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Multicenter Study
. 2021 Dec 1;78(12):1484-1493.
doi: 10.1001/jamaneurol.2021.3723.

Association Between Increased Seizures During Rewarming After Hypothermia for Neonatal Hypoxic Ischemic Encephalopathy and Abnormal Neurodevelopmental Outcomes at 2-Year Follow-up: A Nested Multisite Cohort Study

Lina F Chalak  1 , Athina Pappas  2 , Sylvia Tan  3 , Abhik Das  4 , Pablo J Sánchez  5 , Abbot R Laptook  6 , Krisa P Van Meurs  7 , Seetha Shankaran  2 , Edward F Bell  8 , Alexis S Davis  7 , Roy J Heyne  1 , Claudia Pedroza  9 , Brenda B Poindexter  10   11 , Kurt Schibler  12 , Jon E Tyson  9 , M Bethany Ball  7 , Rebecca Bara  2 , Cathy Grisby  12 , Gregory M Sokol  10 , Carl T D'Angio  13 , Shannon E G Hamrick  11 , Kevin C Dysart  14 , C Michael Cotten  15 , William E Truog  16 , Kristi L Watterberg  17 , Christopher J Timan  5 , Meena Garg  18 , Waldemar A Carlo  19 , Rosemary D Higgins  20 ; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network
Collaborators, Affiliations
Multicenter Study

Association Between Increased Seizures During Rewarming After Hypothermia for Neonatal Hypoxic Ischemic Encephalopathy and Abnormal Neurodevelopmental Outcomes at 2-Year Follow-up: A Nested Multisite Cohort Study

Lina F Chalak et al. JAMA Neurol. .

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Pappas reports grants from the Eunice Kennedy Shriver National Institutes of Child Health and Human Development Neonatal Research Network during the conduct of the study and outside the submitted work. Dr Das, Dr Laptook, Dr Shankaran, Dr Bell, Dr Heyne, Dr Tyson, Dr Grisby, Dr Sokol, Dr D’Angio, Dr Watterberg, and Dr Timan report grants from the Eunice Kennedy Shriver National Institutes of Child Health and Human Development Neonatal Research Network during the conduct of the study. Dr Sánchez reports grants from the Eunice Kennedy Shriver National Institutes of Child Health and Human Development Neonatal Research Network during the conduct of the study and grants from Merck and AstraZeneca outside the submitted work. Dr Davis reports serving on scientific advisory boards for Lansinoh and Regeneron outside the submitted work. Dr Schibler reports grants from Cincinnati Children’s Hospital during the conduct of the study and grants from Eunice Kennedy Shriver National Institutes of Child Health and Human Development outside the submitted work. Dr Cotten reports grants from the Eunice Kennedy Shriver National Institutes of Child Health and Human Development during the conduct of the study and has a patent with royalties paid with CryoCell as a coinventor of a cell-based approach to neuroprotection. Dr Carlo serves stocks from and serving on the board of Mednax outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Consortium Flowchart
The Systematic Monitoring of EEG in Asphyxiated Newborns During Rewarming After Hypothermia Therapy (SMART) study started 1 year following the Optimizing Cooling (OC) trial initiation and 16 of 18 OC trial sites participated in SMART. A total of 120 infants (82%) met the predefined inclusion criteria of completed ambulatory electroencephalography (aEEG) during rewarming with good impedance and 112 (90%) had complete data for death or disability. aThe SMART study period began in January 2012. bOther reasons included parent withdrawal of consent, lack of access, clinical aEEG in place, and poor impedance.
Figure 2.
Figure 2.. Epochs of Electroencephalography (EEG) Monitoring
Boxes include the electrographic seizure occurrence epoch 1 (60-72 h), epoch 2 (72-84 h), epoch 3 (108-120 h), and epoch 4 (120-132 h).
See this image and copyright information in PMC

Comment in

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