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Treatment of benzodiazepine-resistant status epilepticus: Systematic review and network meta-analyses

  • Puneet Jain
    Affiliations
    Epilepsy Program, Division of Neurology, Department of Pediatrics, Hospital for Sick Children (HSC), University of Toronto, Toronto, ON, Canada
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  • Satinder Aneja
    Affiliations
    Department of Pediatrics, Sharda Hospital, Sharda University, Greater Noida, Uttar Pradesh, India
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  • Jessie Cunningham
    Affiliations
    Hospital Library and Archives, Learning Institute, Hospital for Sick Children, Toronto, ON, Canada
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  • Ravindra Arya
    Affiliations
    Comprehensive Epilepsy Center, Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA

    Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
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  • Suvasini Sharma
    Correspondence
    Corresponding author at: Neurology Division, Department of Pediatrics, Lady Harding Medical College (LHMC) and Kalawati Saran Children Hospital, Delhi University, New Delhi, Delhi, India.
    Affiliations
    Epilepsy Program, Division of Neurology, Department of Pediatrics, Hospital for Sick Children (HSC), University of Toronto, Toronto, ON, Canada

    Neurology Division, Department of Pediatrics, Lady Harding Medical College (LHMC) and Kalawati Saran Children Hospital, Delhi University, New Delhi, Delhi, India
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Published:September 25, 2022DOI:https://doi.org/10.1016/j.seizure.2022.09.017

      Highlights

      • Phenobarbital and high-dose levetiracetam are more effective for treatment of benzodiazepine-resistant status epilepticus.
      • Phenobarbital was associated with a higher risk of intubation and cardiovascular instability.
      • Choice of medication may be guided by effectiveness, safety concerns, availability and cost.

      Abstract

      Purpose

      Multiple interventions have been studied for benzodiazepine-resistant status epilepticus (SE) in children and adults. This review aimed to summarize the available evidence and provide estimates of comparative effectiveness and ranking of treatment effects.

      Methods

      All randomized controlled trials studying patients (>1 month of age) with benzodiazepine-resistant SE were included. Outcomes including seizure cessation within 60 min, seizure freedom for 24 h, death, respiratory depression warranting intubation and cardiovascular instability were studied. Conventional and network meta-analyses (NMA) were done.

      Results

      Seventeen studies were included (16 in NMA). Phenobarbital and high-dose levetiracetam were significantly superior to phenytoin with respect to seizure cessation within 60 min. Network ranking demonstrated that phenobarbital had the highest probability of being the best among the studied interventions followed by high-dose levetiracetam and high-dose valproate. Network meta-analysis was limited by predominant indirect evidence and high heterogeneity.On pairwise comparisons, phenobarbital was found to be associated with a higher risk of need for intubation and cardiovascular instability. Levetiracetam had a better safety profile than fosphenytoin.

      Conclusions

      Based on low quality evidence, phenobarbital appears to be the most effective agent for seizure cessation within 60 min of administration in patients with benzodiazepine resistant status epilepticus. High-dose levetiracetam, high-dose valproate and fosphenytoin are probably equally effective. Choice of medication may be guided by effectiveness, safety concerns, availability, cost and systemic co-morbidities.

      Keywords

      1. Introduction

      Status epilepticus (SE) is a common neurological emergency, which may be associated with significant short and long term neurological and systemic morbidity. A staged treatment protocol for management of status epilepticus is generally followed. The first line of treatment is administration of benzodiazepines; intravenous lorazepam, intravenous diazepam or intramuscular midazolam [
      • Leppik I.E.
      • Derivan A.T.
      • Homan R.W.
      • Walker J.
      • Ramsay R.E.
      • Patrick B.
      Double-blind study of lorazepam and diazepam in status epilepticus.
      ,
      • Silbergleit R.
      • Lowenstein D.
      • Durkalski V.
      • Conwit R.
      • Neurological Emergency Treatment Trials (NETT) Investigators
      RAMPART (Rapid Anticonvulsant Medication Prior to Arrival Trial): a double-blind randomized clinical trial of the efficacy of intramuscular midazolam versus intravenous lorazepam in the prehospital treatment of status epilepticus by paramedics.
      ]. However, approximately 30–40% of all patients fail to respond to initial treatment with benzodiazepines [
      • Trinka E.
      • Höfler J.
      • Zerbs A.
      • Brigo F.
      Efficacy and safety of intravenous valproate for status epilepticus: a systematic review.
      ]. The estimates may be higher based on recent population-based studies [
      • Guterman E.L.
      • Betjemann J.P.
      • Aimetti A.
      • et al.
      Association between treatment progression, disease refractoriness, and burden of illness among hospitalized patients with status epilepticus.
      ,
      • Strzelczyk A.
      • Ansorge S.
      • Hapfelmeier J.
      • Bonthapally V.
      • Erder M.H.
      • Rosenow F.
      Costs, length of stay, and mortality of super-refractory status epilepticus: a population-based study from Germany.
      ]. This condition is referred to as Benzodiazepine-resistant SE or established SE. This may be partially explained by the time-dependent changes in GABAA receptor function and transmembrane chloride gradients [
      • Burman R.J.
      • Rosch R.E.
      • Wilmshurst J.M.
      • et al.
      Why won't it stop? The dynamics of benzodiazepine resistance in status epilepticus.
      ].
      Traditionally intravenous phenytoin or phenobarbital have been the agents of choice in benzodiazepine resistant status epilepticus. However phenytoin may cause cardiac arrhythmias, hypotension, extravasation and purple glove syndrome [
      • Trinka E.
      What is the relative value of the standard anticonvulsants: phenytoin and fosphenytoin, phenobarbital, valproate, and levetiracetam?.
      ]. The use of phenytoin is also limited by the speed of infusion, it needs to be infused at the rate of ≤ 1 mg/kg/min, so the infusion takes at least 20 min [
      • DeToledo J.C.
      • Ramsay R.E.
      Fosphenytoin and phenytoin in patients with status epilepticus: improved tolerability versus increased costs.
      ,
      • Popławska M.
      • Borowicz K.K.
      • Czuczwar S.J.
      The safety and efficacy of fosphenytoin for the treatment of status epilepticus.
      ]. In status epilepticus management, time is of the essence, as ongoing seizures lead to incremental brain injury. Fosphenytoin, a phenytoin pro-drug, is a useful alternative to phenytoin, as it can be administered at three times faster than phenytoin. However, higher cost and limited availability in low resource settings is an impediment. Further, there are concerns of respiratory depression with phenobarbital, especially if it is administered after benzodiazepines.
      In the last decade, intravenous formulations of other anti-seizure medications such as levetiracetam and valproate have been used in benzodiazepine resistant status epilepticus. These drugs may offer advantages in terms of safety and improved tolerability, but availability and cost are still limitations. There are now several randomized controlled trials comparing levetiracetam with either phenytoin or fosphenytoin and a few RCTs comparing valproate with phenytoin/fosphenytoin and levetiracetam [
      • Abdelgadir I.
      • Hamud A.
      • Kadri A.
      • et al.
      Levetiracetam for convulsive status epilepticus in childhood: systematic review and meta-analysis.
      ,
      • Angurana S.K.
      • Suthar R.
      Efficacy and safety of levetiracetam vs. phenytoin as second line antiseizure medication for pediatric convulsive status epilepticus: a systematic review and meta-analysis of randomized controlled trials.
      ,
      • Chamberlain J.M.
      • Kapur J.
      • Shinnar S.
      • et al.
      Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (ESETT): a double-blind, responsive-adaptive, randomised controlled trial.
      ,
      • DeMott J.M.
      • Slocum G.W.
      • Gottlieb M.
      • Peksa G.D.
      Levetiracetam vs. phenytoin as 2nd-line treatment for status epilepticus: a systematic review and meta-analysis.
      ,
      • Feng Y.
      • Chen Y.
      • Jia Y.
      • et al.
      Efficacy and safety of levetiracetam versus (fos)phenytoin for second-line treatment of epilepticus: a meta-analysis of latest randomized controlled trials.
      ,
      • Vignesh V.
      • Rameshkumar R.
      • Mahadevan S.
      Comparison of phenytoin, valproate and levetiracetam in pediatric convulsive status epilepticus: a randomized double-blind controlled clinical trial.
      ]. There is also some data on the use of lacosamide in this setting [
      • Misra U.K.
      • Dubey D.
      • Kalita J.
      Comparison of lacosamide versus sodium valproate in status epilepticus: a pilot study.
      ,
      • Strzelczyk A.
      • Zöllner J.P.
      • Willems L.M.
      • et al.
      Lacosamide in status epilepticus: systematic review of current evidence.
      ].
      We aimed to perform a systematic review and a network meta-analysis (NMA) of randomized controlled trials comparing the efficacy and safety of different agents used in benzodiazepine resistant status epilepticus in adults and children. NMA provides estimates of comparative effectiveness and ranking of treatment effects incorporating both direct and indirect comparisons. The results may help to guide clinicians to decide the most appropriate agent for benzodiazepine resistant status epilepticus in their setting.

      2. Methods

      This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) extension statement for network meta-analyses [
      • Hutton B.
      • Salanti G.
      • Caldwell D.M.
      • et al.
      The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations.
      ] and updated 2020 guidelines [
      • Page M.J.
      • Moher D.
      • Bossuyt P.M.
      • et al.
      PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews.
      ]. It was registered with the PROSPERO International prospective register of systematic reviews (CRD42022313496).

      2.1 Search strategy

      Literature search was carried out by searching the following bibliographic databases: MEDLINE (1946–March 31, 2022) with in-process records and daily updates via Ovid; Embase+Embase Classic (1974–2022 week 12) via Ovid; and Cochrane Central Register of Controlled Trials – March 2022. The search strategy consisted of both controlled vocabulary, such as the National Library of Medicine's MeSH (Medical Subject Headings) and Emtree Subject Headings (Embase), and keywords. Some terms that were used included “Status epilepticus”, ``Seizure cessation'' and ``Drug-Related Side Effects and Adverse Reactions.'' Please see supplemental Table 1 for the full list of search terms and controlled vocabulary subject headings. Methodological filters were applied to limit the study types to health technology assessments, systematic reviews, meta-analyses, randomized controlled trials (RCTs) and controlled clinical trials. Conference abstracts were excluded from the search results. Date limits of 1990-current date and English language limits were also applied. See supplemental Table 1 for the detailed search strategy.

      2.2 Types of studies, participants, and intervention

      All randomized controlled trials (RCTs) reporting on children (> 1 month of age) and/or adults with established convulsive status epilepticus (SE), resistant to first line benzodiazepine treatment, were included. Only RCTs were included to minimize bias. Trials enrolling patients with SE irrespective of their response to first-line benzodiazepines were excluded (as these patients may/may not be resistant to benzodiazepines). Trials with duplicate study participants from the same center/study group were also be excluded; most recently published study or study with larger sample size was then included in this scenario. Two authors (PJ, SS) independently agreed on selection of eligible studies and achieved consensus.
      Phenytoin and fosphenytoin were analysed separately as they differ in their administration, adverse effect profile, cost and availability across countries. Levetiracetam was further categorized as low dose (≤ 30 mg/kg/dose) and high dose (> 30 mg/kg/dose). Similarly, valproate was also further categorized as low dose (≤ 30 mg/kg/dose) and high dose (> 30 mg/kg/dose).

      2.3 Data extraction

      The data was extracted as per a pre-designed data abstraction sheet and included author, year of publication, study period, country of origin, study design, presence of blinding, number of study participants, age and sex of study participants, details of intervention in each treatment arm, history of previous epilepsy, etiology, seizure cessation within 60 min, seizure freedom at 24 h, time to seizure cessation, death during hospital admission, respiratory depression requiring intubation/ mechanical ventilation, cardiovascular adverse effects including hypotension and/or arrhythmias, and other adverse effects (extravasation, rash, hepatic dysfunction). Two authors independently extracted the data and any disagreement in the extracted data was resolved by reaching a consensus through discussion.

      2.4 Outcome measures

      The primary outcome measure was the proportion of study participants who achieved seizure cessation within 60 min of initiation/termination of treatment infusion. The secondary outcome measures included proportion of study participants who remain seizure free for 24 h after initiation/termination of treatment infusion, who died during the hospital admission, who develop respiratory depression requiring intubation/ mechanical ventilation, and who developed cardiovascular adverse effects including hypotension and/or arrhythmias.

      2.5 Data analysis

      The analysis was carried out by using ``intention-to-treat'' population for each outcome.

      2.5.1 Conventional meta-analysis

      The meta-analysis was performed for the available primary and secondary outcomes using Review Manager 5.4. The results were presented as percentages, and risk ratios with 95% confidence interval for categorical outcomes. The statistical heterogeneity among studies was assessed by Chi-square and I2 statistics. A fixed-effects model was initially conducted, and if significant heterogeneity found between trials, potential sources of heterogeneity were considered, and where appropriate a random-effects model was used.

      2.5.2 Network meta-analyses

      Network meta-analyses were performed for the primary outcome. Difference in the proportion of patients achieving the outcome was used as the effect estimate. A frequentist, fixed effects, NMA was first performed with phenytoin as the reference treatment. Heterogeneity in the overall model was quantified with I2, whereas significance of the between and within design heterogeneities were tested with respective Q statistics. Full design-by-treatment interaction model was used for network decomposition. Effects of source data quality on network estimates were assessed with relative proportions of direct and indirect evidence, mean path length, and graph parallelism. Pooled network effect estimates and their 95% confidence intervals for all possible comparisons were computed, along with probabilistic rankings for each treatment. For comparisons having both direct and indirect data, node splitting was performed to evaluate the relative magnitude and direction of both effects.
      Next, a Bayesian random effects NMA was performed using Markov Chain Monte-Carlo simulation. Model parameters were optimized by minimizing the potential scale reduction factor. Network effects estimates along with their 95% credible intervals were computed for all possible comparisons. Treatments were probabilistically ranked for their effect with Surface Under Cumulative Ranking (SUCRA) score. All analyses were formed with R version 4.2 using `netmeta' and `gemtc' libraries. Bayesian hierarchical models fitted with `gemtc' relied on `Just Another Gibbs Sampler' using `rjags' dependency.
      The bias in the included studies was done using Risk of Bias (ROB) 2.0 tool; [
      • Sterne J.A.C.
      • Savović J.
      • Page M.J.
      • et al.
      RoB 2: a revised tool for assessing risk of bias in randomised trials.
      ] overall bias, based the five domains, was classified as ``low'', ``some concerns'' or ``high''. To assess the quality of evidence, we used GRADE Profiler software (V.3.6). [
      • Guyatt G.H.
      • Oxman A.D.
      • Schünemann H.J.
      • Tugwell P.
      • Knottnerus A.
      GRADE guidelines: a new series of articles in the Journal of Clinical Epidemiology.
      ] The rating was classified as – no, serious and very serious limitation.

      3. Results

      After screening 3454 records, seventeen studies were included in this systematic review; three studies [
      • Misra U.K.
      • Dubey D.
      • Kalita J.
      Comparison of lacosamide versus sodium valproate in status epilepticus: a pilot study.
      ,
      • Burman R.J.
      • Ackermann S.
      • Shapson-Coe A.
      • Ndondo A.
      • Buys H.
      • Wilmshurst J.M.
      A comparison of parenteral phenobarbital vs. parenteral phenytoin as second-line management for pediatric convulsive status epilepticus in a resource-limited setting.
      ,
      • Chen W.B.
      • Gao R.
      • Su Y.Y.
      • et al.
      Valproate versus diazepam for generalized convulsive status epilepticus: a pilot study.
      ] were excluded from conventional meta-analyses (as single study available for respective comparison) and one study was excluded from NMA [
      • Chamberlain J.M.
      • Kapur J.
      • Shinnar S.
      • et al.
      Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (ESETT): a double-blind, responsive-adaptive, randomised controlled trial.
      ,
      • Vignesh V.
      • Rameshkumar R.
      • Mahadevan S.
      Comparison of phenytoin, valproate and levetiracetam in pediatric convulsive status epilepticus: a randomized double-blind controlled clinical trial.
      ,
      • Burman R.J.
      • Ackermann S.
      • Shapson-Coe A.
      • Ndondo A.
      • Buys H.
      • Wilmshurst J.M.
      A comparison of parenteral phenobarbital vs. parenteral phenytoin as second-line management for pediatric convulsive status epilepticus in a resource-limited setting.
      ,
      • Chen W.B.
      • Gao R.
      • Su Y.Y.
      • et al.
      Valproate versus diazepam for generalized convulsive status epilepticus: a pilot study.
      ,
      • Agarwal P.
      • Kumar N.
      • Chandra R.
      • Gupta G.
      • Antony A.R.
      • Garg N.
      Randomized study of intravenous valproate and phenytoin in status epilepticus.
      ,
      • Chakravarthi S.
      • Goyal M.K.
      • Modi M.
      • Bhalla A.
      • Singh P.
      Levetiracetam versus phenytoin in management of status epilepticus.
      ,
      • Dalziel S.R.
      • Borland M.L.
      • Furyk J.
      • et al.
      Levetiracetam versus phenytoin for second-line treatment of convulsive status epilepticus in children (ConSEPT): an open-label, multicentre, randomised controlled trial.
      ,
      • Handral A.
      • Veerappa B.G.
      • Gowda V.K.
      • Shivappa S.K.
      • Benakappa N.
      • Benakappa A.
      Levetiracetam versus fosphenytoin in pediatric convulsive status epilepticus: a randomized controlled trial.
      ,
      • Khajeh A.
      • Yaghoubinia F.
      • Yaghoubi S.
      • Fayyazi A.
      • Miri Aliabad G.
      Comparison of the effect of phenobarbital versus sodium valproate in management of children with status epilepticus.
      ,
      • Lyttle M.D.
      • Rainford N.E.A.
      • Gamble C.
      • et al.
      Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial.
      ,
      • Misra U.K.
      • Dubey D.
      • Kalita J.
      A randomized controlled trial of lacosamide versus sodium valproate in status epilepticus.
      ,
      • Nalisetty S.
      • Kandasamy S.
      • Sridharan B.
      • Vijayakumar V.
      • Sangaralingam T.
      • Krishnamoorthi N.
      Clinical effectiveness of levetiracetam compared to fosphenytoin in the treatment of benzodiazepine refractory convulsive status epilepticus.
      ,
      • Noureen N.
      • Khan S.
      • Khursheed A.
      • et al.
      Clinical efficacy and safety of injectable levetiracetam versus phenytoin as second-line therapy in the management of generalized convulsive status epilepticus in children: an open-label randomized controlled trial.
      ,
      • Senthil Kumar C.S.
      • Selvakumar P.
      • Kowsik M
      Randomized controlled trial of levetiracetam versus fosphenytoin for convulsive status epilepticus in children.
      ,
      • Su Y.
      • Huang H.
      • Jiang M.
      • et al.
      Phenobarbital versus valproate for generalized convulsive status epilepticus in adults (2): a multicenter prospective randomized controlled trial in China (China 2-P vs. V).
      ,
      • Su Y.
      • Liu G.
      • Tian F.
      • et al.
      Phenobarbital versus valproate for generalized convulsive status epilepticus in adults: a prospective randomized controlled trial in China.
      ,
      • Malamiri R.A.
      • Ghaempanah M.
      • Khosroshahi N.
      • Nikkhah A.
      • Bavarian B.
      • Ashrafi M.R.
      Efficacy and safety of intravenous sodium valproate versus phenobarbital in controlling convulsive status epilepticus and acute prolonged convulsive seizures in children: a randomised trial.
      ]. Eighteen studies were excluded from the review: SE not benzodiazepine resistant [
      • Chitsaz A.
      • Mehvari J.
      • Salari M.
      • Gholami F.
      • Najafi M.-.R.
      A comparative assessment the efficacy of intravenous infusion of sodium valproate and phenytion in the treatment of status epilepticus.
      ,
      • Gilad R.
      • Izkovitz N.
      • Dabby R.
      • et al.
      Treatment of status epilepticus and acute repetitive seizures with i.v. valproic acid vs phenytoin.
      ,
      • Gujjar A.R.
      • Nandhagopal R.
      • Jacob P.C.
      • et al.
      Intravenous levetiracetam vs phenytoin for status epilepticus and cluster seizures: a prospective, randomized study.
      ,
      • Misra U.K.
      • Kalita J.
      • Patel R.
      Sodium valproate vs phenytoin in status epilepticus: a pilot study.
      ,
      • Mundlamuri R.C.
      • Sinha S.
      • Subbakrishna D.K.
      • et al.
      Management of generalised convulsive status epilepticus (SE): a prospective randomised controlled study of combined treatment with intravenous lorazepam with either phenytoin, sodium valproate or levetiracetam–Pilot study.
      ,
      • Nazir M.
      • Tarray R.A.
      • Asimi R.
      • Syed W.A.
      Comparative efficacy of IV phenytoin, IV valproate, and IV levetiracetam in childhood status epilepticus.
      ,
      • Nene D.
      • Mundlamuri R.C.
      • Satishchandra P.
      • et al.
      Comparing the efficacy of sodium valproate and levetiracetam following initial lorazepam in elderly patients with generalized convulsive status epilepticus (GCSE): a prospective randomized controlled pilot study.
      ,
      • Shaner D.M.
      • McCurdy S.A.
      • Herring M.O.
      • Gabor A.J.
      Treatment of status epilepticus: a prospective comparison of diazepam and phenytoin versus phenobarbital and optional phenytoin.
      ,
      • Sreenath T.G.
      • Gupta P.
      • Sharma K.K.
      • Krishnamurthy S.
      Lorazepam versus diazepam-phenytoin combination in the treatment of convulsive status epilepticus in children: a randomized controlled trial.
      ,
      • Treiman D.M.
      • Meyers P.D.
      • Walton N.Y.
      • et al.
      A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group.
      ,
      • Wani G.
      • Imran A.
      • Dhawan N.
      • Gupta A.
      • Giri J.I.
      Levetiracetam versus phenytoin in children with status epilepticus.
      ,
      • Pooja Sharma S.M.
      • Bamnawat Subhash
      Levetiracetam versus phenytoin for treatment of convulsive status epilepticus in pediatric population: a randomized controlled trial.
      ,
      • Kanika Singh A.A.
      • Faridi M.M.A.
      • Sharma S.
      IV Levetiracetam versus IV Phenytoin in childhood seizures: a randomized controlled trial.
      ], third-line treatment reported [
      • Abbaskhanian A.
      • Sheidaee K.
      • Charati J.Y.
      Comparison of the effect of continuous intravenous infusion of sodium valproate and midazolam on management of status epilepticus in children.
      ,
      • Mehta V.
      • Singhi P.
      • Singhi S.
      Intravenous sodium valproate versus diazepam infusion for the control of refractory status epilepticus in children: a randomized controlled trial.
      ], duplicate population [
      • Kapur J.
      • Elm J.
      • Chamberlain J.M.
      • et al.
      Randomized trial of three anticonvulsant medications for status epilepticus.
      ], outcomes reported at 7 days [
      • Amiri-Nikpour M.R.
      • Nazarbaghi S.
      • Eftekhari P.
      • et al.
      Sodium valproate compared to phenytoin in treatment of status epilepticus.
      ], and only nonconvulsive seizures included [
      • Husain A.M.
      • Lee J.W.
      • Kolls B.J.
      • et al.
      Randomized trial of lacosamide versus fosphenytoin for nonconvulsive seizures.
      ]. PRISMA flow diagram is shown in Supplemental Figure 1.
      The study characteristics have been summarized in supplemental Table 2A/2B Studies were done across many countries: India (7 studies), China (3 studies), Iran (2 studies) and 1 each from Australia/New Zealand, Pakistan, South Africa, United Kingdom and United states of America. The study participants included children (10 studies), adults (6 studies) and mixed age group (1 study). Different benzodiazepines through different routes were used for initial treatment across studies (Supplemental Table 2B). Benzodiazepine resistance was defined as refractoriness to either 1 (5 studies) or two doses (12 studies). Outcome assessment also varied: clinical (13 studies), both clinical and EEG (4 studies).
      All studies had low risk of bias [
      • Sterne J.A.C.
      • Savović J.
      • Page M.J.
      • et al.
      RoB 2: a revised tool for assessing risk of bias in randomised trials.
      ] except four studies where ``some concerns'' were noted due to the randomization process (two studies were quasi-randomized [
      • Chakravarthi S.
      • Goyal M.K.
      • Modi M.
      • Bhalla A.
      • Singh P.
      Levetiracetam versus phenytoin in management of status epilepticus.
      ,
      • Handral A.
      • Veerappa B.G.
      • Gowda V.K.
      • Shivappa S.K.
      • Benakappa N.
      • Benakappa A.
      Levetiracetam versus fosphenytoin in pediatric convulsive status epilepticus: a randomized controlled trial.
      ] and two had inadequate information on randomization process [
      • Agarwal P.
      • Kumar N.
      • Chandra R.
      • Gupta G.
      • Antony A.R.
      • Garg N.
      Randomized study of intravenous valproate and phenytoin in status epilepticus.
      ,
      • Senthil Kumar C.S.
      • Selvakumar P.
      • Kowsik M
      Randomized controlled trial of levetiracetam versus fosphenytoin for convulsive status epilepticus in children.
      ]). Seven studies were funded; conflict of interest was unknown in one [
      • Malamiri R.A.
      • Ghaempanah M.
      • Khosroshahi N.
      • Nikkhah A.
      • Bavarian B.
      • Ashrafi M.R.
      Efficacy and safety of intravenous sodium valproate versus phenobarbital in controlling convulsive status epilepticus and acute prolonged convulsive seizures in children: a randomised trial.
      ]. Four studies did not receive any funding and the rest six studies did not declare any sources of funding.

      3.1 Pairwise comparisons

      3.1.1 Efficacy measures

      For the primary outcome of seizure cessation within 60 min of treatment initiation, phenytoin (1 trial; risk ratio 0.53, 95% confidence interval [CI] 0.36, 0.78; p = 0.002) in children and valproate in adults (2 trials; risk ratio 0.65, 95% CI 0.51, 0.82; I2=42, p = 0.0004) were found to be significantly inferior to phenobarbital. Levetiracetam was similar to phenytoin (5 trials; risk ratio 1.05, 95% CI 0.99, 1.11, I2=54; p = 0.12) and fosphenytoin (4 trials; risk ratio 1.05, 95% CI 0.94, 1.17, I2=36; p = 0.42) (Fig. 1). Results for other comparisons are tabulated in Table 1.
      Fig 1:
      Fig. 1Forest plot for the primary outcome ``seizure cessation within 60 min'' for levetiracetam vs phenytoin/fosphenytoin comparison.
      Table 1Primary outcome (Seizure cessation within 60 min of treatment initiation) – Pairwise comparisons.
      ComparisonPopulationNumber of studies/Total number of study participantsRisk ratio with 95% confidence intervalsP valueI
      • Silbergleit R.
      • Lowenstein D.
      • Durkalski V.
      • Conwit R.
      • Neurological Emergency Treatment Trials (NETT) Investigators
      RAMPART (Rapid Anticonvulsant Medication Prior to Arrival Trial): a double-blind randomized clinical trial of the efficacy of intramuscular midazolam versus intravenous lorazepam in the prehospital treatment of status epilepticus by paramedics.
      (%)
      Interpretation
      Phenytoin/valproate-LD [
      • Vignesh V.
      • Rameshkumar R.
      • Mahadevan S.
      Comparison of phenytoin, valproate and levetiracetam in pediatric convulsive status epilepticus: a randomized double-blind controlled clinical trial.
      ,
      • Agarwal P.
      • Kumar N.
      • Chandra R.
      • Gupta G.
      • Antony A.R.
      • Garg N.
      Randomized study of intravenous valproate and phenytoin in status epilepticus.
      ]
      Mixed2/1701.00 (0.88,1.13)1.000Similar
      Phenytoin/Phenobarbital
      • Burman R.J.
      • Ackermann S.
      • Shapson-Coe A.
      • Ndondo A.
      • Buys H.
      • Wilmshurst J.M.
      A comparison of parenteral phenobarbital vs. parenteral phenytoin as second-line management for pediatric convulsive status epilepticus in a resource-limited setting.
      Pediatric1/690.53

      (0.36, 0.78)
      0.002NAPHB better
      Levetiracetam/Phenytoin [
      • Vignesh V.
      • Rameshkumar R.
      • Mahadevan S.
      Comparison of phenytoin, valproate and levetiracetam in pediatric convulsive status epilepticus: a randomized double-blind controlled clinical trial.
      ,
      • Chakravarthi S.
      • Goyal M.K.
      • Modi M.
      • Bhalla A.
      • Singh P.
      Levetiracetam versus phenytoin in management of status epilepticus.
      ,
      • Dalziel S.R.
      • Borland M.L.
      • Furyk J.
      • et al.
      Levetiracetam versus phenytoin for second-line treatment of convulsive status epilepticus in children (ConSEPT): an open-label, multicentre, randomised controlled trial.
      ,
      • Lyttle M.D.
      • Rainford N.E.A.
      • Gamble C.
      • et al.
      Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial.
      ,
      • Noureen N.
      • Khan S.
      • Khursheed A.
      • et al.
      Clinical efficacy and safety of injectable levetiracetam versus phenytoin as second-line therapy in the management of generalized convulsive status epilepticus in children: an open-label randomized controlled trial.
      ]
      Mixed5/12331.05

      (0.99, 1.11)
      0.1254Similar
      Levetiracetam/Phenytoin [
      • Vignesh V.
      • Rameshkumar R.
      • Mahadevan S.
      Comparison of phenytoin, valproate and levetiracetam in pediatric convulsive status epilepticus: a randomized double-blind controlled clinical trial.
      ,
      • Dalziel S.R.
      • Borland M.L.
      • Furyk J.
      • et al.
      Levetiracetam versus phenytoin for second-line treatment of convulsive status epilepticus in children (ConSEPT): an open-label, multicentre, randomised controlled trial.
      ,
      • Lyttle M.D.
      • Rainford N.E.A.
      • Gamble C.
      • et al.
      Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial.
      ,
      • Noureen N.
      • Khan S.
      • Khursheed A.
      • et al.
      Clinical efficacy and safety of injectable levetiracetam versus phenytoin as second-line therapy in the management of generalized convulsive status epilepticus in children: an open-label randomized controlled trial.
      ]
      Pediatric4/11891.03

      (0.92, 1.15)
      0.6460Similar
      Levetiracetam-LD/Phenytoin [
      • Vignesh V.
      • Rameshkumar R.
      • Mahadevan S.
      Comparison of phenytoin, valproate and levetiracetam in pediatric convulsive status epilepticus: a randomized double-blind controlled clinical trial.
      ,
      • Chakravarthi S.
      • Goyal M.K.
      • Modi M.
      • Bhalla A.
      • Singh P.
      Levetiracetam versus phenytoin in management of status epilepticus.
      ]
      Mixed2/1140.93 (0.77, 1.13)0.480Similar
      Levetiracetam-HD/Phenytoin [
      • Dalziel S.R.
      • Borland M.L.
      • Furyk J.
      • et al.
      Levetiracetam versus phenytoin for second-line treatment of convulsive status epilepticus in children (ConSEPT): an open-label, multicentre, randomised controlled trial.
      ,
      • Lyttle M.D.
      • Rainford N.E.A.
      • Gamble C.
      • et al.
      Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial.
      ,
      • Noureen N.
      • Khan S.
      • Khursheed A.
      • et al.
      Clinical efficacy and safety of injectable levetiracetam versus phenytoin as second-line therapy in the management of generalized convulsive status epilepticus in children: an open-label randomized controlled trial.
      ]
      Pediatric3/9751.04 (0.90, 1.20)*0.6167Similar
      Levetiracetam/Fosphenytoin [
      • Chamberlain J.M.
      • Kapur J.
      • Shinnar S.
      • et al.
      Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (ESETT): a double-blind, responsive-adaptive, randomised controlled trial.
      ,
      • Handral A.
      • Veerappa B.G.
      • Gowda V.K.
      • Shivappa S.K.
      • Benakappa N.
      • Benakappa A.
      Levetiracetam versus fosphenytoin in pediatric convulsive status epilepticus: a randomized controlled trial.
      ,
      • Nalisetty S.
      • Kandasamy S.
      • Sridharan B.
      • Vijayakumar V.
      • Sangaralingam T.
      • Krishnamoorthi N.
      Clinical effectiveness of levetiracetam compared to fosphenytoin in the treatment of benzodiazepine refractory convulsive status epilepticus.
      ,
      • Senthil Kumar C.S.
      • Selvakumar P.
      • Kowsik M
      Randomized controlled trial of levetiracetam versus fosphenytoin for convulsive status epilepticus in children.
      ]
      Mixed4/5441.05 (0.94,1.17)0.4236Similar
      Levetiracetam/Fosphenytoin [
      • Chamberlain J.M.
      • Kapur J.
      • Shinnar S.
      • et al.
      Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (ESETT): a double-blind, responsive-adaptive, randomised controlled trial.
      ,
      • Handral A.
      • Veerappa B.G.
      • Gowda V.K.
      • Shivappa S.K.
      • Benakappa N.
      • Benakappa A.
      Levetiracetam versus fosphenytoin in pediatric convulsive status epilepticus: a randomized controlled trial.
      ,
      • Nalisetty S.
      • Kandasamy S.
      • Sridharan B.
      • Vijayakumar V.
      • Sangaralingam T.
      • Krishnamoorthi N.
      Clinical effectiveness of levetiracetam compared to fosphenytoin in the treatment of benzodiazepine refractory convulsive status epilepticus.
      ,
      • Senthil Kumar C.S.
      • Selvakumar P.
      • Kowsik M
      Randomized controlled trial of levetiracetam versus fosphenytoin for convulsive status epilepticus in children.
      ]
      Pediatric4/3831.07

      (0.96, 1.19)
      0.2340Similar
      Levetiracetam-LD/Fosphenytoin [
      • Handral A.
      • Veerappa B.G.
      • Gowda V.K.
      • Shivappa S.K.
      • Benakappa N.
      • Benakappa A.
      Levetiracetam versus fosphenytoin in pediatric convulsive status epilepticus: a randomized controlled trial.
      ,
      • Senthil Kumar C.S.
      • Selvakumar P.
      • Kowsik M
      Randomized controlled trial of levetiracetam versus fosphenytoin for convulsive status epilepticus in children.
      ]
      Pediatric2/1661.01 (0.92, 1.12)0.790Similar
      Levetiracetam-HD/Fosphenytoin [
      • Chamberlain J.M.
      • Kapur J.
      • Shinnar S.
      • et al.
      Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (ESETT): a double-blind, responsive-adaptive, randomised controlled trial.
      ,
      • Nalisetty S.
      • Kandasamy S.
      • Sridharan B.
      • Vijayakumar V.
      • Sangaralingam T.
      • Krishnamoorthi N.
      Clinical effectiveness of levetiracetam compared to fosphenytoin in the treatment of benzodiazepine refractory convulsive status epilepticus.
      ]
      Mixed2/3781.14 (0.87, 1.50)*0.3461Similar
      Levetiracetam-HD/Valproate-HD
      • Chamberlain J.M.
      • Kapur J.
      • Shinnar S.
      • et al.
      Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (ESETT): a double-blind, responsive-adaptive, randomised controlled trial.
      Mixed1/3200.96 (0.76,1.20)0.71NASimilar
      Valproate-LD/ Levetiracetam-LD
      • Vignesh V.
      • Rameshkumar R.
      • Mahadevan S.
      Comparison of phenytoin, valproate and levetiracetam in pediatric convulsive status epilepticus: a randomized double-blind controlled clinical trial.
      Pediatric1/670.93 (0.64–1.35)0.74NASimilar
      Fosphenytoin/Valproate-HD
      • Chamberlain J.M.
      • Kapur J.
      • Shinnar S.
      • et al.
      Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (ESETT): a double-blind, responsive-adaptive, randomised controlled trial.
      Mixed1/2870.95

      (0.75, 1.21)
      0.67NASimilar
      Valproate-LD/ Phenobarbital [
      • Khajeh A.
      • Yaghoubinia F.
      • Yaghoubi S.
      • Fayyazi A.
      • Miri Aliabad G.
      Comparison of the effect of phenobarbital versus sodium valproate in management of children with status epilepticus.
      ,
      • Su Y.
      • Huang H.
      • Jiang M.
      • et al.
      Phenobarbital versus valproate for generalized convulsive status epilepticus in adults (2): a multicenter prospective randomized controlled trial in China (China 2-P vs. V).
      ,
      • Su Y.
      • Liu G.
      • Tian F.
      • et al.
      Phenobarbital versus valproate for generalized convulsive status epilepticus in adults: a prospective randomized controlled trial in China.
      ,
      • Malamiri R.A.
      • Ghaempanah M.
      • Khosroshahi N.
      • Nikkhah A.
      • Bavarian B.
      • Ashrafi M.R.
      Efficacy and safety of intravenous sodium valproate versus phenobarbital in controlling convulsive status epilepticus and acute prolonged convulsive seizures in children: a randomised trial.
      ]
      Mixed4/2820.74 (0.49, 1.10)*0.1485Similar
      Valproate-LD/ Phenobarbital [
      • Khajeh A.
      • Yaghoubinia F.
      • Yaghoubi S.
      • Fayyazi A.
      • Miri Aliabad G.
      Comparison of the effect of phenobarbital versus sodium valproate in management of children with status epilepticus.
      ,
      • Malamiri R.A.
      • Ghaempanah M.
      • Khosroshahi N.
      • Nikkhah A.
      • Bavarian B.
      • Ashrafi M.R.
      Efficacy and safety of intravenous sodium valproate versus phenobarbital in controlling convulsive status epilepticus and acute prolonged convulsive seizures in children: a randomised trial.
      ]
      Pediatric2/1400.82

      (0.37, 1.83)*
      0.6392Similar
      Valproate-LD/ Phenobarbital [
      • Su Y.
      • Huang H.
      • Jiang M.
      • et al.
      Phenobarbital versus valproate for generalized convulsive status epilepticus in adults (2): a multicenter prospective randomized controlled trial in China (China 2-P vs. V).
      ,
      • Su Y.
      • Liu G.
      • Tian F.
      • et al.
      Phenobarbital versus valproate for generalized convulsive status epilepticus in adults: a prospective randomized controlled trial in China.
      ]
      Adult2/1420.65

      (0.51, 0.82)
      0.000442PHB better
      Valproate-LD/Lacosamide
      • Misra U.K.
      • Dubey D.
      • Kalita J.
      Comparison of lacosamide versus sodium valproate in status epilepticus: a pilot study.
      Adult1/661.09

      (0.78, 1.54)
      0.60NASimilar
      Valproate infusion/diazepam infusion
      • Chen W.B.
      • Gao R.
      • Su Y.Y.
      • et al.
      Valproate versus diazepam for generalized convulsive status epilepticus: a pilot study.
      Adult1/660.90

      (0.57, 1.43)
      0.66NASimilar
      *Random effect model.
      Phenytoin (1 trial; risk ratio 0.47, 95% CI 0.27, 0.84; p = 0.01) in children was found to be inferior to Phenobarbital for the outcome of seizure cessation within 24 h (Supplemental Table 3).

      3.1.2 Safety outcomes (Supplemental Table 4–6)

      The rates of deaths were comparable across different interventions. Phenytoin had significantly higher rates of intubation in children than phenobarbital in one study (risk ratio 3.05, 95% CI 1.24, 7.55, p = 0.02). Levetiracetam was safer than fosphenytoin (3 trials; risk ratio 0.62, 95% CI 0.42, 0.91; I2=0, p = 0.01) and fosphenytoin was worse than valproate (1 trial, risk ratio 1.79, 95% CI 1.15, 2.79; p = 0.01). Valproate had lower rates of intubation than phenobarbital (3 trials; risk ratio 0.18, 95% CI 0.04, 0.79; I2=0, p = 0.02). With respect to cardiovascular instability, valproate was safer than phenytoin (2 trials; risk ratio 0.13, 95% CI 0.02, 0.98; I2=0, p = 0.05).

      3.2 Network meta-analysis for primary outcome

      3.2.1 Network geometry

      The network graph (Fig. 2A) showed that 8 interventions have been reported for this outcome with multiple closed loops. The comparisons of Valproate-LD/phenobarbital (4 trials) and phenytoin/levetiracetam-HD (3 trials) had most head-to-head trials. The most frequently reported interventions included phenytoin (7 trials), valproate-LD (7 trials), phenobarbital (5 trials), levetiracetam-HD (5 trials) and levetiracetam-LD (4 trials). Most network estimates resulted from indirect evidence, with most comparisons having a mean path length >2 and unitary parallelism (Fig. 2B).
      Fig 2:
      Fig. 2A. Network graph showing 8 reported interventions for the primary outcome. The size of the bubble is proportional to the risk difference between that intervention and phenytoin. B. Proportion of direct and indirect evidence, mean network path length, and parallelism for each treatment comparison for primary outcome.

      3.2.2 Fixed-effect frequentist meta-analysis

      Phenobarbital and levetiracetam-HD were significantly superior to phenytoin (Fig. 3A). The network risk difference estimates for all possible pairwise comparisons along with their 95% CI are provided in Table 2A.
      Fig 3:
      Fig. 3A- Forest plot for comparison of various interventions vs phenytoin for primary outcome. B- Network forest plot for the for primary outcome (n = 10) with both direct and indirect evidence.
      Table 2Network risk difference estimates (with 95% confidence intervals) from fixed effect frequentist meta-analysis (A) and network risk difference estimates (with 95% credible intervals) from Bayesian Hierarchical Random Effect Network Meta-analysis (B) for outcome ``Seizure cessation within 60 min''. Risk difference <0 favors the drug in the row and risk difference >0 favors the drug in the column. Bold figures indicate statistical significance. Figures in blue indicate presence of direct evidence within the network estimate.
      A - Fixed effect frequentist meta-analysis
      FOS
      0.02 (−0.23; 0.28)LAC
      −0.07 (−0.15; 0.02)−0.09 (−0.34; 0.16)LEV HD
      −0.00 (−0.08; 0.08)−0.02 (−0.28; 0.23)0.06 (−0.03; 0.16)LEV LD
      −0.26 (−0.40; −0.12)−0.28 (−0.52; −0.04)−0.19 (−0.31; −0.07)−0.26 (−0.40; −0.12)PHB
      −0.00 (−0.09; 0.09)−0.02 (−0.27; 0.22)0.06 (0.02; 0.11)−0.00 (−0.09; 0.09)0.26 (0.14; 0.37)PHT
      −0.06 (−0.17; 0.05)−0.08 (−0.35; 0.19)0.01 (−0.10; 0.11)−0.06 (−0.18; 0.07)0.20 (0.04; 0.36)−0.06 (−0.17; 0.05)VPA HD
      −0.04 (−0.16; 0.08)−0.06 (−0.29; 0.17)0.03 (−0.07; 0.13)−0.04 (−0.16; 0.08)0.22 (0.13; 0.31)−0.04 (−0.13; 0.06)0.02 (−0.12; 0.16)VPA LD
      B - Bayesian Hierarchical Random Effect Network Meta-analysis
      FOS
      −0.08 (−0.52, 0.38)LAC
      −0.09 (−0.25, 0.10)−0.003 (−0.44, 0.41)LEV_HD
      −0.02 (−0.22, 0.15)0.06 (−0.43, 0.48)0.06 (−0.16, 0.27)LEV_LD
      −0.36 (−0.65, −0.07)−0.27 (−0.66, 0.10)−0.27 (−0.53, −0.03)−0.33 (−0.61, −0.04)PHB
      −0.06 (−0.26, 0.14)0.03 (−0.41, 0.42)0.03 (−0.13, 0.16)−0.03 (−0.24, 0.17)0.30 (0.09, 0.52)PHT
      −0.003 (−0.27, 0.27)0.07 (−0.45, 0.57)0.08 (−0.21, 0.36)0.02 (−0.29, 0.32)0.36 (−0.05, 0.74)0.053 (−0.27, 0.35)VPA_HD
      −0.14 (−0.40, 0.12)−0.05 (−0.43, 0.30)−0.05 (−0.28, 0.17)−0.12 (−0.37, 0.14)0.22 (0.06, 0.39)−0.09 (−0.28, 0.11)−0.14 (−0.49, 0.24)VPA_LD
      Abbreviations: FOS-Fosphenytoin; LAC-lacosamide; LEV HD-Levetiracetam High dose; LEV LD-Levetiracetam low dose; PHB-Phenobarbital; PHT-Phenytoin; VPA HD-Valproate high dose; VPA LD-Valproate low dose.
      Network ranking (Table 3) showed that phenobarbital (p score=0.99) had the highest probability of being the best among the studied interventions followed by levetiracetam-HD (p score=0.69) and valproate-HD (p score=0.62).
      Table 3Network Rankings for various interventions for the primary outcome ``seizure cessation within 60 min'', by both frequentist fixed effect and Bayesian random effect network meta-analysis.
      Frequentist Fixed Effect Meta-analysisBayesian Random Effect Meta-analysis
      RankInterventionP scoreRankInterventionSUCRA
      1Phenobarbital0.991Phenobarbital0.74
      2Levetiracetam HD0.692Valproate LD0.68
      3Valproate HD0.623Levetiracetam HD0.67
      4Valproate LD0.524Lacosamide0.59
      5Lacosamide0.305Phenytoin0.52
      6Levetiracetam LD0.306Levetiracetam LD0.46
      7Fosphenytoin0.297Valproate HD0.34
      8Phenytoin0.288Fosphenytoin0.02
      Both direct and indirect risk difference estimates were available for ten pairwise comparisons (Fig. 3B). This showed that phenobarbital was superior to both phenytoin (network risk difference estimate 0.26, 95% CI 0.14, 0.37) and valproate-LD (network risk difference estimate 0.22, 95% CI 0.13, 0.31). Levetiracetam-HD was also significantly better than phenytoin (network risk difference estimate 0.06, 95% CI 0.02, 0.11). Rest of the comparisons did not show significant difference. Node-splitting did not show significant inconsistency between direct and indirect evidence for any comparison.
      A high degree of heterogeneity (I2=66.6%; 95% CI: 38.7%, 81.8%) was observed, contributed mainly by significant ``within design'' inconsistency (75.8%, p = 0.0003). Phenobarbital/valproate-LD (68.2%, p = 0.0007) and phenytoin/ levetiracetam-LD (28.3%, p = 0.03) comparisons contributed most to ``within design'' inconsistency. Under the assumption of a full design-by-treatment interaction random effects model, the between-designs inconsistency remained insignificant.

      3.2.3 Bayesian hierarchical random effect meta-analysis

      The network estimates for risk differences for all possible pairwise comparisons along with 95% credible intervals are shown in Table 2B. For eight pairwise comparisons having both direct and indirect evidence to estimate network effects, no significant differences were found. The hierarchical ranking (Table 3) showed phenobarbital had the highest probability of being the best among the analyzed interventions (SUCRA=0.74) followed by valproate-LD (SUCRA=0.68) and levetiracetam-HD (SUCRA=0.67).

      3.3 Grade of evidence

      Regarding the primary outcome measure of seizure control within 60 min, the quality of evidence was high for these comparisons; Levetiracetam HD versus Valproate HD (no difference) and Fosphenytoin versus Valproate HD (no difference); and low to very low quality for all the other comparisons (Supplemental Table 7). For the secondary outcome of need for intubation, the quality of evidence was moderate for these comparisons; Levetiracetam HD versus Valproate HD (favoring Valproate HD), Valproate LD versus Phenobarbital (favoring Valproate) and Fosphenytoin versus Valproate HD (favoring Valproate HD). The quality of evidence for need for intubation was low to very low for all other comparisons. The quality of evidence for the other secondary outcomes such as death, cardiovascular instability and seizure freedom at 24 h was low to very low across all the comparisons.

      4. Discussion

      This systematic review and meta-analysis were aimed at generating best available effectiveness estimates for anti-seizure medications in children and adults with benzodiazepine-resistant status epilepticus, based on the current available evidence. Comparisons between the following agents were studied- fosphenytoin, phenytoin, levetiracetam (HD and LD), valproate (LD and HD), phenobarbital, lacosamide and diazepam infusion; in a total of 17 studies.

      4.1 Efficacy

      Based on low quality of evidence, for primary outcome, phenobarbital was significantly better than phenytoin in children and valproate in adults. Levetiracetam was similar to phenytoin or fosphenytoin. The rates of deaths were comparable across different interventions. With respect to intubation, phenobarbital was safer than phenytoin in children; levetiracetam was safer than fosphenytoin; and valproate was superior to phenobarbital and fosphenytoin. Valproate was also noted to produce less cardiovascular instability when compared to phenytoin.
      Network meta-analysis was limited by predominantly indirect evidence and high heterogeneity. Phenobarbital and levetiracetam-HD were significantly superior to phenytoin with respect to seizure cessation within 60 min. Network ranking demonstrated that phenobarbital had the highest probability of being the best among the studied interventions followed by levetiracetam-HD and valproate-HD. Similar results were obtained in NMA done in children [
      • Zhang Y.
      • Liu Y.
      • Liao Q.
      • Liu Z.
      Preferential antiseizure medications in pediatric patients with convulsive status epilepticus: a systematic review and network meta-analysis.
      ] and adults [
      • Brigo F.
      • Del Giovane C.
      • Nardone R.
      • Trinka E.
      • Lattanzi S.
      Intravenous antiepileptic drugs in adults with benzodiazepine-resistant convulsive status epilepticus: a systematic review and network meta-analysis.
      ]. Phenobarbital has the advantage of easy availability and low cost, a huge benefit in low- and middle-income countries.
      This result however has to be viewed with caution. There were only five trials with small number of patients which evaluated phenobarbital in BZD resistant SE. Four of these compared low-dose valproate with Phenobarbital (total 282 patients), and one compared phenytoin with phenobarbital (69 patients). No direct comparisons of phenobarbital versus levetiracetam were available. Differences in dosages should be also taken into account in interpreting the results. The high relative efficacy of phenobarbital in the network comparisons for seizure cessation within 60 min could possibly be resulting from the high dose of phenobarbital used in the adult studies [
      • Su Y.
      • Huang H.
      • Jiang M.
      • et al.
      Phenobarbital versus valproate for generalized convulsive status epilepticus in adults (2): a multicenter prospective randomized controlled trial in China (China 2-P vs. V).
      ,
      • Su Y.
      • Liu G.
      • Tian F.
      • et al.
      Phenobarbital versus valproate for generalized convulsive status epilepticus in adults: a prospective randomized controlled trial in China.
      ]. These studies used an initial 20 mg/kg loading, which is higher than the 15 mg/kg recommendation [
      • Glauser T.
      • Shinnar S.
      • Gloss D.
      • et al.
      Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the guideline committee of the American Epilepsy Society.
      ]. Further, all five studies emanated from Asia where etiological profile for SE may be different, thus limiting its generalizability [
      • Chetan C.
      • Sharma S.
      • Mathur S.B.
      • Jain P.
      • Aneja S.
      Clinical profile and short-term outcome of pediatric status epilepticus at a tertiary-care center in Northern India.
      ,
      • Gaillard W.
      • Goodkin H.
      • Abend N.
      • et al.
      Etiology of pediatric refractory convulsive status epilepticus. Results from the pediatric status epilepticus research group (pSERG) (S29.005).
      ,
      • Holtkamp M.
      • Othman J.
      • Buchheim K.
      • Meierkord H.
      Predictors and prognosis of refractory status epilepticus treated in a neurological intensive care unit.
      ,
      • Lingappa L.
      • Konanki R.
      • Patel R.
      • Vooturi S.
      • Jayalakshmi S.
      Clinical profile and outcome of refractory convulsive status epilepticus in older children from a developing country.
      ].
      When direct pairwise comparisons were used, based on high quality of evidence, there was no difference between levetiracetam HD versus valproate HD, and fosphenytoin versus Valproate HD with respect to the primary outcome measure (seizure control within 60 min). There is a low quality evidence that phenobarbital may be better than low-dose valproate in the treatment of BZD resistant SE in adults (2 studies, 142 patients).

      4.1.1 Safety

      In the direct comparisons for safety issues, there was a higher risk of need for intubation and cardiovascular instability in the patients treated with phenobarbital, as compared to those treated with valproate, though this evidence was of low to moderate quality. Respiratory depression is a known side effect of phenobarbital. Administration of phenobarbital after benzodiazepines, which also cause respiratory depression, is likely to lead to a higher risk of respiratory depression. Also, even though the direct comparisons of valproate versus phenobarbital, and phenytoin versus phenobarbital favored phenobarbital, this evidence was graded as low quality. Another practical consideration is that high dose phenobarbital infusions are often used in refractory and super-refractory status epilepticus [
      • Tiamkao S.
      • Mayurasakorn N.
      • Suko P.
      • et al.
      Very high dose phenobarbital for refractory status epilepticus.
      ]. Hence, purely from a safety standpoint, it may be desirable to try other medications (phenytoin, levetiracetam or valproate) as second line, and perhaps reserve phenobarbital for refractory SE. However, phenobarbital has the advantages of effectiveness, widespread availability, and low cost. Thus, the choice of second line anti-seizure medication must be modified in a given setting by other considerations including effectiveness, availability, and cost.
      There is low to moderate quality evidence that the safety profile of levetiracetam was better than fosphenytoin, in terms of lesser cardiovascular adverse events. There is low to moderate quality evidence that the safety profile of valproate was better than phenytoin or fosphenytoin, in terms of less requirement for intubation and lesser cardiovascular side effects. However, valproate has been associated with hepatic side effects, in terms of raised transaminases and elevated ammonia levels. Valproate has the risk of hepatotoxicity, and is contra-indicated in patients with liver disease, which may not be evident when the patient is brought convulsing and needs emergency treatment. Valproate is contra-indicated in inherited metabolic including mitochondrial disorders, which may manifest in children with seizures and status epilepticus.
      Another factor of concern is the speed of administration. Levetiracetam, fosphenytoin and valproate can be administered within 10 min, whereas phenytoin and phenobarbital need to be infused over 20 min. Time is of the essence while treating status epilepticus. Other advantages of levetiracetam and valproate include lesser risk of adverse effects as compared to fosphenytoin. Both levetiracetam and valproate are broad spectrum drugs active against all types of seizures, and hence may be a good agent for maintenance therapy after the acute control of seizures in children and adults with genetic generalized epilepsy or when the type of seizure/ epilepsy syndrome is not clear.

      4.2 Strengths and limitations

      This systematic review and meta-analysis were carried out with rigorous methodology. However, the source data comprised of multiple studies with small sample sizes and poor quality of evidence. Further, NMA was limited by predominant indirect evidence and high heterogeneity.
      The studied population was heterogenous with respect to age (children, adults, elderly). The subgroup analyses (conventional meta-anlyses; see Table 1) for pediatric age-group for comparisons levetiracetam/phenytoin, levetiracetam/fosphenytoin, levetiracetam-LD/fosphenytoin and valproate LD-phenobarbital, showed similar results to their respective mixed age-group analyses. There were not enough studies available to do similar meaningful subgroup analyses for NMA. Further, the pathophysiology of status epilepticus and effect of anti-seizure medications on neuronal receptors are similar from children (beyond neonatal period) through adults [
      • Glauser T.
      • Shinnar S.
      • Gloss D.
      • et al.
      Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the guideline committee of the American Epilepsy Society.
      ]. This may allow to take more unified approach to SE management in children and adults.
      The heterogeneity may also arise from variability in reported etiologies of SE, resource-setting and initial benzodiazepines used (agent, dose, route). Important variables like etiology and time to treatment were not uniformly reported/classified across studies. Frequent reliance on clinical seizure cessation alone (and not EEG cessation of seizures) may also affect the robustness of the primary outcome measures.

      5. Conclusion

      Our network meta-analysis of randomized trials, limited by predominant indirect evidence and high heterogeneity, revealed phenobarbital to be the most effective agent for seizure cessation within 60 min of administration in patients with benzodiazepine resistant status epilepticus. However, in direct comparisons, phenobarbital was found to be associated with a higher risk of need for intubation and cardiovascular instability. Further, based on probabilistic rankings, levetiracetam HD was also very effective and ranked higher than levetiracetam LD. Direct comparisons revealed that levetiracetam HD, valproate HD and fosphenytoin are probably equally effective for seizure cessation within 60 min. Levetiracetam had a better safety profile than fosphenytoin. When deciding the drug to be used in patients with benzodiazepine resistant status epilepticus, the choice needs to be decided by patient characteristics (age, underlying co-morbidities such as cardiac or liver disease, seizure type and need for long term anti-seizure medications), drug availability and cost, and evidence of efficacy and safety.

      Funding

      Research presented in this manuscript did not receive any funding from federal, private, or not-for-profit agencies.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgment

      None.

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