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Observational Study
. 2018 Apr 1;75(4):410-418.
doi: 10.1001/jamaneurol.2017.4382.

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

Marina Gaínza-Lein  1   2 , Iván Sánchez Fernández  1   3 , Michele Jackson  1 , Nicholas S Abend  4 , Ravindra Arya  5 , J Nicholas Brenton  6 , Jessica L Carpenter  7 , Kevin E Chapman  8 , William D Gaillard  7 , Tracy A Glauser  5 , Joshua L Goldstein  9 , Howard P Goodkin  6 , Kush Kapur  1 , Mohamad A Mikati  10 , Katrina Peariso  5 , Robert C Tasker  11 , Dmitry Tchapyjnikov  10 , Alexis A Topjian  4 , Mark S Wainwright  9 , Angus Wilfong  12 , Korwyn Williams  13   14 , Tobias Loddenkemper  1 ; Pediatric Status Epilepticus Research Group
Affiliations
Observational Study

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

Marina Gaínza-Lein et al. JAMA Neurol. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Ms Gaínza-Lein reported receiving support from the Epilepsy Research Fund. Dr Sánchez Fernández reported receiving funding by Fundación Alfonso Martín Escudero and the HHV6 Foundation. Dr Gaillard reported receiving income from clinical revenue generated for Children's National Medical Center clinical care; receiving federal support through grants 1P30HD40677-01, 2K12NS052159-06A1 NIMH RO1 MH084961, 1R21MH092615, NSF 095998, CDC 1UO1DP003255, DOD/USAMRAA W81XWH-11-2-0198, and PICORE 527 from the National Institute of Neurological Disorders and Stroke; receiving foundation support from the Epilepsy Foundation of America, American Epilepsy Society, Infantile Epilepsy Research Foundation (Lundbeck), and Citizens United for Research In Epilepsy (CURE); receiving funding for the medical center, which conducts industry-supported trials from which no salary support is derived, from Ovation Pharmaceuticals, King Pharmaceuticals, and PRA International/Eisai; holding stock in Johnson & Johnson, Lily, GlaxoSmithKline, Pfizer, Siemens, and General Electric; and serving on the editorial board of Epilepsia and Epilepsy Research. Dr Glauser reported receiving grants 2U01-NS045911, U10-NS077311, R01-NS065840, and R01-HD073115 from the National Institutes of Health (NIH); receiving consulting fees from Supernus; serving as a paid expert consultant on medico-legal cases for the US Department of Justice; and receiving royalties from a patent license from AssureX Health. Dr Goodkin reported being a member of the clinical standardization team for Sage Therapeutics. Dr Topjian reported receiving grant K23 k23NS075363 from the NIH. Dr Wainwright reported serving as a scientific consultant for Sage Therapeutics, a sponsor of a clinical trial for treatment of super-refractory status epilepticus. Dr Wilfong reported receiving research grant funding for epilepsy from GW Pharm, Novartis, Acorda, Upsher-Smith, Lundbeck, and Eisai as well as receiving royalties from publication of Up To Date chapters on epilepsy. Dr Loddenkemper reported serving on the Laboratory Accreditation Board for Long Term (Epilepsy and Intensive Care Unit) Monitoring, on the council of the American Clinical Neurophysiology Society (as treasurer), and on the American Board of Clinical Neurophysiology; being an associate editor for Seizure, a contributing editor for Epilepsy Currents, and an associate editor for Wyllie’s Treatment of Epilepsy, 6th edition; being part of pending patent applications to detect and predict seizures and to diagnose epilepsy; receiving research support from the Epilepsy Research Fund, the American Epilepsy Society, the Epilepsy Foundation of America, the Epilepsy Therapy Project, the Patient-Centered Outcomes Research Institute, the Pediatric Epilepsy Research Foundation, CURE, and the HHV-6 Foundation as well as research grants from Lundbeck, Eisai, Upsher-Smith, Acorda, and Pfizer; serving as a consultant for Zogenix, Upsher-Smith, and Lundbeck; and receiving speaker honorariums from national societies, including the American Academy of Neurology, American Epilepsy Society, and American Clinical Neurophysiology Society. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Untimely First-line Benzodiazepine (BZD) Treatment and Association With Outcome
A, All 7 patients who died prior to hospital discharge received untimely first-line BZD treatment (≥10 minutes). B, Of the 112 patients (51.4%) who received a continuous infusion as treatment for refractory convulsive status epilepticus, 80 (71.4%) received untimely first-line BZD treatment.
Figure 2.
Figure 2.. Association Between Log Time to First-line Benzodiazepine (BZD) Treatment and Log Convulsive Status Epilepticus (SE) Duration
The x-axis represents the time to the first-line BZD treatment in minutes in a log transformation, and the y-axis represents the duration of the convulsive SE duration in minutes in log transformation. A linear association exists between log time to the first-line BZD treatment and the log convulsive SE duration (95% CI, 0.21-0.44; P < .001).
Figure 3.
Figure 3.. Association Between Log Time to First-line Benzodiazepine (BZD) Treatment and Second- and Third-line Treatments
A, The x-axis represents the time to the first-line BZD treatment in minutes in a log transformation, and the y-axis represents the time to the second-line treatment with non-BZD antiseizure medication (ASM) in minutes in log transformation. A linear association exists between log time to the first-line BZD treatment and log time to the second-line treatment with non-BZD ASM; with every 1 minute change in a log scale of the first-line BZD treatment, the second-line treatment was administered 0.8 log minutes later (95% CI, 0.64-0.95; P < .001). B, The x-axis represents the time to the first-line BZD treatment in minutes in a log transformation, and the y-axis represents the time to the third-line treatment with continuous infusion in minutes also in log transformation. A linear association exists between log time to the first-line BZD treatment and log time to the third-line treatment; with every log minute change of the first-line BZD treatment, the third-line treatment was administered 0.5 log minutes later (95% CI, 0.25-0.78; P < .001).
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