Association of Increased Seizures During Rewarming With Abnormal Neurodevelopmental Outcomes at 2-Year Follow-up: A Nested Multisite Cohort Study
Lina F Chalak, Athina Pappas, Sylvia Tan, Abhik Das, Pablo J Sánchez, Abbot R Laptook, Krisa P Van Meurs, Seetha Shankaran, Edward F Bell, Alexis S Davis, Roy J Heyne, Claudia Pedroza, Brenda B Poindexter, Kurt Schibler, Jon E Tyson, M Bethany Ball, Rebecca Bara, Cathy Grisby, Gregory M Sokol, Carl T D'Angio, Shannon E G Hamrick, Kevin C Dysart, C Michael Cotten, William E Truog, Kristi L Watterberg, Christopher J Timan, Meena Garg, Waldemar A Carlo, Rosemary D Higgins, Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network, Namasivayam Ambalavanan, Monica V Collins, Shirley S Cosby, Myriam Peralta-Carcelen, Vivien A Phillips, David A Randolph, Barbara Alksninis, Robert T Burke, Melinda Caskey, Nicholas Guerina, Angelita M Hensman, Martin Keszler, Mary Lenore Keszler, Andrea M Knoll, Emilee Little, Elizabeth C McGowan, William Oh, Birju A Shah, Ross Sommers, Elisa Vieira, Betty R Vohr, Stephanie Guilford, Satyan Lakshminrusimha, Anne Marie Reynolds, Michael G Sacilowski, Ashley Williams, Karen Wynn, Anna Maria Hibbs, Nancy S Newman, Bonnie S Siner, Eileen K Stork, Michele C Walsh, Arlene Zadell, Michael S Caplan, Richard A Polin, Sally S Adams, Luc P Brion, Lijun Chen, Alicia Guzman, Elizabeth T Heyne, Lizette E Lee, Linda A Madden, Emma Ramon, Pablo J Sánchez, Catherine Twell Boatman, Diana M Vasil, Myra H Wyckoff, Patricia L Ashley, Joanne Finkle, Kimberley A Fisher, Ronald N Goldberg, Ricki F Goldstein, Sandra Grimes, Kathryn E Gustafson, William F Malcolm, Ira Adams-Chapman Deceased, Diane I Bottcher, David P Carlton, Sheena L Carter, Ellen C Hale, Yvonne C Loggins, Colleen Mackie, Ravi M Patel, Barbara J Stoll, Lynn Wineski, Susan Gunn, Heidi M Harmon, Dianne E Herron, Abbey C Hines, Jeffery Joyce, Carolyn Lytle, Lucy C Miller, Heike M Minnich, Lu-Ann Papile, Brenda B Poindexter, Leslie Richard, Lucy C Smiley, Leslie Dawn Wilson, Michael J Acarregui, Vipinchandra Bhavsar, Jane E Brumbaugh, Tarah T Colaizy, John M Dagle, Diane L Eastman, Karen J Johnson, Jonathan M Klein, Julie B Lindower, Steven J McElroy, Cary R Murphy, Glenda K Rabe, Robert D Roghair, Jeffrey L Segar, Jacky R Walker, John A Widness, Dan L Ellsbury, Cheri Gauldin, Anne M Holmes, Kathy Johnson, Howard W Kilbride, Eugenia K Pallotto, Allison Scott, Roopali Bapat, Thomas Bartman, Elizabeth Bonachea, Helen Carey, Michelle Chao, Louis G Chicoine, Bronte Clifford, Marliese Dion Nist, Erin Fearns, Christine A Fortney, Aubry Fowler, Jennifer Fuller, Jennifer L Grothause, Ish Gulati, Julie Gutentag, Cole D Hague, Krista Haines, Brandon Hart, Michael Hokenson, Sudarshan R Jadcherla, Marissa E Jones, Sarah A Keim, Patricia Luzader, Nathalie L Maitre, Sarah McGregor, Pamela Moorehead, Leif D Nelin, Mary Ann Nelin, Nehal A Parikh, Elizabeth Rodgers, Ruth Seabrook, Tiffany Sharp, Edward G Shepherd, Jonathan L Slaughter, Melanie Stein, Rox Ann Sullivan, Jodi A Ulloa, Jon Wispe, Tara Wolfe, Keith O Yeates, Lina Yossef-Salameh, Nahla Zaghoul, Stephanie Wilson Archer, Soraya Abbasi, Judy C Bernbaum, Aasma S Chaudhary, Dara M Cucinotta, Sara B DeMauro, Marsha Gerdes, Hallam Hurt, Haresh Kirpalani, Toni Mancini, Barbara Schmidt, Kyle Binion, Patrick Conway, Osman Farooq, Ronnie Guillet, Cassandra A Horihan, Rosemary L Jensen, Nirupama Laroira, Joan Merzbach, Gary J Myers, Premini Sabaratnam, Ann Marie Scorsone, Holly I M Wadkins, Kelley Yost, Carla M Bann, Margaret M Crawford, Jenna Gabrio, Marie G Gantz, Scott A McDonald, Jamie E Newman, Jeanette O'Donnell Auman, Carolyn M Petrie Huitema, James W Pickett, Annie M VonLehmden, Dennis Wallace, Kristin M Zaterka-Baxter, Valerie Y Chock, Maria Elena DeAnda, Anne M DeBattista, Lynne C Huffman, Casey E Krueger, Ryan E Lucash, Melinda S Proud, David K Stevenson, Heather L Taylor, Hali E Weiss, Teresa Chanlaw, Uday Devaskar, Rachel Geller, Isabell B Purdy, Sofia Aliaga, Janice Bernhardt, Carl L Bose, Cynthia L Clark, Matthew Maxwell Laughon, Diane D Warner, Janice Kay Wereszczak, Conra Backstrom Lacy, Andrea F Duncan, Janell Fuller, Carol H Hartenberger, Jean R Lowe, Robin K Ohls, Sandra Sundquist Beauman, John Barks, Mary K Christensen, Stephanie A Wiggins, Monika Bajaj, Sanjay Chawla, Kirsten Childs, Lilia C De Jesus, Eunice Hinz Woldt, Mary E Johnson, Girija Natarajan, Bogdan Panaitescu, Jeannette E Prentice, Beena G Sood, Lina F Chalak, Athina Pappas, Sylvia Tan, Abhik Das, Pablo J Sánchez, Abbot R Laptook, Krisa P Van Meurs, Seetha Shankaran, Edward F Bell, Alexis S Davis, Roy J Heyne, Claudia Pedroza, Brenda B Poindexter, Kurt Schibler, Jon E Tyson, M Bethany Ball, Rebecca Bara, Cathy Grisby, Gregory M Sokol, Carl T D'Angio, Shannon E G Hamrick, Kevin C Dysart, C Michael Cotten, William E Truog, Kristi L Watterberg, Christopher J Timan, Meena Garg, Waldemar A Carlo, Rosemary D Higgins, Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network, Namasivayam Ambalavanan, Monica V Collins, Shirley S Cosby, Myriam Peralta-Carcelen, Vivien A Phillips, David A Randolph, Barbara Alksninis, Robert T Burke, Melinda Caskey, Nicholas Guerina, Angelita M Hensman, Martin Keszler, Mary Lenore Keszler, Andrea M Knoll, Emilee Little, Elizabeth C McGowan, William Oh, Birju A Shah, Ross Sommers, Elisa Vieira, Betty R Vohr, Stephanie Guilford, Satyan Lakshminrusimha, Anne Marie Reynolds, Michael G Sacilowski, Ashley Williams, Karen Wynn, Anna Maria Hibbs, Nancy S Newman, Bonnie S Siner, Eileen K Stork, Michele C Walsh, Arlene Zadell, Michael S Caplan, Richard A Polin, Sally S Adams, Luc P Brion, Lijun Chen, Alicia Guzman, Elizabeth T Heyne, Lizette E Lee, Linda A Madden, Emma Ramon, Pablo J Sánchez, Catherine Twell Boatman, Diana M Vasil, Myra H Wyckoff, Patricia L Ashley, Joanne Finkle, Kimberley A Fisher, Ronald N Goldberg, Ricki F Goldstein, Sandra Grimes, Kathryn E Gustafson, William F Malcolm, Ira Adams-Chapman Deceased, Diane I Bottcher, David P Carlton, Sheena L Carter, Ellen C Hale, Yvonne C Loggins, Colleen Mackie, Ravi M Patel, Barbara J Stoll, Lynn Wineski, Susan Gunn, Heidi M Harmon, Dianne E Herron, Abbey C Hines, Jeffery Joyce, Carolyn Lytle, Lucy C Miller, Heike M Minnich, Lu-Ann Papile, Brenda B Poindexter, Leslie Richard, Lucy C Smiley, Leslie Dawn Wilson, Michael J Acarregui, Vipinchandra Bhavsar, Jane E Brumbaugh, Tarah T Colaizy, John M Dagle, Diane L Eastman, Karen J Johnson, Jonathan M Klein, Julie B Lindower, Steven J McElroy, Cary R Murphy, Glenda K Rabe, Robert D Roghair, Jeffrey L Segar, Jacky R Walker, John A Widness, Dan L Ellsbury, Cheri Gauldin, Anne M Holmes, Kathy Johnson, Howard W Kilbride, Eugenia K Pallotto, Allison Scott, Roopali Bapat, Thomas Bartman, Elizabeth Bonachea, Helen Carey, Michelle Chao, Louis G Chicoine, Bronte Clifford, Marliese Dion Nist, Erin Fearns, Christine A Fortney, Aubry Fowler, Jennifer Fuller, Jennifer L Grothause, Ish Gulati, Julie Gutentag, Cole D Hague, Krista Haines, Brandon Hart, Michael Hokenson, Sudarshan R Jadcherla, Marissa E Jones, Sarah A Keim, Patricia Luzader, Nathalie L Maitre, Sarah McGregor, Pamela Moorehead, Leif D Nelin, Mary Ann Nelin, Nehal A Parikh, Elizabeth Rodgers, Ruth Seabrook, Tiffany Sharp, Edward G Shepherd, Jonathan L Slaughter, Melanie Stein, Rox Ann Sullivan, Jodi A Ulloa, Jon Wispe, Tara Wolfe, Keith O Yeates, Lina Yossef-Salameh, Nahla Zaghoul, Stephanie Wilson Archer, Soraya Abbasi, Judy C Bernbaum, Aasma S Chaudhary, Dara M Cucinotta, Sara B DeMauro, Marsha Gerdes, Hallam Hurt, Haresh Kirpalani, Toni Mancini, Barbara Schmidt, Kyle Binion, Patrick Conway, Osman Farooq, Ronnie Guillet, Cassandra A Horihan, Rosemary L Jensen, Nirupama Laroira, Joan Merzbach, Gary J Myers, Premini Sabaratnam, Ann Marie Scorsone, Holly I M Wadkins, Kelley Yost, Carla M Bann, Margaret M Crawford, Jenna Gabrio, Marie G Gantz, Scott A McDonald, Jamie E Newman, Jeanette O'Donnell Auman, Carolyn M Petrie Huitema, James W Pickett, Annie M VonLehmden, Dennis Wallace, Kristin M Zaterka-Baxter, Valerie Y Chock, Maria Elena DeAnda, Anne M DeBattista, Lynne C Huffman, Casey E Krueger, Ryan E Lucash, Melinda S Proud, David K Stevenson, Heather L Taylor, Hali E Weiss, Teresa Chanlaw, Uday Devaskar, Rachel Geller, Isabell B Purdy, Sofia Aliaga, Janice Bernhardt, Carl L Bose, Cynthia L Clark, Matthew Maxwell Laughon, Diane D Warner, Janice Kay Wereszczak, Conra Backstrom Lacy, Andrea F Duncan, Janell Fuller, Carol H Hartenberger, Jean R Lowe, Robin K Ohls, Sandra Sundquist Beauman, John Barks, Mary K Christensen, Stephanie A Wiggins, Monika Bajaj, Sanjay Chawla, Kirsten Childs, Lilia C De Jesus, Eunice Hinz Woldt, Mary E Johnson, Girija Natarajan, Bogdan Panaitescu, Jeannette E Prentice, Beena G Sood
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.
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.
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Source: PubMed