Journal article
Effect of depth and duration of cooling on deaths in the NICU among neonates with hypoxic ischemic encephalopathy: a randomized clinical trial
JAMA : the journal of the American Medical Association, Vol.312(24), pp.2629-2639
12/24/2014
DOI: 10.1001/jama.2014.16058
PMCID: PMC4335311
PMID: 25536254
Abstract
Hypothermia at 33.5°C for 72 hours for neonatal hypoxic ischemic encephalopathy reduces death or disability to 44% to 55%; longer cooling and deeper cooling are neuroprotective in animal models.
To determine if longer duration cooling (120 hours), deeper cooling (32.0°C), or both are superior to cooling at 33.5°C for 72 hours in neonates who are full-term with moderate or severe hypoxic ischemic encephalopathy.
A randomized, 2 × 2 factorial design clinical trial performed in 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network between October 2010 and November 2013.
Neonates were assigned to 4 hypothermia groups; 33.5°C for 72 hours, 32.0°C for 72 hours, 33.5°C for 120 hours, and 32.0°C for 120 hours.
The primary outcome of death or disability at 18 to 22 months is ongoing. The independent data and safety monitoring committee paused the trial to evaluate safety (cardiac arrhythmia, persistent acidosis, major vessel thrombosis and bleeding, and death in the neonatal intensive care unit [NICU]) after the first 50 neonates were enrolled, then after every subsequent 25 neonates. The trial was closed for emerging safety profile and futility analysis after the eighth review with 364 neonates enrolled (of 726 planned). This report focuses on safety and NICU deaths by marginal comparisons of 72 hours' vs 120 hours' duration and 33.5°C depth vs 32.0°C depth (predefined secondary outcomes).
The NICU death rates were 7 of 95 neonates (7%) for the 33.5°C for 72 hours group, 13 of 90 neonates (14%) for the 32.0°C for 72 hours group, 15 of 96 neonates (16%) for the 33.5°C for 120 hours group, and 14 of 83 neonates (17%) for the 32.0°C for 120 hours group. The adjusted risk ratio (RR) for NICU deaths for the 120 hours group vs 72 hours group was 1.37 (95% CI, 0.92-2.04) and for the 32.0°C group vs 33.5°C group was 1.24 (95% CI, 0.69-2.25). Safety outcomes were similar between the 120 hours group vs 72 hours group and the 32.0°C group vs 33.5°C group, except major bleeding occurred among 1% in the 120 hours group vs 3% in the 72 hours group (RR, 0.25 [95% CI, 0.07-0.91]). Futility analysis determined that the probability of detecting a statistically significant benefit for longer cooling, deeper cooling, or both for NICU death was less than 2%.
Among neonates who were full-term with moderate or severe hypoxic ischemic encephalopathy, longer cooling, deeper cooling, or both compared with hypothermia at 33.5°C for 72 hours did not reduce NICU death. These results have implications for patient care and design of future trials.
clinicaltrials.gov Identifier: NCT01192776.
Details
- Title: Subtitle
- Effect of depth and duration of cooling on deaths in the NICU among neonates with hypoxic ischemic encephalopathy: a randomized clinical trial
- Creators
- Seetha Shankaran - Department of Pediatrics, Wayne State University, Detroit, MichiganAbbot R Laptook - Department of Pediatrics, Women and Infants Hospital, Brown University, Providence, Rhode IslandAthina Pappas - Department of Pediatrics, Wayne State University, Detroit, MichiganScott A McDonald - Social, Statistical, and Environmental Sciences Unit, RTI International, Research Triangle Park, North CarolinaAbhik Das - Social, Statistical, and Environmental Sciences Unit, RTI International, Rockville, MarylandJon E Tyson - Department of Pediatrics, University of Texas Medical School at HoustonBrenda B Poindexter - Department of Pediatrics, Indiana University School of Medicine, IndianapolisKurt Schibler - Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OhioEdward F Bell - Department of Pediatrics, University of Iowa, Iowa CityRoy J Heyne - Department of Pediatrics, University of Texas Southwestern Medical Center, DallasClaudia Pedroza - Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OhioRebecca Bara - Department of Pediatrics, Wayne State University, Detroit, MichiganKrisa P Van Meurs - Division of Neonatal and Developmental Medicine, Department of Pediatrics, Lucile Packard Children's Hospital, Stanford University School of Medicine, Palo Alto, CaliforniaCathy Grisby - Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OhioCarolyn M Petrie Huitema - Social, Statistical, and Environmental Sciences Unit, RTI International, Rockville, MarylandMeena Garg - Department of Pediatrics, University of California, Los AngelesRichard A Ehrenkranz - Department of Pediatrics, Yale University School of Medicine, New Haven, ConnecticutEdward G Shepherd - Department of Pediatrics, Nationwide Children's Hospital, Ohio State University, ColumbusLina F Chalak - Department of Pediatrics, University of Texas Southwestern Medical Center, DallasShannon E G Hamrick - Department of Pediatrics, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, GeorgiaAmir M Khan - Department of Pediatrics, University of Texas Medical School at HoustonAnne Marie Reynolds - Department of Pediatrics, University at Buffalo, Buffalo, New YorkMatthew M Laughon - Division of Neonatal/Perinatal Medicine, Department of Pediatrics, University of North Carolina, Chapel HillWilliam E Truog - Department of Pediatrics, Children's Mercy Hospital, Kansas City School of Medicine, University of MissouriKevin C Dysart - Department of Pediatrics, Perelman School of Medicine, Children's Hospital of Philadelphia, University of PennsylvaniaWaldemar A Carlo - Division of Neonatology, University of Alabama at BirminghamMichele C Walsh - Department of Pediatrics, Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland, OhioKristi L Watterberg - University of New Mexico Health Sciences Center, Albuquerque, New MexicoRosemary D Higgins - Pregnancy and Perinatology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
- Resource Type
- Journal article
- Publication Details
- JAMA : the journal of the American Medical Association, Vol.312(24), pp.2629-2639
- DOI
- 10.1001/jama.2014.16058
- PMID
- 25536254
- PMCID
- PMC4335311
- NLM abbreviation
- JAMA
- ISSN
- 0098-7484
- eISSN
- 1538-3598
- Publisher
- United States
- Grant note
- UL1 TR000142 / NCATS NIH HHS M01 RR80 / NCRR NIH HHS UG1 HD040492 / NICHD NIH HHS UG1 HD053089 / NICHD NIH HHS U10 HD27856 / NICHD NIH HHS U10 HD68284 / NICHD NIH HHS U10 HD34216 / NICHD NIH HHS U10 HD53089 / NICHD NIH HHS U10 HD27851 / NICHD NIH HHS UL1 TR454 / NCATS NIH HHS UL1 TR6 / NCATS NIH HHS U10 HD68244 / NICHD NIH HHS UL1 TR93 / NCATS NIH HHS U10 HD27880 / NICHD NIH HHS U10 HD53109 / NICHD NIH HHS U10 HD68270 / NICHD NIH HHS U10 HD27904 / NICHD NIH HHS UL1 TR77 / NCATS NIH HHS U10 HD040492 / NICHD NIH HHS M01 RR32 / NCRR NIH HHS U10 HD068244 / NICHD NIH HHS UL1 TR001108 / NCATS NIH HHS U10 HD68278 / NICHD NIH HHS U10 HD27853 / NICHD NIH HHS U10 HD068270 / NICHD NIH HHS UL1 TR42 / NCATS NIH HHS U10 HD21364 / NICHD NIH HHS M01 RR70 / NCRR NIH HHS U10 HD36790 / NICHD NIH HHS U10 HD027904 / NICHD NIH HHS UL1 TR000371 / NCATS NIH HHS U10 HD027856 / NICHD NIH HHS U10 HD027880 / NICHD NIH HHS UL1 RR24128 / NCRR NIH HHS UL1 TR442 / NCATS NIH HHS U10 HD068284 / NICHD NIH HHS U10 HD40689 / NICHD NIH HHS U10 HD021364 / NICHD NIH HHS U10 HD21385 / NICHD NIH HHS UG1 HD068270 / NICHD NIH HHS UG1 HD087229 / NICHD NIH HHS M01 RR633 / NCRR NIH HHS U10 HD68263 / NICHD NIH HHS UL1 TR41 / NCATS NIH HHS U10 HD40492 / NICHD NIH HHS U10 HD21373 / NICHD NIH HHS U10 HD021385 / NICHD NIH HHS U10 HD068263 / NICHD NIH HHS
- Language
- English
- Date published
- 12/24/2014
- Academic Unit
- Stead Family Department of Pediatrics; Neonatology
- Record Identifier
- 9984024519102771
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