Convulsive status epilepticus is the most severe form of epilepsy and requires urgent treatment. We synthesised the current evidence on first-line treatments for controlling seizures in adults with convulsive status epilepticus before, or at, arrival at hospital.
We conducted a systematic review of randomised controlled trials (RCTs) assessing antiepileptic drugs offered to adults as first-line treatments. Major electronic databases were searched.
Four RCTs (1234 adults) were included. None were conducted in the UK and none assessed the use of buccal or intranasal midazolam. Both intravenous lorazepam and intravenous diazepam administered by paramedics were more effective than placebo and, notably, intramuscular midazolam was non-inferior to intravenous lorazepam. Overall, median time to seizure cessation from drug administration varied from 2 to 15 min. Rates of respiratory depression among participants receiving active treatments ranged from 6.4 to 10.6%. Mortality ranged from 2 to 7.6% in active treatment groups and 6.2 to 15.5% in control groups.
Intravenous and intramuscular benzodiazepines are safe and effective in this clinical context. Further research is needed to establish the most clinically and cost-effective first-line treatment and preferable mode of administration. Head-to-head trials comparing buccal versus intranasal midazolam versus rectal diazepam would provide useful information to inform the management of the first stage of convulsive status epilepticus in adults, especially when intravenous or intramuscular access is not feasible. Approaches to improve adherence to clinical guidelines on the use of currently available benzodiazepines for the first-line treatment of convulsive status epilepticus should also be considered.
Convulsive status epilepticus is the most severe form of epileptic attack and a life-threatening neurological emergency, which is associated with substantial mortality and morbidity [1,2,3,4]. The clinical manifestation of convulsive status epilepticus is characterised by a prolonged tonic–clonic seizure or repetitive seizures without full recovery of consciousness between them [2, 5, 6].
Epidemiological studies have documented a global annual incidence of status epilepticus of 7 to 41 cases per 100,000 population. In Europe, the annual incidence of status epilepticus lies between 10 and 16 per 100,000 population, and convulsive status epilepticus accounts for 45–74% of all cases [7,8,9]. Incidence of convulsive status epilepticus tends to be higher in males than females . Mortality of status epilepticus has been reported to range from around 8–33% according to aetiology, with older age being a detrimental factor . A recent meta-analysis of convulsive status epilepticus in high-income countries reported pooled mortality of 15.9% and the authors noted that survival rates have not improved over the last 30 years .
The ultimate goal of treatment is to stop both clinical and electroencephalographic seizure activity as soon as possible as convulsive status epilepticus can worsen with delayed or suboptimal treatment [5, 11,12,13]. Early treatment of convulsive status epilepticus is associated with reduced morbidity and mortality and with a greater proportion of terminated seizures at arrival at the hospital emergency department [14,15,16].
The first-line treatment of status epilepticus is currently benzodiazepines. The UK NICE Clinical Guidance recommends the use of buccal midazolam in the community setting before arrival at the hospital, or the administration of rectal diazepam if buccal midazolam is not available . The Scottish SIGN guideline and the 2010 European Federation of Neurologists recommend intravenous (IV) administration of lorazepam or diazepam if IV access is already established and resuscitation available [12, 18]. To date, few trials have evaluated treatment options for adults and there is uncertainty about the optimal first-line treatment to control seizures before arrival at the hospital.
The objective of this assessment was to synthesise current evidence on first-line pharmacological interventions to control seizures in adults before, or at, arrival at the hospital with the aim to inform clinical practice and future research.
We conducted a systematic review according to current methodological standards and pre-specified its methods in a research protocol (PROSPERO registration: CRD42020201953) (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=201953). This report adheres to the principles of the PRISMA 2020 statement .
Information sources and search strategy
To identify eligible studies in the literature, we developed comprehensive search strategies and searched major electronic databases (Medline, Embase, and PsycInfo, EBSCO CINAHL, and Cochrane CENTRAL). Reference lists of included studies and websites of relevant professional organisations were checked for potentially eligible studies. All searches were conducted in July 2020, with no publication date or language restrictions. Details of the search strategies are reported in Appendix 1.
We included randomised controlled trials (RCTs) assessing pharmacological treatment versus placebo or active treatment for adults (≥ 16 years old) with convulsive status epilepticus. We focused on RCTs because, compared to any other study designs, they are more likely to provide unbiased information on the effects of pharmacological interventions for the treatment of convulsive status epilepticus in the adult population. Patients with a known epilepsy syndrome or with a reversible metabolic cause of seizures were deemed eligible for inclusion. Eligible interventions were any benzodiazepine regardless of their route of administration (e.g. intravenous (IV), intramuscular (IM), intranasal, buccal, rectal, or oromucosal) offered as first-line treatment for convulsive status epilepticus on site either by non-medical staff (i.e. caregiver) or paramedics, or at arrival at the hospital by emergency department staff. Newer antiepileptic drugs (AED) including levetiracetam, sodium valproate, and phenytoin were considered, so far as they were used as first-line treatment in the pre-hospital setting or at arrival at the emergency department. We considered first-line treatment as any immediate pharmacological treatment, which could be repeated once, and second-line treatment as any subsequent pharmacological treatment, which involved the use of another class of drug such as an anticonvulsant. Eligibility of participants was not restricted to a specific definition of status epilepticus. Traditionally, status epilepticus was defined as a seizure lasting 30 or more min, but more recent definitions indicate 5 or more minutes of either continuous seizure activity or repetitive seizures with no recovery of consciousness in between.
The main outcomes of interest were the following: seizure cessation (measured either in terms of number of people with cessation of seizure activity within 5–15 min of study drug administration [or any designated period as specified by trial investigators]; or time to seizure cessation from the time of study drug administration); recurrence of seizures (measured either as number of people with recurrence of seizures within a designated period, or time from seizure cessation to recurrence); and adverse events, namely respiratory depression and 30-day mortality.
Two review authors (MC, MI) independently screened all citations identified by the search strategies, retrieved and assessed for eligibility all potentially relevant full-text articles. The same review authors extracted data on study design, participants characteristics (number of participants in each group, demographic information), characteristics of intervention (provider, dose, and route of administration), and comparator intervention. The risk of bias of included trials was assessed by the same review authors using the revised Cochrane risk of bias tool for randomised trials (RoB 2) . Each risk of bias domain was assessed separately for objective and subjective outcomes. For the risk-of-bias assessment, we categorised seizure cessation, recurrence of seizure, and respiratory depression (without ventilation) as subjective outcomes and mortality and respiratory depression (requiring ventilation) as objective outcomes.
At all stages of the study selection and data collection process, disagreement between reviewers was resolved by consensus or referred to a third review author (CC or MB).
We planned to conduct random-effects meta-analyses and subgroup analyses; however, due to the limited number of identified trials and their heterogeneity in terms of treatment comparisons and reported outcomes, this proved unfeasible. We also considered conducting a systematic review of economic evaluations but failed to identify sufficient evidence in the current literature. Results of each included study were tabulated and summarised narratively for each outcome.
The literature searches identified 191 records. Forty-six additional records were identified from perusing the reference lists of selected studies and the websites of professional organisations. After assessing all potential relevant full-text articles in-depth, 13 articles reporting four studies met our inclusion criteria. Figure 1 presents the flow diagram of studies selection.
PRISMA flow diagram of study selection process | Full size image
The study characteristics of the four included RCTs assessing a total of 1234 adults with convulsive status epilepticus are presented in Table 1 [15, 21,22,23]. The trials varied in size, ranging from 44 to 782 participants. Three trials were conducted in the USA[15, 22, 23] and one in France . Three trials enrolled only adults[15, 21, 23] and the fourth trial included a mixed population of adults (89%) and children (11%) . The RAMPART trial (Rapid Anticonvulsant Medication Prior to Arrival Trial) by Silbergleit et al. recruited adults and children with a bodyweight of at least 13 kg . A publicly available dataset of participant-level data was obtained by contacting the authors and we were able to extract data for the 782 participants over 16 years of age. This assessment reports only the adults’ primary outcomes which were of clear origin, according to the accompanying data dictionary. Treatment comparisons of the trials were: IV lorazepam versus IV diazepam versus placebo ; IV levetiracetam plus clonazepam versus IV clonazepam ; phenobarbital plus phenytoin versus diazepam plus phenytoin ; and IM midazolam versus IV lorazepam . The study by Shaner et al. was published in 1988 when the definition of status epilepticus and treatment regimen were likely to differ from the more recently published studies .
Table 1 Overview of study characteristics of the four included trials
|Study ID||Country||Type of comparison||Study setting||Total number of participants randomised||Number of centres||Primary outcome|
|||USA||2 mg IV lorazepam versus 5 mg IV diazepam versus IV placebo||Paramedics||205||10a||Termination of status epilepticus by arrival at the emergency department|
|||France||2.5 g IV levetiracetam plus IV 1 mg clonazepam versus|
1 mg IV clonazepam plus IV placebo
|Paramedics||203||39b||Cessation of convulsions within 15 min of study drug administration|
|||USA||100 mg/min IV phenobarbital plus 40 mg/min IV phenytoin versus 2 mg/min IV diazepam plus 40 mg/min IV phenytoin||Emergency department||44||1||Cumulative convulsion time|
|||USA||10 mg IM midazolam versus 4 mg IV lorazepam||Paramedics||782||79c||Seizures terminated without need for rescue therapy before arrival at the emergency department|
– IV intravenous; IM intramuscular
The mean age of participants in the four trials ranged from 48 years to 55.9 years in the active treatment arms and from 43.8 years to 53 years in the control groups. In all four trials, about half to three-quarters of the participants were male. In three of the included trials, the most common cause of convulsive status epilepticus was a sub-therapeutic level of antiepileptic drugs [15, 22, 23], while a brain lesion was reported as the most frequent cause in the fourth trial .
Table 2 presents a summary of the characteristics of participants in the four included trials.
|Study ID||Study arm||N analysed||Age, years, mean (SD)||Gender (M/F), n (%)||Ethnicity, %||Final diagnosis, n (%)||Time from onset of convulsive SE to study drug admin; minutes, mean (SD) or median [range]|
|||IV lorazepam||66||49.9 (20.1)||M 46 (70%)|
F 20 (30%)
|IV diazepam||68||50.4 (19.1)||M 41 (60%)|
F 27 (40%)
|IV placebo||71||52.0 (18.2)||M 42 (59%)|
F 29 (41%)
|||IV levetiracetam + clonazepam||68||55 (18)||M 49 (72%)|
F 19 (28%)
|NR||SE: 66 (97.1%)|
Non-epileptic: 2 (2.9%)
|IV placebo + clonazepam||68||53 (18)||M 45 (66%)|
F 23 (34%)
|NR||SE: 64 (94.1%)|
Non-epileptic: 4 (5.9%)
|||IV phenobarbital + phenytoin||18||55.9 (19.4)||M 13 (72%)|
F 5 (28%)
|NR||GCSE*: 18 (100%)|
Other**: 0 (0%)
|IV diazepam + phenytoin||18||43.8 (16.5)||M 9 (50%)|
F 9 (50%)
|NR||GCSE*: 17 (94%)|
Other**: 1 (6%)
|||IM midazolam||391||48 (17)||M 217 (56%)|
F 174 (44%)
|SE: 352 (90%)|
Non-epileptic: 28 (7%)
Undetermined: 11 (3%)
|IV lorazepam||391||49 (18)||M 203 (52%)|
F 188 (48%)
|SE: 348 (89%)|
Non-epileptic: 29 (7%)
Undetermined: 14 (4%)