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JAMA. 2014 Dec 24-31;312(24):2629-39. doi: 10.1001/jama.2014.16058.

Effect of depth and duration of cooling on deaths in the NICU among neonates with hypoxic ischemic encephalopathy: a randomized clinical trial.

Collaborators (156)

Caplan MS, Polin RA, Keszler M, Vohr BR, Hensman AM, Vierira E, Little E, Sommers R, Shah B, Guerina N, McKinley LT, Caskey M, Halbrook A, Burke RT, Hibbs AM, Newman NS, Zadell A, Pallotto EK, Kilbride HW, Gauldin C, Holmes A, Johnson K, Kallapur SG, Alexander B, Fischer EE, Gratton TL, Jackson L, Jennings J, Kirker K, Muthig G, Wuertz S, Goldberg RN, Finkle J, Fisher KA, Grimes S, Laughon MM, Bose CL, Bernhardt J, Clark C, Stoll BJ, Carlton DP, Hale EC, Loggins Y, Archer SW, Sokol GM, Wilson LD, Herron DE, Gunn S, Smiley L, Jadcherla SR, Sánchez PJ, Luzader P, Fortney CA, Besner GE, Parikh NA, Wallace D, Zaterka-Baxter KM, Crawford M, Gabrio J, Gantz MG, Newman JE, Auman JO, Huitema CM, Nolen TL, Stevenson DK, Ball M, Adams MM, Davis AS, Kibler C, Parker JR, Proud MS, Wong RJ, Ambalavanan N, Collins MV, Cosby SS, Devaskar U, Garg M, Chanlaw T, Geller R, Ellsbury DL, Colaizy TT, Brumbaugh JE, Johnson KJ, Campbell DB, Walker JR, Klein JM, Segar JL, Dagle JM, Lindower JB, McElroy SJ, Rabe GK, Roghair RD, Meyer LR, Murphy CR, Bhavsar V, Watterberg KL, Ohls RK, Lacy CB, Beauman S, Hartenberger C, Schmidt B, Kirpalani H, DeMauro SB, Chaudhary AS, Abbasi S, Mancini T, Cucinotta DM, Laroia N, D'Angio CT, Guillet R, Lakshminrusimha S, Wynn K, Wadkins HI, Scorsone AM, Conway P, Sacilowski MG, Guilford S, Williams A, Wyckoff M, Sánchez PJ, Brion LP, Vasil DM, Chen L, Ramon E, Kennedy KA, McDavid E, Arldt-McAlister J, Burson K, Garcia C, Martin K, Rodgers S, Tate PL, Wright SL, Sood BG, Barks J, Bara R, Batts M, De Jesus L, Hayes-Hart K, Johnson ME, Natarajan G, Sulkowski L, Sumner L, Walker N, Weingarden K, Christensen M, Wiggins SA, Gleason CA, Boyle RJ, Clemons T, D'Alton ME, Das A, Redmond CK, Ross MG, Weiner SJ, Willinger M.

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, University of Texas Medical School at Houston.
6
Department of Pediatrics, Indiana University School of Medicine, Indianapolis.
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, Lucile Packard Children's Hospital, Stanford University School of Medicine, 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, Nationwide Children's Hospital, Ohio State University, Columbus.
14
Department of Pediatrics, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia.
15
Department of Pediatrics, University at Buffalo, Buffalo, New York.
16
Division of Neonatal/Perinatal Medicine, Department of Pediatrics, University of North Carolina, Chapel Hill.
17
Department of Pediatrics, Children's Mercy Hospital, Kansas City School of Medicine, University of Missouri.
18
Department of Pediatrics, Perelman School of Medicine, Children's Hospital of Philadelphia, University of Pennsylvania.
19
Division of Neonatology, University of Alabama at Birmingham.
20
Department of Pediatrics, Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland, Ohio.
21
University of New Mexico Health Sciences Center, Albuquerque, New Mexico.
22
Pregnancy and Perinatology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.

Abstract

IMPORTANCE:

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.

DESIGN, SETTING, AND PARTICIPANTS:

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.

INTERVENTIONS:

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.

MAIN OUTCOMES AND MEASURES:

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 AND RELEVANCE:

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.

TRIAL REGISTRATION:

clinicaltrials.gov Identifier: NCT01192776.

PMID:
25536254
PMCID:
PMC4335311
DOI:
10.1001/jama.2014.16058
[Indexed for MEDLINE]
Free PMC Article

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