, Department of Pediatrics, Floating Hospital for Children, Tufts Medical Center, Boston, Massachusetts.
21
University of Rochester School of Medicine and Dentistry, Rochester, New York.
22
Department of Pediatrics, University of California, Los Angeles.
23
Department of Pediatrics, Children's Mercy Hospital, Kansas City, Missouri.
24
University of Missouri Kansas City School of Medicine, Kansas City.
25
Department of Pediatrics, Nationwide Children's Hospital, Columbus, Ohio.
26
Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.

Erratum in

Abstract

Importance:

Hypothermia initiated at less than 6 hours after birth reduces death or disability for infants with hypoxic-ischemic encephalopathy at 36 weeks' or later gestation. To our knowledge, hypothermia trials have not been performed in infants presenting after 6 hours.

Objective:

To estimate the probability that hypothermia initiated at 6 to 24 hours after birth reduces the risk of death or disability at 18 months among infants with hypoxic-ischemic encephalopathy.

Design, Setting, and Participants:

A randomized clinical trial was conducted between April 2008 and June 2016 among infants at 36 weeks' or later gestation with moderate or severe hypoxic-ischemic encephalopathy enrolled at 6 to 24 hours after birth. Twenty-one US Neonatal Research Network centers participated. Bayesian analyses were prespecified given the anticipated limited sample size.

Interventions:

Targeted esophageal temperature was used in 168 infants. Eighty-three hypothermic infants were maintained at 33.5°C (acceptable range, 33°C-34°C) for 96 hours and then rewarmed. Eighty-five noncooled infants were maintained at 37.0°C (acceptable range, 36.5°C-37.3°C).

Main Outcomes and Measures:

The composite of death or disability (moderate or severe) at 18 to 22 months adjusted for level of encephalopathy and age at randomization.

Results:

Hypothermic and noncooled infants were term (mean [SD], 39 [2] and 39 [1] weeks' gestation, respectively), and 47 of 83 (57%) and 55 of 85 (65%) were male, respectively. Both groups were acidemic at birth, predominantly transferred to the treating center with moderate encephalopathy, and were randomized at a mean (SD) of 16 (5) and 15 (5) hours for hypothermic and noncooled groups, respectively. The primary outcome occurred in 19 of 78 hypothermic infants (24.4%) and 22 of 79 noncooled infants (27.9%) (absolute difference, 3.5%; 95% CI, -1% to 17%). Bayesian analysis using a neutral prior indicated a 76% posterior probability of reduced death or disability with hypothermia relative to the noncooled group (adjusted posterior risk ratio, 0.86; 95% credible interval, 0.58-1.29). The probability that death or disability in cooled infants was at least 1%, 2%, or 3% less than noncooled infants was 71%, 64%, and 56%, respectively.

Conclusions and Relevance:

Among term infants with hypoxic-ischemic encephalopathy, hypothermia initiated at 6 to 24 hours after birth compared with noncooling resulted in a 76% probability of any reduction in death or disability, and a 64% probability of at least 2% less death or disability at 18 to 22 months. Hypothermia initiated at 6 to 24 hours after birth may have benefit but there is uncertainty in its effectiveness.

Trial Registration:

clinicaltrials.gov Identifier: NCT00614744.

PMID:
29067428
PMCID:
PMC5783566
DOI:
10.1001/jama.2017.14972
[Indexed for MEDLINE]
Free PMC Article

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