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Original Investigation
April 2018

Association of Time to Treatment With Short-term Outcomes for Pediatric Patients With Refractory Convulsive Status Epilepticus

Author Affiliations
  • 1Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 2Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile
  • 3Department of Child Neurology, Hospital Sant Joan de Déu, Universidad de Barcelona, Barcelona, Spain
  • 4Division of Neurology, The Children’s Hospital of Philadelphia, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia
  • 5Division of Neurology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio
  • 6Department of Neurology and Pediatrics, The University of Virginia Health System, Charlottesville
  • 7Department of Epilepsy, Neurophysiology, and Critical Care Neurology, Children's National Health System, George Washington University School of Medicine and Health Sciences, Washington, DC
  • 8Departments of Pediatrics and Neurology, Children’s Hospital Colorado, University of Colorado School of Medicine, Aurora
  • 9Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program, Northwestern University Feinberg School of Medicine, Chicago, Illinois
  • 10Division of Pediatric Neurology, Duke University Medical Center, Duke University, Durham, North Carolina
  • 11Division of Critical Care, Departments of Neurology, Anesthesiology, Perioperative and Pain Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 12Section of Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
  • 13Barrows Neurological Institute, Phoenix Children’s Hospital, Department of Pediatrics, University of Arizona School of Medicine, Phoenix
  • 14Department of Neurology, Mayo Clinic, Scottsdale, Arizona
JAMA Neurol. 2018;75(4):410-418. doi:10.1001/jamaneurol.2017.4382
Key Points

Question  Several studies have shown an association of prompt treatment with status epilepticus duration, but what is the association with other outcome measures, such as death?

Findings  In this multicenter observational study of 218 children with refractory convulsive status epilepticus, a delay in first-line benzodiazepine treatment was associated with death, the need for continuous infusions, longer convulsive duration, and more frequent hypotension.

Meaning  These findings may change the perception of acute seizure and status epilepticus treatment, tentatively converting it into an extremely time-sensitive emergency that is similar to stroke or other cardiovascular events.


Importance  Treatment delay for seizures can lead to longer seizure duration. Whether treatment delay is associated with major adverse outcomes, such as death, remains unknown.

Objective  To evaluate whether untimely first-line benzodiazepine treatment is associated with unfavorable short-term outcomes.

Design, Setting, and Participants  This multicenter, observational, prospective cohort study included 218 pediatric patients admitted between June 1, 2011, and July 7, 2016, into the 11 tertiary hospitals in the United States within the Pediatric Status Epilepticus Research Group. Patients, ranging in age from 1 month to 21 years, with refractory convulsive status epilepticus (RCSE) that did not stop after the administration of at least 2 antiseizure medications were included. Patients were divided into 2 cohorts: those who received the first-line benzodiazepine treatment in less than 10 minutes and those who received it 10 or more minutes after seizure onset (untimely). Data were collected and analyzed from June 1, 2011, to July 7, 2016.

Main Outcomes and Measures  The primary outcome was death during the related hospital admission. The secondary outcome was the need for continuous infusion for seizure termination. Multivariate analysis of mortality controlled for structural cause, febrile RCSE, age, and previous neurological history (including previous RCSE events). Use of continuous infusions was additionally adjusted for generalized RCSE, continuous RCSE, and 5 or more administrations of antiseizure medication.

Results  A total of 218 patients were included, among whom 116 (53.2%) were male and the median (interquartile range) age was 4.0 (1.2-9.6) years. The RCSE started in the prehospital setting for 139 patients (63.8%). Seventy-four patients (33.9%) received their first-line benzodiazepine treatment in less than 10 minutes, and 144 (66.1%) received untimely first-line benzodiazepine treatment. Multivariate analysis showed that patients who received untimely first-line benzodiazepine treatment had higher odds of death (adjusted odds ratio [AOR], 11.0; 95% CI, 1.43 to ∞; P = .02), had greater odds of receiving continuous infusion (AOR, 1.8; 95% CI, 1.01-3.36; P = .047), had longer convulsive seizure duration (AOR, 2.6; 95% CI, 1.38-4.88; P = .003), and had more frequent hypotension (AOR 2.3; 95% CI, 1.16-4.63; P = .02). In addition, the timing of the first-line benzodiazepine treatment was correlated with the timing of the second-line (95% CI, 0.64-0.95; P < .001) and third-line antiseizure medications (95% CI, 0.25-0.78; P < .001).

Conclusions and Relevance  Among pediatric patients with RCSE, an untimely first-line benzodiazepine treatment is independently associated with a higher frequency of death, use of continuous infusions, longer convulsion duration, and more frequent hypotension. Results of this study raise the question as to whether poor outcomes could, in part, be prevented by earlier administration of treatment.