Lina F Chalak1, Athina Pappas2, Sylvia Tan3, Abhik Das4, Pablo J Sánchez5, Abbot R Laptook6, Krisa P Van Meurs7, Seetha Shankaran2, Edward F Bell8, Alexis S Davis7, Roy J Heyne1, Claudia Pedroza9, Brenda B Poindexter10,11, Kurt Schibler12, Jon E Tyson9, M Bethany Ball7, Rebecca Bara2, Cathy Grisby12, Gregory M Sokol10, Carl T D'Angio13, Shannon E G Hamrick11, Kevin C Dysart14, C Michael Cotten15, William E Truog16, Kristi L Watterberg17, Christopher J Timan5, Meena Garg18, Waldemar A Carlo19, Rosemary D Higgins20. 1. Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas. 2. Department of Pediatrics, Wayne State University, Detroit, Michigan. 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, Nationwide Children's Hospital, Ohio State University College of Medicine, Columbus. 6. Department of Pediatrics, Women & Infants Hospital, Brown University, Providence, Rhode Island. 7. Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine and Lucile Packard Children's Hospital, Palo Alto, California. 8. Department of Pediatrics, University of Iowa, Iowa City. 9. Department of Pediatrics, University of Texas Medical School at Houston, Houston. 10. Department of Pediatrics, Indiana University School of Medicine, Indianapolis. 11. Emory University Hospital Midtown, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia. 12. Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 13. University of Rochester School of Medicine and Dentistry, Rochester, New York. 14. Department of Pediatrics, University of Pennsylvania, Philadelphia. 15. Department of Pediatrics, Duke University, Durham, North Carolina. 16. Department of Pediatrics, Children's Mercy Hospital, Kansas City, Missouri. 17. University of New Mexico Health Sciences Center, Albuquerque. 18. Department of Pediatrics, University of California, Los Angeles. 19. Division of Neonatology, University of Alabama at Birmingham, Birmingham. 20. Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.
Abstract
IMPORTANCE: Compared with normothermia, hypothermia has been shown to reduce death or disability in neonatal hypoxic ischemic encephalopathy but data on seizures during rewarming and associated outcomes are scarce. OBJECTIVE: To determine whether electrographic seizures are more likely to occur during rewarming compared with the preceding period and whether they are associated with abnormal outcomes in asphyxiated neonates receiving hypothermia therapy. DESIGN, SETTING, AND PARTICIPANTS: This prespecified nested cohort study of infants enrolled in the Optimizing Cooling (OC) multicenter Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network trial from December 2011 to December 2013 with 2 years' follow-up randomized infants to either 72 hours of cooling (group A) or 120 hours (group B). The main trial included 364 infants. Of these, 194 were screened, 10 declined consent, and 120 met all predefined inclusion criteria. A total of 112 (90%) had complete data for death or disability. Data were analyzed from January 2018 to January 2020. INTERVENTIONS: Serial amplitude electroencephalography recordings were compared in the 12 hours prior and 12 hours during rewarming for evidence of electrographic seizure activity by 2 central amplitude-integrated electroencephalography readers blinded to treatment arm and rewarming epoch. Odds ratios and 95% CIs were evaluated following adjustment for center, prior seizures, depth of cooling, and encephalopathy severity. MAIN OUTCOMES AND MEASURES: The primary outcome was the occurrence of electrographic seizures during rewarming initiated at 72 or 120 hours compared with the preceding 12-hour epoch. Secondary outcomes included death or moderate or severe disability at age 18 to 22 months. The hypothesis was that seizures during rewarming were associated with higher odds of abnormal neurodevelopmental outcomes. RESULTS: A total of 120 newborns (70 male [58%]) were enrolled (66 in group A and 54 in group B). The mean (SD) gestational age was 39 (1) weeks. There was excellent interrater agreement (κ, 0.99) in detection of seizures. More infants had electrographic seizures during the rewarming epoch compared with the preceding epoch (group A, 27% vs 14%; P = .001; group B, 21% vs 10%; P = .03). Adjusted odd ratios (95% CIs) for seizure frequency during rewarming were 2.7 (1.0-7.5) for group A and 3.2 (0.9-11.6) for group B. The composite death or moderate to severe disability outcome at 2 years was significantly higher in infants with electrographic seizures during rewarming (relative risk [95% CI], 1.7 [1.25-2.37]) after adjusting for baseline clinical encephalopathy and seizures as well as center. CONCLUSIONS AND RELEVANCE: Findings that higher odds of electrographic seizures during rewarming are associated with death or disability at 2 years highlight the necessity of electroencephalography monitoring during rewarming in infants at risk. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01192776.
IMPORTANCE: Compared with normothermia, hypothermia has been shown to reduce death or disability in neonatal hypoxic ischemic encephalopathy but data on seizures during rewarming and associated outcomes are scarce. OBJECTIVE: To determine whether electrographic seizures are more likely to occur during rewarming compared with the preceding period and whether they are associated with abnormal outcomes in asphyxiated neonates receiving hypothermia therapy. DESIGN, SETTING, AND PARTICIPANTS: This prespecified nested cohort study of infants enrolled in the Optimizing Cooling (OC) multicenter Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network trial from December 2011 to December 2013 with 2 years' follow-up randomized infants to either 72 hours of cooling (group A) or 120 hours (group B). The main trial included 364 infants. Of these, 194 were screened, 10 declined consent, and 120 met all predefined inclusion criteria. A total of 112 (90%) had complete data for death or disability. Data were analyzed from January 2018 to January 2020. INTERVENTIONS: Serial amplitude electroencephalography recordings were compared in the 12 hours prior and 12 hours during rewarming for evidence of electrographic seizure activity by 2 central amplitude-integrated electroencephalography readers blinded to treatment arm and rewarming epoch. Odds ratios and 95% CIs were evaluated following adjustment for center, prior seizures, depth of cooling, and encephalopathy severity. MAIN OUTCOMES AND MEASURES: The primary outcome was the occurrence of electrographic seizures during rewarming initiated at 72 or 120 hours compared with the preceding 12-hour epoch. Secondary outcomes included death or moderate or severe disability at age 18 to 22 months. The hypothesis was that seizures during rewarming were associated with higher odds of abnormal neurodevelopmental outcomes. RESULTS: A total of 120 newborns (70 male [58%]) were enrolled (66 in group A and 54 in group B). The mean (SD) gestational age was 39 (1) weeks. There was excellent interrater agreement (κ, 0.99) in detection of seizures. More infants had electrographic seizures during the rewarming epoch compared with the preceding epoch (group A, 27% vs 14%; P = .001; group B, 21% vs 10%; P = .03). Adjusted odd ratios (95% CIs) for seizure frequency during rewarming were 2.7 (1.0-7.5) for group A and 3.2 (0.9-11.6) for group B. The composite death or moderate to severe disability outcome at 2 years was significantly higher in infants with electrographic seizures during rewarming (relative risk [95% CI], 1.7 [1.25-2.37]) after adjusting for baseline clinical encephalopathy and seizures as well as center. CONCLUSIONS AND RELEVANCE: Findings that higher odds of electrographic seizures during rewarming are associated with death or disability at 2 years highlight the necessity of electroencephalography monitoring during rewarming in infants at risk. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01192776.
Authors: Steven P Miller; Vijay Ramaswamy; David Michelson; A James Barkovich; Barbara Holshouser; Nathaniel Wycliffe; David V Glidden; Douglas Deming; J Colin Partridge; Yvonne W Wu; Stephen Ashwal; Donna M Ferriero Journal: J Pediatr Date: 2005-04 Impact factor: 4.406
Authors: Hannah C Glass; Courtney J Wusthoff; Renée A Shellhaas; Tammy N Tsuchida; Sonia Lomeli Bonifacio; Malaika Cordeiro; Joseph Sullivan; Nicholas S Abend; Taeun Chang Journal: Neurology Date: 2014-03-07 Impact factor: 9.910
Authors: An N Massaro; R B Govindan; Gilbert Vezina; Taeun Chang; Nickie N Andescavage; Yunfei Wang; Tareq Al-Shargabi; Marina Metzler; Kari Harris; Adre J du Plessis Journal: J Neurophysiol Date: 2015-06-10 Impact factor: 2.714
Authors: Divyen K Shah; Mark T Mackay; Shelly Lavery; Susan Watson; A Simon Harvey; John Zempel; Amit Mathur; Terrie E Inder Journal: Pediatrics Date: 2008-06 Impact factor: 7.124