First-line medication dosing in pediatric refractory status epilepticus

Alejandra Vasquez; Marina Gaínza-Lein; Nicholas S Abend; Marta Amengual-Gual; Anne Anderson; Ravindra Arya; J Nicholas Brenton; Jessica L Carpenter; Kevin Chapman; Justice Clark; Raquel Farias-Moeller; William D Gaillard; Tracy Glauser; Joshua L Goldstein; Howard P Goodkin; Rejean M Guerriero; Kush Kapur; Yi-Chen Lai; Tiffani L McDonough; Mohamad A Mikati; Lindsey A Morgan; Edward J Novotny; Adam P Ostendorf; Eric T Payne; Katrina Peariso; Juan Piantino; James J Riviello; Kumar Sannagowdara; Robert C Tasker; Dmitry Tchapyjnikov; Alexis Topjian; Mark S Wainwright; Angus Wilfong; Korwyn Williams; Tobias Loddenkemper; Pediatric Status Epilepticus Research Group (pSERG)

doi:10.1212/WNL.0000000000010828

First-line medication dosing in pediatric refractory status epilepticus

Neurology. 2020 Nov 10;95(19):e2683-e2696. doi: 10.1212/WNL.0000000000010828. Epub 2020 Sep 10.

Authors

Alejandra Vasquez¹, Marina Gaínza-Lein¹, Nicholas S Abend¹, Marta Amengual-Gual¹, Anne Anderson¹, Ravindra Arya¹, J Nicholas Brenton¹, Jessica L Carpenter¹, Kevin Chapman¹, Justice Clark¹, Raquel Farias-Moeller¹, William D Gaillard¹, Tracy Glauser¹, Joshua L Goldstein¹, Howard P Goodkin¹, Rejean M Guerriero¹, Kush Kapur¹, Yi-Chen Lai¹, Tiffani L McDonough¹, Mohamad A Mikati¹, Lindsey A Morgan¹, Edward J Novotny¹, Adam P Ostendorf¹, Eric T Payne¹, Katrina Peariso¹, Juan Piantino¹, James J Riviello¹, Kumar Sannagowdara¹, Robert C Tasker¹, Dmitry Tchapyjnikov¹, Alexis Topjian¹, Mark S Wainwright¹, Angus Wilfong¹, Korwyn Williams¹, Tobias Loddenkemper²; Pediatric Status Epilepticus Research Group (pSERG)

Collaborators

Pediatric Status Epilepticus Research Group (pSERG):
Seema Bansal, Sarah Kelley, Carl Stafstrom, Eric Kossoff, Christa Habela, Dalila Lewis, Tony Stanfield, Claudine Sculier, Cristina Barcia Aguilar, Arnold Sansevere, Melissa Sacco, Abby Duncan, Jordan McCoy, Kathryn DaSilva-Chiodo, Robert Faist, Daniel Santel, Victor LaFay, Peggy Clark, Sarah Borror, Andrea Debs, Caitlin Clohessy, Amanda Weber, Asri Yuliati, Aimee Luat, Azara Singh, Ashley Helseth, David Turner, Cecilia Fernandes, Linh Tran, Melissa McLean, Anuranjita Nayak, James J Riviello Jr, Kurt Hecox, Rupa Nallamothu, Rebecca Rehborg, David Goldstein, Erin Heinzen Cox, Colin Malone, Olivia Thornburg, Zachary Grinspan, Natasha Basma, Brian Appavu, Brian Burrows, Beata Dyar, Laura Mishler, Jacqueline Lee-Eng, Madison Streb, Cecil Hahn, Saptharishi Rishi Lalgudi Ganesan, Linda Huh, Nela Martic

Affiliations

¹ From the Division of Epilepsy and Clinical Neurophysiology (A.V., M.G.-L., M.A.-G., J.C., T.L.), Department of Neurology, Boston Children's Hospital, Harvard Medical School, MA; Division of Child and Adolescent Neurology (A.V., E.T.P.), Department of Neurology, Mayo Clinic, Rochester, MN; Instituto de Pediatría, Facultad de Medicina (M.G.-L.), Universidad Austral de Chile, Valdivia; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Division of Neurology (N.S.A.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Neurology and Developmental Neuroscience (A.A., J.J.R.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH; Department of Neurology and Pediatrics (J.N.B., H.P.G.), University of Virginia Health System, Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Neurology (R.F.-M., K.S.), Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric Neurology (R.M.G.), Washington University Medical Center, Washington University School of Medicine, St. Louis, MO; Department of Neurology (K.K.), Boston Children's Hospital, Harvard Medical School, MA; Section of Pediatric Critical Medicine (Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Child Neurology (T.L.M.), Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY; Division of Pediatric Neurology (T.L.M.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Neurology (L.A.M., E.J.N., M.S.W.), Division of Pediatric Neurology, University of Washington, Seattle; Center for Integrative Brain Research (E.J.N.), Seattle Children's Research Institute, WA; Department of Pediatrics (A.P.O.), Nationwide Children's Hospital, The Ohio State University, Columbus; Department of Pediatrics (J.P.), Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland; Division of Critical Care (R.C.T.), Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Critical Care and Pediatrics (A.T.), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine; and Department of Child Health (A.W., K.W.), University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital.
² From the Division of Epilepsy and Clinical Neurophysiology (A.V., M.G.-L., M.A.-G., J.C., T.L.), Department of Neurology, Boston Children's Hospital, Harvard Medical School, MA; Division of Child and Adolescent Neurology (A.V., E.T.P.), Department of Neurology, Mayo Clinic, Rochester, MN; Instituto de Pediatría, Facultad de Medicina (M.G.-L.), Universidad Austral de Chile, Valdivia; Servicio de Neuropsiquiatría Infantil (M.G.-L.), Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago; Division of Neurology (N.S.A.), The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania; Pediatric Neurology Unit (M.A.-G.), Department of Pediatrics, Hospital Universitari Son Espases, Universitat de les Illes Balears, Palma, Spain; Section of Neurology and Developmental Neuroscience (A.A., J.J.R.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Neurology (R.A., T.G., K.P.), Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH; Department of Neurology and Pediatrics (J.N.B., H.P.G.), University of Virginia Health System, Charlottesville; Center for Neuroscience (J.L.C., W.D.G.), Children's National Medical Center, George Washington University School of Medicine and Health Sciences, Washington, DC; Departments of Pediatrics and Neurology (K.C.), Children's Hospital Colorado, University of Colorado School of Medicine, Aurora; Department of Neurology (R.F.-M., K.S.), Division of Pediatric Neurology, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee; Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program (J.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL; Division of Pediatric Neurology (R.M.G.), Washington University Medical Center, Washington University School of Medicine, St. Louis, MO; Department of Neurology (K.K.), Boston Children's Hospital, Harvard Medical School, MA; Section of Pediatric Critical Medicine (Y.-C.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Division of Child Neurology (T.L.M.), Department of Neurology, Columbia University Medical Center, Columbia University, New York, NY; Division of Pediatric Neurology (T.L.M.), Ann & Robert H. Lurie Children's Hospital of Chicago, IL; Division of Pediatric Neurology (M.A.M., D.T.), Duke University Medical Center, Duke University, Durham, NC; Department of Neurology (L.A.M., E.J.N., M.S.W.), Division of Pediatric Neurology, University of Washington, Seattle; Center for Integrative Brain Research (E.J.N.), Seattle Children's Research Institute, WA; Department of Pediatrics (A.P.O.), Nationwide Children's Hospital, The Ohio State University, Columbus; Department of Pediatrics (J.P.), Division Pediatric Neurology, Neuro-Critical Care Program, Oregon Health and Science University, Portland; Division of Critical Care (R.C.T.), Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, MA; Critical Care and Pediatrics (A.T.), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine; and Department of Child Health (A.W., K.W.), University of Arizona College of Medicine and Barrow's Neurological Institute at Phoenix Children's Hospital. tobias.loddenkemper@childrens.harvard.edu.

Abstract

Objective: To identify factors associated with low benzodiazepine (BZD) dosing in patients with refractory status epilepticus (RSE) and to assess the impact of BZD treatment variability on seizure cessation.

Methods: This was a retrospective study with prospectively collected data of children with convulsive RSE admitted between June 2011 and January 2019. We analyzed the initial and total BZD dose within 10 minutes of treatment initiation. We used logistic regression modeling to evaluate predictors of low BZD dosing and multivariate Cox regression analysis to assess the impact of low BZD dosing on time to seizure cessation.

Results: We included 289 patients (55.7% male) with a median age of 4.3 (1.3-9.5) years. BZDs were the initial medication in 278 (96.2%). Of those, 161 patients (57.9%) received a low initial dose. Low initial BZD doses occurred in both out-of-hospital (57 of 106; 53.8%) and in-hospital (104 of 172; 60.5%) settings. One hundred three patients (37.1%) received low total BZD dose. Male sex (odds ratio [OR] 2, 95% confidence interval [CI] 1.18-3.49; p = 0.012), older age (OR 1.1, 95% CI 1.05-1.17; p < 0.001), no prior diagnosis of epilepsy (OR 2.1, 95% CI 1.23-3.69; p = 0.008), and delayed BZD treatment (OR 2.2, 95% CI 1.24-3.94; p = 0.007) were associated with low total BZD dose. Patients who received low total BZD dosing were less likely to achieve seizure cessation (hazard ratio 0.7, 95% CI 0.57-0.95).

Conclusion: BZD doses were lower than recommended in both out-of-hospital and in-hospital settings. Factors associated with low total BZD dose included male sex, older age, no prior epilepsy diagnosis, and delayed BZD treatment. Low total BZD dosing was associated with decreased likelihood of Seizure cessation.

Classification of evidence: This study provides Class III evidence that patients with RSE who present with male sex, older age, no prior diagnosis of epilepsy, and delayed BZD treatment are more likely to receive low total BZD doses. This study provides Class III evidence that in pediatric RSE low total BZD dose decreases the likelihood of seizure cessation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Age Factors
Anticonvulsants / administration & dosage*
Anticonvulsants / therapeutic use
Benzodiazepines / administration & dosage*
Child
Child, Preschool
Dose-Response Relationship, Drug
Drug Resistant Epilepsy / drug therapy*
Drug Resistant Epilepsy / physiopathology
Female
Guideline Adherence / statistics & numerical data*
Humans
Infant
Levetiracetam / therapeutic use
Male
Multivariate Analysis
Phenobarbital / therapeutic use
Phenytoin / analogs & derivatives
Phenytoin / therapeutic use
Practice Guidelines as Topic*
Proportional Hazards Models
Retrospective Studies
Sex Factors
Status Epilepticus / drug therapy*
Status Epilepticus / physiopathology
Time-to-Treatment / statistics & numerical data*

Substances

Anticonvulsants
Benzodiazepines
Levetiracetam
Phenytoin
fosphenytoin
Phenobarbital