title: Effect of depth and duration of cooling on deaths in the NICU among neonates with hypoxic ischemic encephalopathy: a randomized clinical trial.
abstract: OBJECTIVE
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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).
  
  
  RESULTS
  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%.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT01192776.
authors.affiliation: Department of Pediatrics, Wayne State University, Detroit, Michigan.
authors.forename: Seetha
authors.initials: S
authors.lastname: Shankaran
authors.affiliation: Department of Pediatrics, Women and Infants Hospital, Brown University, Providence, Rhode Island.
authors.forename: Abbot R
authors.initials: AR
authors.lastname: Laptook
authors.affiliation: Department of Pediatrics, Wayne State University, Detroit, Michigan.
authors.forename: Athina
authors.initials: A
authors.lastname: Pappas
authors.affiliation: Social, Statistical, and Environmental Sciences Unit, RTI International, Research Triangle Park, North Carolina.
authors.forename: Scott A
authors.initials: SA
authors.lastname: McDonald
authors.affiliation: Social, Statistical, and Environmental Sciences Unit, RTI International, Rockville, Maryland.
authors.forename: Abhik
authors.initials: A
authors.lastname: Das
authors.affiliation: Department of Pediatrics, University of Texas Medical School at Houston.
authors.forename: Jon E
authors.initials: JE
authors.lastname: Tyson
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis.
authors.forename: Brenda B
authors.initials: BB
authors.lastname: Poindexter
authors.affiliation: Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Kurt
authors.initials: K
authors.lastname: Schibler
authors.affiliation: Department of Pediatrics, University of Iowa, Iowa City.
authors.forename: Edward F
authors.initials: EF
authors.lastname: Bell
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas.
authors.forename: Roy J
authors.initials: RJ
authors.lastname: Heyne
authors.affiliation: Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Claudia
authors.initials: C
authors.lastname: Pedroza
authors.affiliation: Department of Pediatrics, Wayne State University, Detroit, Michigan.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Bara
authors.affiliation: Division of Neonatal and Developmental Medicine, Department of Pediatrics, Lucile Packard Children's Hospital, Stanford University School of Medicine, Palo Alto, California.
authors.forename: Krisa P
authors.initials: KP
authors.lastname: Van Meurs
authors.affiliation: Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Cathy
authors.initials: C
authors.lastname: Grisby
authors.affiliation: Social, Statistical, and Environmental Sciences Unit, RTI International, Rockville, Maryland.
authors.forename: Carolyn M Petrie
authors.initials: CM
authors.lastname: Huitema
authors.affiliation: Department of Pediatrics, University of California, Los Angeles.
authors.forename: Meena
authors.initials: M
authors.lastname: Garg
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Ehrenkranz
authors.affiliation: Department of Pediatrics, Nationwide Children's Hospital, Ohio State University, Columbus.
authors.forename: Edward G
authors.initials: EG
authors.lastname: Shepherd
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas.
authors.forename: Lina F
authors.initials: LF
authors.lastname: Chalak
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia.
authors.forename: Shannon E G
authors.initials: SE
authors.lastname: Hamrick
authors.affiliation: Department of Pediatrics, University of Texas Medical School at Houston.
authors.forename: Amir M
authors.initials: AM
authors.lastname: Khan
authors.affiliation: Department of Pediatrics, University at Buffalo, Buffalo, New York.
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Reynolds
authors.affiliation: Division of Neonatal/Perinatal Medicine, Department of Pediatrics, University of North Carolina, Chapel Hill.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Laughon
authors.affiliation: Department of Pediatrics, Children's Mercy Hospital, Kansas City School of Medicine, University of Missouri.
authors.forename: William E
authors.initials: WE
authors.lastname: Truog
authors.affiliation: Department of Pediatrics, Perelman School of Medicine, Children's Hospital of Philadelphia, University of Pennsylvania.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Dysart
authors.affiliation: Division of Neonatology, University of Alabama at Birmingham.
authors.forename: Waldemar A
authors.initials: WA
authors.lastname: Carlo
authors.affiliation: Department of Pediatrics, Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Michele C
authors.initials: MC
authors.lastname: Walsh
authors.affiliation: University of New Mexico Health Sciences Center, Albuquerque, New Mexico.
authors.forename: Kristi L
authors.initials: KL
authors.lastname: Watterberg
authors.affiliation: Pregnancy and Perinatology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.
authors.forename: Rosemary D
authors.initials: RD
authors.lastname: Higgins
mesh_terms: D000138:Acidosis / Q000209:etiology; D001145:Arrhythmias, Cardiac / Q000209:etiology; D002658:Developmental Disabilities; D005260:Female; D006470:Hemorrhage / Q000209:etiology; D006801:Humans; D007036:Hypothermia, Induced / Q000009:adverse effects; D020925:Hypoxia-Ischemia, Brain / Q000628:therapy*; D007223:Infant; D007231:Infant, Newborn; D007363:Intensive Care Units, Neonatal; D008297:Male; D016019:Survival Analysis; D013696:Temperature; D013927:Thrombosis / Q000209:etiology; D013997:Time Factors