Whole-Body Cooling for Birth Asphyxia in Term Infants

NCT00005772 | Completed Phase 3 DMC

• 28 other identifiers: NICHD-NRN-0021U10HD021364U10HD021373U10HD021385U10HD021397U10HD027851U10HD027853U10HD027856U10HD027871U10HD027880U10HD027904U10HD034216U10HD040461U10HD040492U10HD040498U10HD040521U10HD040689M01RR000030M01RR000039M01RR000044M01RR000070M01RR000080M01RR000633M01RR000750M01RR006022M01RR007122M01RR008084M01RR016587
• Study Type: interventional
• Target: 208
• Locations: 1 country
• Sites: 16

Brief Summary

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. Surviving children were given neurodevelopmental examinations at 18-22 months corrected age and again at school age (6-7 years of age).

Conditions

Infant, Newborn; Hypoxia-Ischemia, Brain

Keywords

NICHD Neonatal Research Network; Hypoxic-ischemic encephalopathy (HIE); Hypothermia; Neonatal depression; Perinatal asphyxia

Outcome Measures

Primary Outcomes (1)

• Death or moderate or severe disability

  18-22 months corrected age

Secondary Outcomes (7)

• Length of hospital stay

  Until discharge

• Frequency of multi-organ dysfunction

  Until discharge

• Withdrawal of support

  Until discharge

• Post-neonatal deaths

  18-22 months corrected age

• Multiple disability

  18-22 months corrected age

Study Arms (2)

Hypothermia

EXPERIMENTAL

Induced Whole-body hypothermia (with a target esophageal temperature of 33.5°C) for 96 hours

Device: Induced hypothermia

Normothermic

PLACEBO COMPARATOR

Placebo: Normothermic control group (with esophageal temperature at or near 37.0°C) for 96 hours

Device: Control

Interventions

Induced hypothermia DEVICE

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

Hypothermia

Control DEVICE

Control group: standard care

Normothermic

Eligibility Criteria

• Age: Up to 6 Hours
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• At least 36 weeks gestation
• 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

You may not qualify if:

• Inability to randomize by 6 hours of age
• 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

Sponsors & Collaborators

• NICHD Neonatal Research Network: lead
• National Center for Research Resources (NCRR): collaborator

Study Sites (16)

University of Alabama at Birmingham

Birmingham, Alabama, 35233, United States

Location

Stanford University

Palo Alto, California, 94304, United States

Location

Yale University

New Haven, Connecticut, 06504, United States

Location

University of Miami

Miami, Florida, 33136, United States

Location

Emory University

Atlanta, Georgia, 30303, United States

Location

Indiana University

Indianapolis, Indiana, 46202, United States

Location

Harvard University

Cambridge, Massachusetts, 02138, United States

Location

Wayne State University

Detroit, Michigan, 48201, United States

Location

University of New Mexico

Albuquerque, New Mexico, 87131, United States

Location

RTI International

Durham, North Carolina, 27705, United States

Location

Cincinnati Children's Medical Center

Cincinnati, Ohio, 45267, United States

Location

Case Western Reserve University, Rainbow Babies and Children's Hospital

Cleveland, Ohio, 44106, United States

Location

Brown University, Women & Infants Hospital of Rhode Island

Providence, Rhode Island, 02905, United States

Location

University of Tennessee

Memphis, Tennessee, 38163, United States

Location

University of Texas Southwestern Medical Center at Dallas

Dallas, Texas, 75235, United States

Location

University of Texas Health Science Center at Houston

Houston, Texas, 77030, United States

Location

Related Publications (21)

• 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.

  PMID: 14510323 BACKGROUND

• Shankaran S. Neonatal encephalopathy: treatment with hypothermia. J Neurotrauma. 2009 Mar;26(3):437-43. doi: 10.1089/neu.2008.0678.

  PMID: 19281415 BACKGROUND

• 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.

  PMID: 19762176 BACKGROUND

• 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.

  PMID: 16221780 RESULT

• 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.

  PMID: 12165594 RESULT

• 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.

  PMID: 17079582 RESULT

• 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.

  PMID: 18534246 RESULT

• 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.

  PMID: 18720323 RESULT

• 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.

  PMID: 18762517 RESULT

• 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.

  PMID: 18829776 RESULT

• 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.

  PMID: 19020525 RESULT

• 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.

  PMID: 19252411 RESULT

• 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.

  PMID: 19948631 RESULT

• 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.

  PMID: 20921569 RESULT

• 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.

  PMID: 3124102 RESULT

• 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.

  PMID: 35835616 DERIVED

• 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.

  PMID: 33038899 DERIVED

• 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.

  PMID: 27776752 DERIVED

• 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.

  PMID: 26387012 DERIVED

• 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.

  PMID: 24019415 DERIVED

• 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.

  PMID: 22646631 DERIVED

Related Links

• NICHD Neonatal Research Network

MeSH Terms

Conditions

Hypoxia-Ischemia, Brain; Hypothermia

Interventions

Hypothermia, Induced

Condition Hierarchy (Ancestors)

Brain Ischemia; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Hypoxia, Brain; Vascular Diseases; Cardiovascular Diseases; Hypoxia; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Body Temperature Changes

Intervention Hierarchy (Ancestors)

Cryotherapy; Therapeutics

Study Officials

• Seetha Shankaran, MD

  Wayne State University

  PRINCIPAL INVESTIGATOR

• Abbot R. Laptook, MD

  Brown University, Womens and Infants Hospital of Rhode Island

  PRINCIPAL INVESTIGATOR

• Michele C. Walsh, MD MS

  Case Western Reserve University

  PRINCIPAL INVESTIGATOR

• Ronald N. Goldberg, MD

  Duke University

  PRINCIPAL INVESTIGATOR

• Barbara J. Stoll, MD

  Emory University

  PRINCIPAL INVESTIGATOR

• Brenda B. Poindexter, MD MS

  Indiana University

  PRINCIPAL INVESTIGATOR

• Abhik Das, PhD

  RTI International

  PRINCIPAL INVESTIGATOR

• Krisa P. Van Meurs, MD

  Stanford University

  STUDY DIRECTOR

• Waldemar A. Carlo, MD

  University of Alabama at Birmingham

  PRINCIPAL INVESTIGATOR

• Neil N. Finer, MD

  University of California, San Diego

  PRINCIPAL INVESTIGATOR

• Kurt Schibler, MD

  Children's Hospital Medical Center, Cincinnati

  PRINCIPAL INVESTIGATOR

• Shahnaz Duara, MD

  University of Miami

  PRINCIPAL INVESTIGATOR

• Dale L. Phelps, MD

  University of Rochester

  PRINCIPAL INVESTIGATOR

• Pablo J. Sanchez, MD

  University of Texas, Southwestern Medical Center at Dallas

  PRINCIPAL INVESTIGATOR

• Kathleen A. Kennedy, MD MPH

  The University of Texas Health Science Center, Houston

  PRINCIPAL INVESTIGATOR

• T. Michael O'Shea, MD

  Wake Forest University

  PRINCIPAL INVESTIGATOR

• Richard A. Ehrenkranz, MD

  Yale University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 1, 2000
• First Posted: June 2, 2000
• Study Start: October 1, 1999
• Primary Completion: May 1, 2003
• Study Completion: July 1, 2010
• Last Updated: March 22, 2019

Record last verified: 2019-03

Locations

US (16)