Study: Common treatment for brain injury not effective for some newborns

(Press-News.org) Therapeutic hypothermia, the only evidence-based treatment for newborns born with neonatal encephalopathy (NE) at or after 36 weeks, is not effective for reducing death or moderate/severe disability in newborns born between 33 and 35 weeks, according to a new study. The research will be presented at the Pediatric Academic Societies (PAS) 2023 Meeting, held April 27-May 1 in Washington, D.C.

Researchers examined the effectiveness of whole-body therapeutic hypothermia—a commonly used treatment to lower newborns’ body temperature and protect against the effects of moderate or severe NE—in younger newborns. NE is a brain condition experienced at or near birth, often caused by reduced oxygen to the brain. While evidence supports the use of therapeutic hypothermia for newborns born at 36 weeks or later, many clinicians use the treatment for infants at 35 weeks’ gestation or less.

The trial enrolled 168 newborns born between 33-36 weeks who had NE. Half of these newborns received therapeutic hypothermia, while the other half maintained a normal temperature for 72 hours. Trial participants received a brain MRI at seven to 21 days and neuro-developmental testing with hearing and vision assessment at 18-22 months.

Researchers found a 77% probability of increased death compared to newborns for whom researchers maintained a normal temperature. The researchers found no evidence that therapeutic hypothermia reduced the combined outcome of death or moderate/severe disability among trial participants. Outcomes were assessed at 18-22 months old.

“Despite no evidence supporting its use in younger newborns, clinicians continue to use therapeutic hypothermia in newborns younger than 36 weeks,” said Roger G. Faix, M.D., professor of pediatrics/neonatology at the University of Utah and presenting author. “These study findings are clear: therapeutic hypothermia is ineffective in more premature newborns.”

The trial, which was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health, was conducted in 16 Neonatal Research Network NICUs between 2015 and 2020.

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EDITOR:

Dr. Faix will present “Randomized Trial of Targeted Temperature Management with Whole Body Hypothermia for Moderate and Severe Neonatal Encephalopathy (NE) in Premature Infants 33-0/7 to 35-6/7 wk Gestational Age (GA)” on Sunday, April 30 at 8:00 a.m. ET.

Reporters interested in an interview with Dr. Faix should contact Amber Fraley at amber.fraley@pasmeeting.org.

The PAS Meeting connects thousands of pediatricians and other health care providers worldwide. For more information about the PAS Meeting, please visit www.pas-meeting.org.

About the Pediatric Academic Societies Meeting

The Pediatric Academic Societies (PAS) Meeting is the premier North American scholarly child health meeting. The PAS Meeting connects thousands of pediatricians and other health care providers worldwide. The PAS Meeting is produced through a partnership of four pediatric organizations that are leaders in the advancement of pediatric research and child advocacy: American Pediatric Society, Society for Pediatric Research, Academic Pediatric Association and American Academy of Pediatrics. For more information, please visit www.pas-meeting.org. Follow us on Twitter @PASMeeting and like us on Facebook  PASMeeting.

Abstract

Randomized trial of targeted temperature management with whole body hypothermia for moderate and severe neonatal encephalopathy (NE) in premature infants 33-0/7 to 35-6/7 wk gestational age (GA)

Presenting Author

Roger E. Faix, M.D.

Organization

University of Utah

Topic

Neonatal Clinical Trials

Background

Although randomized trials supporting safety and efficacy of therapeutic hypothermia (TH) for NE are generally confined to infants ≥36 wk GA, some clinicians use TH in more premature infants. It is unclear if developmental differences alter efficacy and safety of TH for NE in less mature infants.

Objective

Determine whether whole body hypothermia initiated < 6 hrs age for infants 33-35 wk GA and ≥1500 g birthweight (BW) with moderate to severe NE is safe and reduces death or moderate/severe disability at 18-22 mo corrected age. 

Design/Methods

Eligible infants were enrolled at 16 Neonatal Research Network (NRN) NICUs after informed consent and randomized to hypothermia (target esophageal temperature [Tes] 33.5°C) or normothermia (Tes 36.5-37.3°C) for 72 h. Exclusion and qualifying criteria for NE were the same as prior NRN hypothermia trials except for requirement of an abnormal level of consciousness in modified Sarnat scoring. Surveillance for pre-selected safety events within 108 h of baseline (insertion of Tes probe) was conducted, including cranial ultrasound obtained < 24 h after baseline. All survivors were to receive brain MRI at 10-17 d age and neuro-developmental assessment (including Bayley III) at 18-22 mo corrected age. Criteria for moderate and severe disability were as defined in prior NRN hypothermia trials. Bayesian analysis using intention-to-treat was pre-specified since accrual was anticipated to be limited (target 168 over 5 yr) and insufficient for conventional frequentist analysis. Independent Data Safety Monitoring Committee reviewed accruing data at specified intervals to assess interim feasibility, safety and efficacy. 

Results

168 infants were enrolled over 63 months (6/2015-9/2020). Covid restrictions required follow-up for some at >22 mo. Analysis by group awaits 1 pending follow-up visit. Of 168 enrollees assessed for follow-up by 10/19/2022, primary outcome is known for 151 (89.9%; Fig 1), with death before follow-up occurring in 27 (17.9% of 151). Target Tes for each group was achieved (Fig 2 displays mean Tes).

Conclusion(s)

Therapeutic hypothermia (TH) is currently the only evidence-based treatment to reduce the combined outcome of death or moderate/severe disability in infants at 36 weeks gestation or greater who experience hypoxia-ischemia near or at the time of birth in high income countries. Two of the trials that support the use of TH included a small number of infants at 35 weeks gestation, leading many clinicians to use TH in infants at 35 weeks gestation or less. Data to assess the effectiveness and safety of TH among infants less than or equal to 35 weeks who are at greater risk for problems of prematurity are lacking. Our trial was designed to assess TH in infants from 33-0/7 to 35-6/7 weeks. Over 5.5 years we enrolled 168 infants who were randomized to receive TH at a core temperature 0f 33-34 degrees C. for 72 hours or normothermia (core temperature of 36.5-37.3 degrees C.). The outcome of death or moderate/severe disability was assessed at 18-22 months. We found no evidence that TH reduced death or moderate/severe disability in this population. TH was associated with a 77% probability of increased death compared to infants maintained normothermic. This study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health.

Tables and Images

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