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JAMA. 2017 Jul 4;318(1):57-67. doi: 10.1001/jama.2017.7218.

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.

Author information

1
Department of Pediatrics, Wayne State University, Detroit, Michigan.
2
Department of Pediatrics, Women and Infants Hospital, Brown University, Providence, Rhode Island.
3
Social, Statistical and Environmental Sciences Unit, RTI International, Research Triangle Park, North Carolina.
4
Social, Statistical and Environmental Sciences Unit, RTI International, Rockville, Maryland.
5
Department of Pediatrics, McGovern Medical School, the University of Texas Health Science Center at Houston.
6
Department of Pediatrics, Indiana University School of Medicine, Indianapolis7Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
7
Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
8
Department of Pediatrics, University of Iowa, Iowa City.
9
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas.
10
Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine and Lucile Packard Children's Hospital, Palo Alto, California.
11
Department of Pediatrics, University of California, Los Angeles.
12
Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut.
13
Department of Pediatrics, Indiana University School of Medicine, Indianapolis.
14
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, the Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
15
Department of Pediatrics, University at Buffalo, Buffalo, New York.
16
Department of Pediatrics, Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland, Ohio.
17
Division of Neonatology, University of Alabama at Birmingham.
18
University of New Mexico Health Sciences Center, Albuquerque.
19
Department of Pediatrics, Nationwide Children's Hospital-The Ohio State University, Columbus.
20
Department of Pediatrics, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia.
21
Department of Pediatrics, University of Michigan, Ann Arbor.
22
Department of Pediatrics, Duke University, Durham, North Carolina.
23
Department of Pediatrics, Children's Mercy Hospital and University of Missouri Kansas City School of Medicine, Kansas City.
24
Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.

Abstract

Importance:

Hypothermia for 72 hours at 33.5°C for neonatal hypoxic-ischemic encephalopathy reduces death or disability, but rates continue to be high.

Objective:

To determine if cooling for 120 hours or to a temperature of 32.0°C reduces death or disability at age 18 months in infants with hypoxic-ischemic encephalopathy.

Design, Setting, and Participants:

Randomized 2 × 2 factorial clinical trial in neonates (≥36 weeks' gestation) with hypoxic-ischemic encephalopathy at 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network between October 2010 and January 2016.

Interventions:

A total of 364 neonates were randomly assigned to 4 hypothermia groups: 33.5°C for 72 hours (n = 95), 32.0°C for 72 hours (n = 90), 33.5°C for 120 hours (n = 96), or 32.0°C for 120 hours (n = 83).

Main Outcomes and Measures:

The primary outcome was death or moderate or severe disability at 18 to 22 months of age adjusted for center and level of encephalopathy. Severe disability included any of Bayley Scales of Infant Development III cognitive score less than 70, Gross Motor Function Classification System (GMFCS) level of 3 to 5, or blindness or hearing loss despite amplification. Moderate disability was defined as a cognitive score of 70 to 84 and either GMFCS level 2, active seizures, or hearing with amplification.

Results:

The trial was stopped for safety and futility in November 2013 after 364 of the planned 726 infants were enrolled. Among 347 infants (95%) with primary outcome data (mean age at follow-up, 20.7 [SD, 3.5] months; 42% female), death or disability occurred in 56 of 176 (31.8%) cooled for 72 hours and 54 of 171 (31.6%) cooled for 120 hours (adjusted risk ratio, 0.92 [95% CI, 0.68-1.25]; adjusted absolute risk difference, -1.0% [95% CI, -10.2% to 8.1%]) and in 59 of 185 (31.9%) cooled to 33.5°C and 51 of 162 (31.5%) cooled to 32.0°C (adjusted risk ratio, 0.92 [95% CI, 0.68-1.26]; adjusted absolute risk difference, -3.1% [95% CI, -12.3% to 6.1%]). A significant interaction between longer and deeper cooling was observed (P = .048), with primary outcome rates of 29.3% at 33.5°C for 72 hours, 34.5% at 32.0°C for 72 hours, 34.4% at 33.5°C for 120 hours, and 28.2% at 32.0°C for 120 hours.

Conclusions and Relevance:

Among term neonates with moderate or severe hypoxic-ischemic encephalopathy, cooling for longer than 72 hours, cooling to lower than 33.5°C, or both did not reduce death or moderate or severe disability at 18 months of age. However, the trial may be underpowered, and an interaction was found between longer and deeper cooling. These results support the current regimen of cooling for 72 hours at 33.5°C.

Trial Registration:

clinicaltrials.gov Identifier: NCT01192776.

PMID:
28672318
PMCID:
PMC5793705
DOI:
10.1001/jama.2017.7218
[Indexed for MEDLINE]
Free PMC Article

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