Study Results
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Basic Information
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COMPLETED
PHASE3
208 participants
INTERVENTIONAL
1999-10-31
2010-07-31
Brief Summary
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Detailed Description
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This large multicenter trial tested whether cerebral cooling initiated within 6 hours of birth and continued for 72 hours would reduce the risk of death and moderate to severe neurodevelopmental injury at 18-22 months corrected age. Infants at least 36 weeks gestation with an abnormal blood gas within 1 hour of birth, or a history of an acute perinatal event and a 10-min Apgar score \<5, or continued need for ventilation were screened. Following a neurological exam, those with moderate to severe encephalopathy were randomized to a 72-hour period of total body cooling (cooling blanket, followed by slow re-warming). The study was conducted in two phases: Phase I (20 infants) were examined for the safety of an esophageal temperature of 34-35 C; Phase II (main trial, 200 infants) were evaluated for the safety and efficacy of an esophageal temperature of 33-34 C. Cardio-respiratory, electroencephalograms (EEGs), renal, metabolic, and hematologic status, and esophageal and abdominal skin temperature were monitored during the 72 hours of intervention.
Neurodevelopmental outcome was assessed at 18-22 mos of age by masked certified examiners. The outcome at 18-22 months showed that whole-body cooling reduces the risk of death or moderate to severe disability in infants with hypoxic ischemic encephalopathy.
Surviving infants were assessed at 6-7 years (school age).
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Hypothermia
Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours
Induced hypothermia
Whole-body cooling using the Blanketrol II or III Units in the Automatic Control Mode with a YSI 400 series temperature probe placed in the distal esophagus over a 96-hour period
Normothermic
Placebo: Normothermic control group (with esophageal temperature at or near 37.0°C) for 96 hours
Control
Control group: standard care
Interventions
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Induced hypothermia
Whole-body cooling using the Blanketrol II or III Units in the Automatic Control Mode with a YSI 400 series temperature probe placed in the distal esophagus over a 96-hour period
Control
Control group: standard care
Eligibility Criteria
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Inclusion Criteria
* Any blood gas (cord, postnatal) done within the first 60 minutes had a pH less than or equal to 7.0
* Any blood gas (cord postnatal) done within the first 60 minutes had a base deficit greater than or equal to 16 mEq/L
* All infants must have seizures or signs of moderate to severe encephalopathy before randomization
Exclusion Criteria
* Presence of known chromosomal anomaly or major congenital anomaly
* Severe intrauterine growth restriction (weight less than 1800g)
* All blood gases done within the first 60 minutes had a pH less than 7.15 and a base deficit less than 10 mEq/L
* Infants in extremis for whom no additional intensive therapy will be offered by attending neonatologist
* Parents refuse consent
* Attending neonatologist refuses consent
6 Hours
ALL
No
Sponsors
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National Center for Research Resources (NCRR)
NIH
NICHD Neonatal Research Network
NETWORK
Responsible Party
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Principal Investigators
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Seetha Shankaran, MD
Role: PRINCIPAL_INVESTIGATOR
Wayne State University
Abbot R. Laptook, MD
Role: PRINCIPAL_INVESTIGATOR
Brown University, Womens and Infants Hospital of Rhode Island
Michele C. Walsh, MD MS
Role: PRINCIPAL_INVESTIGATOR
Case Western Reserve University
Ronald N. Goldberg, MD
Role: PRINCIPAL_INVESTIGATOR
Duke University
Barbara J. Stoll, MD
Role: PRINCIPAL_INVESTIGATOR
Emory University
Brenda B. Poindexter, MD MS
Role: PRINCIPAL_INVESTIGATOR
Indiana University
Abhik Das, PhD
Role: PRINCIPAL_INVESTIGATOR
RTI International
Krisa P. Van Meurs, MD
Role: STUDY_DIRECTOR
Stanford University
Waldemar A. Carlo, MD
Role: PRINCIPAL_INVESTIGATOR
University of Alabama at Birmingham
Neil N. Finer, MD
Role: PRINCIPAL_INVESTIGATOR
University of California, San Diego
Kurt Schibler, MD
Role: PRINCIPAL_INVESTIGATOR
Children's Hospital Medical Center, Cincinnati
Shahnaz Duara, MD
Role: PRINCIPAL_INVESTIGATOR
University of Miami
Dale L. Phelps, MD
Role: PRINCIPAL_INVESTIGATOR
University of Rochester
Pablo J. Sanchez, MD
Role: PRINCIPAL_INVESTIGATOR
University of Texas, Southwestern Medical Center at Dallas
Kathleen A. Kennedy, MD MPH
Role: PRINCIPAL_INVESTIGATOR
The University of Texas Health Science Center, Houston
T. Michael O'Shea, MD
Role: PRINCIPAL_INVESTIGATOR
Wake Forest University
Richard A. Ehrenkranz, MD
Role: PRINCIPAL_INVESTIGATOR
Yale University
Locations
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University of Alabama at Birmingham
Birmingham, Alabama, United States
Stanford University
Palo Alto, California, United States
Yale University
New Haven, Connecticut, United States
University of Miami
Miami, Florida, United States
Emory University
Atlanta, Georgia, United States
Indiana University
Indianapolis, Indiana, United States
Harvard University
Cambridge, Massachusetts, United States
Wayne State University
Detroit, Michigan, United States
University of New Mexico
Albuquerque, New Mexico, United States
RTI International
Durham, North Carolina, United States
Cincinnati Children's Medical Center
Cincinnati, Ohio, United States
Case Western Reserve University, Rainbow Babies and Children's Hospital
Cleveland, Ohio, United States
Brown University, Women & Infants Hospital of Rhode Island
Providence, Rhode Island, United States
University of Tennessee
Memphis, Tennessee, United States
University of Texas Southwestern Medical Center at Dallas
Dallas, Texas, United States
University of Texas Health Science Center at Houston
Houston, Texas, United States
Countries
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References
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Shankaran S, Laptook A. Challenge of conducting trials of neuroprotection in the asphyxiated term infant. Semin Perinatol. 2003 Aug;27(4):320-32. doi: 10.1016/s0146-0005(03)00047-8.
Shankaran S. Neonatal encephalopathy: treatment with hypothermia. J Neurotrauma. 2009 Mar;26(3):437-43. doi: 10.1089/neu.2008.0678.
Higgins RD, Shankaran S. Hypothermia for hypoxic ischemic encephalopathy in infants > or =36 weeks. Early Hum Dev. 2009 Oct;85(10 Suppl):S49-52. doi: 10.1016/j.earlhumdev.2009.08.015. Epub 2009 Sep 17.
Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, Fanaroff AA, Poole WK, Wright LL, Higgins RD, Finer NN, Carlo WA, Duara S, Oh W, Cotten CM, Stevenson DK, Stoll BJ, Lemons JA, Guillet R, Jobe AH; National Institute of Child Health and Human Development Neonatal Research Network. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. 2005 Oct 13;353(15):1574-84. doi: 10.1056/NEJMcps050929.
Shankaran S, Laptook A, Wright LL, Ehrenkranz RA, Donovan EF, Fanaroff AA, Stark AR, Tyson JE, Poole K, Carlo WA, Lemons JA, Oh W, Stoll BJ, Papile LA, Bauer CR, Stevenson DK, Korones SB, McDonald S. Whole-body hypothermia for neonatal encephalopathy: animal observations as a basis for a randomized, controlled pilot study in term infants. Pediatrics. 2002 Aug;110(2 Pt 1):377-85. doi: 10.1542/peds.110.2.377.
Ambalavanan N, Carlo WA, Shankaran S, Bann CM, Emrich SL, Higgins RD, Tyson JE, O'Shea TM, Laptook AR, Ehrenkranz RA, Donovan EF, Walsh MC, Goldberg RN, Das A; National Institute of Child Health and Human Development Neonatal Research Network. Predicting outcomes of neonates diagnosed with hypoxemic-ischemic encephalopathy. Pediatrics. 2006 Nov;118(5):2084-93. doi: 10.1542/peds.2006-1591.
Oh W, Perritt R, Shankaran S, Merritts M, Donovan EF, Ehrenkranz RA, O'Shea TM, Tyson JE, Laptook AR, Das A, Higgins RD. Association between urinary lactate to creatinine ratio and neurodevelopmental outcome in term infants with hypoxic-ischemic encephalopathy. J Pediatr. 2008 Sep;153(3):375-8. doi: 10.1016/j.jpeds.2008.03.041. Epub 2008 May 9.
Mietzsch U, Parikh NA, Williams AL, Shankaran S, Lasky RE. Effects of hypoxic-ischemic encephalopathy and whole-body hypothermia on neonatal auditory function: a pilot study. Am J Perinatol. 2008 Aug;25(7):435-41. doi: 10.1055/s-0028-1083842. Epub 2008 Aug 21.
Laptook A, Tyson J, Shankaran S, McDonald S, Ehrenkranz R, Fanaroff A, Donovan E, Goldberg R, O'Shea TM, Higgins RD, Poole WK; National Institute of Child Health and Human Development Neonatal Research Network. Elevated temperature after hypoxic-ischemic encephalopathy: risk factor for adverse outcomes. Pediatrics. 2008 Sep;122(3):491-9. doi: 10.1542/peds.2007-1673.
Shankaran S, Pappas A, Laptook AR, McDonald SA, Ehrenkranz RA, Tyson JE, Walsh M, Goldberg RN, Higgins RD, Das A; NICHD Neonatal Research Network. Outcomes of safety and effectiveness in a multicenter randomized, controlled trial of whole-body hypothermia for neonatal hypoxic-ischemic encephalopathy. Pediatrics. 2008 Oct;122(4):e791-8. doi: 10.1542/peds.2008-0456.
Parikh NA, Lasky RE, Garza CN, Bonfante-Mejia E, Shankaran S, Tyson JE. Volumetric and anatomical MRI for hypoxic-ischemic encephalopathy: relationship to hypothermia therapy and neurosensory impairments. J Perinatol. 2009 Feb;29(2):143-9. doi: 10.1038/jp.2008.184. Epub 2008 Nov 20.
Lasky RE, Parikh NA, Williams AL, Padhye NS, Shankaran S. Changes in the PQRST intervals and heart rate variability associated with rewarming in two newborns undergoing hypothermia therapy. Neonatology. 2009;96(2):93-5. doi: 10.1159/000205385. Epub 2009 Mar 2.
Laptook AR, Shankaran S, Ambalavanan N, Carlo WA, McDonald SA, Higgins RD, Das A; Hypothermia Subcommittee of the NICHD Neonatal Research Network. Outcome of term infants using apgar scores at 10 minutes following hypoxic-ischemic encephalopathy. Pediatrics. 2009 Dec;124(6):1619-26. doi: 10.1542/peds.2009-0934.
Kwon JM, Guillet R, Shankaran S, Laptook AR, McDonald SA, Ehrenkranz RA, Tyson JE, O'Shea TM, Goldberg RN, Donovan EF, Fanaroff AA, Poole WK, Higgins RD, Walsh MC; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Clinical seizures in neonatal hypoxic-ischemic encephalopathy have no independent impact on neurodevelopmental outcome: secondary analyses of data from the neonatal research network hypothermia trial. J Child Neurol. 2011 Mar;26(3):322-8. doi: 10.1177/0883073810380915. Epub 2010 Oct 4.
MacKay VL, Welch SK, Insley MY, Manney TR, Holly J, Saari GC, Parker ML. The Saccharomyces cerevisiae BAR1 gene encodes an exported protein with homology to pepsin. Proc Natl Acad Sci U S A. 1988 Jan;85(1):55-9. doi: 10.1073/pnas.85.1.55.
Bonifacio SL, Chalak LF, Van Meurs KP, Laptook AR, Shankaran S. Neuroprotection for hypoxic-ischemic encephalopathy: Contributions from the neonatal research network. Semin Perinatol. 2022 Nov;46(7):151639. doi: 10.1016/j.semperi.2022.151639. Epub 2022 Jun 10.
Pappas A, Shankaran S, McDonald SA, Carlo WA, Laptook AR, Tyson JE, Das A, Skogstrand K, Hougaard DM, Higgins RD. Blood Biomarkers and 6- to 7-Year Childhood Outcomes Following Neonatal Encephalopathy. Am J Perinatol. 2022 May;39(7):732-749. doi: 10.1055/s-0040-1717072. Epub 2020 Oct 10.
Shankaran S, Laptook AR, McDonald SA, Hintz SR, Barnes PD, Das A, Higgins RD; Eunice Kennedy Shriver National Institute of Child Health, and Human Development Neonatal Research Network. Acute Perinatal Sentinel Events, Neonatal Brain Injury Pattern, and Outcome of Infants Undergoing a Trial of Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy. J Pediatr. 2017 Jan;180:275-278.e2. doi: 10.1016/j.jpeds.2016.09.026. Epub 2016 Oct 21.
Shankaran S, McDonald SA, Laptook AR, Hintz SR, Barnes PD, Das A, Pappas A, Higgins RD; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Neonatal Magnetic Resonance Imaging Pattern of Brain Injury as a Biomarker of Childhood Outcomes following a Trial of Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy. J Pediatr. 2015 Nov;167(5):987-93.e3. doi: 10.1016/j.jpeds.2015.08.013. Epub 2015 Sep 16.
Vohr BR, Stephens BE, McDonald SA, Ehrenkranz RA, Laptook AR, Pappas A, Hintz SR, Shankaran S, Higgins RD, Das A; Extended Hypothermia Follow-up Subcommittee of the NICHD Neonatal Research Network. Cerebral palsy and growth failure at 6 to 7 years. Pediatrics. 2013 Oct;132(4):e905-14. doi: 10.1542/peds.2012-3915. Epub 2013 Sep 9.
Shankaran S, Pappas A, McDonald SA, Vohr BR, Hintz SR, Yolton K, Gustafson KE, Leach TM, Green C, Bara R, Petrie Huitema CM, Ehrenkranz RA, Tyson JE, Das A, Hammond J, Peralta-Carcelen M, Evans PW, Heyne RJ, Wilson-Costello DE, Vaucher YE, Bauer CR, Dusick AM, Adams-Chapman I, Goldstein RF, Guillet R, Papile LA, Higgins RD; Eunice Kennedy Shriver NICHD Neonatal Research Network. Childhood outcomes after hypothermia for neonatal encephalopathy. N Engl J Med. 2012 May 31;366(22):2085-92. doi: 10.1056/NEJMoa1112066.
Related Links
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NICHD Neonatal Research Network
Other Identifiers
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NICHD-NRN-0021
Identifier Type: -
Identifier Source: org_study_id
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