Moderate Hypothermia in Neonatal Hypoxic Ischemic Encephalopathy

This study was a multicenter, randomized, controlled pilot trial of moderate systemic hypothermia (33°C) vs normothermia (37°C) for 48 hours in infants with neonatal encephalopathy instituted within 6 hours of birth or hypoxic-ischemic event.

Study Overview

• Status: Completed
• Conditions: Hypoxic Ischemic Encephalopathy; Neonatal Asphyxial Encephalopathy
• Intervention / Treatment: Other: hypothermia; Other: normothermia

Detailed Description

The trial tested the ability to initiate systemic hypothermia in outlying hospitals and participating tertiary care centers, and determined the incidence of adverse neurologic outcomes of death and developmental scores at 12 months by Bayley II or Vineland tests between normothermic and hypothermic groups. This trial identified potential safety outcomes, compared the adverse effects of hypothermia among hypoxic-ischemic encephalopathy (HIE) infants in the normothermic and hypothermic treatment groups, and obtained rates of adverse outcomes.

• Study Type: Interventional
• Enrollment (Actual): 65
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 months and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

One clinical indication of hypoxic-ischemic injury

• cord gas pH ≤ 7.0 or base deficit ≥13,
• initial infant gas pH < 7.1,
• Apgar score ≤5 at 10 minutes,
• continued resuscitation after 5 min,
• fetal bradycardia with heart rate < 80 beats per minute lasting ≥15 min,
• postnatal event O2 sat <70% or arterial O2<35 for 20 min with ischemia

And two neurologic findings of neonatal encephalopathy, abnormalities of:

• tone,
• reflexes,
• state of consciousness,
• seizures,
• posturing,
• autonomic dysfunction

Exclusion Criteria:

• Maternal chorioamnionitis,
• sepsis at birth,
• birth weight or head circumference <10%,
• presumed chromosomal abnormality

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Hypothermia; If randomized to hypothermia, plastic bags filled with ice wrapped in a washcloth were applied to the head and body for approximately 2 hours, then the infant was placed on an adult-size, water-circulating, cooling blanket (Cincinnati Sub-Zero Blanketrol II®, Cincinnati, OH), servo-controlled to rectal temperature to 33 ± 0.5 °C for 48 hours at the participating tertiary care center. Rewarming by 0.5°C per hour was begun after 48 hours of hypothermia.	Other: hypothermia; Systemic hypothermia by Cincinnati Sub-Zero Blanketrol II®, servo-controlled to 33.0 degrees C rectal temperature, started within 6hours of hypoxic ischemic birth, and continued for 48hours; Other Names: whole body cooling
PLACEBO_COMPARATOR: Normothermia; If randomized to normothermia, rectal temperatures were maintained at 37 ± 0.5 °C per standard neonatal intensive care unit practice, using adult-size, water-circulating, cooling blanket (Cincinnati Sub-Zero Blanketrol II®, Cincinnati, OH), servo-controlled to rectal temperature of 37 ± 0.5 if baby was febrile.	Other: normothermia; Rectal temperatures in neonates receiving normothermia were maintained at 37.0+or -0.5 degrees C, using overhead warmer or Cincinnati Sub-Zero Blanketrol II®, servo-controlled to rectal temperature of 37.0 degrees C.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Death or severely abnormal Psychomotor Development Index scores on Bayley II	Death or severe outcomes	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
bradycardia	number of patients with heart rate < 80 bpm	0-96 hours

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
coagulopathy	Mean Prothrombin time	1-4 days of life
Death	numbers of patients who are withdrawn from support or die from multiorgan system failure	by 12 months of age

Collaborators and Investigators

• Sponsor: Medical University of South Carolina
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS)
• Investigators: Principal Investigator: Dorothea D JENKINS, MD, Medical University of South Carolina

Publications and helpful links

General Publications

• Eicher DJ, Wagner CL, Katikaneni LP, Hulsey TC, Bass WT, Kaufman DA, Horgan MJ, Languani S, Bhatia JJ, Givelichian LM, Sankaran K, Yager JY. Moderate hypothermia in neonatal encephalopathy: efficacy outcomes. Pediatr Neurol. 2005 Jan;32(1):11-7. doi: 10.1016/j.pediatrneurol.2004.06.014.
• Eicher DJ, Wagner CL, Katikaneni LP, Hulsey TC, Bass WT, Kaufman DA, Horgan MJ, Languani S, Bhatia JJ, Givelichian LM, Sankaran K, Yager JY. Moderate hypothermia in neonatal encephalopathy: safety outcomes. Pediatr Neurol. 2005 Jan;32(1):18-24. doi: 10.1016/j.pediatrneurol.2004.06.015.
• Jenkins DD, Lee T, Chiuzan C, Perkel JK, Rollins LG, Wagner CL, Katikaneni LP, Bass WT, Kaufman DA, Horgan MJ, Laungani S, Givelichian LM, Sankaran K, Yager JY, Martin R. Altered circulating leukocytes and their chemokines in a clinical trial of therapeutic hypothermia for neonatal hypoxic ischemic encephalopathy*. Pediatr Crit Care Med. 2013 Oct;14(8):786-95. doi: 10.1097/PCC.0b013e3182975cc9.
• Jenkins DD, Rollins LG, Perkel JK, Wagner CL, Katikaneni LP, Bass WT, Kaufman DA, Horgan MJ, Languani S, Givelichian L, Sankaran K, Yager JY, Martin RH. Serum cytokines in a clinical trial of hypothermia for neonatal hypoxic-ischemic encephalopathy. J Cereb Blood Flow Metab. 2012 Oct;32(10):1888-96. doi: 10.1038/jcbfm.2012.83. Epub 2012 Jul 18.

Study record dates

Study Major Dates

• Study Start: June 1, 1999
• Primary Completion (ACTUAL): June 1, 2004
• Study Completion (ACTUAL): June 1, 2004

Study Registration Dates

• First Submitted: May 23, 2016
• First Submitted That Met QC Criteria: July 5, 2016
• First Posted (ESTIMATE): July 11, 2016

Study Record Updates

• Last Update Posted (ESTIMATE): July 11, 2016
• Last Update Submitted That Met QC Criteria: July 5, 2016
• Last Verified: July 1, 2016

More Information

Terms related to this study

• Keywords: hypothermia treatment
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Central Nervous System Diseases; Nervous System Diseases; Signs and Symptoms, Respiratory; Body Temperature Changes; Hypoxia, Brain; Brain Ischemia; Ischemia; Brain Diseases; Hypoxia; Hypothermia; Hypoxia-Ischemia, Brain
• Other Study ID Numbers: NS38062; R01NS038062 (NIH)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: upon request