Benzodiazepine administration patterns before escalation to second-line medications in pediatric refractory convulsive status epilepticus

doi:10.1111/epi.17043

Observational Study

. 2021 Nov;62(11):2766-2777.

doi: 10.1111/epi.17043. Epub 2021 Aug 21.

Benzodiazepine administration patterns before escalation to second-line medications in pediatric refractory convulsive status epilepticus

Theodore Sheehan¹, Marta Amengual-Gual^{1

2}, Alejandra Vasquez^{1

3}, Nicholas S Abend⁴, Anne Anderson⁵, Brian Appavu⁶, Ravindra Arya⁷, Cristina Barcia Aguilar^{1

8}, J Nicholas Brenton⁹, Jessica L Carpenter¹⁰, Kevin E Chapman¹¹, Justice Clark¹, Raquel Farias-Moeller¹², William D Gaillard¹⁰, Marina Gaínza-Lein^{1

13}, Tracy A Glauser⁷, Joshua L Goldstein¹⁴, Howard P Goodkin⁹, Réjean M Guerriero¹⁵, Linda Huh¹⁶, Michele Jackson¹, Kush Kapur¹⁷, Robert Kahoud^{18

19}, Yi-Chen Lai²⁰, Tiffani L McDonough²¹, Mohamad A Mikati²², Lindsey A Morgan²³, Edward J Novotny²³, Adam P Ostendorf²⁴, Eric T Payne²⁵, Katrina Peariso⁷, Juan Piantino²⁶, Latania Reece¹, James J Riviello⁵, Tristan T Sands²¹, Kumar Sannagowdara¹², Renee Shellhaas²⁷, Garnett Smith²⁷, Robert C Tasker²⁸, Dmitry Tchapyjnikov^{22

29}, Alexis A Topjian³⁰, Mark S Wainwright²³, Angus Wilfong⁶, Korwyn Williams⁶, Bo Zhang¹⁷, Tobias Loddenkemper¹; Pediatric Status Epilepticus Research Group

Affiliations

¹ Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
² Pediatric Neurology Unit, Department of Pediatrics, Son Espases University Hospital, University of the Balearic Islands, Palma, Spain.
³ Division of Child and Adolescent Neurology, Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
⁴ Division of Neurology, Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁵ Section of Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
⁶ Department of Pediatrics, University of Arizona College of Medicine and Barrow Neurological Institute at Phoenix Children's Hospital, Phoenix, Arizona, USA.
⁷ Division of Neurology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.
⁸ Department of Child Neurology, La Paz University Hospital, Autonomous University of Madrid, Madrid, Spain.
⁹ Department of Neurology and Pediatrics, University of Virginia Health System, Charlottesville, Virginia, USA.
¹⁰ Center for Neuroscience, Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA.
¹¹ Departments of Pediatrics and Neurology, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado, USA.
¹² Department of Neurology, Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
¹³ Faculty of Medicine, Austral University of Chile, Valdivia, Chile.
¹⁴ Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
¹⁵ Division of Pediatric and Developmental Neurology, Departments of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.
¹⁶ Division of Neurology, Department of Paediatrics, BC Children's Hospital, University of British Columbia, Vancouver, Canada.
¹⁷ Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
¹⁸ Division of Pediatric Critical Care Medicine, Department of Pediatrics, Mayo Clinic, Rochester, Minnesota, USA.
¹⁹ Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
²⁰ Section of Pediatric Critical Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
²¹ Division of Child Neurology, Department of Neurology, Columbia University Medical Center, Columbia University, New York, New York, USA.
²² Division of Pediatric Neurology, Duke University Medical Center, Duke University, Durham, North Carolina, USA.
²³ Departments of Neurology and Pediatrics, Division of Pediatric Neurology, University of Washington, Seattle Children's Hospital, Seattle, Washington, USA.
²⁴ Department of Pediatrics, Nationwide Children's Hospital, Ohio State University, Columbus, Ohio, USA.
²⁵ Division of Neurology, Department of Pediatrics, Alberta Children's Hospital, Calgary, Alberta, Canada.
²⁶ Division of Neurology, Doernbecher Children's Hospital, Oregon Health & Science University, Portland, Oregon, USA.
²⁷ Department of Pediatrics, Division of Pediatric Neurology, University of Michigan, Ann Arbor, Michigan, USA.
²⁸ Division of Critical Care, Departments of Neurology, Anesthesiology, and Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
²⁹ Department of Pediatrics, Montana Children's Hospital, Kalispell Regional Medical Center, Kalispell, Montana, USA.
³⁰ Critical Care and Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

PMID: 34418087
PMCID: PMC9292193
DOI: 10.1111/epi.17043

Observational Study

Benzodiazepine administration patterns before escalation to second-line medications in pediatric refractory convulsive status epilepticus

Theodore Sheehan et al. Epilepsia. 2021 Nov.

. 2021 Nov;62(11):2766-2777.

doi: 10.1111/epi.17043. Epub 2021 Aug 21.

Authors

Affiliations

¹ Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
² Pediatric Neurology Unit, Department of Pediatrics, Son Espases University Hospital, University of the Balearic Islands, Palma, Spain.
³ Division of Child and Adolescent Neurology, Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
⁴ Division of Neurology, Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁵ Section of Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
⁶ Department of Pediatrics, University of Arizona College of Medicine and Barrow Neurological Institute at Phoenix Children's Hospital, Phoenix, Arizona, USA.
⁷ Division of Neurology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.
⁸ Department of Child Neurology, La Paz University Hospital, Autonomous University of Madrid, Madrid, Spain.
⁹ Department of Neurology and Pediatrics, University of Virginia Health System, Charlottesville, Virginia, USA.
¹⁰ Center for Neuroscience, Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA.
¹¹ Departments of Pediatrics and Neurology, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado, USA.
¹² Department of Neurology, Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
¹³ Faculty of Medicine, Austral University of Chile, Valdivia, Chile.
¹⁴ Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
¹⁵ Division of Pediatric and Developmental Neurology, Departments of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.
¹⁶ Division of Neurology, Department of Paediatrics, BC Children's Hospital, University of British Columbia, Vancouver, Canada.
¹⁷ Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
¹⁸ Division of Pediatric Critical Care Medicine, Department of Pediatrics, Mayo Clinic, Rochester, Minnesota, USA.
¹⁹ Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
²⁰ Section of Pediatric Critical Medicine, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
²¹ Division of Child Neurology, Department of Neurology, Columbia University Medical Center, Columbia University, New York, New York, USA.
²² Division of Pediatric Neurology, Duke University Medical Center, Duke University, Durham, North Carolina, USA.
²³ Departments of Neurology and Pediatrics, Division of Pediatric Neurology, University of Washington, Seattle Children's Hospital, Seattle, Washington, USA.
²⁴ Department of Pediatrics, Nationwide Children's Hospital, Ohio State University, Columbus, Ohio, USA.
²⁵ Division of Neurology, Department of Pediatrics, Alberta Children's Hospital, Calgary, Alberta, Canada.
²⁶ Division of Neurology, Doernbecher Children's Hospital, Oregon Health & Science University, Portland, Oregon, USA.
²⁷ Department of Pediatrics, Division of Pediatric Neurology, University of Michigan, Ann Arbor, Michigan, USA.
²⁸ Division of Critical Care, Departments of Neurology, Anesthesiology, and Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
²⁹ Department of Pediatrics, Montana Children's Hospital, Kalispell Regional Medical Center, Kalispell, Montana, USA.
³⁰ Critical Care and Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

PMID: 34418087
PMCID: PMC9292193
DOI: 10.1111/epi.17043

Abstract

Objective: This study was undertaken to evaluate benzodiazepine (BZD) administration patterns before transitioning to non-BZD antiseizure medication (ASM) in pediatric patients with refractory convulsive status epilepticus (rSE).

Methods: This retrospective multicenter study in the United States and Canada used prospectively collected observational data from children admitted with rSE between 2011 and 2020. Outcome variables were the number of BZDs given before the first non-BZD ASM, and the number of BZDs administered after 30 and 45 min from seizure onset and before escalating to non-BZD ASM.

Results: We included 293 patients with a median (interquartile range) age of 3.8 (1.3-9.3) years. Thirty-six percent received more than two BZDs before escalating, and the later the treatment initiation was after seizure onset, the less likely patients were to receive multiple BZD doses before transitioning (incidence rate ratio [IRR] = .998, 95% confidence interval [CI] = .997-.999 per minute, p = .01). Patients received BZDs beyond 30 and 45 min in 57.3% and 44.0% of cases, respectively. Patients with out-of-hospital seizure onset were more likely to receive more doses of BZDs beyond 30 min (IRR = 2.43, 95% CI = 1.73-3.46, p < .0001) and beyond 45 min (IRR = 3.75, 95% CI = 2.40-6.03, p < .0001) compared to patients with in-hospital seizure onset. Intermittent SE was a risk factor for more BZDs administered beyond 45 min compared to continuous SE (IRR = 1.44, 95% CI = 1.01-2.06, p = .04). Forty-seven percent of patients (n = 94) with out-of-hospital onset did not receive treatment before hospital arrival. Among patients with out-of-hospital onset who received at least two BZDs before hospital arrival (n = 54), 48.1% received additional BZDs at hospital arrival.

Significance: Failure to escalate from BZDs to non-BZD ASMs occurs mainly in out-of-hospital rSE onset. Delays in the implementation of medical guidelines may be reduced by initiating treatment before hospital arrival and facilitating a transition to non-BZD ASMs after two BZD doses during handoffs between prehospital and in-hospital settings.

Keywords: benzodiazepine; epilepsy; pediatric; seizure; status epilepticus; treatment.

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Conflict of interest statement

J.N.B. has served as a consultant for Novartis. T.A.G. is funded by National Institutes of Health (NIH) grants 2U01‐NS045911, U10‐NS077311, R01‐NS053998, R01‐NS062756, R01‐NS043209, R01‐LM011124, and R01‐NS065840; has received consulting fees from Supernus, Sunovion, Eisai, and UCB; serves as an expert consultant for the US Department of Justice and has received compensation for work as an expert on medicolegal cases; and receives royalties from a patent license. E.J.N. is on the professional advisory board of the Epilepsy Foundation of America and served on an advisory board for Zogenix. J.J.R.'s spouse is an editor for UpToDate. D.T. receives research funding from Children's Miracle Network Hospitals and has previously received consultation fees from Gerson Lehrman Group, Guidepoint, IQVIA, and bioStrategies Group. R.S. receives research funding from PCORI, NIH, the Pediatric Epilepsy Research Foundation, and the University of Michigan; receives royalties from UpToDate for authorship of topics related to neonatal seizures, is a consultant for the Epilepsy Study Consortium, and is an associate editor for Neurology. M.S.W. serves as a scientific consultant and on the clinical advisory board for Sage Pharmaceuticals. A.W. receives research funding from Novartis, Eisai, Pfizer, UCB, Acorda, Lundbeck, GW Pharma, Upsher‐Smith, and Zogenix and receives publication royalties from UpToDate. T.L. serves on the Council of the American Clinical Neurophysiology Society, on the American Board of Clinical Neurophysiology, as founder and consortium principal investigator of pSERG, as an associate editor for Wyllie's Treatment of Epilepsy 6th and 7th editions, and as a member of the New Onset Refractory Status Epilepticus Institute, PACS1 Foundation, and CCEMRC; served as associate editor of Seizure and served on the Laboratory Accreditation Board for Long Term (Epilepsy and Intensive Care Unit) Monitoring in the past; is part of patent applications to detect and predict clinical outcomes, and to manage, diagnose, and treat neurological conditions, epilepsy, and seizures; is coinventor of the TriVox Health technology, and T.L. and Boston Children's Hospital might receive financial benefits from this technology in the form of compensation in the future; received research support from the Epilepsy Research Fund, the NIH, the Epilepsy Foundation of America, the Epilepsy Therapy Project, and the Pediatric Epilepsy Research Foundation; received research grants from Lundbeck, Eisai, Upsher‐Smith, Mallinckrodt, Sunovion, Sage, Empatica, and Pfizer, including past device donations from various companies, including Empatica, SmartWatch, and Neuro‐electrics; in the past, served as a consultant for Zogenix, Upsher‐Smith, Amzell, Engage, Elsevier, UCB, Grand Rounds, Advance Medical, and Sunovion; performs video electroencephalography long‐term and intensive care unit (ICU) monitoring, electroencephalography, and other electrophysiological studies at Boston Children's Hospital and affiliated hospitals and bills for these procedures, and evaluates pediatric neurology patients and bills for clinical care; and has received speaker honoraria from national societies including the AAN, AES, and ACNS, and for grand rounds at various academic centers. T.L.'s wife, Dr. Karen Stannard, is a pediatric neurologist, and she performs video electroencephalography long‐term and ICU monitoring, electroencephalography, and other electrophysiological studies and bills for these procedures, and she evaluates pediatric neurology patients and bills for clinical care. None of the other authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Figures

**FIGURE 1**
Bar graph representing the number of benzodiazepines (BZDs) administered before the first non‐BZD antiseizure medication (ASM) from the beginning of status epilepticus (SE), in the entire cohort (blue), subpopulation of patients with out‐of‐hospital SE onset (orange), and subpopulation of patients with in‐hospital SE onset (yellow)

**FIGURE 2**
Bar graphs representing the number of benzodiazepines (BZDs) administered after 30 min from seizure onset and before the first non‐BZD antiseizure medication (ASM) in the entire cohort (A), subpopulation of patients with out‐of‐hospital status epilepticus onset (B), and subpopulation of patients with in‐hospital status epilepticus onset (C). The colors of the stacked bars represent the number of BZDs already administered during the first 30 min after seizure onset. For example, in the entire cohort (A), 76 patients received one BZD after the first 30 min from seizure onset and before the first non‐BZD ASM (second bar); of those 76 patients, 32 patients had not received any BZD within the first 30 min (blue section of the second bar), 26 patients had received one BZD (orange section of the second bar), 10 patients had received two BZDs (gray section), et cetera

**FIGURE 3**
Bar graphs representing the number of benzodiazepines (BZDs) administered after 45 min from seizure onset and before the first non‐BZD antiseizure medication (ASM) in the entire cohort (A), subpopulation of patients with out‐of‐hospital status epilepticus onset (B), and subpopulation of patients with in‐hospital status epilepticus onset (C). The colors of the stacked bars represent the number of BZDs already administered during the first 45 min after seizure onset. For example, in the entire cohort (A), 59 patients received one BZD after the first 45 min from seizure onset and before the first non‐BZD ASM (second bar); of those 59 patients, 25 patients had not received any BZD within the first 45 min (blue section of the second bar), 16 patients had received one BZD (orange section of the second bar), 10 patients had received two BZDs (gray section), et cetera

See this image and copyright information in PMC

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References

1. Chin RF, Neville BG, Peckham C, Bedford H, Wade A, Scott RC, et al. Incidence, cause, and short‐term outcome of convulsive status epilepticus in childhood: prospective population‐based study. Lancet. 2006;368:222–9. - PubMed
1. Coeytaux A, Jallon P, Galobardes B, Morabia A. Incidence of status epilepticus in French‐speaking Switzerland: (EPISTAR). Neurology. 2000;55:693–7. - PubMed
1. DeLorenzo RJ, Hauser WA, Towne AR, Boggs JG, Pellock JM, Penberthy L, et al. A prospective, population‐based epidemiologic study of status epilepticus in Richmond, Virginia. Neurology. 1996;46:1029–35. - PubMed
1. Hesdorffer DC, Logroscino G, Cascino G, Annegers JF, Hauser WA. Incidence of status epilepticus in Rochester, Minnesota, 1965–1984. Neurology. 1998;50:735–41. - PubMed
1. Loddenkemper T, Syed TU, Ramgopal S, Gulati D, Thanaviratananich S, Kothare SV, et al. Risk factors associated with death in in‐hospital pediatric convulsive status epilepticus. PLoS One. 2012;7:e47474. - PMC - PubMed

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[1] Chin RF, Neville BG, Peckham C, Bedford H, Wade A, Scott RC, et al. Incidence, cause, and short‐term outcome of convulsive status epilepticus in childhood: prospective population‐based study. Lancet. 2006;368:222–9. - PubMed

[2] Chin RF, Neville BG, Peckham C, Bedford H, Wade A, Scott RC, et al. Incidence, cause, and short‐term outcome of convulsive status epilepticus in childhood: prospective population‐based study. Lancet. 2006;368:222–9. - PubMed

[3] Coeytaux A, Jallon P, Galobardes B, Morabia A. Incidence of status epilepticus in French‐speaking Switzerland: (EPISTAR). Neurology. 2000;55:693–7. - PubMed

[4] Coeytaux A, Jallon P, Galobardes B, Morabia A. Incidence of status epilepticus in French‐speaking Switzerland: (EPISTAR). Neurology. 2000;55:693–7. - PubMed

[5] DeLorenzo RJ, Hauser WA, Towne AR, Boggs JG, Pellock JM, Penberthy L, et al. A prospective, population‐based epidemiologic study of status epilepticus in Richmond, Virginia. Neurology. 1996;46:1029–35. - PubMed

[6] DeLorenzo RJ, Hauser WA, Towne AR, Boggs JG, Pellock JM, Penberthy L, et al. A prospective, population‐based epidemiologic study of status epilepticus in Richmond, Virginia. Neurology. 1996;46:1029–35. - PubMed

[7] Hesdorffer DC, Logroscino G, Cascino G, Annegers JF, Hauser WA. Incidence of status epilepticus in Rochester, Minnesota, 1965–1984. Neurology. 1998;50:735–41. - PubMed

[8] Hesdorffer DC, Logroscino G, Cascino G, Annegers JF, Hauser WA. Incidence of status epilepticus in Rochester, Minnesota, 1965–1984. Neurology. 1998;50:735–41. - PubMed

[9] Loddenkemper T, Syed TU, Ramgopal S, Gulati D, Thanaviratananich S, Kothare SV, et al. Risk factors associated with death in in‐hospital pediatric convulsive status epilepticus. PLoS One. 2012;7:e47474. - PMC - PubMed

[10] Loddenkemper T, Syed TU, Ramgopal S, Gulati D, Thanaviratananich S, Kothare SV, et al. Risk factors associated with death in in‐hospital pediatric convulsive status epilepticus. PLoS One. 2012;7:e47474. - PMC - PubMed

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Benzodiazepine administration patterns before escalation to second-line medications in pediatric refractory convulsive status epilepticus

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Benzodiazepine administration patterns before escalation to second-line medications in pediatric refractory convulsive status epilepticus

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