Benzodiazepine-refractory Status Epilepticus Research Articles

Evaluation of the Use of Ketamine in Prehospital Seizure Management: A Retrospective Review of the ESO Database

Objectives Benzodiazepines are the primary antiseizure medication used by Emergency Medical Services (EMS) for seizures. Available literature in the United States and internationally shows 30% to 40% of seizures do not terminate with benzodiazepines called benzodiazepine refractory status epilepticus (BRSE). Ketamine is a potential treatment for BRSE due to its unique pharmacology. However, its application in the prehospital setting is mostly documented in case reports. Little is known about its use by EMS professionals for seizure management, whether as initial treatment or for BRSE, creating an opportunity to describe its current use and inform future research. Methods We performed a retrospective review of 9-1-1 EMS encounters with a primary or secondary impression of seizure using the ESO Data Collaborative from 2018 to 2021. We isolated encounters during which ketamine was administered. We excluded medication administrations prior to EMS arrival and encounters without medication administration. Subgroup analysis was performed to control for airway procedure as an indication for ketamine administration. We also evaluated for co-administration with other antiseizure medications, dose and route of administration, and response to treatment. Results We identified 99,576 encounters that met inclusion. There were 2,531/99,576 (2.54%) encounters with ketamine administration and 50.7% (1,283/2,531) received ketamine without an airway procedure. There were 616 cases (48%, 616/1,283) where ketamine was given without another antiseizure medication (ASM) and without any airway procedure. The remaining 667 (52%) cases received ketamine with at least one other ASM, most commonly midazolam (89%, 593/667). Adjusted for the growth in the ESO dataset, ketamine use by EMS professionals during encounters for seizures without an airway procedure increased from 0.90% (139/15,375) to 1.45% (416/28,651) an increase of 62% over the study period. Conclusions In this retrospective review of the ESO Data Collaborative, ketamine administration for seizure encounters without an airway procedure increased over the study period, both as a single agent and with another ASM. Most ketamine administrations were for adult patients in the south and in urban areas. The frequency of BRSE, the need for effective treatment, and the growth in ketamine use warrant prospective prehospital research to evaluate the value of ketamine in prehospital seizure management.

Standardizing the Treatment for Pediatric Status Epilepticus: A Quality Improvement Study

AbstractApproximately 30 to 40% of children with generalized convulsive status epilepticus remain refractory to benzodiazepines. Due to inconsistences in our approach for these patients in the emergency department, we initiated a quality improvement project to standardize the treatment process.A plan, do, study, act (PDSA) format was used for the project that involved creating a treatment algorithm based on the American Epilepsy Society (AES) guidelines, educating the staff on the treatment recommendations, and then collecting clinical data. We selected time to second-line anticonvulsant therapy as our primary outcome measure. Following the implementation of the treatment algorithm and order set, we performed comparative analyses of the pre- and post-implementation cohorts.A total of 21 pre- and 36 post-implementation patients were identified. Baseline data demonstrated no difference in age or gender. Post-implementation patients received second-line therapy sooner (24 vs. 39 minutes, p = 0.001) and more post patients received second-line therapy within the AES guideline's time frame (83 vs. 52%, p = 0.012) compared with the pre-implementation patients. In a multivariable analysis, post-implementation patients had a higher likelihood of receiving second-line therapy within the AES-recommended time frame (odds ratio [OR] = 5.78; 95% confidence interval [CI]: 1.49–22.48; p = 0.011). Age, gender, intubation status, anticonvulsants given prior to emergency department (ED), and treatment by a pediatric ED specialist were not associated with increased odds of provider adherence to AES guidelines.In conclusion, a standardized approach utilizing a treatment algorithm for patients with pediatric benzodiazepine refractory status epilepticus was associated with reduced time to administration of second-line anticonvulsant therapy and better compliance with AES guidelines in a mixed pediatric and adult ED setting.

Management of status epilepticus in pregnancy: a clinician survey

BackgroundStatus epilepticus in pregnancy (SEP) is rare and life-threatening for both mother and fetus. There are well-established guidelines for the management of women with epilepsy during pregnancy; however, there is little evidence guiding the management of SEP, leading to uncertainty among treating physicians. Therefore, this survey aims to investigate the real-world practices of physicians treating SEP to explore management approaches for improvements in care.MethodsAn anonymous, electronic survey was created and distributed to neurointensivists and neurologists between September and December 2021.ResultsOne hundred physicians initiated the survey and 95 completed it in full: 87 (87%, 87/100) identified neurology as their primary specialty, 31 had subspecialty training in neurocritical care, and 48 had subspecialty training in epilepsy and/or clinical neurophysiology. Over half of the survey respondents (67%, 67/100) reported having participated in the management of SEP, with 48.9% (49/98) having done so in the past year. Most survey respondents (73%, 73/100) reported that their management approach to SEP is different than that of non-pregnant patients. Survey respondents were more likely to involve epilepsy consultants when treating SEP (58.5%, 58/99) and the vast majority involved Obstetrics/Maternal Fetal Medicine consultants (90.8%, 89/98). Survey respondents showed a clear preference for levetiracetam (89.7%, 87/97) in the treatment of benzodiazepine refractory status epilepticus followed by lacosamide (61%, 60/98) if an additional second line agent was needed. Valproate and phenobarbital were unlikely to be used. There was less agreement for the management of refractory and super-refractory SEP.ConclusionsLevetiracetam is the most frequently used anti-seizure medication (ASM) for benzodiazepine-refractory SEP. Survey participants tended to manage SEP differently than in non-pregnant patients including greater involvement of interdisciplinary teams as well as avoidance of ASMs associated with known teratogenicity.

Third-Generation Antiseizure Medication in the Treatment of Benzodiazepine-Refractory Status Epilepticus in Poststroke Epilepsy: A Retrospective Observational Register-Based Study.

Status epilepticus in poststroke epilepsy is a challenging condition because of multiple vascular comorbidities and the advanced age of patients. Data on third-generation antiseizure medication (ASM) in this condition are limited. The aim of this study was to evaluate the efficacy of third-generation ASMs in the second- or third-line therapy of benzodiazepine-refractory status epilepticus in poststroke epilepsy following acute ischemic stroke. Data on the effectiveness of third-generation ASMs in patients with status epilepticus in poststroke epilepsy were gathered from two German Stroke Registries and the Mainz Epilepsy Registry. We included only cases with epilepsy remote to the ischemic event. No patients with acute symptomatic seizures were included. The following third-generation ASMs were included: brivaracetam, lacosamide, eslicarbazepine, perampanel, topiramate, and zonisamide. The assessment of effectiveness was based on seizure freedom within 48 h since the start of therapy with the respective ASM. Seizure freedom was evaluated both clinically (clinical evaluation at least three times per day) and by daily electroencephalogram records. Of the 138 patients aged 70.8 ± 8.1 years with benzodiazepine-refractory status epilepticus in ischemic poststroke epilepsy, 33 (23.9%) were treated with lacosamide, 24 (17.4%) with brivaracetam, 23 (16.7%) with eslicarbazepine, 21 (15.2%) with perampanel, 20 (14.5%) with topiramate, and 17 (12.3%) with zonisamide. Seizure freedom within 48 h was achieved in 66.7% of patients with lacosamide, 65.2% with eslicarbazepine, 38.1% with perampanel, 37.5% with brivaracetam, 35.0% with topiramate, and 35.3% with zonisamide (p < 0.05 for comparison of lacosamide or eslicarbazepine to other ASMs). Based on these data, lacosamide and eslicarbazepine might be more favorable in the treatment of refractory status epilepticus in poststroke epilepsy, when administered as second- or third-line ASMs before anesthesia. Because of the fact that these ASMs share the same mechanism of action (slow inactivation of sodium channels), our findings could motivate further research on the role that this pharmaceutical mechanism of action has in the treatment of poststroke epilepsy. This study was registered at ClinicalTrials.gov (NCT05267405).

Tolerability and pharmacokinetics of intravenous allopregnanolone with and without midazolam pretreatment in two healthy dogs.

The neurosteroid allopregnanolone (ALLO) is under investigation as a treatment for benzodiazepine-refractory status epilepticus (SE). Here we assess the cardiopulmonary safety of intravenous ALLO by itself and after a clinically recommended dose of midazolam (MDZ) in two healthy adult beagles. Each dog received ALLO (1 mg/kg, IV), and after a washout period of 2 weeks, the dog was dosed with MDZ (0.2 mg/kg, IV) followed 10 min later by ALLO. Behavioral state, vital signs, arterial blood gasses, blood chemistries, and plasma ALLO concentrations were monitored for up to 6 h after dosing. The dogs appeared sleepy but were fully responsive after both treatments. No depression of mean arterial pressure or respiratory rate was noted. Blood gas measurements failed to show evidence of drug-induced acute respiratory acidosis. Estimated maximum plasma ALLO concentrations were in the range of 1500 to 3000 ng/mL. The results indicate that intravenous ALLO can be used safely to treat benzodiazepine-refractory SE, even when administered shortly after a benzodiazepine.

Direct activation of KCC2 arrests benzodiazepine refractory status epilepticus and limits the subsequent neuronal injury in mice

Hyperpolarizing GABAAR currents, the unitary events that underlie synaptic inhibition, are dependent upon efficient Cl- extrusion, a process that is facilitated by the neuronal specific K+/Cl- co-transporter KCC2. Its activity is also a determinant of the anticonvulsant efficacy of the canonical GABAAR-positive allosteric: benzodiazepines (BDZs). Compromised KCC2 activity is implicated in the pathophysiology of status epilepticus (SE), a medical emergency that rapidly becomes refractory to BDZ (BDZ-RSE). Here, we have identified small molecules that directly bind to and activate KCC2, which leads to reduced neuronal Cl- accumulation and excitability. KCC2 activation does not induce any overt effects on behavior but prevents the development of and terminates ongoing BDZ-RSE. In addition, KCC2 activation reduces neuronal cell death following BDZ-RSE. Collectively, these findings demonstrate that KCC2 activation is a promising strategy to terminate BDZ-resistant seizures and limit the associated neuronal injury.

An Expected Score Approach to Ordinal Outcomes in a Bayesian, Response Adaptive, Randomized Trial

Ordinal outcomes are common in medicine and can be analyzed in many ways, but the distribution of ordinal data can present unique challenges. The proposed KESETT study is a three-armed, randomized trial comparing two doses of ketamine plus levetiracetam to levetiracetam alone for treating patients with benzodiazepine-refractory status epilepticus. A Bayesian, adaptive clinical trial is proposed employing an ordinal primary outcome at 60 min ranging from 1 (improving consciousness and seizure cessation) to 5 (life-threatening event/death). Based on a previous study, the ordinal outcome is expected to have a bimodal distribution, with the effect of treatment expected to be nonproportional across the outcome scale. As such, approaches relying on assuming proportionality of the odds are not appropriate. We propose for this scenario an analytic approach to compare ordinal outcomes using the expected score derived from the posterior distribution for each treatment group. This approach requires minimal assumptions, maintains the benefit of using the full ordinal scale, is interpretable, and can be used in a Bayesian analysis framework. We compare this new approach under multiple simulated scenarios to three traditional frequentist approaches. The new approach controls Type I error and power, resulting in a sizable reduction in sample size relative to a nonparametric test.

An Emergency Department Quality Improvement Project for Intravenous Levetiracetam Administration

Background: Levetiracetam is a readily available, safe anticonvulsive medication. It is frequently administered as IV piggyback with a pump, carrier fluid, and tubing. The Established Status Epilepticus Treatment Trial demonstrated levetiracetam being similarly effective to previously used treatments in doses up to 4500 mg administered over 10 minutes. Objective: We sought to compare usage, cost, and waste of IV piggyback with IV push administration of levetiractam following implementation of an IV push protocol in an academic emergency department. Methods: A three-month review of levetiracetam administration was done following protocol implementation using IV push for initial treatment of benzodiazepine-refractory status epilepticus. The review quantified the number of IV push vs IV piggyback doses for all indications and evaluated cost of supplies necessary for administration. Results: During the study period, 137 patients received 142 doses of IV levetiracetam. Fifty-one doses (36%) were given as IV push rather than IV piggyback. The majority of doses 116 (82%) were 1000-2000 mg and 11 doses (8%) 3500-4500 mg. Estimated three-month savings with complete transition of IV piggyback to IV push would exceed $6000 just in our ED. The amount of sterile solution carrier fluid was also reduced and IV pump time freed. Conclusion: Implementation of an emergency department IV push levetiracetam protocol resulted in cost savings. Opportunities remain to improve clinical implementation practices. Medication administration represents one crucial target area where healthcare systems can implement policies to reduce waste and commit to climate-smart health care.

Treatment of Toxin-Related Status Epilepticus With Levetiracetam, Fosphenytoin, or Valproate in Patients Enrolled in the Established Status Epilepticus Treatment Trial

We describe a subset of patients with toxin-related precipitants of seizures/status epilepticus enrolled in the Established Status Epilepticus Treatment Trial (ESETT). The ESETT was a prospective, double-blinded, adaptive trial evaluating levetiracetam, valproate, and fosphenytoin as second-line agents in benzodiazepine-refractory status epilepticus in adults and children. The primary outcome was the absence of seizures and improvement in the level of consciousness 1 hour after study drug administration. In this post hoc analysis, the safety and efficacy of second-line agents in a subset of patients with toxin-related seizures are described. A total of 249 adults and 229 children were enrolled in the ESETT. Toxin-related seizures occurred in 29 (11.6%) adults and 1 child (0.4%). In adults, men were more likely to have toxin-related seizures than women (25 of 145, 17.2% versus 4 of 104, 3.9%). The most common toxin-related precipitants were alcohol withdrawal and cocaine, 11(37%) of 30 patients each. Cocaine was used with other substances by most patients 10 (91%) of 11, most commonly with an opioid 7 (64%) of 11. For alcohol withdrawal-related seizures, treatment successes with levetiracetam, valproate, and fosphenytoin were 3 (100%) of 3, 3 (50%) of 6, and 1 (50%) of 2, respectively. For cocaine-related seizures, treatment success was 1 (14%) of 7 for levetiracetam, 0 (0%) of 1 for valproate, and 1 (33%) of 3 for fosphenytoin. One patient who used cocaine and an opioid received fosphenytoin and developed life-threatening hypotension. In the ESETT, approximately 1 in 10 adult patients with status epilepticus presented with a toxin-related seizure. Alcohol withdrawal and cocaine/opioid use were the most common toxin-related precipitants. Toxin-related benzodiazepine-refractory status epilepticus was successfully treated with a single dose of second-line antiseizure medication in 42% of the patients.

Comparison of the efficacy and safety of levetiracetam and phenytoin in the treatment of established status epilepticus: A systematic review and meta-analysis

Status epilepticus (SE) is the second most critical neurological illness after cerebrovascular disease. Phenytoin has traditionally been considered the second-line drug of first choice after failure of first-line treatment using benzodiazepines. In recent years, levetiracetam has been proposed as a potential substitute for phenytoin. To comprehensively evaluate the efficacy and safety of levetiracetam and phenytoin in the treatment of patients with established SE, we integrated the data from 11 eligible studies and conducted a systematic review and meta-analysis. The PubMed, Web of Science, Cochrane Library, and Embase databases were searched to identify eligible articles reporting outcomes including clinical seizure cessation within 60 min, clinical recurrence rate within 24 h, good final outcome at discharge, and adverse events (AEs) of treatment with levetiracetam and phenytoin. Our study included a total of 11 trials including a total of 1933 patients. The outcomes showed that the pooled Risk Raito (RR) of clinical seizure cessation within 60 min was 1.08 (95% CI = 1.02–1.14, P = 0.01). The pooled RR of clinical recurrence rate within 24 h was 1.03 (95% CI = 0.66–1.59, P = 0.91). The pooled RR of AEs was 0.83 (95% CI = 0.57–1.21, P = 0.34). The pooled RRs of life-threatening hypotension and acute respiratory depression were 0.29 (95% CI = 0.10–0.81, P = 0.02) and 0.63 (95% CI = 0.40–0.98, P = 0.04), respectively. Levetiracetam might be more effective than phenytoin for the treatment of established SE and is associated with a lower incidence of more serious AEs. Levetiracetam can be used as an alternative to phenytoin for the treatment of benzodiazepine-refractory SE.

Levetiracetam Versus Phenytoin or Fosphenytoin for Second-Line Treatment of Pediatric Status Epilepticus: A Meta-Analysis.

To synthesize the available evidence examining the efficacy and safety of levetiracetam compared with phenytoin or fosphenytoin in benzodiazepine-refractory pediatric status epilepticus. We searched (from inception until April 27, 2020) Ovid MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials. Two reviewers, independently and in duplicate, screened citations and manuscripts for eligible randomized controlled trials. Independently and in duplicate, we performed data abstraction, risk of bias assessment, and certainty assessment using Grading of Recommendations, Assessment, Development, and Evaluation. We performed meta-analyses using random-effect models or, if insufficient data, presented findings narratively. We identified seven randomized controlled trials (n = 1,575). Pooled analysis demonstrated low certainty evidence for no difference of levetiracetam on time to seizure cessation (mean difference, -3.11 min; 95% CI, -6.67 to 0.45), early seizure cessation (relative risk, 1.09, 95% CI, 0.95-1.26), or late seizure cessation (relative risk, 1.05; 95% CI, 0.93-1.18). Adverse event outcomes were limited by low event numbers. We found low certainty evidence for less respiratory depression with levetiracetam (relative risk, 0.28; 95% CI, 0.12-0.69). The efficacy of levetiracetam is comparable with phenytoin or fosphenytoin in children with benzodiazepine-refractory status epilepticus (low certainty evidence). Levetiracetam may cause less respiratory depression. Clinicians and guideline developers should weigh safety profiles when choosing between these agents.

Early Exposure of Fosphenytoin, Levetiracetam, and Valproic Acid After High‐Dose Intravenous Administration in Young Children With Benzodiazepine‐Refractory Status Epilepticus

Fosphenytoin (FOS) and its active form, phenytoin (PHT), levetiracetam (LEV), and valproic acid (VPA) are commonly used second-line treatments of status epilepticus. However, limited information is available regarding LEV and VPA concentrations following high intravenous doses, particularly in young children. The Established Status Epilepticus Treatment Trial, a blinded, comparative effectiveness study of FOS, LEV, and VPA for benzodiazepine-refractory status epilepticus provided an opportunity to investigate early drug concentrations. Patients aged ≥2 years who continued to seizure despite receiving adequate doses of benzodiazepines were randomly assigned to FOS, LEV, or VPA infused over 10 minutes. A sparse blood-sampling approach was used, with up to 2 samples collected per patient within 2 hours following drug administration. The objective of this work was to report early drug exposure of PHT, LEV, and VPA and plasma protein binding of PHT and VPA. Twenty-seven children with median (interquartile range) age of 4 (2.5-6.5) years were enrolled. The total plasma concentrations ranged from 69 to 151.3 μg/mL for LEV, 11.3 to 26.7 μg/mL for PHT and 126 to 223 μg/mL for VPA. Free fraction ranged from 4% to 19% for PHT and 17% to 51% for VPA. This is the first report in young children of LEV concentrations with convulsive status epilepticus as well as VPA concentrations after a 40 mg/kg dose. Several challenges limited patient enrollment and blood sampling. Additional studies with a larger sample size are required to evaluate the exposure-response relationships in this emergent condition.

Ketamine as adjunct to midazolam treatment following soman-induced status epilepticus reduces seizure severity, epileptogenesis, and brain pathology in plasma carboxylesterase knockout mice

Delayed treatment of cholinergic seizure results in benzodiazepine-refractory status epilepticus (SE) that is thought, at least in part, to result from maladaptive trafficking of N-methyl-d-aspartate (NMDA) and gamma-aminobutyric acid type A (GABAA) receptors, the effects of which may be ameliorated by combination therapy with the NMDA receptor antagonist ketamine. Our objective was to establish whether ketamine and midazolam dual therapy would improve outcome over midazolam monotherapy following soman (GD) exposure when evaluated in a mouse model that, similar to humans, lacks plasma carboxylesterase, greatly reducing endogenous scavenging of GD. In the current study, continuous cortical electroencephalographic activity was evaluated in male and female plasma carboxylesterase knockout mice exposed to a seizure-inducing dose of GD and treated with midazolam or with midazolam and ketamine combination at 40 min after seizure onset. Ketamine and midazolam combination reduced GD-induced lethality, seizure severity, and the number of mice that developed spontaneous recurrent seizure (SRS) compared with midazolam monotherapy. In addition, ketamine–midazolam combination treatment reduced GD-induced neuronal degeneration and microgliosis. These results support that combination of antiepileptic drug therapies aimed at correcting the maladaptive GABAA and NMDA receptor trafficking reduces the detrimental effects of GD exposure. Ketamine may be a beneficial adjunct to midazolam in reducing the epileptogenesis and neuroanatomical damage that follows nerve agent exposure and pharmacoresistant SE.

4512 Allopregnanolone Dose Finding for Status Epilepticus Treatment by Pharmacokinetic-Pharmacodynamic Modeling using Quantitative EEG in Dogs

OBJECTIVES/GOALS: Allopregnanolone (ALLO), a modulator of GABAA receptors, may be useful as a treatment for human and canine benzodiazepine-refractory status epilepticus (SE). Our objective was to develop a phamacokinetic-pharmacodynamic (PKPD) model relating ALLO plasma concentrations to electroencephalographic (EEG) effects in dogs. METHODS/STUDY POPULATION: Four healthy dogs and one dog with epilepsy that had implanted intracranial electrodes were utilized. ALLO doses ranging from 1-6 mg/kg were administered IV over 5 min. EEG data were collected during four IM doses (1-2 mg/kg). Blood samples were collected up to 6 hr following dosing. ALLO concentrations were measured using HPLC-MS/MS. Power density was determined in EEG bands using a custom algorithm. A two-compartment link PKPD model was developed to describe the relation between ALLO plasma concentration and change in EEG power in the alpha, beta, delta and theta bands. RESULTS/ANTICIPATED RESULTS: ALLO caused a rapid increase in absolute power density in all EEG bands measured (1-4, &gt;4 – 8, &gt;8 – 12, &gt;12 – 25, and &gt;25 – 100 Hz). The onset of effect was rapid (1-3 min) and demonstrated by frequency band and dose analysis. Concentration-EEG data were best fit by a two-compartment PK model and sigmoidal Emax PD indirect link model. The beta frequency band was most sensitive, showing increases in power at the lowest ALLO concentrations. The EC50 concentration for the beta frequency was ~270 ng/mL. The EC50 values for effects on the other frequency bands were ~500-700 ng /mL. In conclusion, IV ALLO causes a rapid effect on EEG that can be used to determine minimal plasma concentrations associated with target engagement. DISCUSSION/SIGNIFICANCE OF IMPACT: Dose selection for future clinical trials will use the effective concentrations determined here in conjunction with studies in animal status epilepticus models. Studies are planned in client owned dogs with epilepsy to evaluate clinical efficacy in dogs and as nonclinical proof-of-concept evidence supporting translational studies in people. CONFLICT OF INTEREST DESCRIPTION: Michael Rogawski and Dorota Zolkowska are named as inventors on patent applications claiming use of neuroactive steroids including allopregnanolone and ganaxolone in the treatment of status epilepticus.

Patient and Surrogate Postenrollment Perspectives on Research Using the Exception From Informed Consent: An Integrated Survey

It is important for researchers interested in trials using the exception from informed consent to understand the views and experiences of enrolled individuals. Previous studies have shown that patient and surrogate attitudes are generally positive. These studies were small and did not include pediatric patients, and interviews were often conducted long after trial enrollment. This study sought to explore attitudes toward exception from informed consent in a larger sample and more contemporaneous setting. A 10-item paper-and-pencil survey was integrated into the Established Status Epilepticus Treatment Trial, a randomized trial of 3 treatments for benzodiazepine-refractory status epilepticus in pediatric and adult patients. Primary domains included attitudes toward trial enrollment, exception from informed consent, and community consultation. Simple descriptive statistics, χ2, and Fisher's exact tests were conducted. Of 317 patients and surrogates, 90% agreed with or were neutral about the statement "I am glad that I/my family member was included in the Established Status Epilepticus Treatment Trial research study," whereas 10% disagreed. Twenty-seven percent disagreed with enrollment in the study without prospective consent. Black participants were more likely than white, other race, and unknown-race participants to disagree with enrollment without prospective consent (36% versus 23%, 14%, and 14%, respectively). Participants indicated that patients (81%), their families (65%), and those at risk for seizures (51%) were most important to include in community consultation. This study aimed to explore attitudes toward exception from informed consent enrollment among participants at all sites in a large, multicenter exception from informed consent trial. General acceptance of trial enrollment was high; acceptance of exception from informed consent specifically was somewhat lower, especially among black participants. Our findings provide further support for targeted community consultation focusing on individuals with connections to the disease under study. Future research should focus on communication in the postenrollment period, especially with individuals who may have concerns about exception from informed consent.

Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (ESETT): a double-blind, responsive-adaptive, randomised controlled trial

Benzodiazepine-refractory, or established, status epilepticus is thought to be of similar pathophysiology in children and adults, but differences in underlying aetiology and pharmacodynamics might differentially affect response to therapy. In the Established Status Epilepticus Treatment Trial (ESETT) we compared the efficacy and safety of levetiracetam, fosphenytoin, and valproate in established status epilepticus, and here we describe our results after extending enrolment in children to compare outcomes in three age groups. In this multicentre, double-blind, response-adaptive, randomised controlled trial, we recruited patients from 58 hospital emergency departments across the USA. Patients were eligible for inclusion if they were aged 2 years or older, had been treated for a generalised convulsive seizure of longer than 5 min duration with adequate doses of benzodiazepines, and continued to have persistent or recurrent convulsions in the emergency department for at least 5 min and no more than 30 min after the last dose of benzodiazepine. Patients were randomly assigned in a response-adaptive manner, using Bayesian methods and stratified by age group (<18 years, 18-65 years, and >65 years), to levetiracetam, fosphenytoin, or valproate. All patients, investigators, study staff, and pharmacists were masked to treatment allocation. The primary outcome was absence of clinically apparent seizures with improved consciousness and without additional antiseizure medication at 1 h from start of drug infusion. The primary safety outcome was life-threatening hypotension or cardiac arrhythmia. The efficacy and safety outcomes were analysed by intention to treat. This study is registered in ClinicalTrials.gov, NCT01960075. Between Nov 3, 2015, and Dec 29, 2018, we enrolled 478 patients and 462 unique patients were included: 225 children (aged <18 years), 186 adults (18-65 years), and 51 older adults (>65 years). 175 (38%) patients were randomly assigned to levetiracetam, 142 (31%) to fosphenyltoin, and 145 (31%) were to valproate. Baseline characteristics were balanced across treatments within age groups. The primary efficacy outcome was met in those treated with levetiracetam for 52% (95% credible interval 41-62) of children, 44% (33-55) of adults, and 37% (19-59) of older adults; with fosphenytoin in 49% (38-61) of children, 46% (34-59) of adults, and 35% (17-59) of older adults; and with valproate in 52% (41-63) of children, 46% (34-58) of adults, and 47% (25-70) of older adults. No differences were detected in efficacy or primary safety outcome by drug within each age group. With the exception of endotracheal intubation in children, secondary safety outcomes did not significantly differ by drug within each age group. Children, adults, and older adults with established status epilepticus respond similarly to levetiracetam, fosphenytoin, and valproate, with treatment success in approximately half of patients. Any of the three drugs can be considered as a potential first-choice, second-line drug for benzodiazepine-refractory status epilepticus. National Institute of Neurological Disorders and Stroke, National Institutes of Health.

Clinical Effectiveness of Levetiracetam Compared to Fosphenytoin in the Treatment of Benzodiazepine Refractory Convulsive Status Epilepticus.

To determine whether levetiracetam is an alternative to fosphenytoin to control Benzodiazepine Refractory Status Epilepticus (BRSE) in pediatric population and also to compare the acute drug related side-effects and ventilation requirement among the both arms of anti-epileptic drug therapy. All consecutive children admitted with BRSE were randomized to group A, who received fosphenytoin at 20mg/kg phenytoin equivalents (PE) dose and group B who received levetiracetam at 40mg/kg over 10min. Time to terminate seizure (response latency) was measured. If seizure remained refractory after 20min of test drug administration, appropriate drug escalation was made according to pediatrician's discretion. All primary and secondary outcome measures were compared between the two therapeutic groups. Of 61 children enrolled over 18 mo period, 29 (47.5%) were randomized to group A and 32 (52.5%) were randomized to Group B. Baseline characteristics were comparable between the two groups. Among 61 children, 58(98%) required Pediatric Intensive Care Unit (PICU) admission and among those 5(8.2%) children required mechanical ventilation. Duration of PICU stay, hospital stay, the response latency and seizure recurrence were compared between both groups. Significant number of children received additional anti-epileptic drugs (AEDs) in fosphenytoin group [9/29(31%)] compared to levetiracetam group [2/32(7%)] to control seizure. Levetiracetam may be an effective alternative to fosphenytoin in management of BRSE in children but multicentric trials with large sample size are needed to substantiate this observation.

Abstract 134: Patients’ Perspectives on Enrollment in Research Using the Exception From Informed Consent: An Integrated Survey

Introduction: Relatively minimal data exist regarding perspectives of patients (or surrogate decision-makers) after enrollment in clinical trials using the exception from informed consent (EFIC) for emergency research, a regulation essential for resuscitation research. Prior studies have shown that attitudes are generally positive but have enrolled a small proportion of participants and may have been subject to selection bias. Methods: As part of the study protocol, a 10-item paper-and-pencil survey was integrated into the protocol for all sites of the Established Status Epilepticus Treatment Trial (ESETT) trial, a randomized trial of three treatments for benzodiazepine-refractory status epilepticus in pediatric and adult patients. All patients (or surrogate) were given the survey after being asked for consent to continue in ESETT. Primary domains included acceptance of trial enrollment, acceptance of EFIC, and views on which population to include in community consultation. Response items primarily used a 5-point Likert scale. Simple descriptive statistics were tabulated. Results: In total, 317 of 443 patients/surrogates completed the survey (71.6% response). Only 7.3% (23/317) disagreed with the statement “I am glad that my family member/I was included in the ESETT research study,” and 24.9% (79/317) disagreed with being included under EFIC. When asked whom researchers should consult during community consultation, 81.1% (257/317) said patients who have had seizures, 64.7% (205/317) said their family members, and individuals at particular risk for seizures (50.8%) (161/317) were most frequently chosen. Only 26.5% (84/317) felt that members of the general public should be consulted. Conclusions: This is the largest study to date of participants’ perspectives on being enrolled in an EFIC trial. Rates of enrollment acceptance were relatively high; acceptance of EFIC specifically was slightly lower. There is much greater support for consulting individuals with connections to the disease under study than the general public or other groups. These findings further suggest that targeted community consultation may be appropriate and the importance of clear communication with participants after enrollment regarding reasons for EFIC use.

267 Research Protocol Training Through an Electronic Learning Module and in Situ Simulation

We describe the process of clinical staff training of a complex emergency research study through a layered approach to disseminating study protocol information to clinical staff. The Established Status Epilepticus Treatment Trail (ESETT) seeks to compare effectiveness of fos-phenytoin, levetiracetam, or valproic acid in subjects with benzodiazepine-refractory status epilepticus. ESETT is an EFIC trial in which qualifying subjects can be enrolled by the clinical staff within minutes of ED admission often in the absence of the research team. An e-learning module was created to emphasize crucial clinical care elements of the protocol including: the importance of benzodiazepine dosing and timing, rationale for use of Exception From Informed Consent (EFIC), study drug dosing and administration, the post-infusion assessments, and how to contact the study team. A seizure SIM scenario was drafted based on clinical learning objectives for a successful ESETT enrollment including: recognizing a potential ESETT subject as a patient with seizures despite adequate benzodiazepine dosing (without coordinator prompting); proper study drug administration and follow-up assessments. The study protocol assist device (iPod touch) was set to practice mode and mock-drug (saline) was loaded into the study drug kit. On the day of the SIM, a seizure code was called into ED dispatch and clinical staff to treat a high-fidelity SIM mannequin in status epilepticus. The clinical staff administered mock benzodiazepine doses and then identified the seizing SIM mannequin as a potential ESETT subject. Clinical staff located the ESETT study drug box, verified inclusion/exclusion and study dose, utilized the administered mock study drug and followed the prompts from the protocol assist device through the first post infusion assessment. Immediately after the in situ SIM, a SIM de-brief occurred that included the clinical staff (physicians, nurses and pharmacy staff) and the clinical research team (co-investigator, lead coordinator). The LMS report showed 40/45 (89%) of ED RN staff viewed the e-learning module. During the SIM debriefing, clinical staff and the research team jointly identified logistical barriers to address including: study poster location, slow iPod, procedure to un-blind study drug, proper “next steps for care” in the event of study drug failure. The feedback from the ED staff was that they learn better by doing (kinesthetic learning style). “Hands on is always the best, easier to learn when you get to see and do.” In situ simulation (SIM) is used in clinical education and training, but evidence on its utility for protocol training in research trials is limited. A layered approach to disseminating study protocol information to clinical staff including an e-learning module and kinesthetic learning through an in situ SIM helped the clinical staff incorporate protocol training into their clinical care.

DRESS after IV phenytoin associated with cytochrome P450 CYP2C9*3 homozygosity

Phenytoin is a first-generation antiepileptic drug, which is used in the treatment of focal seizures and as standard of care for patients with benzodiazepine-refractory status epilepticus. Elimination of phenytoin occurs primarily via CYP enzyme–dependent hepatic clearance. The first step is the para-hydroxylation from active phenytoin to inactive hydroxy-phenytoin, which is dependent on CYP2C9 and, to a lesser extent, on CYP2C19. A considerable disparity in CYP2C9 alleles exists, and the frequency varies among different ancestry groups, the CYP2C9*3 allele being less frequent in Caucasians and more frequent in Asian populations.1,2 Homozygosity for the CYP2C9*3 allele leads to a significant reduction in enzyme activity, resulting in increased plasma levels of phenytoin.3