ANNALS OF EMERGENCY MEDICINE
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2014
Systematic Review Snapshot TAKE-HOME MESSAGE There is a lack of high-quality evidence to support one medication over another in the treatment of benzodiazepine-resistant convulsive status epilepticus. METHODS DATA SOURCES The authors searched MEDLINE and EMBASE up to April 2013, using the term “status epilepticus” and the names of the 5 drugs of interest. The bibliographies of these selected articles were then screened for additional sources. STUDY SELECTION Eligibility for review was based on presentation of original data that included patients with convulsive status epilepticus unresponsive to benzodiazepines who subsequently received one of the 5 study drugs. DATA EXTRACTION AND SYNTHESIS Reviewers assessed each study according to the Oxford Centre of Evidence-Based Medicine level of evidence. Prospective studies were further evaluated for risk of bias with the Cochrane Collaboration’s Tool for Assessment of Risk. Data were extracted with a standardized form. After exclusion of case reports, meta-analysis was performed with an inverse variance weighting and random-effects model to provide an overall estimate of efficacy. Statistical heterogeneity was calculated by I2.
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no.
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2014
What Is the Best First-Line Agent for Benzodiazepine-Resistant Convulsive Status Epilepticus? EBEM Commentators
Rachel Berkowitz, MD Department of Emergency Medicine New York University School of Medicine Bellevue Hospital Center New York, NY
Alex Koyfman, MD Division of Emergency Medicine University of Texas Southwestern Medical Center Parkland Memorial Hospital Dallas, TX
Results Summary estimates for efficacy in terminating benzodiazepine-resistant status epilepticus.* Drug Valproate Phenobarbital Levetiracetam Phenytoin
Efficacy (95% Confidence Interval), % 75.7 73.6 68.5 50.2
(63.7–84.8) (58.3–84.8) (56.2–78.7) (43.2–66.1)
No. of Studies
No. of Patients
Heterogeneity, I2, %
8 2 8 8
250 42 204 294
12.7 0 12 16.5
*Windows for termination of seizure varied across studies. Lacosamide studies had too few patients to conduct a meta-analysis.
The initial search identified 2,754 articles, of which 102 were considered relevant, and then 6 articles were added after back-tracing of references. Among these, 23 articles (reporting 794 episodes of status epilepticus) met the inclusion criteria for data extraction and meta-analysis. The group was composed of 1 randomized doubleblind trial (level 1B), 5 open-label trials (level 2B), and 17 case series (level 4). Of the 6 prospective studies, 5 were deemed to have high risk of bias.
selected articles, including study design, patient demographics, features of seizure, definition of status epilepticus, and intervention and response characteristics such as doses administered and time to seizure cessation. Despite these discrepancies, statistical heterogeneity based on I2 was minimal. There were inadequate data to provide an estimate for the efficacy of lacosamide.
There were numerous sources of clinical heterogeneity among the
Status epilepticus is a neurologic emergency associated with high
Commentary
Annals of Emergency Medicine 1
Systematic Review Snapshot morbidity and mortality. Benzodiazepines are generally accepted as firstline treatment; however, controversy surrounds further management.1 Historically, most protocols have endorsed phenytoin or fosphenytoin when benzodiazepines are ineffective. Yet this recommendation is based on limited data, and it is well known that phenytoin carries many adverse effects such as hypotension, dysrhythmia, neurotoxicity, and infusion site reactions.2 Many practitioners have adopted other agents, even some not specifically licensed for use in status epilepticus, such as valproate and levetiracetam. For status epilepticus refractory to benzodiazepines, the American College of Emergency Physicians gave a level B recommendation to phenytoin, fosphenytoin, and valproate, and a level C recommendation to levetiracetam, propofol, and barbiturates. No medication received a level A recommendation.3 The data provided by this metaanalysis suggest that valproate, phenobarbital, and levetiracetam have similar efficacy and are superior to phenytoin; however, there are several limitations that warrant caution before application of these data to clinical decisions: the analysis was based predominantly on retrospective case series; the prospective studies were generally considered to be at high risk of bias, the one exception
2 Annals of Emergency Medicine
being a randomized controlled trial comparing valproate and phenobarbital.4 Although the I2 values suggest only modest statistical heterogeneity, some of the variability may be clinically important. For example, treatment response was defined as seizure termination within time frames ranging from 3 minutes to 48 hours and in many cases was not specified. A final limitation is the lack of sensitivity analysis to determine the robustness of the findings, particularly in light of the low quality of evidence and wide confidence intervals. Limited endorsements can be made for valproate, phenobarbital, and levetiracetam as first-line therapy for benzodiazepine-resistant status epilepticus. When choosing among them, one must take several important factors into consideration, such as cause of seizure, the patient’s maintenance medication, and individual comorbidities that might increase the risk of adverse effects. For example, intravenous valproate can be hepatotoxic and phenobarbital has been associated with respiratory depression and hypotension. In contrast, levetiracetam has a very favorable adverse effect profile.1 Lacosamide has shown promise as a potential agent in status epilepticus; however, conclusive data are lacking.5 Likewise, there is a need for more randomized controlled studies investigating some of the more established
agents to determine whether any deserve a higher position in status epilepticus algorithms. Editor’s Note: This is a clinical synopsis, a regular feature of the Annals’ Systematic Review Snapshot (SRS) series. The source for this systematic review snapshot is: Yasiry Z, Shorvon SD. The relative effectiveness of five antiepileptic drugs in treatment of benzodiazepine-resistant convulsive status epilepticus: a metaanalysis of published studies. Seizure. 2014;23:167-174. http://dx.doi.org/10. 1016/j.seizure.2013.12.007. 1. Brophy GM, Bell R, Claassen J, et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care. 2012;1791:3-12. 2. Gallop K. Review article: phenytoin use and efficacy in the ED. Emerg Med Australas. 2010;22:108-118. 3. Huff JS, Melnick ER, Tomaszewski CA, et al. Clinical policy: critical issues in the evaluation and management of adult patients presenting to the emergency department with seizures. Ann Emerg Med. 2014;63:437-447. 4. Malamiri RA, Ghaempanah M, Khosroshahi N, et al. Efficacy and safety of intravenous sodium valproate versus phenobarbital in controlling convulsive status epilepticus and acute prolonged convulsive seizures in children: a randomised trial. Eur J Paediatr Neurol. 2012;16:536-541. 5. Santamarina E, Toledo M, Sueiras M. Usefulness of intravenous lacosamide in status epilepticus. J Neurol. 2013;260:3122-3128.
Michael Brown, MD, MSc, Alan Jones, MD, and David Newman, MD, serve as editors of the SRS series.
Volume
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no.
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:
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2014
-
2014
Systematic Review Snapshot TAKE-HOME MESSAGE There is a lack of high-quality evidence to support one medication over another in the treatment of benzodiazepine-resistant convulsive status epilepticus. METHODS DATA SOURCES The authors searched MEDLINE and EMBASE up to April 2013, using the term “status epilepticus” and the names of the 5 drugs of interest. The bibliographies of these selected articles were then screened for additional sources. STUDY SELECTION Eligibility for review was based on presentation of original data that included patients with convulsive status epilepticus unresponsive to benzodiazepines who subsequently received one of the 5 study drugs. DATA EXTRACTION AND SYNTHESIS Reviewers assessed each study according to the Oxford Centre of Evidence-Based Medicine level of evidence. Prospective studies were further evaluated for risk of bias with the Cochrane Collaboration’s Tool for Assessment of Risk. Data were extracted with a standardized form. After exclusion of case reports, meta-analysis was performed with an inverse variance weighting and random-effects model to provide an overall estimate of efficacy. Statistical heterogeneity was calculated by I2.
Volume
-,
no.
-
:
-
2014
What Is the Best First-Line Agent for Benzodiazepine-Resistant Convulsive Status Epilepticus? EBEM Commentators
Rachel Berkowitz, MD Department of Emergency Medicine New York University School of Medicine Bellevue Hospital Center New York, NY
Alex Koyfman, MD Division of Emergency Medicine University of Texas Southwestern Medical Center Parkland Memorial Hospital Dallas, TX
Results Summary estimates for efficacy in terminating benzodiazepine-resistant status epilepticus.* Drug Valproate Phenobarbital Levetiracetam Phenytoin
Efficacy (95% Confidence Interval), % 75.7 73.6 68.5 50.2
(63.7–84.8) (58.3–84.8) (56.2–78.7) (43.2–66.1)
No. of Studies
No. of Patients
Heterogeneity, I2, %
8 2 8 8
250 42 204 294
12.7 0 12 16.5
*Windows for termination of seizure varied across studies. Lacosamide studies had too few patients to conduct a meta-analysis.
The initial search identified 2,754 articles, of which 102 were considered relevant, and then 6 articles were added after back-tracing of references. Among these, 23 articles (reporting 794 episodes of status epilepticus) met the inclusion criteria for data extraction and meta-analysis. The group was composed of 1 randomized doubleblind trial (level 1B), 5 open-label trials (level 2B), and 17 case series (level 4). Of the 6 prospective studies, 5 were deemed to have high risk of bias.
selected articles, including study design, patient demographics, features of seizure, definition of status epilepticus, and intervention and response characteristics such as doses administered and time to seizure cessation. Despite these discrepancies, statistical heterogeneity based on I2 was minimal. There were inadequate data to provide an estimate for the efficacy of lacosamide.
There were numerous sources of clinical heterogeneity among the
Status epilepticus is a neurologic emergency associated with high
Commentary
Annals of Emergency Medicine 1
Systematic Review Snapshot morbidity and mortality. Benzodiazepines are generally accepted as firstline treatment; however, controversy surrounds further management.1 Historically, most protocols have endorsed phenytoin or fosphenytoin when benzodiazepines are ineffective. Yet this recommendation is based on limited data, and it is well known that phenytoin carries many adverse effects such as hypotension, dysrhythmia, neurotoxicity, and infusion site reactions.2 Many practitioners have adopted other agents, even some not specifically licensed for use in status epilepticus, such as valproate and levetiracetam. For status epilepticus refractory to benzodiazepines, the American College of Emergency Physicians gave a level B recommendation to phenytoin, fosphenytoin, and valproate, and a level C recommendation to levetiracetam, propofol, and barbiturates. No medication received a level A recommendation.3 The data provided by this metaanalysis suggest that valproate, phenobarbital, and levetiracetam have similar efficacy and are superior to phenytoin; however, there are several limitations that warrant caution before application of these data to clinical decisions: the analysis was based predominantly on retrospective case series; the prospective studies were generally considered to be at high risk of bias, the one exception
2 Annals of Emergency Medicine
being a randomized controlled trial comparing valproate and phenobarbital.4 Although the I2 values suggest only modest statistical heterogeneity, some of the variability may be clinically important. For example, treatment response was defined as seizure termination within time frames ranging from 3 minutes to 48 hours and in many cases was not specified. A final limitation is the lack of sensitivity analysis to determine the robustness of the findings, particularly in light of the low quality of evidence and wide confidence intervals. Limited endorsements can be made for valproate, phenobarbital, and levetiracetam as first-line therapy for benzodiazepine-resistant status epilepticus. When choosing among them, one must take several important factors into consideration, such as cause of seizure, the patient’s maintenance medication, and individual comorbidities that might increase the risk of adverse effects. For example, intravenous valproate can be hepatotoxic and phenobarbital has been associated with respiratory depression and hypotension. In contrast, levetiracetam has a very favorable adverse effect profile.1 Lacosamide has shown promise as a potential agent in status epilepticus; however, conclusive data are lacking.5 Likewise, there is a need for more randomized controlled studies investigating some of the more established
agents to determine whether any deserve a higher position in status epilepticus algorithms. Editor’s Note: This is a clinical synopsis, a regular feature of the Annals’ Systematic Review Snapshot (SRS) series. The source for this systematic review snapshot is: Yasiry Z, Shorvon SD. The relative effectiveness of five antiepileptic drugs in treatment of benzodiazepine-resistant convulsive status epilepticus: a metaanalysis of published studies. Seizure. 2014;23:167-174. http://dx.doi.org/10. 1016/j.seizure.2013.12.007. 1. Brophy GM, Bell R, Claassen J, et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care. 2012;1791:3-12. 2. Gallop K. Review article: phenytoin use and efficacy in the ED. Emerg Med Australas. 2010;22:108-118. 3. Huff JS, Melnick ER, Tomaszewski CA, et al. Clinical policy: critical issues in the evaluation and management of adult patients presenting to the emergency department with seizures. Ann Emerg Med. 2014;63:437-447. 4. Malamiri RA, Ghaempanah M, Khosroshahi N, et al. Efficacy and safety of intravenous sodium valproate versus phenobarbital in controlling convulsive status epilepticus and acute prolonged convulsive seizures in children: a randomised trial. Eur J Paediatr Neurol. 2012;16:536-541. 5. Santamarina E, Toledo M, Sueiras M. Usefulness of intravenous lacosamide in status epilepticus. J Neurol. 2013;260:3122-3128.
Michael Brown, MD, MSc, Alan Jones, MD, and David Newman, MD, serve as editors of the SRS series.
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no.
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:
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2014
